Oct 25, 2014
- ?C .• -"') . -- - ~
THE VETERINARY CLINICS OF NORTH AMERICA SMALL ANIMAL PRACTICE
Vaccines and Vaccinations
RICHARD B. FORD, DVM, MS, GUEST EDITOR
SE RVI,OS Of DOCUMEHTA~O £ K ffrwif V.T.A.D.
Nl ... S .. t...H..St2 ..... _ Oass . ............. _ .... _ •. ___ _
VOLUME 31 NUMBER 3
W.B. SAUNDERS COMPANY A Harcourt Health Sciences Company PHILADELPI-llA LONDON TORONTO MONTREAL
I COMPRA I
MAY 2001
W.B. SAUNDERS COMPANY A Harcourt Health Sciences Company
The Curtis Center • Independence Square West • Philadelphia, Pennsylvania 19106
http://www.harcourthealth.com
THE VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE May 2001 Editor: John Vassallo
Volume 31, Number 3 ISSN 0195-5616
Copyright © 2001 by W.B. Saunders Company. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information retrieval system, without
' . written permission from the Publisher.
The appearance of the code at the top of the first page of an article in this periodical indicates the consent of the W.B. Saunders Company that copies of the article may be made for personal or internal use, or for the personal or internal use of specific clients, for those registered with the Copyright Clearance Center, Inc. (222 Rosewood Drive, Danvers, MA 01923: (978) 750-8400; www.copyright.com).This consent is given on the condition that the copier pay the stated per-copy fee for that article through the Copyright Clearance Center, Inc. for copying beyond that permitted by Sections 107 or 108 of the US Copyright Law. lhis consent does not extend to other kinds of copying, such as copying for general distribution, for advertising or promotional purposes, for creating new collective works, or for resale. Absence of the code indicates that the material may not be processed through the Copyright Clearance Center, Inc:
The ideas and opinions expressed in The Veterinary Clinics of North America: Small Animal Practice do not necessarily reflect those of the Publisher. The Publisher does not assume any responsibility for any injury and lor damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other health care professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Mention of any product in this issue should not be construed as endorsement by the contributors, editors, or the Publisher of the product or manufacturers' claims.
The Veterinary Clinics of North America: Small Animal Practice (ISSN 0195--5616) is published bimonthly by W.B. Saunders Company. Corporate and editorial offices: The Curtis Center, Independence Square West, Philadelphia, PA 19l06-3399. Accounting and circulation offices: 6277 Sea Harbor Drive, Orlando, FL 32887-4800. Periodicals postage paid at Orlando, FL 32862, and additional mailing offices. Subscription prices are $145.00 per year (U.S. individuals), $195.00 per year (U.s. institutions), $177.00 per year (Canadian individuals), $249.00 per year (Canadian institutions), $199.00 per year (foreign individuals), and $249.00 per year (foreign institutions). Foreign air speed delivery is included in all Clinics subscription prices. All prices are subject to change without notice. POSTMASTER: Send address changes to The Veterinary Clinks of North America: Small Animal Practice, W.B. Saunders Company, Periodicals Fulfillment, Orlando, FL 32887-4800. Customer Service: 1-800-654-2452 (US). From outside of the US, call 1-407-345-4000.
The Veterinary Clinics of North America: Small Animal Practice is also published in Italian by Antonio Delfino Editore, Via Udine 32/40,00161 Rome, Italy; and in Japanese by Gakusosha Company Ltd., 2-16-28 Nishikata, Bunkyo-ku, Tokyo 113, Japan.
The Veterinary Clinics of North America: Small Animal Practice is covered in Current Conceptsl Agriculture, Science Citation Index, ASCA, Index Medicus, Biology and Environmental Sciences, Excerpta Medica, and BIOSIS.
Printed in the United States of America.
VACCINES AND VACCINATIONS
GUEST EDITOR RICHARD B. FORD, DVM, MS, Diplomate, American College of Veterinary Internal
Medicine; Professor, Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina
CONTRIBUTORS DEBORAH J. BRIGGS, MS, PhD, Rabies Laboratory, Kansas State University, College of
Veterinary Medicine, Manhattan, Kansas
M. GAYNE FEARNEYHOUGH, BS, DVM, Prior Director, Oral Rabies Vaccination Program, Texas Department of Health, Zoonosis Control Division, Austin, Texas from 1993-2000. Currently in private veterinary practice, San Antonio, Texas and Director of AeroVace Co., a company for the aerial delivery of wildlife vaccine.
DUANE FLEMMING, DVM, JD, Diplomate, American College of Veterinary Ophthalmologists; Contra Costa Animal Eye Clinic, Pleasant Hill, California
RICHARD B. FORD, DVM, MS, Diplomate, American College of Veterinary Internal Medicine; Professor, Department of Medicine, North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina
CRAIG E. GREENE, DVM, MS, Professor, Department of Small Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, Georgia
DAVID R. HUSTEAD, DVM, International Technical Director, Fort Dodge Animal Health, Overland Park, Kansas
E. KATHRYN MEYER, VMD, Veterinary Behavior Clinic, Potomac, Maryland; Former Coordinator, United States Pharmacopeia Veterinary Practitioners' Reporting Program, United States Pharmacopeia, Rockville, Maryland
GREGORY K. OGILVIE, DVM, Diplomate, American College of Veterinary Internal Medicine; Professor of Oncology and Internal Medicine, Animal Cancer Center, College of Veterinary Medicine, Department of Clinical Sciences, Veterinary Teaching Hospital, Colorado State University, Fort Collins, Colorado
JAMES RICHARDS, DVM, Director, Cornell Feline Health Center, College of Veterinary Medicine, Cornell University, Ithaca, New York
ILONA RODAN, DVM, Diplomate, American Board of Veterinary Practitioners; Director, Cat Care Clinic, Madison, Wisconsin
iii
RONALD D. SCHULTZ, PhD, Professor, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin
KRISTEN SCHWEITZER, BS, Rabies Laborat0,!l' Kansas State University, College of Veterinary Medicine, Manhattan, Kansas ...
KENT R. VAN KAMPEN, DVM, PhD, The Van Kampen Group, Inc., Hoover, Alabama
iv CONTRfBUTORS
VACCINES AND VACCINATIONS
CONTENTS
Preface Richard B. Ford
Vaccines and Vaccinations: The Strategic Issues Richard B. Ford
The rapid proliferation of companion animal vaccines, advances in diagnostic and vaccine technology, and concerns over vaccine safety are clearly among the most important issues practicing veterinarians face as we enter the 21st century. Although many would argue that these are already issues, the future promises to be especially challenging as the vaccines we currently use and the protocols we recommend undergo unprecedented review.
Feline Vaccination Guidelines James Richards and TIona Rodan
The 1998 Report of the American Association of Feline Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vaccines was developed to help veterinary practitioners formulate vaccination protocols for cats. The current panel report updates information, addresses questions, and speaks to concerns raised by the 1998 report. In addition it reviews vaccine licensing, labeling, and liability issues and suggests ways to successfully incorporate vaccination protocol changes into a private practice setting.
Canine Vaccination Craig E. Greene, Ronald D. Schultz, and Richard B. Ford
New technologies for vaccine development and infectious disease diagnosis are likely to be introduced in the near future. With this
VETERINARY CLINICS OF NORTII AMERICA: SMALL~LPRACTICE
VOLUME 31 • NUMBER 3 • MAY 2001
xi
439
455
473
v
new technology comes the opportunity to vaccinate companion animals against even more infectious agents than is currentlx practiced in the United States. As we look forward, it
-becomes particularly important to review current vaccination standards applied to dogs with respect to current knowledge of duration of immunity, awareness of incidence, iWd likelihood of injurious or even fatal adverse events associated with vaccination, and individual risk factors that dictate which vaccines are most appropriate at which stage of life.
Vaccine-Associated Adverse Events E. Kathryn Meyer
Although vaccination plays a vital role in maintaining animal health, there are risks associated with this medical procedure. Veterinarians are beginning to reexamine dogmatic vaccine protocols and consider both risks and benefits of vaccination, with special emphasis on adverse event information generated by practitioner experience. The current status of postmarketing surveillance for commercially available veterinary vaccines is presented, along with a discussion of the strengths and limitations of surveillance programs. An overview of adverse events commonly reported by veterinarians is included, along with practical information on how veterinarians can share their observations and learn about adverse events reported by their colleagues.
The Potential for Liability in the Use an~ Misuse of Veterinary Vaccines Duane Flemming
The lack of specific rules regarding the use of animal vaccines by veterinarians leaves them vulnerable to legal action for negligence or breach of warranty. A veterinarian's liability may depend on the answers to the questions asked in this article. The answers ultimately depend on the specific circumstances of the case. Although no one can ensure that he or she is never going to be sued, veterinarians can go a long way in defending themselves against these kinds of allegations by conforming to the standards of practice as they apply to the care and use of vaccines; by adhering closely to the doctrines of informed consent; and by not providing undue warranty to the vaccine product he or she sells.
Recent Advances in the Treatment of Vaccine-Associated Sarcomas Gregory K. Ogilvie
This article reviews the background information about vaccineassociated sarcomas followed by diagnostic procedures essential to understand how to determine the extent of the primary and metastatic tumor as well as to understand the general health of
493
515
525
vi CONTENTS
the patient. It also addresses the importance of understanding the nonmedical needs of the client who is faced with this perplexing problem.
Recombinant Vaccine Technology in Veterinary Medicine Kent R. Van Kampen
Recombinant technology is relatively new to veterinary medicine. It combines safety, purity, potency, and efficacy in the vaccine. Its positive features include not exposing the vaccinate to the pathogen, the lack of need for adjuvants, and stability that allows some vaccine to remain viable at ambient temperatures. These recombinants can receive multiple genetic inserts and present an opportunity to have multiple combination vaccines for use in animals. Licensed recombinant vaccines in veterinary medicine include those protecting against Lyme disease, pseudorabies, rabies, canine distemper, Newcastle disease, and a strain of avian influenza.
What You Can and Cannot Learn From Reading a Vaccine Label David R. Hustead
Although most veterinarians look at vaccine labels each day, they rarely see them. When practitioners sense a need to read labels, they find that the labeling answers some of their basic questions but that these labels often fail to address many relevant issues. In addition, veterinarians find that the issues addressed are often presented simplistically and that the labels are sometimes just wrong. This article addresses what practitioners need to do to better understand the products most of them use on a daily basis.
Rabies Postexposure Prophylaxis: Human and Domestic Animal Considerations M. Gayne Fearneyhough
The emphasis on rabies control and prevention in the United States seems to be a function of our perception of proximity of the threat. Wildlife rabies epizootics within a state may be of little concern to the uninformed urban dweller. Additionally, many parts of the western United States are free of terrestrial rabies; were it not for the presence of bat rabies, people in those areas would likely interpret rabies control as a minor public health concern. It is essential that federal, state, and local public health programs emphasize the importance of rabies control through activities that include rabies education, sponsorship of legislated requirements for domestic animal vaccination, support for local animal control programs, and the promotion of recommendations
CONTENTS
535
539
557
vii
that encourage the appropriate use of postexposure prophylaxis. We are almost guaranteed that rabies is going to remain a majQr public health issue well into the next century because of expanding wildlife rabies epizootics, identification of new rabies viral variants with increased public fl'ealth concern, emotional and legal concerns associated with rabilili exposure, and increasing national cost associated with rabies control and prevention. Nevertheless, the development of new laboratory technology that allows an understanding of the epidemiologic nature of the rabies virus based on an evolving genetic history and the interrelationship with wildlife reservoirs should allow access to valuable tools for rabies control. When combined with programs using new developments in oral rabies vaccine that can immunize whole populations of wildlife reservoirs, that technology offers encouragement in our effort to control one of the diseases of antiquity.
Im·portation of Dogs and Cats to Rabies-Free Areas of the World Deborah J. Briggs and Kristen Schweitzer
Public pressure from a very mobile society has caused the governments of many rabies-free areas to reevaluate lengthy quarantine systems. In some areas a policy of vaccination, certification, and rabies antibody testing have been implemented to reduce the length of time a dog or cat must spend in quarantine. This has caused an increasing need for pet owners and veterinarians to understand quarantine regulations and shipping methods.
Index
573
585
Subscription Information Inside back cover
viii CONTENTS
f
- '
FORTHCOMING ISSUES
July 2001
ENDOSCOPY
Lynda Melendez, DVM, MS, Guest Editor
September 2001
ENDOCRINOLOGY
Ellen Behrend, VMD, PhD, and Robert Kemppainen, DVM, PhD, Guest Editors
November 2001
CRITICAL CARE: C ARDIOVASCULAR Focus Nishi Dhupa, BVM, MRCVS, Guest Editor
RECENT ISSUES
Mars:h 2001
C LINICAL THERIOGENOLOGY
Autumn P. Davidson, DVM, Guest Editor
January 2001
LAMENESS
Walter C. Renberg, DVM, MS, and James K. Roush, DVM, MS, Guest Editors
November 2000
R ESPIRATORY MEDICINE AND SURGERY
Philip Padrid, RN, DVM, Guest Editor
VISIT OUR WEB SITE
For more information about Clinics: http://www.harcourthealth.com
A
VACCINES AND VACCINATIONS
PREFACE
RICHARD B. FORD, DVM, MS, DIPLOMATE ACVIM
Guest Editor
By its very nature, the concept of change is a bitter pill ... after all, change not only defies tradition, it challenges intellect and fosters uncertainty. Perhaps it should be no surpirse that recent presentations and publications suggesting dogs and cats receive fewer vaccines, and do so less often, have provoked significant controversy, concern, and even confusion among companion animal practitioners.
So why change? Vaccination is what we do well, and its what many veterinarians do most! Historically speaking, vaccination is a service that veterinary medicine has provided to pets for well over 50 years ... and with exceptional results. What better health value is there, in fact, than a vaccine capable of preventing infection by highly contagious, virulent organisms such as rabies virus, feline panleukopenia virus, or canine parvovirus? That dogs and cats derive substantial health benefits from vaccination programs is unquestioned. But, is there a "down-side" to vaccination? Have we, in fact, reached a point of diminishing returns with respect to vaccination?
In this issue of The Veterinary Clinics of North America: Small Animal Practice, we have attempted to address the controversies and the concerns over recommended changes in vaccination protocols for dogs and cats. The reader must understand that this publication is neither the final word on companion animal vaccination nor is it intended to represent national vaccination standards. Instead, it is a compilation of articles that specifically target the foremost vaccination issues of importance to practicing veterinarians. Objectively, the articles published in this issue will enable practitioners to make an informed decision regarding which vaccines to use and how often to administer them.
In separate articles, an in-depth review of key controversies is presented followed by two articles outlining the most current vaccination guidelines for dogs and for cats. Supporting references are included. These three articles set the stage for the papers that follow. A review of the table of contents will reveal that some of the most contentious issues surrounding the vaccine controversy are addressed: vaccine-associated adverse events (i.e., adverse reactions), use of adjuvanted vaccine in cats, feline vaccine-associated fibrosarcoma, and new
xi
vaccine technology (recombinant vaccines). Of significant importance to veterinarians are the legal issues surrounding decisions to vaccinate in a 1l\anner not specifically recommended on the manufacturers' label (package insert). Two articles, one on interpreting the vaccine label and another that specifically addresses practitioner liability related to vlft:cination are included. Finally, two highly informative articles on rabies imm4Pization, postexposure immunoprophylaxis and the latest update on importation of dogs and cats to rabies-free areas of the world, are presented.
Back, then, to the original question. Are we, in fact, vaccinating dogs and cats with too many vaccines, too often? In the absence of national vaccination standards and routine monitoring, only the individual practitioner can answer this question. Vaccination is a medical procedure that mandates clinical assessment of the patient's health status and risk of exposure to infectious disease when deciding which vaccine(s) to administer and when. All of us who have contributed to this issue hope that the information provided will represent a compelling starting point for at least reviewing vaccination protocols in place within individual practices.
As the editor of this issue, I want to extend my sincere thanks to each of the contributing authors who have willingly shared much of their valuable time and expertise in preparing manuscripts on what must be considered one of the most important topics facing companion animal medicine today. In addition, I want to acknowledge Mr. John VassaUo, editor of The Veterinary Clincis of North America: Small Animal Practice, for his suggestions, his patience, and his assistance in completing this issue.
Professor of Medicine North Carolina State University College of Veterinary Medicine Raleigh, NC 27606
xii
RICHARD B. FORD, DVM, MS, DIPLOMATE ACVIM Guest Editor
PREFACE
VACCINES AND VACCINATIONS 0195--5616/ 01 $15.00 + .00
VACCINES AND VACCINATIONS The Strategic Issues
Richard B. Ford, DVM, MS
The rapid proliferation of companion animal vaccines, advances in diagnostic and vaccine technology, and concerns over vaccine safety are clearly among the most important issues practicing veterinarians face as we enter the twenty-first century. Although many would argue that these are already issues, the future promises to be especially challenging as the vaccines we currently use and the protocols we recommend undergo unprecedented review.
Over the course of many years, veterinary medicine has done an excellent job of educating pet owners on the importance of vaccinating adult dogs and cats annually. There is absolutely no debate over the health benefits that millions of animals have derived from widespread availability of low-cost and highly effective vaccines. Nevertheless, a growing awareness of vaccine-associated fibrosarcomas in cats and a plausible relation between vaccination and immune-mediated disease (e.g., hemolytic anemia, thrombocytopenia, polyarthritis) have motivated pet owners and veterinarians to question the risk versus benefit associated with annual vaccination of adult dogs and cats. In 1998, the American Association of Feline Practitioners published the report of an advisory panel on feline vaccines/ in which it was recommended that adult cats be vaccinated every 3 years rather than annually against just one antigen: feline parvovirus (panleukopenia). Reaction to this report was profound. Veterinarians throughout North America voiced strong con-
From the Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE
VOLUME 31 • NUMBER 3 • MAY 2001 439
440 FORD '. , ....
cems that anything other than annual vaccination of adult cats was inappropriate, irrational, and quite pos~bly detrimental. Now, approximately 3 years later, the "every 3 years" recommendation for feline parvovirus remains in place and has, in ~fact, been extended to include feline herpesvirus-1 and feline calicivirus.22,24 Indeed, change is happening.
It is important to note, however, that the strategic issues surrounding vaccination protocols are by no means limited to whether or not a particular vaccine should be administered at intervals of 1 or 3 years. There are many other reasons why companion animal practitioners should be compelled to review which vaccines are recommended and how protocols are assigned to individual patients. For example, what is the realistic risk of exposure considering the environment in which an individual animal lives? What is the realistic risk of infection based on the patient's age? Are we overvaccinating our patients? What is the justification for incorporating new vaccines into the practice? Should antibody titers be performed in lieu of annual vaccination? Does the practice, in fact, have a unified vaccination policy? To assume that all dogs and cats in the practice should be vaccinated every year with every licensed vaccine is wrong. Vaccination is a medical procedure, and it is the clinician's obligation to assess an individual patient's health status in relation to age, living environment, and risk of exposure and infection when making such medical decisions.
All this considered, are we vaccinating individual patients too often with too many vaccines? Most authors would agree that the answer to this question is "yes." The reader is reminded, however, despite all the controversy, there are many strategic issues behind these public proclamations of overvaccination that justify the need to challenge the vaccination paradigms we have lived with for the past 50 or more years. The discussion that follows addresses a number of the primary concerns that, in effect, are promoting a comprehensive review of companion animal vaccination protocols. These issues are likely to take on even more importance in the future as new vaccines continue to be introduced and as more veterinarians take time to report adverse events associated with vaccination.
ANNUAL VACCINATION
In 1989, the American Veterinary Medical Association (AVMA) Council on Biologic and Therapeutic Agents published immunization guidelines for dogs and cats.2 In its report, booster vaccinations for all canine and feline vaccines were recommended annually (vaccines for canine Lyme disease, canine corona virus, canine giardiasis, feline infec-
VACClNES AND VACClNATIONS 441
tious peritonitis, feline Bordetella bronchiseptica, feline giardiasis, and feline Microsporum canis were not available at the time these recommendations were made). As recently as 1996, a survey of vaccination practices conducted in veterinary schools throughout North American indicated that annual revaccination of adult dogs and cats was routinely performed.19 It is reasonable to assume that most practitioners currently recommend annual booster vaccinations to their companion animal clientele.
Nevertheless, recent publications4• 17, 18, 20, 21, 25 and the 2000 Report of the American Association of Feline Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vaccines22 suggest that conventional guidelines fail to address realistic duration of immunity (001) for at least some of the vaccines licensed for cats. At issue is the fact that a protective immune response is likely to persist for several years after vaccination and, in fact, routine administration of annual booster vaccines to dogs and cats is not necessary. Despite the absence of published 001 studies, a growing body of data supports recommendations for booster vaccination that include administering core vaccines (e.g., feline panleukopenia, herpesvirus-I, calicivirus, canine distemper, canine parvovirus, rabies) at 3-year (or longer) intervals in adult animals. In fact, some licensed vaccines (e.g., B. bronchiseptica, leptospirosis, feline chlamydia) may not consistently provide a I-year duration of immunity and thus are justifiably administered to "at-risk" patients every 6 months, despite a product label (insert) that stipulates "annual booster recommended."17. 21
Companion animal vaccination guidelines are currently undergOing critical scrutiny by representatives from private practice, industry, and academia. Despite widespread recommendations for annual revaccination, information available today suggests that current vaccination practices in North America do not necessarily correspond with the body of knowledge pertaining to 001 derived from licensed vaccines. As a direct result, companion animal practitioners should expect significant changes in the current standard of practice pertaining to the administration of vaccines to dogs and cats.
Among the most significant changes anticipated in the future is the recommendation to discontinue routine administration of annual booster vaccinations to adult dogs (distemper virus and parvovirus) and cats (parvovirus [panleukopenia], feline herpesvirus-I, and calicivirus). The incidence of canine distemper, canine parvovirus, and feline panleukopenia among vaccinated adult (> 1 year of age) animals is virtually zero. Furthermore, protection derived from vaccination against 'these viruses seems to be sustained for periods as long as 5 or 6 years.5• 10. 23. 24 Future
" 442 FORD
vaccination standards for adult dogs and cats seem likely to center around conservative booster intervals e,very 3 years for selected vaccines.
Vaccines intended to proted again~t diseases such as B. bronchiseptica, canine parainfluenza virus, and feline leukemia virus (FeLV) are not known to provide protection against challenge for more than 1 year. Annual boosters are likely to continue to be recommended for those animals considered at risk of exposure to diseases caused by these organisms. Although annual boosters are still recommended, the actual risk:benefit ratio derived from FeLV and feline infectious peritonitis virus vaccination simply does not seem to justify the number of cats receiving annual vaccines.
TITERS VERSUS ANNUAL VACCINATION
What is the feasibility of performing annual antibody titers in patients rather than subjecting them to annual booster vaccination?
Despite the fact that a number of laboratories offer selected canine and feline antibody titers to veterinarians, there are a number of significant factors that, in this author's opinion, do not justify offering this service to clientele on a routine basis. In addition to the fact that antibody concentration does not necessarily correlate with protection against disease, there are other compelling reasons behind the fact that widespread acceptance and use of antibody determinations is not likely to happen in clinical practice. First, standardized methods for determining antibody concentration in serum for the various vaccine antigens have not been achieved. The risk lies in the fact that a single serum sample divided three times and sent to three different laboratories is quite likely to yield three different titers, and quite possibly three different interpretations. What may be deemed "protective" by one laboratory could well be labeled "susceptible" by another. Furthermore, it is important to note that a vaccinated dog or cat that does not have a significant concentration of antibody may, in fact, have excellent immunity. A "negative" antibody titer does not necessarily correlate with susceptibility to infection. Likewise, the presence of antibody, even at high levels, does not guarantee immunity subsequent to exposure.7• 15. 17
It should also be noted that over the next 5 to 10 years recombinant (genetically engineered) vaccines are likely to become the predominant technology used by manufacturers in the production of companion animal biologics. Although measurable antibody titers are expected to be associated with some of these products, others are not likely to produce antibody that is measurable in vitro. The ability of recombinant vaccines to provoke immunity through cell-mediated immune (eMI) mechanisms further complicates in vivo assay of immune responses,
VACCINES AND VACCINATIONS 443
because measuring CMI responses is complex and availability is quite limited.
SELECTION OF ANTIGENS
Not only is it perceived that veterinarians are vaccinating too often, but it has been suggested that pets are inoculated with vaccines containing an excessive combination of antigens. There is no immunologic evidence to support the hypothesis that the immune system of dogs and cats is being "overwhelmed" by the frequent administration of various vaccines. In fact, the real issue at hand for the future is to determine which vaccines are, in fact, indicated and which are not. Surveys of companion animal practitioners and veterinary teaching hospitals on vaccination protocols indicate that there is considerable diversity of opinion withiri the profession on which vaccines should and should not be administered.
In the future, vaccination protocols for dogs and cats are likely to center on recommendations for administering so-called "core" and "noncore" vaccines. Core vaccines are those recommended for administration to every dog and cat presented to the practice. Recommendations for designating a particular vaccine as core are determined by (1) severity of disease, (2) transmissibility to other animals, and (3) the potential for a particular infection to be zoonotic. Conversely, noncore vaccines would be recommended to clientele when a known or likely risk is anticipated or when an animal's lifestyle represents a reasonable risk after exposure to an infectious agent. Examples include FeLV, feline infectious peritonitis virus, and canine Lyme disease vaccine.
Another issue pertaining to the selection of vaccines is the administration of modified-live virus (MLV) versus killed virus vaccine. Although recommendations against administration of multivalent MLV vaccines were made 10 years ago,26 most veterinarians continue to administer MLV biologics. This is certainly justified, as these products do provide a superior sustained immune response. Furthermore, there are no data demonstrating that there are significant advantages in using killed virus vaccines as compared with MLV vaccines. The suggestion that MLV vaccines pose an unreasonable safety risk is largely anecdotal and without scientific merit. Unfortunately, killed virus vaccines have generally not proved to be suitable alternatives.
Selection of Antigens in the Shelter Environment
Selecting core versus noncore antigens is somewhat more complex when applied to an animal shelter environment. As veterinarians who
444 FORD
practice shelter medicine can attest, there are no standatdized formulae for immunization success within anim'l,ls shelters considering the innumerable variables in the equation, including shelter finances, "kill versus nonkill" policy, staff experience and mow ledge base with infectious disease (from cleaning to screening), census, concurrent illnesses, holding times, season of the year, construction, and air exchange, just to name a few.
In developing a vaccination program for an animal shelter, a few assumptions must be taken into consideration:
• Assume infectious disease exposure has already occurred or is going to occur.
• Assume that puppies and kittens are at considerably more risk than adult dogs and cats.
• Assume that healthy-appearing infected adults are the critical reservoir of infection for puppies and kittens.
• Assume that vaccination does not preclude the development of clinical disease.
• Assume that routine cleaning and routine use of isolation facilities are not likely to prevent disease outbreaks.
There are three approaches to managing infectious disease in shelters .
Darwinian Approach
Do not screen and do not vaccinate any animals, ever. Those that survive are the fittest-they win. Although that is the most economical approach, the downside is the risk of rampant infectious diseases among susceptible animals, especially the young, living in the shelter.
Filtered Approach
Using skilled personnel trained to recognize sick animals, simply screen and remove (or euthanatize) those animals that are obviously sick. It is a daily (at least) job, and it obviously does nothing to prevent those who are about to become sick from spreading their illness.
Unlimited Funds Approach
Vaccinate every animal on admission to the facility, hold them in isolation for 14 days, and ensure they are examined and monitored by a veterinarian. Those that survive the quarantine period are escorted to the main facility, where they enter environmentally controlled housing,
VACCINES AND VACCINATIONS 445
get two square meals a day, and have unlimited access to a graduate student doing animal-bond research.
It is not likely that anyone of these approaches is going to effectively eliminate or even contain infectious disease outbreaks in a shelter. Vaccination is simply not the cornerstone of infectious disease control within a shelter environment. Facility construction, especially the ability to isolate, the ability to move air, and the ability to clean effectively, become especially critical factors. TIUs is not to suggest that vaccination has no role whatsoever in shelter medicine, however. Personal experience suggests that routine inoculation of dogs and cats with core vaccines (as defined previously) is indicated at the time the animal enters the facility. The benefit of administering noncore vaccines (such as canine corona virus and FeLV) to shelter animals does not seem to justify the cost.
VACCINE SAFETY
Among the most important issues facing practitioners today is that of vaccine safety. For most vaccines currently on the market, it must still be assumed that the benefits of vaccination, when performed in accordance with currently published standards, far outweigh the risk of vaccine-induced illness or disease. Recent reports have raised serious concerns within the profession over the relation between vaccination and delayed adverse events, specifically vaccine-associated fibrosarcoma in cats6, 11, 12. 16 and immune-mediated disease in dogs.S' 13 Determining which vaccines pose a risk to which animals, and when, simply cannot be determined with the information available today. It is still the practitioner who assumes responsibility not only for recommending a particular vaccination protocol but for any consequences that might arise as a result of administering a vaccine (see section on liability).
Concern over the risks associated with the use of attenuated (MLV) vaccines, disease caused by residual virulence, and disease attributed to contamination during manufacture has sustained the market for inactivated products. There are significant advantages associated with using attenuated vaccines, including rapid onset, sustained protection, the ability to stirnulate CMI, and the ability to immunize by way of natural routes, which argue against the decision to offer only killed vaccines to companion animal patients.
Adverse Event
Information on the behavior of individual vaccines used under typical field conditions is maintained by the manufacturers and reported
446 FORD ,'"
to the US Department of Agriculture Center for Veterihary Biologics.27
Such postmarketing surveillance also ;;erves as an alert system for the rapid detection of vaccine-related events that seem to be unusual in nature or frequency. The single most significant factor that serves to compromise the effectiveness of the postmarketing surveillance program is the lack of adverse event reporting by practitioners. In many instances, not even deaths associated with vaccine administration are consistently reported.
An adverse event is any undesirable occurrence after the use of an irnmunobiologic product, including illness or reaction, whether or not the product caused the event. Anecdotal surveys suggest that adverse event reports from veterinarians dramatically underrepresent the number of reactions observed and regarded to be vaccine associated. Despite efforts to categorize adverse events based on type, there are still no uniform standards used by practitioners or manufacturers to classify frequency and type of event. The US Department of Agriculture has developed adverse event reporting guidelines that practitioners should use when addressing known or suspected adverse events associated with administration of any vaccine. Reporting criteria to include when reporting a vaccine-associated adverse event include:
• Patient information • Patient signalment (age, breed, sex) • Pertinent history • Case identification number (if applicable)
• Adverse event • Description of the event (e.g., onset of signs after inoculation,
clinical signs/ lesions) • Supporting laboratory data, including normal and abnormal
findings (if applicable) • Date of inoculation • Date signs were first noticed • Outcome • List of all irnmunobiologic products administered" that might
be associated with the adverse event, including: • Product brand name • Serial or lot number • Product code number
• Administration information (each vaccine administered), including: • Dose • Route
' For combination products, list the product code and serial number of each vial as well as the product code of the combination package.
VACCINES AND VACCINATIONS 447
• Site • Needle size • Administration of concurrent (nonbiologic) drugs • Date vaccine was reconstituted
• Personal information • Name, address, and telephone number of veterinarian • Name, address, and telephone number of owner/ agent
Although only a few reports specifically address various causes of adverse events, reactions have been attributed to preservatives, purity, contamination, virulence of attenuated agents, adjuvant, route of administration, concurrent administration of other vaccines, and ordinal number of the vaccine administration (most immediate reactions occur subsequent to administration of the first vaccine dose as opposed to the second or third vaccine dose in: a series). Neither the cause nor the exact frequency of delayed reactions such as tumor formation or immunemediated disease is known.
Reporting of adverse events remains the responsibility of the practitioner who administers the vaccine and observes the reaction. Reports should be made directly to the vaccine manufacturer, usually to the technical service section.
Feline Vaccine-Associated Fibrosarcoma
Over the past decade, the cause-and-effect relation between vaccination and fibrosarcoma in cats has been central to the concerns of veterinarians and pet owners with regard to vaccine-induced disease. Estimates of tumor prevalence range from 1 in 10,000 to 1 in 1000 cats vaccinated and are most frequently reported to be associated with the administration of FeLV and killed rabies vaccinesY' 12. 16 Tumors are aggressive and have a high rate of recurrence. Although the etiopathogenesis is not completely understood, there is compelling evidence to support a relation between postvaccination inflammation and tumor formation. Of particular concern is the role that adjuvants such as aluminum hydroxide, a common component of killed vaccines used in human beings and animals, seem to take in mediating the inflammatory response that culminates in tumor development.
Veterinarians are encouraged to follow the research reports and recommendations of the AVMA Feline Vaccine-Associated Sarcoma Task Force when developing vaccination recommendations for cats. Until a definitive statement can be made about the adjuvant-inflammationtumor relation, it is this author's recommendation that veterinarians restrict administration of feline vaccines to nonadjuvanted biologics
448 FORD .. .
when feasible. When it is the decision .of the practice to proceed with the use of adjuvanted vaccine in cats, .it is recommended that every effort be made to conduct a thorough risk assessment so as to offer the client and the patient the most effective but safest level of protection.
Multidose Vials
Veterinarians are advised to administer vaccine from single-dose vials only. Administering vaccine from a multidose, or TANK, vial (typically 10 do·ses per vial) containing killed virus carries the risk of delivering significantly different concentrations of adjuvant to each patient. Depending on the thoroughness with which the multi dose vaccine is mixed before each dose is administered, the adjuvant concentration in the doses withdrawn can be highly variable.
LIABILITY
Discussions with vaccine manufacturers, practicing veterinarians, attorneys, and representatives from the AVMA Liability Trust suggest that there is considerable confusion among practicing veterinarians over the use of vaccines in a manner not specifically recommended by the manufacturer (as published in the package insert) and the liability assumed when a vaccine causes, or is presumed to cause, a serious or expensive injury to the patient.
It has been found that vaccination protocols for companion animals vary considerably throughout North America. Furthermore, it is the veterinarian who, after assessing the various risk factors unique to the individual patient, makes recommendations as to which type of vaccine and which choice of antigen are to be administered as well as which product is to be used, when, and how often. Veterinarians are not obligated to follow the recommendation outlined in the package insert for a specific product (see the article on vaccination liability in this issue). Discretion in the administration of vaccines is acceptable as long as it meets the provision defined as the "standard of practice." The standard of practice for administering vaccines is to recommend the most appropriate antigens (vaccines) at the most appropriate stages of life and to use the most efficacious but safest products available.
RISK ASSESSMENT
Providing effective imrnunoprophylaxis does not require that all dogs and cats presented for vaccination be inoculated with each of the
VACCINES AND VACCINATIONS 449
antigens for which a vaccine is currently licensed. Intrinsic and extrinsic factors related to the individual patient as well as factors unique to the infectious agent should be taken into consideration when establishing recominendations and assigning a vaccination protocol to an individual animal.
Core vaccines are recommended for administration to all dogs and cats seen by the practice. Recommendations for determining which antigens are deemed "core" should be based on whether (1) the consequences of infection are particularly severe (e.g., canine parvovirus, feline panleukopenia), (2) the infection is zoonotic and potentially puts human health at risk (e.g., rabies), and (3) the disease is prevalent and easily transmitted such that it poses a significant risk to the population at large (e.g., feline herpesvirus and calicivirus). The decision to vaccinate with a noncore vaccine should be based on the clinician's assessment of the individual animal's risk profile and take into consideration information about the patient, the patient's environment, and the infectious agent.
Host Factors
Suboptimal response to vaccination is possible among animals that are malnourished, have concurrent infection or illness, or are receiving regular doses of immune-suppressive drugs. Additional intrinsic factors considered to influence the outcome of infection include heritable resistance (and possible susceptibility) factors as well as stress. Age at the time of exposure is an important independent variable in assessing an individual's risk. Although no age group can be considered entirely free of risk, kittens and puppies less than 6 months of age are generally regarded as being more susceptible to infection than adults after exposure and thus represent the primary target population for vaccination. The presence of maternal antibody is an intrinsic host factor known to protect a kitten after exposure to an infectious agent; however, interference with vaccine antigen by maternal antibody is the single most common cause of vaccination failure. Failure to vaccinate a puppy or kitten at an age when maternal antibody has declined sufficiently increases an animal's risk of infection after exposure.
Environmental Factors
Population density and opportunity for exposure to other animals are among the most critical issues affecting an individual animal's risk of exposure to an infectious agent. Puppies and kittens living in cluster
450 FORD " populations are at substantially higher risk of infection than are those living in one- or two-pet households. Ftl.rthermore, the introduction of new animals into a household or clust~ poses a potential risk to the entire population. Geographic distribution of various infectious agents may represent significantly different exposure risk in different parts of North America and should be considered when determining which noncore vaccines would be most appropriate.
In multiple-animal households, sustained high ambient temperatures and humidity, in addition to a housing environment with fewer than 12 air exchanges per hour, increase the risk of an animal's exposure to respiratory pathogens. In kennels, a single puppy with parvovirus puts all other non vaccinated puppies at risk for as long as 1 month because of the long survival time of the virus in the environment.
Agent Factors
Independent agent-associated variables such as virulence, dose, and mutation do influence the outcome of infection but are difficult to objectively assess in the clinical setting. In the domain of risk assessment, it is the interaction between the agent and the host that dictates the outcome after exposure and infection. The severity of an infection, particularly a viral infection, is highly variable within a population of animals with similar exposure to the same agent. Clinical illness with the exact same pathogen may range from inapparent or mild to severe acute illness to chronic or latent infection.
RECOMBINANT VACCINE TECHNOLOGY
Recombinant vaccines are among the newest products in the rapidly emerging biotechnology/ vaccine market. The technologic advance behind these products is their ability to isolate and splice (or recombine) gene-sized fragments of DNA from one organism and to transfer them to another organism by way of a vector virus or plasmid DNA. It has already been demonstrated that the hybrid organism resulting from the in vitro exchange of genetic material has tremendous potential to deliver safe and immunogenic DNA into the host animal and, as such, represents a truly new generation of vaccine development for the veterinary profession. The recombinant vaccines currently being introduced into companion animal practice seem to provide an exceptionally safe product, although efficacy and duration of immunity still have to be established for each product. Nucleic acid or "naked" DNA vaccines have been developed, and some have already been shown to be effective against certain companion animal diseases. The DNA vaccines are com-
VACCINES AND VACCINATIONS 451
pletely unique in that only DNA is inoculated; it subsequently transfects host cells to produce vaccine antigen.
The technology behind recombinant vaccines is quite sophisticated and has quickly moved routine vaccination of dogs and cats from the level of the whole organism to the subcellular level. The practice of administering attenuated live agents or whole killed products is likely to change in the near future. I , 3, 10, 14 As we enter the twenty-first century, it is anticipated that even newer technologies will be introduced, giving rise to veterinary-label vaccines that are safer, have exceptional efficacy, and have a duration of immunity that persists for several years if not for the life of the patient. Veterinarians· are encouraged to become familiar with recombinant vaccines so as to understand the basic technology behind their development and .to become familiar with the potential advantages and disadvantages of each new product as it is introduced. Then, the clinician, considering conventional and recombinant vaccines, should be able to administer the most appropriate product only as often as necessary to prevent significant disease.
OVER-THE-COUNTER SALES OF VACCINES
It could be argued that over-the-counter sales of vaccines for companion animals is an insignificant issue that has little impact on an individual practice. Medical and ethical considerations justify discouraging this practice, however. The number of vaccines available in the companion animal market is overwhelming. Although many of the products available are sold under the label of major biologic manufacturers, many other products are not. This raises important questions regarding safety and efficacy studies of at least some of products on the market. Rabies vaccines can be, and are, sold to nonveterinarians through catalog sales (Omaha Vaccine Company, Omaha, NE) in 23 states. In effect, rabies vaccine can be sold' and administered by nonveterinarians throughout the United States. The implications are not insignificant when, for example, a dog or cat vaccinated by a nonveterinarian bites a person or if the nonveterinarian owner elects to administer rabies vaccine to a pet that is a wolf-dog hybrid, regardless of prevailing laws prohibiting such practice.
Although vaccination protocols among individual veterinary practices do vary, the protocol recommended by at least some companies offering catalog sales of vaccine is, quite simply, wrong. Advising customers to administer vaccine to puppies at 5 weeks, then at 6 weeks, and then every 2 weeks until they reach 18 weeks of age is simply not in accordance with the standard of practice in the United States. There is no rationale behind the recommendation to vaccinate puppies or
452 FORD
.~
kittens at intervals of less than 2 weeks. Nevertheless, the resources to monitor and address these standards do..not exist, and the companies that make these recommendations are JUlder no legal obligation to change.
Nosodes
The fact that pet owners are concerned about vaccination recommendations traditionally offered by veterinarians is apparent from the proliferation of antivaccination web sites, in which animal owners, breeders, and veterinarians offer alternative approaches, largely homeopathic, to protecting pets against infectious diseases. Their concerns center predominantly on "immune-system overload" and vaccine-induced disease. One of the proposed alternative approaches to vaccination of dogs and cats involves the administration of nos ode vaccines. Nosodes are products prepared from infected tissues, infected discharges, or the actual pathogenic organism that causes the disease one is attempting to immunize against. All nosodes are administered orally, but according to various web site resources, they do not need to be swallowed. What prevents the nos ode from actually infecting the animal and causing illness is the fact that the final product undergoes what is referred to as homeopathic dilution and "potentization." Apparently, infectious material is subjected to multiple dilutions such that the quantity of infectious material remaining is insignificant to cause disease or is absent. Dosing recommendations seem to vary but generally entail administering either a three-drop dose ("small animals") or a six-drop dose ("large" animals) orally. A dose is given on 3 days of the first week (of life?), once weekly for the next 3 weeks, once monthly for the next 6 months, and once every 6 months thereafter. To the author's knowledge, only one controlled study on the efficacy of a canine parvovirus nosode has been conducted. Subsequent to administration of the parvovirus nosode, dogs were orally challenged with virulent parvovirus. Results showed that 100% of the control dogs and 100% of the "vaccinates" became infected with parvovirus (R.D. Schultz, personal communication, 2000).
References
1. Adams LG, Ford RB, Gershwin LJ, et al: Recombinant vaccine technology. Veterinary exchange. Compend Contin Educ Pract Vet 19(suppl):5-16, 1997
2. American Veterinary Medical Association Council on Biologic and Therapeutic Agents: Canine and feline immunization guidelines. JAVMA 195:314-317, 1989
3. Babiuk LA, Lewis }, Van Den Hurk S, et al: DNA immunization: Present and future. Adv Vet Med 41:163-179, 1999
VACCINES AND VACCINATIONS 453
4. Bowlin CL: Proceedings from Perspectives on Vaccines in Feline Practice, Eighth Annual Feline Practitioners Seminar, Columbus, OH, 1996
5. Burr H, Coyne M, Gay C, et aI: Duration of Imrrnrnity in Companion Animals after Natural Infection and Vaccination. Research Report, Exton, PA, Pfizer Animal Health. 1998
6. Burr H, Coyne M, Hall 1, et aI: Injection Site Sarcoma and the Vaccination of Cats. Research Report, Exton, PA, Pfizer Animal Health, 2000
7. Dodds WJ: More bumps on the vaccine road. Adv Vet Med 41:715-732, 1999 8. Duval 0, Giger U: Vaccine-associated immune-mediated hemolytic anemia in the dog.
J Vet Intern Med 10:290--295, 1996 9. Elston T, Rodan I, Hemming 0, et al: 1998 Report of the American Association of
Feline Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vaccine. JAVMA 212:227-241,1998
10. Ford RB, Schultz RD: Vaccines and vaccinations: Issues for the twenty-first Century. In Bonagura JD (ed): Current Veterinary Therapy XIII. Philadelphia, WE Saunders, 2000, pp 250--253
11. Hendrick MI, Goldschmidt MH: Do injection site reactions induce fibrosarcomas in cats? JAVMA 199:968, 1991
12. Hendrick MI, Kass PH, McGill LD, et al: Postvaccinal sarcomas in cats. J Nat! Cancer Inst 86:341-343, 1994a
13. Hogenesch H, Azcona-Olivera 1, Scott-Moncrieff C, et aI: Vaccine-,induced autoimmunity in the dog. Adv Vet Med 41:733-747, 1999
14. Horzinek MC: Vaccination: A philosophical view. Adv Vet Med 41:1--<i, 1999 15. Hustead DR, Carpenter T, Sawyer 0 , et aI: Vaccination issues of concern to prac
titioners. JAVMA 214:1000--1002, 1999 16. Kass PH, Barnes WG, Spangler WL, et al : Epidemiologic evidence for a causal relation
between vaccination and fibrosarcoma tumorigenesis in cats. JAVMA 203:396-405, 1993 17. Kruth SA, Ellis, JA: Vaccination of dogs and cats: General principles and duration of
immunity. Can Vet J 39:423-426, 1998 18. Larson RL, Bradley JS: Immunologic principles and immunization strategy. Compend
Contin Educ Pract Vet 18:963-971, 1996 19. Mansfield PO: Vaccination of dogs and cats in veterinary teaching hospitals in North
America. JAVMA 208:1242-1247, 1996 20. Paul MA, Wolf AM: Vaccinations: What's right? What's not? Proceedings of a Sympo
sium held at the North American Veterinary Conference, Schering Plough, Orlando, FL,1999
21. Phillips TR, Schultz RD: Canine and feline vaccines. In Kirk RW (ed): Current Veterinary Therapy XI. Philadelphia, WE Saunders, 1992, pp 202-206
22. Richards 1, Rodan I, Elston T, et al: 2000 Report of the American Association of Feline Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vaccines, AAFP / AFM, Nashville, TN, 2000
23. Schultz R: Current and future canine and feline vaccination programs. Vet Med 93:233-254, 1998
24. Scott FW, Geissinger eM: Long-term immunity in cats vaccinated with an inactivated trivalent vaccine. Am J Vet Res 60:652--<i58, 1999
25. Smith CA: Are we vaccinating too much? JAVMA 207:421-425, 1995 26. Tlzard I: Risks associated with use of live vaccines. JAVMA 196:1851-1858, 1990 27. US Department of Agriculture Center for Veterinary Biologics: Animal Immunobiologic
Vigilance. Ames, lA, US Department of Agriculture Center for Veterinary Biologics, 1996
Address reprint requests to
Richard B. Ford, DVM, MS College of Veterinary Medicine
North Carolina State University 4700 Hillsborough Street
Raleigh, NC 27606
e-mail: [email protected]
VACCINES AND VACCINATIONS 0195-5616/ 01 $15.00 + .00
FELINE VACCINATION GUIDELINES
James Richards, DVM, and ilona Rodan, DVM
The 1998 Report of the American Association of Feline Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vaccines14 was developed to help veterinary practitioners formulate vaccination protocols for cats. The current panel report updates information, addresses questions, and speaks to concerns raised by the 1998 report. In addition, it reviews vaccine licensing, labeling, and liability issues and suggests ways to successfully incorporate vaccination protocol changes into a private practice setting. The material in the 1998 report is not fully reproduced here, and readers are referred to the 1998 report for more detailed information.
Vaccines play an important role in the control of infectious diseases. Most vaccines do not induce complete protection from infection or disease, however, nor do they induce the same degree of protection in all animals. Factors that negatively affect an individual animal's ability to respond to vaccination include maternal antibody interference, congenital or acquired immunodeficiencies, concurrent disease, inadequate nutrition, immunosuppressive medication, and stress (e.g., overcrowding, poor sanitation) .20 Every effort should be made to ensure that
Portions of this article were previously published in the 2000 Report of the American Association of Feline Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vaccines, American Association of Feline Practitioners, Nashville, TN, 2000.
Written in collaboration with Thomas . Elston, DVM; Duane Flemming DVM, JD; Richard Ford, DVM, MS; Steven Henry, DVM; David Hustead, DVM; Michael Lappin, DVM, PhD; Michael Paul, DVM; David Rosen, DVM; Margie Scherk, DVM; Fred Scott, DVM, PhD; and Link Welborn, DVM.
From the Cornell Feline Health Center, College of Veterinary Medicine, Cornell University, Ithaca, New York UR); and Cat Care Clinic, Madison, Wisconsin (IR)
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE
VOLUME 3} • NUMBER 3 • MAY 200} 455
456 RICHARDS & RODAN
.,. patients are healthy before vaccination. Because vaccination alone does not completely protect animals from infe.ction and disease, environmental conditions should be addressed and,..exposure to infectious agents should be minimized.
The overall objectives of vaccination are to vaccinate the largest possible number of individuals in the population at risk, vaccinate each individual no more frequently than necessary, and vaccinate only against infectious agents to which individuals have a realistic risk of exposure and subsequent development of disease. Kittens younger than 16 weeks of age are generally more susceptible to infection than are adult cats and typically develop more severe disease. They represent the principal target population for vaccination.40 Maternal antibody interference is the most common reason why some animals are not immuniZed after vaccination, and it is also the reason why a series of vaccinations is necessary for kittens younger than 12 weeks of age.20 Vaccination needs of adult cats should be assessed at least once yearly and, if necessary, modified on the basis of an assessment of their risk.
VACCINE SELECTION AND ADMINISTRATION
It is recommended that administration sites for parenteral vaccine be chosen in accordance with the guidelines established by the American Association of Feline Practitioners and adopted by the Vaccine-Associated Feline Sarcoma Task Force (Table 1).46 Use of multiple-dose vials is discouraged, because inadequate mixing may result in unequal distribution of antigen and adjuvant, possibly resulting in decreased efficacy or an increased likelihood of adverse events; iatrogenic contamination is an additional risk. The panel discourages the use of polyvalent vaccines other than those containing combinations of feline panleukopenia virus, feline herpesvirus-l (FHY-l), and feline calicivirus (FCV), exclusively. This opinion is based on the belief that as the number of antigens in a vaccine increases, so too does the probability of associated adverse events. Additionally, use of polyvalent vaccines may force practitioners to administer vaccine antigens not needed by the patient.
Feline Panleukopenia
Feline panleukopenia is caused by feline parvovirus (FPV). The virus remains infectious for months to years in the environment and is primarily spread via the fecal-oral route. Fomites (e.g., cages, food bowls, litter boxes, health care workers) play an important role in the transmission of the organism. Clinical signs of infection include lethargy, an-
FELINE VACCINATION GUIDELINES 457
orexia, vomiting, diarrhea, fever, and profound panleukopenia; mortality is highest in young susceptible catsY In utero infection with FPV is a common cause of cerebellar hypoplasiaY
Va'ccination against FPV is highly recommended for all cats. Immunity to feline panleukopenia is primarily through antibody response to natural infection, vaccination, or passive transfer of maternal antibodies from queen to kittens. Maternal antibody may interfere with immunization when antibody titers are high during the neonatal period. Maternal antibody titers generally wane sufficiently to allow immunization by 12 weeks of age.47 Immunity conferred by feline panleukopenia vaccines is considered to be excellent, and most vaccinated animals are completely protected from infection and clinical disease. Serologic and challenge exposure data indicate that a parenteral FPV vaccine induces immunity that is sustained for at least 7 years.4S• 49 After the initial series of vaccinations and revaccination 1 year later, cats should be vaccinated no more frequently than once every 3 years.
Modified-live virus (MLV) vaccines and adjuvanted inactivated virus vaccines for parenteral administration as well as an MLV vaccine for topical (intranasal) administration are available and effective. Experimental studies have shown that intranasal administration of canine parvovirus-2 vaccines to puppies is less effective than parenteral administration in overcoming maternal antibody interference (Ronald Schultz, PhD, personal communication, 2000). The most likely reasons are that fewer virus particles reach lymphoid tissue when the product is given
._ intranasally compared with parenteral administration and viral replication in lymphoid tissue is required for immunization with MLV parvovirus vaccines. Although studies have not been performed in cats, the same phenomenon may occur in this species. Caution is appropriate when contemplating the use of intranasal FPV vaccines for primary immunization of kittens, especially those residing in environments where exposure to FPV is likely.
It has been found recently that some cats with panleukopenia-like disease were infected with canine parvovirus-2b. Studies show that FPV vaccines provide excellent protection not only from FPV but also from canine parvovirus-2b; thus, canine parvovirus infection should not be a concern for cats immunized as a result of vaccination with FPV vaccines.39
Serious adverse events associated with FPV vaccines are rare. Tumor formation at the site of a topically administered vaccine has not been reported. Vaccination of pregnant queens with modified-live FPV vaccines may possibly result in neurologic disease in developing fetuses52
;
the same concern applies to kittens vaccinated at less than 4 weeks of age. The use of MLV vaccines should be avoided in pregnant queens and kittens less than 1 month of age.52• 62
* Tab
le 1
. A
ME
RIC
AN
AS
SO
CIA
TIO
N O
F F
ELI
NE
PR
AC
TIT
ION
ER
S A
ND
AC
AD
EM
Y O
F F
ELI
NE
ME
DIC
INE
FE
LIN
E V
AC
CIN
E P
AN
EL
00
R
EC
OM
ME
ND
ED
FO
R V
AC
CIN
AT
ION
OF
CA
TS
An
tig
en
Fel
ine
par
vo
vir
us·
Fel
ine
herp
esvi
rus-
! an
d f
elin
e ca
lici
viru
s
Fel
ine
herp
esvi
rus-
! an
d f
elin
e ca
lici
viru
s
Va
ccin
e T
ype
s
ML
V v
acci
ne f
or p
aren
tera
l ad
min
istr
atio
n M
LV
vac
cine
for
top
ical
ad
min
istr
atio
n A
djuv
ante
d in
acti
vate
dvi
rus
vacc
ine
for
pare
nter
al
adm
inis
trat
ion
Com
bine
d M
LV
vac
cine
fo
r pa
rent
eral
ad
min
istr
atio
n C
ombi
ned
adju
van
ted
in
acti
vate
d-vi
rus
vacc
ine
for
pare
nter
al
adm
inis
trat
ion
Com
bine
d M
LV
vac
cine
fo
r to
pica
l ad
min
istr
atio
n
Pri
ma
ry V
acc
ina
tio
n
Ca
ts <
12
We
eks
Old
C
ats
2:
12
W
ee
ks O
ld
Bo
ost
er
Va
ccin
ati
on
If 2
: 6
wee
ks o
ld,
Adm
inis
ter
two
dose
s ye
ar a
fter
pri
mar
y
vacc
inat
e at
3
to 4
wee
ks a
par
t va
ccin
atio
n, t
hen
init
ial
visi
t an
d
ever
y 3
to 4
w
eeks
unt
il
2:
12 w
eeks
o
ldt
no m
ore
freq
uent
ly t
han
ever
y 3
yea
rs
If >
6 w
eeks
old
, A
dmin
iste
r tw
o do
ses
1 ye
ar a
fter
pri
mar
y
vacc
inat
e at
3
to 4
wee
ks a
par
t va
ccin
atio
n, t
hen
init
ial
visi
t an
d
ever
y 3
year
s ev
ery
3 to
4
wee
ks u
ntil
2
: 12
wee
ks
old
t If
> 6
wee
ks o
ld,
Adm
inis
ter
one
dose
va
ccin
ate
at
init
ial
visi
t an
d ev
ery
3 to
4
wee
ks u
ntil
2
: 12
wee
ks
old
t
1 ye
ar a
fter
pri
mar
y va
ccin
atio
n, t
hen
ever
y 3
year
s
Co
mm
en
ts
Hig
hly
reco
mm
ende
d fo
r aU
cat
s; i
n m
ost
cats
, pr
otec
tion
der
ived
aft
er
adm
inis
trat
ion
of b
oost
er
vacc
inat
ion
1 ye
ar a
fter
pri
mar
y
vacc
inat
ion
is s
ust
aine
d fo
r at
le
ast
3 ye
ars
and
pro
babl
y 5
to 6
ye
ars
or m
ore;
MLV
vac
cine
s sh
ou
ld n
ot b
e ad
min
iste
red
to
pre
gn
ant
qu
een
s o
r ki
tten
s <
4 w
eeks
old
H
ighl
y re
com
men
ded
for
aU
cat
s;
ML
V v
acci
ne S
hOl'd
nbt
be
adm
inis
tere
d to
pre
gn
ant
quee
ns
Hig
hly
reco
mm
ende
d fo
r al
l ca
ts;
may
be
used
as
an a
lter
nati
ve t
o th
e pa
rent
eral
pro
duct
; m
ay; b
e pr
efer
able
to
pare
nter
ally
ad
min
iste
red
vacc
ines
in
cats
re
ared
in
or e
n te
ring
en
viro
nmen
ts i
n w
hich
vir
al
up
per
res
pira
tory
tra
ct d
isea
se i
s en
dem
ic (
e.g.
, so
me
catt
erie
s,
boar
ding
fac
ilit
ies,
she
lter
s);
ML
V
vacc
ine
shou
ld n
ot
be
adm
inis
tere
d to
pre
gn
ant
quee
ns
Rab
ies
Adj
uvan
ted
inac
tiva
ted-
No
t el
igib
le f
or
Adm
inis
ter
one
dose
1
year
aft
er p
rim
ary
Hig
hly
reco
mm
ende
d fo
r al
l ca
ts;
viru
s va
ccin
e fo
r va
ccin
atio
n va
ccin
a ti
on,
then
ra
bies
vac
cina
tion
of
cats
is
pare
nter
al
ever
y ye
arll
requ
ired
by
law
in
som
e re
gion
s ad
min
istr
atio
n ev
ery
of t
he c
ount
ry,
and
vet
erin
aria
ns
year
§ sh
ould
com
ply
wit
h st
ate
and
loca
l st
atue
s re
gard
ing
type
of
vacc
ine
to b
e us
ed a
nd
vacc
inat
ion
inte
rval
R
abie
s A
djuv
ante
d in
acti
vate
d-N
ot
elig
ible
for
A
dmin
iste
r on
e do
se
1 ye
ar a
fter
pri
mar
y H
ighl
y re
com
men
ded
for
all
cats
; vi
rus
vacc
ine
for
vacc
inat
ion
vacc
inat
ion
then
ra
bies
vac
cina
tion
of
cats
is
pare
nter
al
ever
y 3
year
sll
requ
ired
by
la w
in
som
e re
gion
s ad
min
istr
a ti
on e
very
of
the
cou
ntry
, an
d v
eter
inar
ians
3
year
s§
sho
uld
com
ply
wit
h st
ate
and
loca
l st
atue
s re
gard
ing
type
of
vacc
ine
to b
e us
ed a
nd
vacc
inat
ion
inte
rval
R
abie
s C
anar
ypox
vir
us-v
ecto
red
Adm
inis
'ter
one
Adm
inis
ter
one
dose
1
year
aft
er p
rim
ary
The
rec
ombi
nant
rab
ies
viru
s re
com
bina
nt v
acci
ne
dose
to
ca ts
as
vacc
inat
ion,
the
n va
ccin
e ap
pro
ved
can
be
used
an
fo
r pa
rent
eral
yo
ung
as 8
ev
ery
year
an
alt
erna
tive
to
prod
ucts
ad
min
istr
atio
n w
eeks
old
ap
prov
ed f
or a
nnua
l us
e; t
his
pro
du
ct d
oes
not
cont
ain
an
adju
vant
and
pos
tvac
cina
tion
in
flam
mat
ion
at t
he v
acci
ne s
ite
seem
s to
be
min
imal
; ho
wev
er,
wh
eth
er u
se o
f th
is p
rod
uct
is
asso
ciat
ed w
ith
a de
crea
sed
like
liho
od o
f va
ccin
e-as
soci
ated
sa
rcom
a fo
rmat
ion
is n
ot
pres
entl
y k
no
wn
F
elin
e le
ukem
ia
Adj
uvan
ted
and
A
dmin
iste
r tw
o A
dmin
iste
r tw
o do
ses
Ann
uall
y R
ecom
men
ded
for
cats
tha
t ar
e no
t vi
rus
nona
djuv
ante
d do
ses
3 to
4
3 to
4 w
eeks
apart~
rest
rict
ed t
o a
clos
ed,
indo
or,
inac
tiva
ted-
viru
s w
eeks
ap
art
to
FeL
V-n
egat
ive
envi
ronm
ent;
mos
t va
ccin
es f
or p
aren
tera
l ca
ts a
s y
ou
ng
im
port
ant
for
cats
< 1
6 w
eeks
old
; ad
min
istr
atio
n as
8 w
eeks
no
t re
com
men
ded
for
cats
~ 16
~
old~
wee
ks o
ld w
ith
min
imal
to
no r
isk
01
of
exp
osur
e to
FeL
V-i
nfec
ted
cats
'"
Tabl
e co
ntin
ued
aI' f
ollo
win
g pa
ge
~
0\ o
Ta
ble
1.
AM
ER
ICA
N A
SS
OC
IAT
ION
OF
FE
LIN
E P
RA
CT
ITIO
NE
RS
AN
D A
CA
DE
MY
OF
FE
LIN
E M
ED
ICIN
E F
ELI
NE
VA
CC
INE
PA
NE
L R
EC
OM
ME
ND
ED
FO
R V
AC
CIN
AT
ION
OF
CA
TS
(C
on
tinu
ed
).
An
tig
en
Chl
amyd
ia p
sitta
ci
Fel
ine
infe
ctio
us
per
iton
itis
vir
us
Mic
rosp
orum
can
is
Va
ccin
e T
ype
s
Mod
ifie
d-li
ve v
acci
ne f
or
pare
nter
al
adm
inis
trat
ion
Adj
uvan
ted
inac
tiva
ted
vacc
ine
for
pare
nter
al
adm
inis
trat
ion
MLV
vac
cine
for
top
ical
ad
min
istr
atio
n
Adj
uvan
ted
inac
tiva
ted
vacc
ine
for
pare
nter
al
adm
inis
trat
ion
Pri
ma
ry V
acc
ina
tio
n
Ca
ts <
12
We
eks
Old
If 2
: 9
wee
ks o
ld
adm
inis
ter
two
dose
s 3
to 4
w
eeks
ap
art
No
t ap
pro
ved
fo
r ca
ts <
16
wee
ks o
ld
No
t ap
prov
ed
for
cats
< 1
6 w
eeks
old
Ca
ts 2
: 12
W
ee
ks O
ld
Bo
ost
er
Va
ccin
ati
on
Adm
inis
ter
two
dose
s A
nnua
lly
3 to
4 w
eeks
ap
art
Adm
inis
ter
two
dose
s A
nnua
lly
3 to
4 w
eeks
ap
art
to c
ats
2:
16 w
eeks
o
ld
Fir
st d
ose
No
t st
ipul
ated
ad
min
iste
red
SC t
o ca
ts 2
: 16
wee
ks
old
; se
cond
dos
e ad
min
iste
red
SC 1
2 to
16
days
aft
er t
he
firs
t do
se;
thir
d do
se a
dmin
iste
red
SC 2
6 to
30
days
af
ter
the
seco
nd
do
se
Co
mm
en
ts
No
t re
com
men
ded
for
rout
ine
use;
ca
n be
con
sid e
red
for
use
in c
a ts
in m
ulti
ple-
cat
envi
ronm
ents
w
her
e C
. ps
ittac
i in
fect
ions
as
soci
ated
wit
h cl
inic
al d
isea
se
have
bee
n do
cum
ente
d N
ot r
ecom
men
ded
for
rput
ine
use
at t
his
tim
e; t
her
!is
insu
ffic
ient
ev
iden
ce t
o su
pp
ort
the
co
nclu
sion
th
at t
he v
acci
ne
indu
ces
clin
ical
ly r
elev
ant
prot
ecti
on
No
t re
com
men
ded
for
rout
ine
use;
va
ccin
atio
n m
ay b
e co
nsid
ered
as
on
e co
mp
on
ent
of a
co
mpr
ehen
sive
con
trol
pro
gram
in
mul
tipl
e-ca
t en
viro
nmen
ts i
n w
hich
M.
cani
s in
fect
ion
is
ende
mic
or
as a
djun
ctiv
e tr
eatm
ent
to h
aste
n re
solu
tio'
n of
cl
inic
al s
igns
in
indi
vidu
al c
ats
II'> el
Bor
de/e
lla
brol
lchi
sep/
ica
Gia
rdia
lam
blia
ML
V f
or t
opic
al
adm
inis
trat
ion"
Ad
juv
ante
d i
nact
ivat
ed
vacc
ine
for
pare
nter
al
adm
inis
trat
ion
Ad
min
iste
r on
e do
se (
0.2
mL
) in
tran
asal
ly t
o ca
ts ~ 4
wee
ks
old
Ad
min
iste
r th
e fi
rst
do
se t
o ca
ts 8
wee
ks
old
and
a
seco
nd d
ose
3 to
4 w
eeks
la
ter
Adm
inis
ter
one
do
se
No
t st
ipu
late
d
(0.2
mL
) in
tran
asal
ly
Ad
min
iste
r tw
o d
oses
A
nnua
lly
3 to
4 w
eeks
ap
art
Par
ente
ral
vacc
ines
sh
ou
ld b
e ad
min
iste
red
su
bcu
tan
eou
sly
or
intr
amus
cula
rly.
-C
ause
of
feli
ne p
anle
ukop
enia
. tF
or
kitt
ens
that
are
orp
han
ed o
r at
hig
h r
isk
of
expo
sure
, va
ccin
atio
n w
hen
as
yo
un
g a
s 4
wee
ks
old
may
be
indi
cate
d.
tFo
r ki
tten
s th
at a
re o
rph
aned
or
at h
igh
ris
k o
f ex
posu
re,
vacc
inat
ion
wh
en a
s y
ou
ng
as
10-1
4 d
ays
old
may
be
indi
cate
d.
§A s
peci
fic
rou
te o
f ad
min
istr
atio
n m
ay b
e re
quir
ed;
see
pro
du
ct i
nfor
mat
ion
for
deta
ils.
No
t re
com
men
ded
for
rou
tine
' use
; va
ccin
atio
n m
ay b
e co
nsid
ered
fo
r ca
ts e
nter
ing
or
resi
ding
in
mul
tipl
e-ca
t en
viro
nmen
ts w
here
B.
bro
llchi
sept
ica
infe
ctio
ns
asso
ciat
ed w
ith
cli
nica
l di
seas
e h
ave
bee
n d
ocu
men
ted
N
ot
reco
mm
end
ed f
or r
outi
ne u
se;
vacc
inat
ion
may
be
cons
ider
ed a
s on
e co
mp
on
ent
of a
co
mpr
ehen
sive
con
trol
pro
gra
m
in m
ulti
ple-
cat
envi
ronm
ents
in
w
hich
G.
lal1
lblia
inf
ecti
ons
asso
ciat
ed w
ith
cli
nica
l di
seas
e ha
ve b
een
do
cum
ente
d
IIM
ost
ofte
n, t
he p
rod
uct
ap
pro
ved
for
use
an
nu
ally
is
give
n fo
r in
itia
l va
ccin
atio
n fo
llow
ed 1
yea
r la
ter
and
ev
ery
3 y
ears
aft
er t
hat
by
adm
inis
trat
ion
of
the
pro
du
ct
app
rov
ed f
or u
se e
ver
y 3
yea
rs;
ho
wev
er,
vacc
inat
ion
inte
rval
mu
st c
om
ply
wit
h l
ocal
an
d s
tate
sta
tute
s.
~FeLV t
esti
ng i
s re
com
men
ded
bef
ore
vacc
inat
ion;
inf
ecte
d ca
ts d
o n
ot d
eriv
e an
y b
enef
it f
rom
vac
cina
tion
. -"
Thi
s p
rod
uct
is
no
t th
e sa
me
as t
he B
. br
ol1c
ilise
ptic
a va
ccin
e ap
pro
ved
for
use
in
do
gs;
the
pro
du
ct a
pp
rov
ed f
or u
se i
n d
og
s sh
ou
ld n
ot
be u
sed
in
cats
. M
LV
=
m
odif
ied-
live
vir
us;
FeL
V
=
feli
ne l
euke
mia
vir
us;
SC
=
subc
utan
eous
ly.
~
462 RICHARDS & RODAN
Feline Viral Rhinotracheitis and Feline Calicivirus Infection ...
" l'
Feline viral rhinotracheitis caused by FHV-1 and FeV infection account for up to 90% of all cases of infectious upper respiratory tract disease in catsY Both viruses are shed in ocular, nasal, and pharyngeal secretions of infected catsY Organisms are transmitted from cat to cat directly through sneezed macrodroplets or indirectly via contaminated fomitesY The disease is self-limiting; however, infected cats may develop chronic oculonasal disease. Latent infection is lifelong for cats infected with FHV-1; reactivation can occur during periods of stress or after corticosteroid administration. Some cats infected with FCV become persistently infected and shed virus for prolonged periods (months to years). Although rarely serious in adult cats, disease caused by these viruses may be severe, and sometimes fatal, in kittens. Lameness and chronic oral inflammatory syndromes have been linked to calicivirus infection and vaccination with modified-live calicivirus vaccines.3• 7. 10. 11.
45. 57 Risk of exposure to either FHV-1 or FCV is high, because both organisms are widespread in the feline population.
Vaccination against FHV-1 and FCV is highly recommended for all cats. Immunity is through humoral and cell-mediated immune responses to natural infection or vaccination or through passive transfer of maternal antibodies from queen to kittens. Maternal antibody may interfere with induction of a systemic immune response; however, by the time that kittens are 12 weeks . of age, maternal antibody titers wane sufficiently to allow parenteral immunization. Topically administered (intranasal, conjunctival) vaccines are capable of inducing a local immune response in the face of high maternal antibody titers. 27 Serologic and challenge exposure data indicate that parenteral FHV-1 and FCV vaccines induce protection that lasts at least 3 years.48• 49 After the initial series of vaccinations and revaccination 1 year later, cats should be vaccinated once every 3 years. . Regardless of the route of administration, FHV-1 and FCV vaccines induce only relative but not complete protection. At best, these vaccines induce an immune response that lessens the severity of disease; vaccinates are not immune to infection nor are they protected from all signs of disease. 2o Currently available FCV vaccines probably do not induce protection from all isolates of the virus.9
MLV and inactivated virus vaccines for parenteral administration and MLV vaccines for topical (intranasal and conjunctival) administration are available. If a susceptible cat is born into or is entering an environment in which viral upper respiratory tract disease is endemic (e.g., some catteries, boarding facilities, shelters), the use of a topical product may be advantageous. Administration of such products to kittens as young as 10 to 14 days of age could be considered in these
FELINE VACCINATION GUIDELINES 463
situations; however, products that also contain modified-live FPV antigens should not be administered to kittens younger than 4 weeks of age.62 Adverse events associated with vaccination against FHV-l and FCV . include mild transient fever, sneezing, conjunctivitis, oculonasal discharge, lameness, and, for parenteral products, pain at the injection site.9
•11 Sneezing, conjunctivitis, oculonasal discharge, and ulceration of
the nasal philtrum are believed to occur more frequently with vaccines licensed for topical use. Tumor formation at the site of a topically administered vaccine has not been reported.
Rabies
Rabies is transmitted mainly through bite wounds of infected mammals. More cats than dogs develop rabies in the United States29; although they are relatively resistant to rabies, both species serve as potential sources of infection for human beings.21, 29 Treatment is ineffective in cats that develop clinical signs and should not be attempted because of the high potential for zoonotic infection.21 All instances of suspected or known rabies virus infection must be reported to local health department officials. Proper precautions and quarantine procedures as outlined by local regulations and described in the Compendium of Animal Rabies Prevention and Control, 200026 should be followed.
Although vaccine-associated sarcomas have been reported to develop in association with administration of a variety of vaccines, current data suggest that they are more frequently associated with administration of feline leukemia virus (FeLV) vaccines and adjuvanted raoies virus vaccines.28 Inflammatory reactions are commonly observed at sites where adjuvanted rabies virus vaccines have been administered, and concern has arisen regarding the possible association between these reactions and vaccine-associated sarcomas.35 With the exception of a recently approved canarypox virus-vectored recombinant feline rabies virus vaccine (PureVax Feline Rabies Vaccine; Merial Limited, Iselin, NJ), all rabies virus vaccines currently on the market contain adjuvants. In rats, inflammation induced by the recombinant product seems to be rninirnal,34 but whether the use of this vaccine is associated with a reduced likelihood of vaccineassociated sarcoma formation in cats is not yet known. The recombinant product is currently licensed only for annual administration.
Rabies virus vaccination is highly recommended for all cats and is required by law in some states and municipalities. Manufacturers are required by the US Department of Agriculture to establish, by means of experimental challenge exposure studies, the minimum duration of immunity for the rabies virus vaccines that they sell, and products approved for use every year or every 3 years are available. Statutes governing the administration of rabies virus vaccines vary considerably
464 RICHARDS & RODAN ,
"
throughout the United States; veterinarians should com}:>ly with the legal requirements of their area,
Feline Leukemia Virus Infection
FeLV infects domestic cats throughout the world, Transmission is through transfer of virus in the saliva or nasal secretions resulting from prolonged intimate contact (e,g" mutual grooming), biting, or sharing of food and water utensils, The virus may also be transmitted by transfusion of blood from an infected cat, in utero, or through the milk,33 Exposure to virus persisting in the environment on fomites or in aerosolized secretions is not an efficient means of viral transmission, Clinical signs of FeLV infection are primarily related to neoplasia, anemia, and diseases resulting from immunosuppression,
Kittens are the most susceptible to infection; resistance increases with maturity, Experimental data demonstrate that kittens younger than 16 weeks of age are most susceptible to infection, with cats older than this being relatively resistant. 23 Cats at greatest risk include outdoor cats (free-roaming pets, stray 'cats, and feral cats), Also at risk are cats residing in open multiple-cat environments, cats living with FeLV-infected cats, and cats reSiding in households with unknown FeLV status,
The decision to vaccinate an individual cat against FeLV infection should be based on the cat's age and its risk of exposure, Vaccination against FeLV is recommended for cats at risk of exposure (i,e" cats not restricted to a closed, FeLV-negative, indoor environment), especially those younger than 4 months of age, Vaccination is not recommended for cats with minimal to no risk of exposure, especially those older than 4 months of age, The ability of a particular vaccine brand to induce an immune response sufficient to resist persistent viremia varies from study to study, 53 Because protection is not induced in all vaccinates, preventing exposure to infected cats remains the single best way to prevent FeLV infection, Vaccination against FeLV does not diminish the importance of testing cats to identify those that are viremic, It is of critical importance that viremic cats not be in contact with other cats, especially those younger than 4 months of age, As a result, the FeLV infection status of all cats should be determinedY Adverse events associated with vaccination against FeLV include local swelling or pain, transient lethargy or fever, and postvaccination granuloma formation, Although vaccine-associated sarcomas have been reported to develop in association with administration of other vaccines, current data suggest that they are more frequently associated with administration of FeLV vaccines and adjuvanted rabies virus vaccines,28 If vaccination is deemed appropriate, annual revaccination is recommended, Cats should be tested for FeLV infection before initial vaccination and when there is a possibility that they have been exposed to FeLV since they were vaccinated, The enzyme-linked immu-
FELINE VACCINATION GUIDELINES 465
nosorbent assay is the preferred screening test; the indirect immunofluorescent assay is the preferred confirmatory testY Individuals confirmed to be infected with FeLV need not receive FeLV vaccines, but they should be segregated from uninfected cats.
Chlamydiosis
Chlamydia psittaci is a bacterial pathogen of the conjunctiva and respiratory tract of cats. Transmission is through direct cat-to-cat contact; fomite transmission is less likely, because the organism is unstable in the environment. Serous conjunctivitis, which may initially affect only one eye, is the most common clinical sign. Sneezing or nasal discharge may develop, but if it does develop, it is usually mild. Clinical signs are usually evident 5 to 10 days after infection and resolve with appropriate antimicrobial treatment.18 Isolation rates have been reported to range from approximately 1% for cats without signs of respiratory tract disease to approximately 14% for cats with concurrent upper respiratory tract disease. 56 The highest rates of infection are reported for cats between 5 weeks and 9 months of age.61 Immunity conferred by C. psittaci vaccines is similar to that conferred by FHV-1 and FCV vaccines in that vaccinates are protected from severe clinical disease but not from infection.20 The frequency of adverse systemic events associated with C. psittaci vaccines is higher than that associated with other commonly used vaccines; reactions include lethargy, depression, anorexia, lameness, and fever 7 to 21 days after vaccination.55 Because signs of disease associated with C. psittaci infection are comparatively mild and respond favorably to treatment, and because adverse events associated with the use of C. psittaci vaccines are of greater concern than adverse events associated with the use of many other products, routine vaccination against C. psittaci infection is not recommended. Vaccination may be considered for cats in multiple-cat environments, where infections associated with clinical disease have been confirmed. If vaccination is deemed appropriate, annual revaccination is recommended.
Feline Infectious Peritonitis
Feline coronaviruses (FCoVs) vary considerably in pathogenic potential and have historically been grouped into two biotypes: feline enteric coronaviruses, which typically cause subclinical to mild enteric infections, and feline infectious peritonitis (FIP) viruses, which cause FIP. Currently, FIP viruses are believed to be generated as mutant variants in feline enteric coronavirus-infected cats.58• 59 FCoVs are widespread ill
feline populations worldwide, with seropositivity rates highest in crowded multiple-cat environmentsY Transmission of the virus is
466 RlCHARDS & RODAN
mainly via the fecal-oral route. In environments in which FCo V infection is endemic (e.g., most multiple-cat eo.vironments), 35% to 70% of cats are shedding FCoVs in the stool at auY given time. 16, 22 Most infected cats remain healthy, although a few (usually between 1% and 5%) ultimately develop FIP. Affected cats rarely survive regardless of treatment.43 Kittens are most often affected with FIP, but the disease reportedly can develop in cats of all ages. A genetic predisposition has been suggested, with higher disease incidence in certain lines. 15, 43
Considerable controversy surrounds the ability of the currently available FIP vaccine (Primucell-FIP; Pfizer Animal Health, Exton, PA) to prevent disease, Some studies demonstrate protection from diseaseI9, 24;
others show little benefit from vaccination,36, 51 Antibody-dependent enhancement of disease in vaccinates has been demonstrated in experimental challenge exposure studies,SO but it is uncertain whether antibody-dependent enhancement occurs in a natural setting. Discrepancies between study results are probably attributable to differences in test methodology (e,g., strain and dose of challenge virus, genetic predisposition of the test animals), Protection from disease has not been demonstrated in animals vaccinated when younger than 16 weeks of age. Most kittens born and reared in environments in which FCo V infection is endemic are infected before reaching this age. l , 22 In these instances, vaccination of infected cats has not proven beneficial, At this time, there is no evidence that the vaccine induces clinically relevant protection, and its use is not recommended.
Dermatophytosis
Dermatophytosis in cats is primarily caused by infection with Microsporum canis. A variety of clinical manifestations, including transitory clinical disease and chronic infection with or without clinical signs, have been reported. Although successful treatment of individual cats is usually straightforward, elimination of endemic infection from multiplecat environments is expensive, labor-intensive, and time-consuming.38
An M. canis vaccine (Fel-O-Vax MC-K; Fort Dodge Animal Health, Overland Park, KS) is approved for use as an aid in the prevention and treatment of clinical signs associated with M, canis infection, Vaccination has not been demo!"lstrated to prevent infection or to eliminate M. canis organisms from infected cats. As a result, routine vaccination against M. canis infection is not recommended, At the time of this writing, the product has not been independently evaluated for efficacy. Based on studies conducted by the manufacturer, it is reasonable to consider vaccination as adjunctive treatment for individual infected cats 4 months of age or older to hasten resolution of clinical signs, If the vaccine
FELINE VACCINATION GUIDELINES 467
induces an immune response that accelerates lesion resolution, the number of infectious fungal spores produced by vaccinates may be reduced as well; thus, it is reasonable to consider vaccination as one component of a comprehensive treatment program in multiple-cat environments in which M. canis infection is endemic. Nonetheless, the ability of this product to hasten elimination of endemic infections from such environments has not been evaluated. The revaccination interval is not stipulat~d on the label. Major adverse events reportedly associated with the use of this product are pain, temporary hair loss, and formation of sterile abscesses or granulomas at the vaccine site.38
Bordetel/a bronchiseptica Infection
Bordetella bronchiseptica is a small, aerobic, gram-negative coccobacillus long recognized as a respiratory tract pathogen of several species of animals. The natural route of transmission in cats is believed to be via the aerosol or intranasal route.8 Experimental challenge exposure studies have shown that B. bronchiseptica can act as a primary pathogen in cats; inoculation of specific-pathogen-free kittens results in self-limiting disease characterized by variable degrees of fever, nasal or ocular discharge, sneezing, induced or spontaneous coughing, pulmonary rales, and submandibular lymphadenopathy.8 Bronchopneumonia associated with naturally occurring B. bronchiseptica infection has been reported in kittens and adult cats.60 Other factors, including nutritional status, overcrowding, coinfection with other agents such as FeV or FHV-1, and suboptimal hygiene, may influence the outcome of exposure.41
• 54
Seroprevalence surveys suggest that exposure to the organism is common, with infection rates varying from population to population. The highest r'!tes of seropositivity (often over 80%) are found among cats in rescue shelters and multiple-cat households, especially when there is a history of respiratory tract disease. The lowest rates are found among cats in households with few cats and no history of respiratory tract disease.4•
37 Similarly, isolation rates vary. B. bronchiseptica was isolated from the oropharynx in 19 of 614 (3.1%) asymptomatic cats and from the distal trachea in 6 of 614 (1%) asymptomatic cats from shelters in Lousiana.25 In a recent survey of 740 cats in the United Kingdom, none of the household cats were found to be infected, but 9% of cats from breeding colonies and 19% of cats from rescue shelters were found to be carrying the organism.5 In the same survey, 9% of healthy cats and 14% of cats with respiratory tract disease tested positive for the organism. An additional finding was a strong positive association between oropharyngeal isolation of B. bronchiseptica and residence in households containing dogs with a recent history of respiratory tract disease.
468 RICHARDS & RODAN
Definitive diagnosis of disease associated with B. bronchiseptica infection may be difficult, in part, because signs of infection often mimic those associated with FHV-l or FeV infection. Isolation of B. bronchiseptica from a cat with respiratory tract disease is supportive of the diagnosis, but carriage of the organism in asymptomatic cats 'precludes establishing a direct cause-and-effect relation. Resolution of disease with appropriately chosen antimicrobial medication might suggest a causative role for B. bronchiseptica, but the self-limiting nature of many cases of viral upper respiratory tract disease prevents attributing disease resolution solely to antimicrobial treatment.
A vaccine (Protex-Bb; Intervet) to prevent disease caused by infection with B. bronchiseptica has recently been licensed. The product contains a live reduced-virulence culture of B. bronchiseptica and is licensed for administration via the intranasal route in cats 4 weeks of age and older. Efficacy of the vaccine has not been independently evaluated; however, in studies conducted by the manufacturer to gain vaccine licensure, vaccinated 4-week-old specific-pathogen-free cats experienced less severe signs of disease than did unvaccinated controls when exposed to challenge 3 weeks after vaccination. Similar results were obtained when 8-week-old kittens were exposed to challenge 72 hours after vaccination. As of this writing, studies to evaluate the duration of protection induced by the vaccine have not been completed and the revaccination interval is not yet stipulated on the label. Routine use of this. vaccine is not recommended. It is reasonable to consider vaccinating cats entering or residing in multiple-cat environments (e.g., shelters, catteries, boarding facilities) where disease associated with B. bronchiseptica infection has been confirmed. The ability of the product to reduce the prevalence of infection or the severity of disease in such environments has not been evaluated, however.
Giardiasis
Infection of cats with the protozoan CiardUi lamblia is associated with acute or chronic gastrointestinal disease ranging in severity from subclinical to severe.32• 64 Because infected cats shed cysts intermittently, diagnosis of C. lamblia infection is often cumbersome and usually requires multiple fecal examinations. Several methods of diagnosis are available, including examination of a fecal smear, the zinc sulfate centrifugation method, and use of an enzyme-linked immunosorbent assay to test feces .64 There are currently no approved treatment methods for cats, and although treatment commonly controls signs of disease, it is uncertain that it clears infection.63 Treatment effectiveness is highly variable, and resistant organisms are commonly encounteredY· 63 C. lamblia is
FELINE VACCINATION GUIDELINES 469
transmitted via the fecal-oral route; cysts may be ingested from contaminated water, from direct cat-to-cat transmission especially in crowded environments (e.g., through mutual grooming), from exposure to contarnfuated litter boxes, and from consuming prey.30· 31 Giardiasis is a recognized zoonotic disease, but the role of cats in transmission of the organism is not well established.2• 6. 64
A vaccine has recently been licensed by the US Department of Agriculture (Fel-O-Vax Giardia; Fort Dodge Animal Health) as an aid in the prevention of disease associated with G. lamblia infection and reduction in the severity of shedding of cysts. This vaccine is composed of quantified, homogenated, and chemically inactivated G. lamblia trophozoites, and it contains an adjuvant commonly found in other feline products from the manufacturer but different from the adjuvant in the manufacturer's canine product. The vaccine is approved for use in cats 8 weeks of age and older. At the time of this writing, the vaccine has not been independently evaluated for efficacy, but in studies conducted by the manufacturer to gain vaccine licensure, vaccinates had a statistically significant reduction in severity of clinical signs (diarrhea), duration of cyst shedding, and prevalence of infection (percentage of cats with trophozoites at the end of the trial) compared with control animals. Protection was demonstrated to persist for at least 1 year after vaccination.
Routine use of this vaccine is not recommended, but because vaccinates had less severe clinical disease and shed cysts for a shorter time, it is reasonable to consider vaccination as part of a comprehensive control program in environments where exposure to G. lamblia is clinically significant. When parasite exposure is ongoing, revaccination at annual intervals is recommended. Some vaccinates may shed cysts subsequent to G. lamblia exposure; thus, proper hygiene and sanitation practices should be implemented even with vaccinated cats. The ability of this product to aid in hastening elimination of endemic infection from multiple-cat environments has not been evaluated.
References
1. Addie DO, Jarrett 0: A study of naturally occurring feline coronavirus infections in kittens. Vet Rec 130:133--137, 1992
2. Barr SC: Enteric protozoal infections. In "Greene CE (ed): Infectious Diseases of the Dog and Cat, ed 2. Philadelphia, WB Saunders, 1998, pp 482-491
3. Bennett 0 , Gaskell RM, Mills A, et al: Detection of feline calicivirus antigens in the joints of infected cats. Vet Rec 124:329-332, 1989
4. Bergman IE, Vemooij J, Zegers EM: Prevalence of antibodies against Bordetella bronchiseptica in cats with a history of respiratory disease. Vet Q 19(suppl):S50--51, 1997
5. Binns SH, Dawson 5, Speakman AJ, et aI: Prevalence and risk factors for feline Bordetella bronchiseptica infection. Vet Rec 144:575-580, 1999
(,t' 470 RICHARDS & RODAN
6. Bowman D : Feline giardiasis. CFHC Information Bulletin 13:1-3, 1994 7. Church R: Lameness in kittens after vaccinatiqn. Vet Rec 125:609, 1989 8. Coutts AJ, Dawson S, Binns S, et al: Studies on natural transmission of Bordetella '
bronchiseptica in cats. Vet Microbiol 48:19- 27, 1~ 9. Dawson S, Gaskell RM: Problems with respiratory virus vaccination in cats. Compend
Contin Educ Pract Vet 15:1347-1354, 1993 10. Dawson S, Bennett 0, Carter SO, et al: Acute arthritis of cats associated with feline
calicivirus infection. Res Vet Sci 56:133-143, 1994 11 . Dawson S, McArdle F, Bennett 0 , et al: Investigation of vaccine reactions and break
downs after feline calicivirus vaccination. Vet Rec 132:346-350, 1993 12. de Lahunta A: Comments on cerebellar ataxia and its congenital transmission in cats
by feline panleukopenia virus. JAVMA 158:901-906, 1971 13. Edwards 0, Elston T, Loar A, et al: American Association of Feline Practitioners and
the Academy of Feline Medicine recommendations for feline leukemia virus testing and recommendations for feline immunodeficiency virus testing. American Association of Feline Practitioners Meeting, Nashville TN, 1996
14. Elston T, Rodan I, Flemming 0, et al: 1998 Report of the American Association of Feline Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vaccines. JAVMA 212:227-241, 1998
15. Foley]E, Pedersen NC: The inheritance of susceptibility to feline infectious peritonitis in purebred catteries. Feline Pract 24:14-22, 1996
16. Foley ]E, Poland A, Carlson J, et al: Patterns of feline coronavirus infection and fecal shedding from cats in multiple-cat environments. JAVMA 210:1307-1312, 1997
17. Ford RB: Viral upper respiratory infection in cats. Compend Contin Educ Pract Vet 13:593-602, 1991
18. Ford RB, Levy JK: Infectious diseases of the respiratory tract. In Sherding RG (ed): The Cat: Diseases and Clinical Management. New York, Churchill Livingstone, 1994, pp 489-500
19. Gerber JD, Ingersoll ]D, Gast AM, et al: Protection against feline infectious peritonitis by intranasal inoculation of temperature-sensitive FIPV vaccine. Vaccine 8:536-542, 1990
20. Greene CE: Immunoprophylaxis and immunotherapy. In Infectious Diseases of the Dog and Cat, ed 2. Philadelphia, WB Saunders, 1998, pp 717-750
21. Greene CE, Dreesen OW: Rabies. In Greene CE (ed): Infectious Diseases of the Dog and Cat, ed 2. 'Philadelphia, WB Saunders, 1998, pp 114-126
22. Harpold LM, Legendre AM, Kennedy MA, et al: Fecal shedding of feline coronavirus in adult cats and kittens in an Abyssinian cattery. JAVMA 215:948-951, 1999
23. Hoover EA, Olsen RG, Hardy WD, Jr, et al: Feline leukemia virus infection: Agerelated variation in response of cats to experimental infection. J Nat! Cancer Inst 57:365-369, 1976
24. Hoskins]D, Taylor HW, Lomax TL: Independent evaluation of a modified-live feline infectious peritonitis virus-vaccine under experimental conditions (Louisiana experience). Feline Pract 23:72-73, 1995
25. Hoskins ]D, Williams J, Roy AF, et al: Isolation and characterization of Bordetella bronchiseptica from cats in southern Louisiana. Vet Immunol Immunopathol 65:173-176, 1998
26. Jenkins SR, Auslander M, Conti L, et al: Compendium of animal rabies prevention and control, 2000. JAVMA 216:338-343, 2000
27. Johnson RP, Povey RC: Vaccination against feline viral rhino tracheitis in kittens with maternally derived feline viral rhinotracheitis antibodies. JAVMA 186:149-152, 1985
28. Kass PH, Barnes WG, Spangler WL, et al: Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats. JAVMA 203:396-405,1993
29. Krebs }W, Smith JS, Rupprecht CE, et al: Rabies surveillance in the United States during 1997. JAVMA 213:1713-1728, 1998
30. Lappin MR: Protozoal and miscellaneous infections. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine, ed 5. Philadelphia, WB Saunders, 2000, pp 408-417
FELINE VACCINATION GUIDELINES 471
31. Leib MS, Zajac AM: Giardia: diagnosis and treatment. In Bonagura JD, Kirk RW (eds): Current Veterinary Therapy XII. Philadelphia, WB Saunders, 1995, pp 716-720
32. Leib MS, Zajac AM: Giardiasis in dogs and cats. Vet Med (U.s.) 94:79J-802, 1999 33. Levy JK: FeLV and non-neoplastic FeLV-related disease. In Ettinger S1, Feldman EC
(eds): Textbook of Veterinary Internal Medicine, ed 5. Philadelphia, WB Saunders, 2000, pp 424-432
34. Macy DW, Chretin J: Local postvaccinal reactions of a recombinant rabies vaccine. Vet Forum 16:44-49, 1999
35. Macy DW, Hendrick MJ: The potential role of inflammation in the development of postvaccinal sarcomas in cats. Vet Clin North Am Small Anim Pract 26:103-109, 1996
36. McArdle F, Tennant B, Bennett M, et al: Independent evaluation of a modified-live F1PV vaccine under experimental conditions (University of Uverpool experience). Feline Pract 23:67-71, 1995
37. McArdle HC, Dawson S, Coutts AJ, et al: Seroprevalence and isolation rate of Bordetella bronchiseptica in cats in the UK. Vet Rec 135:506-507, 1994
38. Moriello KA, DeBoer DJ: Dermatophytosis: Advances in therapy and control. In August JR (ed): Consultations in Feline Internal Medicine, ed 3. Philadelphia, WB Saunders, 1997, pp 177-190
39. Olson L, Larson L, Schultz R: Canine parvovirus (CPV-2b) infection in cats. In Proceedings of the 79th Annual Meeting-Conference of Research Workers in Animal Diseases. Chicago, IL, November ·8-10, 1998
40. Pedersen NC: Basic and clinical immunology. In Holzworth J (ed): Diseases of the Cat: Medicine and Surgery. Philadelphia, WB Saunders, 1987, pp 146-181
41. Pedersen NC: Common infectious diseases of multi-cat environments. In Pratt PW (ed): Feline Husbandry: Diseases and Management in the Multi-Cat Environment. Goleta, CA, American Veterinary Publications, 1991, pp 163-288
42. Pedersen NC: Feline calicivirus infection. In Feline Infectious Diseases. Goleta, CA, American Veterinary Publications, 1988, pp 61-67
43. Pedersen NC: An overview of feline enteric coronavirus and infectious peritonitis virus-infections. Feline Pract 23:7-20, 1995
44. Pollock RVH, Postorino NC: Feline panleukopenia and other enteric viral diseases. In Sherding RG (ed): The Cat: Diseases and Clinical Management. New York, Churchill Uvingstone, 1994, pp 479-487
45. Reubel GH, Hoffmann DE, Pedersen NC: Acute and chronic faucitis of domestic cats. A feline calicivirus-induced disease. Vet Clin North Am Small Anim Pract 22:1347-1360,1992
46. Richards JR: Feline sarcoma task-force meets. JAVMA 210:310-311, 1997 47. Scott F: Viral diseases: Panleukopenia. In Holzworth J (ed): Diseases of the Cat:
Medicine and Surgery. Philadelphia, WB Saunders, 1987, pp 182-193 48. Scott FW, Geissinger C: Duration of immunity in cats vaccinated with an inactivated
feline panleukopenia, herpesvirus, and calicivirus vaccine. Feline Pract 25:12-19, 1997 49. Scott FW, Geissinger CM: Long-term immunity in cats vaccinated with an inactivated
trivalent vaccine. Am J Vet Res 60:652-658, 1999 50. Scott FW, Olsen CW, Corapi WV: Antibody-dependent enhancement of feline infectious
peritonitis virus infection. Feline Pract 23:77~0, 1995 51. Scott FW, Corapi WV, Olsen CW: Independent evaluation of a modified-live FIPV
vaccine under experimental conditions (Cornell experience). Feline Pract 23:74-76,1995 52. Sharp NIH, Davis BI, Guy JS, et al: Hydranencephaly and cerebellar hypoplasia in two
kittens attributed to intrauterine parvovirus infection. J Comp Pathol 121:39-53, 1999 53. Sparkes AH: Feline leukemia virus-a review of immunity and vaccination. J Small
Anim Pract 38:187-194,1997 54. Speakman AI, Dawson S, Binns SH, et al: Bordetella bronchiseptica infection in the cat. J
Small Anim Pract 40:252-256, 1999 55. Starr RM: Reaction rate in cats vaccinated with a new controlled-titer feline panleuko
penia-rhinotracheitis-calicivirus-Chlamydia psittaci vaccine. Cornell Vet 83:311-323, 1993 56. Sykes IE, Anderson GA, Studdert VP, et al: Prevalence of feline Chlamydia psittaci and
feline herpesvirus 1 in cats with upper respiratory tract disease. J Vet Intern Med 13:153-162, 1999
472 RICHARDS & ROOAN
57. Tenorio AP, Franti CE, Madewell BR, et al: arronic oral infection"s of cats and their relationship to persistent oral carriage of feline calici-, immunodeficiency, or leukemia viruses. Vet Immunol Immunopathol 29:1-14, 1991
58. Vennema H, Poland A, Hawkins KF, et al: A comparison of the genomes of FECVs and Fll'Vs and what they tell us about the rera"tionships between feline coronaviruses and their evolution. Feline Pract 23:40-44, 1995
59. Vennema H, Poland A, Foley J, et al: Feline infectious peritonitis viruses arise by mutation from endemic feline enteric coronaviruses. Virology 243:150-157, 1998
60. Welsh RD: Bordetella branchiseptica infections in cats. J Am Anirn Hosp Assoc 32:153-158,1996
61. Wills J, Howard P, Gruffydd-Jones T, et aI: Prevalence of Chlamydia psittaci in different cat populations in Britain. J Small Anirn Pract 29:327-339, 1988
62. Wolf AM: Other feline viral diseases. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine, ed 5. Philadelphia, WB Saunders, 2000, pp 444--453.
63. Zajac AM: Giardiasis. Cornpend Contin Educ Pract Vet 14:604-611, 1992 64. Zajac AM: Giardiasis. In August JR (ed): Consultations in Feline Internal Medicine, ed
2. Philadelphia, WB Saunders, 1994, pp 83-86
Address reprint requests to
James Richards, DVM Cornell Feline Health Center
College of Veterinary Medicine Cornell University
PO Box 13 Ithaca, NY 14853
VACCINES AND VACCINATIONS 0195-5616/ 01 $15.00 + .00
CANINE VACCINATION
Craig E. Greene, DVM, MS, Ronald D. Schultz, P.hD, and Richard B. Ford, DVM, MS
Despite the concerns over recommendations to reduce the frequency and number of vaccines administered annually to dogs and cats, the need for companion animal vaccines and vaccinations continues to be a fundamental part of health management programs in the twenty-first century. What is happening now, however, is an effort by academicians and practitioners to review companion animal vaccination standards in the United States. The American Association of Feline Practitioners and the Academy of Feline Medicine, in a consensus paper compiled by a panel of experts, have already published the latest vaccination recommendations for cats27 (the reader is referred to the article on feline vaccination in this issue).
What constitutes the ideal vaccination protocol goes beyond a document of vaccine recommendations used at a veterinary teaching hospital or compiled by a panel of academicians. Instead, a vaccination protocol selected for use within a practice entails identifying preventable diseases that pose a serious risk to the individual animal, and vaccinating that animal at an early age, hopefully prior to exposure to the pathogen, with a product that provides long term immunity and has minimal risk of causing adverse reactions. There are currently a number of products that meet these requirements.
What follows is an objective and clinically relevant review of the canine vaccines licensed for use in North America today and a discus-
From the Department of Small Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, Georgia (CEG); Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin (RDS); and Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina (RBF)
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANlMAL PRACTICE
VOLUME 31 • NUMBER 3 • MAY 2001 473
474 GREENE et aJ .. ,
sion of the facts that have compelled so many authors to challenge existing vaccination practices. This article is not intended to establish new vaccination standards for dogs, n01,.should it be used as a template for a national canine vaccination protocol. Nevertheless, change is in the wind, and revised recommendations for canine vaccination can be anticipated. The material presented in this article serves as a guide for clinicians willing to consider proposed canine vaccination recommendations as they apply to individual patients. Table 1 represents a summary of the information presented in this article.
WHY CHANGE?
Is it really necessary to revise vaccination recommendations for dogs? Many would challenge that premise. After all, vaccination practice over the last 20 years has, in fact, worked well; canine distemper, canine parvovirus, and canine rabies are virtually nonexistent among vaccinates. Yet, despite the obvious successes attributable to companion animal vaccination, veterinarians must be willing to at least review, if not revise, vaccination practice standards as new vaccines are introduced and new vaccine technologies are developed. The objective, quite simply, is to administer the most appropriate vaccine(s) at the most appropriate stage of life and to do so with the best product(s) available. What should not occur is complacency and regimentation with respect to selection and administration of vaccines. Yet, that does happen.
The demand among veterinarians that vaccines be simple to administer and timesaving has led to the long-term and widespread use of polyvalent vaccines. Twenty-five years ago, the most commonly used polyvalent products contained three vaccines (distemper-hepatitis-leptospirosis) . Today, products containing eight or more vaccines per dose are routinely administered to dogs. Furthermore, polyvalent vaccines are routinely administered annually with seemingly little regard for the actual risk of infection. This is a disturbing trend. Annual administration of polyvalent vaccine implies that each vaccine antigen, whether of bacterial or viral origin, in each polyvalent product induces the same degree of immunity for the same duration in every patient. Immunologically, this is irrational. Depending on the vaccine and based on the results of controlled challenge studies, dogs derive protective immunity that persists for as little as a few months to as long as 7 or more years.2,
4,7, 14, I B, 20. 25, 29. 30 Convenience rather than science seems to be the driving force behind conventional recommendations listed on vaccine "labels" (product inse;ts). Even the 1995 ruling by US Department of Agriculture that manufacturers of new veterinary biologic agents must document the duration of immunity listed on the label (this ruling does not apply
Text continued on page 480
"'" '-l c.n
Tab
le 1
. R
EC
OM
ME
ND
ED
GU
IDE
LIN
ES
FO
R T
HE
AD
MIN
IST
RA
TIO
N"
OF
VA
CC
INE
S T
O D
OG
S
Vac
cine
Can
ine
dist
empe
r vi
rus
(CD
V)
(ML
V)
Rec
om
bin
ant
can
ine
dis
tem
per
vir
us
(rC
DV
)
Dis
tem
per-
mea
sles
(M
LV
) (a
dmin
iste
r in
tram
uscu
larl
y on
ly)
Can
ine
aden
ovir
us-1
(C
AV
-l)
(MLV
or
kill
ed)
Can
ine
aden
ovir
us-
2 (C
AV
-2)
(ML
V o
r ki
lled
)
Pri
mar
y V
acci
nati
on
(pup
py)
2, 3
, an
d 4
mon
ths
of a
ge
2, 3
, an
d 4
mon
ths
of a
ge
One
dos
e be
twee
n 6
and
12
wee
ks o
f ag
e on
ly (
one
ML
V-C
DV
or rC
ov
vacc
ine
foll
ow
s-d
iste
mp
er-
mea
sles
vac
cine
at
14-1
6 w
eeks
of
age)
T
wo
dose
s ev
ery
3-4
wee
ks
unti
l 12
wee
ks o
f ag
e
2, 3
, an
d 4
mon
ths
of a
ge
Pri
mar
y V
acci
nati
on
(adu
lt)
Bo
ost
ert
One
dos
e A
nnua
l
Tw
o do
ses,
3-4
wee
ks
Ann
ual
apar
t
Not
ind
icat
ed f
or u
se
Not
rec
omm
ende
d in
fem
ale
dogs
ove
r 12
wee
ks o
f ag
e
Tw
o do
ses
3-4
wee
ks
Ann
ual
apar
t
One
dos
e (i
f us
ing
Ann
ual
MLV
) T
wo
dos
es 3
-4 w
eeks
ap
art
(if
usin
g ki
lled
)
Rec
om
men
dat
ion'
Hig
hiy
reco
mm
elld
ed:
Des
pite
ann
ual
boos
ter
reco
mm
enda
tion
s, a
du
lt d
ogs
chal
leng
ed 7
yea
rs
(Roc
kbom
str
ain)
and
5 y
ears
(O
nder
step
oort
str
ain)
al
ter
MLV
vac
cina
tion
wer
e pr
otec
ted.
A b
oost
er
vacc
inat
ion
inte
rval
of
ever
y 3
year
s in
adu
lt d
ogs
is
reas
onab
le.
Hig
hly
reco
mm
elld
ed:
May
be
used
int
erch
ange
ably
wit
h M
LV
-CO
V v
acci
ne.
Lev
el o
f pr
otec
tion
con
ferr
ed b
y th
e rC
ov v
acci
ne i
s co
mpa
rabl
e to
tha
t pr
ovid
ed b
y M
LV v
acci
nes.
Dur
atio
n of
im
mun
ity
for
rCov
has
no
t be
en e
stab
lish
ed b
eyon
d 1
year
. O
ptio
llai-
llot
reco
mm
elld
ed fo
r ro
lltill
e II
$<
: In
tend
ed t
o pr
ovid
e te
mpo
rary
pro
tect
ion
in y
oung
dog
s on
ly.
Indi
cate
d fo
r us
e in
hou
seho
lds/
kenn
els
whe
re
dist
empe
r is
a r
ecog
nize
d pr
oble
m.
Do
not
adm
inis
ter
to f
emal
e do
gs o
ver
12 w
eeks
of
age.
Not
rec
omm
ende
d: I
nfec
tiou
s ca
nine
hep
atit
is i
s un
com
mon
in
the
Uni
ted
Stat
es.
Con
side
ring
the
low
(t
o ab
sent
) pr
eval
ence
, th
e ri
sk o
f "h
epat
itis
blu
e-ey
e"
reac
tion
s an
d th
e fa
ct t
hat
CA
V-2
cro
ss-p
rote
cts
agai
nst
CA
Y-I
, us
e of
vac
cine
s co
ntai
ning
thi
s an
tige
n is
not
rec
omm
end
ed f
or u
se i
n ro
uti
ne
vacc
inat
ion
pr
otoc
ols.
Re
com
men
ded:
Dem
onst
rate
d cr
oss-
prot
ecti
on a
gain
st
cani
ne h
epat
itis
(C
AV
-I)
and
CA
V-2
, on
e of
the
age
nts
know
n to
be
asso
ciat
ed w
ith
infe
ctio
us
trac
heob
ronc
hiti
s. U
sual
ly c
ombi
ned
wit
h C
OV
and
C
PV v
acci
ne.
Cur
rent
ly,
this
pro
duct
is n
ot a
vaH
able
as
a m
onov
alen
t va
ccin
e.
Adu
lt d
ogs
chal
leng
ed 7
yea
rs a
fter
CA
V-2
MLV
va
ccin
atio
n w
ere
fou
nd
to
be
prot
ecte
d ag
ain
st t
he
mor
e vi
rule
nt C
AY
-I.
Tabi
e cO
lltill
ued
all
follo
win
g pa
ge
II:> ~
Tab
le 1
. R
EC
OM
ME
ND
ED
GU
IDE
LIN
ES
FO
R T
HE
AD
MIN
IST
RA
TIO
W O
F V
AC
CIN
ES
TO
DO
GS
(C
ontin
ued)
Va
ccin
e
Par
ain
flu
enza
vir
us
(CPi
V)
(ML
V)
Bor
dete
lla b
ronc
hise
ptic
a (k
ille
d ba
cter
in)
(ad
min
iste
r pa
rent
era
lly)
Bor
dete
lla b
ronc
hise
ptic
a (l
ive
avir
ulen
t ba
cter
in)
+
par
ain
flu
enza
vir
us
(ML
V)
(top
ical
[in
tran
asal
] us
e o
nly
)
Bor
dete
lla b
l'Onc
hise
ptic
a (l
ive
avir
ulen
t ba
cter
in)
+
par
ain
flu
enza
vir
us
(ML
V)
+ c
anin
e ad
enov
irus
-2 (
ML
V)
(top
ical
[in
tran
asal
] us
e on
ly)
Pri
ma
ry V
acc
ina
tio
n
(pu
pp
y)
2, 3
, an
d 4
mon
ths
of a
ge
6-S
wee
ks o
f ag
e, t
hen
IG-1
2 w
eeks
of
age
Adm
inis
ter
a si
ngle
dos
e as
ea
rly
as 2
wee
ks o
f ag
e (s
ee p
rod
uct
lit
erat
ure
for
spec
ific
age
re
co
mm
en
d a
Ho
ns)
Adm
inis
ter
a si
ngle
dos
e at
n
ot
less
tha
n 8
wee
ks o
f ag
e
Pri
ma
ry V
acc
ina
tio
n
(ad
ult
)
One
do
se
Tw
o do
ses
2-4
wee
ks
apar
t
Not
sti
pula
ted,
al
thou
gh a
sin
gle
do s
e is
re
com
men
ded
A s
ingl
e do
se i
s re
com
men
ded
Bo
oste
rt
Ann
ual
Ann
ual
Ann
ual
or
1 w
eek
befo
re
poss
ible
exp
osur
e
Ann
ual
Re
com
me
nd
ati
on
Rec
omm
ende
d: U
sual
ly c
ombi
ned
wit
h C
OV
an
d C
AY
va
ccin
e. C
urre
ntly
, th
is p
rod
uct
is
no
t av
aila
ble
as a
m
onov
alen
t va
ccin
e.
Opt
iona
l: T
he p
aren
tera
l va
ccin
e m
ay b
e le
ss e
ffic
acio
us
than
the
top
ical
B.
bron
chis
eptic
a pl
us p
arai
nflu
enza
vi
rus
vacc
ines
in
thei
r ab
ilit
y to
sti
mul
ate
a lo
cal
imm
un
e re
spon
se (
uppe
r re
spir
ator
y tr
act)
. O
ptio
"al:
For
use
in
dogs
hou
sed
in k
enne
ls,
shel
ters
, o
r po
unds
, or
bef
ore
boar
ding
in
kenn
....
TIl
ansi
ent
(3-1
0 da
ys)
coug
hing
, sn
eezi
ng,
or
nasa
l di
scha
rge
occu
rs i
n a
smal
l pe
rcen
tage
of
vacc
inat
es.
Ant
imic
robi
al
ther
apy
may
be
indi
cate
d (d
oxyc
ycli
ne o
r 5
-7 d
ays)
to
man
age
post
vacc
inat
ion
up
per
res
pira
tory
sig
ns
(per
Sis
ten
t co
ugh
and
nasa
l di
scha
rge)
. T
opic
ally
ad
min
iste
red
vac
cin
es f
or c
anin
e in
fect
iou
s tr
ache
obro
nchi
tis
may
pro
vide
a s
up
erio
r lo
cal
imm
un
e re
spon
se c
ompa
red
wit
h pa
rent
eral
ly
adm
inis
tere
d v
acci
nes
. R
ecom
men
ded:
For
use
in
dogs
con
side
red
to b
e at
ris
k of
ex
posu
re t
o an
y of
the
pat
hoge
ns l
iste
d.
Top
ical
ly a
dmin
iste
red
vacc
ines
for
can
ine
infe
ctio
us
trac
heob
ronc
hiti
s m
ay p
rovi
de a
sup
erio
r lo
cal
imm
un
e re
spon
se c
ompa
red
wit
h pa
rent
eral
ly
adm
inis
tere
d v
acci
nes
.
"" :::}
Can
ine
parv
ovir
us
(ML
V)
Can
ine
parv
ovir
us
(kil
led)
Bor
relia
bur
gdor
feri
; L
yme
borr
elio
sis
(kil
led
bact
erin
)
Borr
elia
bur
gdor
feri
; re
com
bina
nt L
yme
borr
elio
sis
oute
r su
rfac
e pr
otei
n A
2, 3
, an
d 4
mon
ths
of a
ge
One
dos
e
2, 3
, an
d 4
mon
ths
of a
ge
Tw
o do
ses
3-4
wee
ks
apar
t
Init
ial
dose
may
be
give
n T
wo
dose
s 3-
4 w
eeks
at
12
wee
ks o
f ag
e an
d a
apar
t re
quir
ed s
econ
d do
se 3
-4
wee
ks l
ater
In
itia
l do
se m
ay b
e gi
ven
Tw
o do
ses
2-3
wee
ks
at 9
wee
ks o
f ag
e an
d a
ap
art
requ
ired
sec
ond
dose
2-3
w
eeks
lat
er
~
Ann
ual
Ann
ual
Ann
ual
Ann
ual
Hig
hly
reco
mm
ende
d: A
ltho
ugh
annu
al b
oost
ers
are
reco
mm
end
ed b
y va
ccin
e m
anuf
actu
rers
, st
ud
ies
have
sh
ow
n p
rote
ctio
n ag
ains
t ch
alle
nge
7 ye
ars
afte
r va
ccin
atio
n w
ith
MLV
vac
cine
. It
has
bee
n su
gges
ted
that
ad
ult
dog
s va
ccin
ated
aga
inst
par
vovi
rus
wit
h M
LV v
acci
ne r
emai
n in
un
un
e fo
r at
lea
st 3
yea
rs a
fter
va
ccin
atio
n.
Adu
lt d
ogs
chal
leng
ed 7
yea
rs a
fter
par
vovi
rus
MLV
va
ccin
atio
n w
ere
foun
d to
be
prot
ecte
d.
Rec
omm
elld
ed:
A s
uita
ble
alte
rnat
ive
to t
he M
LV c
anin
e pa
rvov
irus
vac
cine
. K
ille
d pa
rvov
irus
pro
duct
s ar
e su
scep
tibl
e to
mat
erna
l an
tibo
dy i
nter
fere
nce
in p
up
pie
s as
old
as
16 w
eeks
(o
r ol
der?
).
Alt
houg
h an
nual
boo
ster
s ar
e re
com
men
ded
by v
acci
ne
man
ufac
ture
rs,
stu
die
s h
ave
show
n p
rote
ctio
n ag
ains
t ch
alle
nge
16 m
onth
s af
ter
vacc
inat
ion
wit
h ki
lled
va
ccin
e.
Opt
iona
l: L
yme
dise
ase
has
lim
ited
reg
iona
l pr
eval
ence
. R
ecom
men
dati
on f
or u
se i
s li
mit
ed t
o do
gs w
ith
a kn
own
high
ris
k of
exp
osur
e.
Opt
iollJ
lI: L
yme
dise
ase
has
lim
ited
reg
iona
l pr
eval
ence
. R
ecom
men
dati
on f
or u
se i
s st
rict
ly l
imit
ed t
o do
gs
wit
h a
know
n hi
gh r
isk
of e
xpos
ure.
Mos
t au
thor
s re
com
men
d th
e re
com
bina
nt L
yme
vacc
ine
over
the
ki
lled
bac
teri
n fo
r re
ason
s of
saf
ety
(few
er a
dver
se
reac
tion
s).
Tabl
e cO
lltill
ued
all
follo
win
g pa
ge
"" '-l
00
Ta
ble
1.
RE
CO
MM
EN
DE
D G
UID
ELI
NE
S F
OR
TH
E A
DM
INIS
TR
AT
ION
" O
F V
AC
CIN
ES
TO
DO
GS
(C
ontin
ued)
Va
ccin
e
Can
ine
coro
nav
iru
s (k
ille
d an
d M
LV)
Lept
ospi
ra i
nter
roga
ns (
L.
cQui
coln
com
bin
ed w
ith
L.
icf
erol
laem
orrl
Ulg
iae)
(k
ille
d ba
cter
in)
(now
ava
ilab
le w
ith
sero
vars
gri
ppot
ypllO
sa
and
pom
ona)
Gia
rdia
(ki
lled
)
Pri
ma
ry V
acc
ina
tio
n
(pu
pp
y)
Eve
ry 2
-4 w
eeks
of
age
unti
l 12
wee
ks o
f ag
e (M
LV
); be
gin
as e
arly
as
6 w
eeks
of
age
and
ad
min
iste
r ev
ery
2-3
wee
ks,
wit
h th
e fi
nal
dose
at
12 w
eeks
of
age
(kil
led)
12 a
nd 1
6 w
eeks
; d
o n
ot
adm
irti
ster
to
dogs
les
s th
an 1
2 w
eeks
of
age
Init
ial
dose
may
be
give
n at
8 w
eeks
of
age;
a
seco
nd d
ose
sho
uld
be
give
n 2
-3 w
eeks
lat
er
Pri
mar
y V
acc
inat
ion
(a
du
lt)
Bo
ost
ert
One
dos
e (i
f us
ing
Ann
ual
ML
V)
Tw
o do
ses
2-3
wee
ks
apar
t (i
f us
ing
kill
ed)
Tw
o d
oses
2~ w
eek
s A
nnua
l; s
ome
auth
ors
apar
t re
com
men
d a
boos
ter
ever
y 6
mon
ths
in
dogs
con
side
red
to b
e at
sig
nifi
cant
ris
k of
ex
pos
ure
Tw
o do
ses
2-3
wee
ks
Ann
ual
apar
t
Re
com
me
nd
ati
on
Opt
iona
i: P
reva
lenc
e of
cli
nica
l ca
ses
of c
onfi
rmed
can
ine
coro
nav
iru
s in
fect
ion
doe
s n
ot j
ust
ify
rout
ine
inoc
ulat
ion
of a
U d
ogs.
Cli
nica
l in
fect
ions
are
mos
t li
kely
to
occu
r in
pup
pies
les
s th
an 6
wee
ks o
f ag
e.
Cli
nica
l si
gns
are
mil
d an
d ty
pica
lly
reso
lve
spon
tane
ousl
y.
The
aut
hors
cur
rent
ly r
ecom
men
d th
at a
nim
al s
helt
ers
nol
use
cor
onav
iru
s va
ccin
e in
rou
tine
vaC
,fina
tion
prog
ram
s be
caus
e of
add
itio
nal
cost
4n
curr
ed b
y do
ing
so a
nd t
he l
ack
of b
enef
it.
Exp
erie
nce
has
sho
wn
no
ad
dit
ion
al i
ncre
ase
in i
nfe
ctio
us
ente
riti
s am
ong
adul
ts o
r pu
ppie
s su
bseq
uent
to d
isco
ntin
uing
ca
nin
e co
ron
avir
us
vacc
ine
in s
helt
ers.
O
ptio
nai:
Ane
cdot
al r
epor
ts f
rom
vet
erin
aria
ns a
nd
bree
ders
sug
gest
tha
t th
e in
cide
nce
of p
ostv
acci
nati
on
reac
tion
s (a
cute
an
aph
yla
xis)
in
pupp
ies
«1
2 w
eeks
of
age
) an
d s
mal
l-br
eed
dogs
is
high
.
Not
rec
omm
ende
d Jo
r ro
utin
e lis
e: T
he
vacc
ine
pre
ven
t,
oocy
st s
hedd
ing
bu
t do
es n
ot
prev
ent
infe
ctio
n.
Alt
houg
h gi
ardi
asis
is
the
mos
t co
mm
on i
ntes
tina
l pa
rasi
te a
mon
g pe
ople
in
the
Uni
ted
Sta
tes,
the
sou
rce
of h
um
an i
nfec
tion
is
con
tam
inat
ed w
ater
. L
nfec
tions
in
dog
s an
d c
ats
are
not
like
ly t
o be
zoo
noti
c.
"" ~
Rab
ies
J-ye
ar (
kill
ed)
(rou
te o
f ad
min
istr
atio
n m
ay
not
be o
pti
on
al-s
ee
prod
uct
lite
ratu
re f
or
deta
ils)
Rab
ies
3-ye
ar (
kill
ed)
(rou
te o
f ad
min
istr
atio
n m
ay
not
be o
pti
on
al-s
ee
prod
uct
lit
erat
ure
for
deta
ils)
Ad
min
iste
r on
e d
ose
as
earl
y as
3 m
onth
s of
age
Th
e 3-
year
rab
ies
vacc
ine
may
be
used
as
an
alte
rnat
ive
to t
he l
-yea
r ra
bie
s va
ccin
e fo
r in
itia
l an
d s
ubse
quen
t do
ses
(loc
al s
tatu
tes
appl
y);
adm
inis
ter
one
dos
e as
ea
rly
as 3
mon
ths
of a
ge
Adm
inis
ter
a si
ngle
do
se
n,e
3-y
ear
rabi
es
vacc
ine
may
be
use
d
as a
n al
tern
ativ
e to
th
e I-
year
rab
ies
vacc
ine
for
init
ial
and
sub
sequ
ent
dose
(l
ocal
sta
tute
s ap
ply)
; ad
min
iste
r a
sing
le d
ose
l-ye
ar r
abie
s va
ccin
e m
ay b
e u
sed
as
a b
oost
er v
acci
ne
wh
en
dogs
are
req
uire
d to
be
vacc
inat
ed a
nn
ual
ly
agai
nst
rabi
es (
loca
l st
atut
es a
pply
) S
econ
d r
abie
s va
ccin
atio
n
is r
ecom
men
ded
1 y
ear
afte
r ad
min
istr
atio
n of
th
e in
itia
l do
se
rega
rdle
ss o
f th
e an
imal
's a
ge a
t th
e ti
me
the
first
dos
e is
ad
min
iste
red
; d
epen
din
g o
n l
ocal
st
atu
tes,
boo
ster
va
ccin
es s
houl
d be
ad
min
iste
red
annu
ally
or
eve
ry 3
yea
rs
"'R
oute
of
adm
inis
trat
ion
is
sub
cuta
neo
us
or i
ntr
amu
scu
lar
un
less
oth
erw
ise
not
ed b
y th
e m
anuf
actu
rer.
t A
s re
com
men
ded
by t
he m
anuf
actu
rer.
/I>
Req
llire
d: M
LV v
acci
nes
are
no
t av
aila
ble;
sta
te a
nd l
ocal
st
atut
es g
over
n th
e fr
eque
ncy
of a
dmin
istr
atio
n fo
r pr
oduc
ts l
abel
ed a
s "l
-yea
r ra
bies
."
The
rab
ies
(J -y
ear)
vac
cine
is
gene
rall
y ad
min
iste
red
as
an i
niti
al d
ose
foll
owed
1 y
ear
late
r by
adm
inis
trat
ion
of t
he r
abie
s (3
-yea
r) v
acci
ne;
stat
e an
d lo
cal
stat
utes
m
ay d
icta
te o
ther
wis
e.
Req
llire
d: S
tate
and
loc
al s
tatu
tes
gove
rn t
he f
requ
ency
of
adm
inis
trat
ion
for
prod
ucts
lab
eled
as
rabi
es (
3-ye
ar);
th
ese
stat
utes
var
y th
roug
hout
the
Uni
ted
Sta
tes.
T
he r
abie
s (J
-yea
r) v
acci
ne i
s ge
nera
lly
adm
inis
tere
d as
al
l in
itia
l do
se f
ollo
wed
1 y
ear
late
r by
adm
inis
trat
ion
of t
he r
abie
s (3
-yea
r) v
acci
ne;
stat
e an
d l
ocal
sta
tute
s m
ay d
icta
te o
ther
wis
e.
480 GREENE et aJ " ,I
to vaccines licensed before 1995) is not likely to change "annual booster" recommendations stipulated by manufaGturers. It is important to understand that manufacturers are not manda~d to establish the full duration of immunity but only to document what they claim. Studies to establish the maximum duration of immunity that would meet USDA guidelines are not economically feasible.
The recommendation that virtually all canine vaccines be administered annually to adult dogs has been embraced by the veterinary profession for many years. Interestingly, however, for most vaccines administered to dogs today, there are no scientific studies at all establishing a 12-month duration of immunity. Vaccine efficacy studies for most vaccines in use today challenged vaccinates just 3 to 4 weeks after the last inoculation. The paradigm that adult dogs and cats require annual boosters for all the commonly administered vaccines is being challenged. We simply cannot continue to arbitrarily administer vaccines without regard for the number and type of vaccine antigens in the product and without realistic consideration of the risk of infection facing the individual animalY· 15. 16, 22, 24
CANINE DISTEMPER
Modified live virus (MLV) vaccines have been most effective in protecting dogs against canine distemper. Inactivated whole viral vaccines are not effective; however, a vectored recombinant vaccine is currently available. In puppies, distemper vaccination is performed at 3- to 4-week intervals, with the earliest inoculation being given when the puppy is 6 to 8 weeks of age. Most distemper vaccines used in North America today overcome maternal immunity by the time puppies are 12 weeks of age. Vaccination in puppies is usually continued until they reach 16 weeks of age. Dogs older than 12 weeks of age at the time they are presented for initial vaccination should receive at least two canine distemper virus (CDV) inoculations 2 to 3 weeks apart. The minimum duration of immunity, as determined by challenge, to attenuated (MLV) CDV is at least 7 years for vaccines using the Rockport strain of CDV, although that for vaccines using the Onderstepoort strain is at least 5 years.2,29
The recombinant CDV vaccine is a canary pox-vectored vaccine that expresses distemper fusion and hemagglutinin glycoproteins.23 Dogs receiving this vaccine must receive at least two doses initially. The reported duration of immunity is at least 12 months. Annual booster vaccination is recommended when using this product.
A combined distemper-measles vaccine is still available. At a stage of life when administration of MLV CDV vaccine is expected to fail, measles vaccine is capable of causing a heterotypic immune response in
CANlNE VACCINATION 481
the presence of high concentrations of maternally derived distemper antibody. Some veterinarians still recommend administration of a' CDVmeasles virus vaccine to puppies between 6 and 9 weeks of age. This product should not be used in female puppies over 12 weeks of age, because maternal antibodies to CDV and measles may develop. These antibodies would be transferred to subsequent offspring at a level that could interfere with both measles and CDV vaccination in the puppies. Therefore, antibodies would interfere with the protective effects of the MV-CDV vaccination and the heterotypic MV would not provide early protection from CDV Administration of a combined MLV CDV-measles virus vaccine should be limited to those puppies in which the nursing status is unknown or that are likely to face CDV exposure as puppies. Measles vaccine is not indicated in dogs over 16 weeks of age.
INFECTIOUS CANINE HEPATITIS (CANINE ADENOVIRUS INFECTION)
Vaccination for canine adenovirus infection, the cause of infectious canine hepatitis (ICH), is usually done in combination with that for distemper and other diseases beginning when puppies are 6 to 8 weeks of age. Attenuated (MLV) adenovirus vaccines are generally used in the United States because of their ability to produce a superior immune response, but inactivated products are still available in the U.S. and marketed in many countries. Vaccination for ICH reduced the prevalence of a disease that was once widespread. Outbreaks or isolated cases still occur when vaccination of puppies is delayed or incomplete. Shedding of modified viruses and high stability outside the host have been responsible for inadvertent immunization of many dogs. Vaccines for ICH contain either a killed homologous canine adenovirus-l (CAV-l) or a closely related respiratory isolate, MLV canine 'adenovirus-2 (CAV-2). The former is generally shed in the urine, and the latter is shed in upper respiratory secretions; however, the amount that is shed varies between individual products. Another side effect of attenuated CAV-l vaccine is its ability to produce anterior uveitis and corneal edema with opacification (''blue eye") in a small percentage of dogs. It is not documented that CAV-2 vaccines cause uveitis. Although inactivated vaccines produce a lesser serologic response, they are not shed by the host, nor do they cause anterior uveitis. In the absence of exposure to virulent virus, periodic boosters of inactivated adenovirus vaccine might be required to sustain immunity.
The half-life of maternal antibody to ICH is similar to that of CDV: approximately 8.5 days. By the time a puppy reaches 14 to 16 weeks of age, maternal antibody is not usually detectable. Vaccination for ICH is
.f
482 GREENE et aI "
thus typically combined with that for CD~ The initial vaccines can be administered when puppies are 6 to 8 weeks of age and every 3 to 4 weeks until they reach 16 weeks of age. Although booster inoculation is recommended annually in adult dogs, challenge studies have demonstrated that the duration of immunity is at least 7 years when attenuated CAV-2 is used as the vaccine antigen.29 The duration of immunity of killed CAV-2 vaccine and the MLV CAV-2 (intranasal) is not k..'1own.
MLV CAV-2 has been shown to immunize dogs against the respiratory (CAV-2) and hepatic (CAV-l) adenoviruses. Considering the risks associated with administration of CAV-l to dogs, the use of the MLV CAV-l vaccine is not recommended.
CANINE INFECTIOUS TRACHEOBRONCHITIS
Infectious tracheobronchitis (ITB), or kennel cough, is a complex clinical infection caused by a number of respiratory pathogens that can infect dogs alone or in combination. Causative viruses include distemper (CDV), adenovirus (CAV-2), parainfluenza virus, herpesvirus, and Reovirus. Bordetella bronchiseptica is a recognized bacterial pathogen.4, 13 Secretory antibody (not that in serum) provides protection against infections of the upper respiratory mucosal surfaces. Parenteral and intranasal vaccines exist for CAV-2, parainfluenza virus, and B. bronchiseptica. Although protection against most agents develops after routine vaccination programs, vaccines against some agents such as herpesvirus or Reovirus are not available. The duration of immunity produced by many vaccines against respiratory p~thogens has not been well established, but the labels of most products recommend annual boosters. It is unlikely that dogs derive significant immunity beyond 12 months subsequent to intranasal vaccination. For intranasal B. bronchiseptica vaccine, the duration of immunity may actually be less than 12 months.
The performance of parenterally administered infectious tracheobronchitis (ITB) vaccines is quite different from that of intranasally (topically) administered vaccine. Parenterally administered vaccine for ITB provides a duration of immunity of up to 7 months or longer depending on the antigen.7, 29 It is not known whether parenteral administration of ITB antigens culminates in the development of an effective local (upper respiratory tract) immune response. Maternal antibody interferes with parenterally administered vaccine. On the other hand, vaccine labeled for intranasal (topical) administration can be administered in puppies as young as 3 weeks of age (depending on the product), seems to induce a local immune response that is not interfered with by maternal antibody, and has a relatively rapid onset (3-5 days). It should be noted that although pneumonia caused by virulent B. bronchiseptica
CANINE VACCINATION 483
has been reported in immunocompromised human beings, inadvertent nasal or ocular exposure to avirulent live canine B. bronchiseptica vaccine is not known to have caused clinical illness or symptoms in human beings . .
Vaccination with separate parenteral products usually begins in puppies at 6 weeks of age and is safe for pregnant animals. Animals should receive at least two doses 2 to 4 weeks apart, and complete protection is not expected until 2 to 3 weeks after the second vaccination. Intranasal parainfluenza and Bordetella vaccines may protect within 72 hours after their use; thus, they can be used to help prevent illness in an outbreak in a kennel or in pets before hospitalization or boardingY Vaccination against respiratory pathogens does not induce sterile immunity. In other words, vaccinated animals that are challenged are expected to become infected and may exhlbit a mild short clinical illness. Clinical signs of upper respiratory infection may develop subsequent to intranasal administration of vaccine. Signs are generally mild or unnoticeable.
CANINE PARVOVIRAL ENTERITIS
Canine parvovirus-2 (CPV-2) vaccines are available as inactivated or MLV products. Recombinant vaccines are not currently available but are being developed. MLV products offer faster, more effective protection against disease and shedding of virulent virus after challenge than inactivated vaccines. For this reason, older dogs that are housed with younger susceptible animals should be vaccinated with MLV vaccines. In case of an outbreak, MLV vaccines should always be used. MLV CPV-2 products are consistently shed in the feces of vaccinated dogs. Infected contact animals may develop weak positive reactions on fecal parvovirus enzyme-linked immunosorbent assay (ELISA) tests but will not develop disease. Maternal antibody blockade is the predominant reason that parvoviral vaccination is inconsistent in protecting pups during their primary vaccination series. 10, 16 Attenuated or inactivated vaccines do not break through maternal immunity as effectively as virulent canine parvovirus, To overcome the period of maternal antibody blockade, manufacturers have raised the titers or lowered their serial passage.B, 2B, 29
Recommendations for use of these potent parvoviral vaccines are a complete series beginning at 6 weeks of age. Repeat vaccines are given every 3 to 4 weeks until dogs are 16 weeks old despite the fact that some products have label claims of protection by 12 weeks of age, The last inoculation should be given at 16 weeks of age for breeds such as Doberman Pinschers and Rottweilers, which have been identified as being poorly responsive to CPV vaccination. In the absence of maternal immunity, where pups are presented after 16 weeks of age, one MLV
".
484 GREENE et aI .'
CPV-2 inoculation may be sufficient for protection agaillst parvoviral infection. Vaccination with MLV CDV with concurrent CPV-2 vaccination does not cause immunosuppression as h~ been observed in coinfection with virulent CPV-2 virus. Alternating between distemper and parvoviral vaccines in young puppies on a weekly or longer interval is thus not needed or recommended.
If an animal recovers from a documented parvoviral infection, it is recommended to wait 4 weeks before vaccinating it so that the immune response is recovered. Immunity to parvoviral infection is probably lifelong; however, boosters are given because of the convenience afforded by combination products. Because of the great environmental resistance of parvoviruses, young pups should be kept away from parks, boarding facilities, and dog shows until the vaccination series is complete. Veterinarians should attempt to limit suspected parvovirus-infected dogs from coming into contact with susceptible puppies in their veterinary hospital waiting rooms and wards. Vaccination of cats against feline panleukopenia protects them against CPV-2b infection.
There has been a genetic and resultant antigenic shift of canine parvovirus since its initial evolution in 1978. Nevertheless, cross-protection still exists between the old CPV-2 strains in the vaccine and the new field isolates (CPV-2a and CPV-2b). Similarly, immunodiagnostic tests based on monoclonal antibodies to original isolates are still sensitive in detecting newer strains of virus. Newer field isolates can infect cats. There is limited evidence to suggest that vaccines based on 2b strains do not infect cats.
Duration of immunity of MLV CPV-2 vaccines is several years (at least 7 years based on challenge studies),29 and overvaccination is a consideration. The duration of immunity subsequent to administration of inactivated (killed) CPV products has been shown to protect puppies from challenge for at least 16 months after vaccination.25 Under field conditions, dogs may be partially protected by weaker MLV or inactivated products yet still boost their immunity when exposed to virulent virus.
CORONAVIRAL INFECTION
Most vaccines licensed for canine coronavirus (CCV) are inactivated canine coronaviral or feline coronaviral strains. One attenuated (MLV) canine coronaviral product exists. Manufacturers recommend that two doses of vaccine be given 2 to 3 weeks apart beginning in puppies at 6 to 8 weeks of age, with the last one being given at least after 12 weeks of age. The vaccines seem to be safe; however, allergic reactions may occur more commonly when inactivated coronaviral vaccines are com-
CANINE VACCINATION 485
bined with leptospiral bacterins. To avoid potential interactions, CCV vaccine could be used in puppies between 6 and 9 weeks of age, and Leptospira vaccination could be instituted thereafter. Otherwise, the clinician may prefer to decide whether or not it is important or necessary that both products be administered.
CCV challenge studies are not indicative of "protection" since it is not possible to produce experimental disease in dogs over 12 weeks of age. Furthermore, manufacturer recommendations to administer CCV booster vaccines annually are difficult to justify based on the fact that CCV does not cause disease in adult dogs. CCV produces significantly less morbidity and minimal mortality compared with CPV-2. Experimentally, combined infections with CPV-2 and CCV have been shown to produce clinical disease that is more severe than with either infection alone. I Nevertheless, it has also been shown that vaccination with CPV can prevent clinical disease when both viruses are present.19
• 28
The routine and frequent use of CCV vaccine in dogs is difficult to rationalize. Clinical infection typically occurs in puppies 6 weeks of age or yOl.\Ilger. Some studies have suggested that the duration and quality of immunity derived from natural exposure and infection are actually preferred over attempts to immunize by way of vaccination.28 In the absence of reliable commercial or in-hospital diagnostic assays for CCV, the prevalence of clinical disease associated with CCV infection in dogs is unknown but is considered to be extremely low, even in high-density shelter environments. Yet CCv, both killed and MLV, is commercially incorporated into several multivalent vaccines combined with distemper, adenovirus, parainfluenza virus, and parvovirus antigens. The fact that multivalent vaccines containing CCV outsell vaccines that do not contain CCV in the United States suggests that routine CCV inoculation of dogs throughout life is common. CCV vaccine is considered to be among the least important vaccine antigens given to dogs today, however, and has been identified by several authors as a vaccine that, quite simply, is not needed.9,28
LEPTOSPIROSIS
Most leptospiral vaccines for dogs contain inactivated serovars of canicola and icterohaemorrhagiae. Vaccination with these products is not recommended in animals less than 9 weeks of age because of the allergenic nature of these products. Leptospira bacterin is usually used to reconstitute the lyophilized components in combination vaccines. Leptospira bacterins may not produce as high a level or as long a duration of immunity as other agents. Although postvaccination titers often decline to undetectable levels, unpublished challenge studies suggest that immu-
486 GREENE et aI
nity in some dogs is sustained for 1 year. Inactivated Lep£ospira vaccines may not, however, protect against the .. carrier state that may develop after exposure to virulent organisms. Qne vaccine manufacturer has employed a technology that involves separating surface proteins, or immunogens, of Leptospira from extraneous cellular debris, thereby avoiding the need to use whole-cell bacteria. It is not known whether or not this technology can reducethe incidence of adverse events in young dogs and toy breeds over that recognized with conventional wholecell bacterins. Leptospiral vaccines have been considered optional by veterinarians in many areas because of the perceived low incidence of the disease, short duration of immunity, and risk of postvaccinal hypersensitivity. The use of Leptospira vaccine is probably responsible for the reduced prevalence of disease caused by L. canicola and L. icterohaemorrhagiae.
Recently, it has been shown that the incidence of confirmed cases of canine leptospirosis may be increasing in the United States.S
•33 Further
more, dogs are being diagnosed with infections by serovars of L. interrogans that we do not routinely vaccinate against. Serovars of L. grippotyphosa, L. pomona, L. bratislava, and others are reported throughout the United States and have been linked to acute renal failure. 6• 33 Another interesting point is that many of these reports are on dogs living exclusively in urban areas. The risk of infection is not limited to dogs living outdoors in rural environments. Vaccines containing conventionally used serovars of L. canicola and L. icterohaemorrhagiae do not cross-protect against other serovars known to infect dogs.s
Less than 2 years ago, Leptospira vaccines were introduced that are believed to protect against serovars L. grippotyphosa and L. pomona. Additional Leptospira serovars are likely to be introduced in the near future. Nevertheless, the incidence of acute anaphylaxis among young dogs (especially those under 12 weeks of age) and toy breeds (regardless of age) makes the decision to include routine vaccination of dogs with all available Leptospira serovars difficult. Without regional incidence data for canine leptospirosis, practitioners still have insufficient information at their disposal to make a reasonable risk:benefit analysis regarding use of leptospira vaccines.
LYME BORRELIOSIS
Commercial inactivated (killed) whole-cell bacterins and one recombinant outer surface protein A (OspA) vaccine is licensed in the United States.14, 26 In Europe, the vaccines are of the whole-cell type. Vaccines have been shown by challenge studies conducted by the manufacturer of the recombinant outer surface protein A vaccine to provide a duration
CANINE VACCINATION 487
of immunity for up to 1 year. Vaccination protected challenged dogs from spirochetemia and clinical limping episodes as compared with unvaccinated dogs. Lyme borreliosis vaccines are recommended by the manufacturer for use in dogs as young as 9 to 12 weeks of age,' and primary vaccination consists of two inoculations 3 weeks apart. Immunization should be given early in life to high-risk dogs living in endemic regions. It should be noted that all vaccines stimulate antibody that produces a positive test result with the indirect fluorescent antibody serodiagnostic test. Dogs having a positive indirect fluorescent antibody test should be retested using either of two tests: the Western blot technique, which may discriminate between infection and vaccine-induced antibody, or the recently introduced in-hospital ELISA test (SNAP 3Dx Assay; IDEXX Laboratories, Westbrook, ME), which has been shown to react only to antibody from a unique C6 surface peptide.21 The ELISA test does not cross-react to antibody produced by any of the commercially available vaccines on the -market in the United States.
Claims of hypersensitivity induced by whole-cell Lyme vaccines have been reported. The most common observation is postvaccination lameness among dogs that did not show clinical or serologic evidence of infection. Unfortunately, the vaccines contain a limited number of strains, which may not cross-protect against the known isolates of B. burgdorferi. Routine testing of dogs using the in-hospital ELISA test in regions of the United States where Lyme borreliosis is suspected or is known to occur in human beings can provide new information pertaining to the regional incidence of infection among the canine population. Today, that information is largely extrapolated from human incidence data maintained by the Centers for Disease Control and Prevention. In the meantime, routine vaccination of dogs against B. burgdorferi is not indicated outside regions of known high disease prevalence.
GIARDIASIS
Infection with the protozoan Giardia Lamblia is known to affect mammals and birds worldwide. Differences exist in the pathogenicity and host range of various strains. Colonization of the intestinal lumen results in intestinal villus shortening and malabsorptive diarrhea. Neonatal animals are most susceptible to infection.3 Areas with impounded unfiltered surface water that is used for recreation or drinking are most often associated with infection. Unsanitary conditions can lead to endemic infections. An inactivated adjuvanted vaccine is available for vaccination of puppies and kittens. The first dose can be given in animals as young as 8 weeks of age. Neither routine or annual revaccination is indicated
~
00
Tab
le 2
. D
OC
UM
EN
TE
D M
INIM
UM
DU
RA
TIO
N O
F I
MM
UN
ITY
' O
F I
ND
IVID
UA
L V
AC
CIN
E A
NT
IGE
NS
US
ED
IN
DO
GS
Du
rati
on
of
Imm
unit
y b
y
Co
rrel
atio
n o
f D
ura
tio
n o
f Im
mun
ity
by
Ser
olo
gy
T
iter
wit
h V
acci
ne
Ch
alle
ng
e (a
nti
bo
dy
tit
er)
Imm
unit
y R
efer
ence
s
Can
ine
dist
empe
r-M
LV
7
year
s 15
yea
rs
SN
Ab
: str
ong
2,29
(R
ockp
ort
stra
in)
Can
ine
dist
empe
r-M
LV
5
year
s 9
year
s S
N A
b: s
tron
g 29
(O
rder
step
oort
str
ain)
Can
ine
dist
empe
r (R
eco
mbi
nant
) 1
year
N
ot d
emo
nst
rate
d N
ot
Mer
ial,
Ltd
. de
mon
stra
ted
Can
ine
parv
ovir
us-M
LV
7
yea
rs
7 ye
ars
HI
AB
: str
ong
2,29
Can
ine
parv
ovir
us-k
ille
d 16
mon
ths
No
t re
port
ed
Hl
or
SN
: str
ong
7,2
5,
29
Can
ine
coro
navi
rus-
ML
V o
r ki
lled
C
an n
ot b
e de
term
ined
N
ot
repo
rted
S
N A
b: s
tron
g
Can
ine
aden
ovir
us 2
-ML
V
7 ye
ars
q vpPlr~
SN
Ah:
~trnn(7
29
• J ----
-_ .
. ---
----
-·0
Can
ine
aden
ov
iru
s-l t
N
ot
appl
icab
le
Not
app
lica
ble
~
Can
ine
para
infl
uenz
a-M
LV
U
npub
lish
ed s
tud
y d
emon
stra
ted
Unp
ubli
shed
stu
dy
dem
on
stra
ted
D
oes
not
Unr
elea
sed .
(top
ical
ly a
dmin
iste
red)
pr
otec
tio
n "
in e
xces
s of
1
min
imal
ant
ibod
y de
tect
ed
corr
elat
e re
sear
ch r
epor
t y
ear"
aft
er v
acci
nati
on
afte
r va
ccin
atio
n
Can
ine
para
infl
uenz
a-ki
lled
N
ot
repo
rted
2
year
s N
eutr
aliz
ing
Ab
4 ~
(par
ente
rall
y ad
min
iste
red)
Bor
dete
lla b
rollc
i1is
eptic
a O
nly
shor
t-te
rm (
up t
o 3
wee
ks)
Not
rep
orte
d D
oes
not
Unr
elea
sed
(par
ente
rall
y ad
min
iste
red
stu
dies
are
pub
lish
ed
cor(
elat
e re
sear
ch r
epor
t
"" a>
~
Bor
dete
lla b
rol1
eiTi
sept
iea
(top
ical
ly a
dm
inis
tere
d)
Borr
elia
bur
gdor
feri
-who
le b
acte
rin
Borr
elia
bur
gdor
feri
-rec
ombi
nant
o
ute
r su
rfac
e p
rote
in A
Lept
ospi
ra i
nter
rogn
l1s
ealli
eola
L.
iet
eroh
aem
orrh
agia
e
Lept
ospi
ra i
nter
rogn
ns
L. g
ripp
otyp
hosn
L.
pom
ona
Gia
rdia
sis
Rab
ies-
kill
ed
Un
pu
bli
shed
stu
dy
dem
on
stra
ted
pr
otec
tion
"in
exc
ess
of
1 y
ear"
aft
er v
acci
nati
on
156
to 2
07 d
ays
1 y
ear
Up
to
14 m
on
ths
No
t re
po
rted
No
t re
port
ed
39 m
on
ths
Un
pu
bli
shed
stu
dy
dem
on
stra
ted
si
gnif
ican
t "a
gg
luti
nat
ing
an
tib
od
y"
tite
r pe
rsis
ted
"in
ex
cess
of
1 y
ear"
aft
er
vacc
inat
ion
No
t re
po
rted
Not
rep
orte
d
~12 m
on
ths
wit
h b
oth
ser
ov
ars
No
t re
port
ed
No
t re
port
ed
7 ye
ars
Doe
s n
ot
Unr
elea
sed
corr
elat
e re
sear
ch r
epo
rt
Ab
tite
r d
oes
no
t P
acka
ge i
nser
t co
rrel
ate
wit
h
imm
un
ity
Ab
tite
r d
oes
no
t P
acka
ge i
nser
t co
rrel
ate
wit
h
imm
un
ity
Neu
tral
izin
g I
gG
14
tite
rs a
re
prot
ecti
ve
Un
kn
ow
n
Un
kn
ow
n
Cha
llen
ge
stu
die
s re
quir
ed
'Th
e du
rati
on o
f im
mun
ity
list
ed f
or i
ndiv
idua
l an
tige
ns r
epre
sent
s th
e le
ngth
of
tim
e do
gs w
ere
foU
owed
be
fore
cha
Uen
ge o
r be
fore
mea
suri
ng a
ntib
ody;
it
does
re
pres
ent
the
max
imum
pos
sibl
e du
rati
on o
f im
mun
ity.
A
ltho
ugh
a m
odif
ied-
live
can
ine
aden
ovir
us-l
vac
cine
is
still
ava
ilab
le a
t th
is w
riti
ng,
use
of t
his
prod
uct
in c
lini
cal
prac
tice
is
not
reco
mm
ende
d.
MLV
= m
odif
ied
live
vir
us;
SN =
ser
um n
eutr
aliz
ing
(in
refe
renc
e to
met
hod
of d
eter
min
ing
anti
body
tit
er);
Ab
= a
ntib
ody;
HI
= h
emag
glut
inat
ion
inhi
biti
on.
]I!
490 GREENE et al
with this product, except in the unusual situation where recurrent exposure and infection are documented a,pd cannot be controlled using conventional hygienic methods. This va~cine has been shown to diminish fecal shedding of the infectious cysts for up to 1 year. The vaccine also reduces the rate and quantity of infection when given before exposure. If the prevalence of infection is high in a group of animals or in a specific area, this vaccine might be an adjunct to help control the disease. It is not recommended for administration to all dogs, and its use must be coupled with other management procedures. The current vaccine has been shown to cause granuloma-like masses at the inoculation site.
It is important to note that accurate identification of Giardia in dogs with diarrhea is not as straightforward as it may seem. As such, falsepositive diagnoses of giardiasis are probably common. Conventional saline fecal flotation techniques are not adequate to diagnose Giardia cysts in feces. Furthermore, direct fecal examination is limited by the experience of the microscopist and by the fact that many other structures in the feces of dogs such as yeast bodies are easily confused with Giardia cysts. Feces should be subjected to centrifugal flotation in a 33% zinc sulfate solution. The slide should be scanned with a X 10 objective magnification.
RABIES
Rabies vaccines have been extremely effective in reducing the prevalence of this disease in dogs. As a result, the prevalence of human disease has decreased substantially, although the relative prevalence of feline rabies has increased in the United States. In most countries, inactivated (killed) vaccines are used. Inactivated virus vaccines have been shown to provide a minimum duration and level of immunity comparable to those of MLV products. They often contain high viral content and potent adjuvants, however, which can sometimes produce acute or chronic hypersensitivity reactions. An avipoxvirus-vectored recombinant rabies vaccine that produces minimal inflammatory reactions has been licensed for use in catsY A single rabies vaccine is generally administered in animals 3 to 4 months of age. A second dose should be administered 1 year after the first dose regardless of the dog's age. Subsequent boosters are required every 1 or 3 years thereafter as mandated by state law or local statutes.
CONCLUSIONS
New technologies for vaccine developmentll, 32 and infectious disease diagnosis21 are likely to be introduced in the near future. With this
CANINE VACCINATION 491
new technology comes the opportunity to vaccinate companion animals against even more infectious agents than is currently practiced in the United States today. As we look forward, it becomes particularly important to review current vaccination standards applied to dogs with respect to current knowledge of duration of immunity (Table 2), awareness of the incidence and likelihood of injurious or even fatal adverse events associated with vaccination, and individual risk factors that dic~ tate which vaccines are most appropriate at which stage of life.
References
1. Appel MjG: Does canine coronavirus augment the effects of subsequent parvovirus infection? Vet Med (Praha) 83:360-366, 1988
2. Appel MjG, Gillespie JH: Canine distemper virus. Virology Monographs 11:1-97, 1972 3. Barr SC: Giardiasis in dogs and cats. Compend Contin Educ Pract Vet 16:603-{;14, 1994 4. Binn LN, Eddy GA, Lazar EC, et al: Viruses recovered from laboratory dogs with
respiratory disease. Proc Soc Exp BioI Med 126:140-145, 1967 5. Bolin CA: Diagnosis of leptospirosis: A reemerging disease of companion animals.
Semin Vet Med Surg (Small Anim) 11:166-171, 1996 6. Brown CA, Roberts AW, Miller MA, et al: Leptospira interrogans serovar grippotyphosa . infection in dogs. jAVMA 209:1265-1267, 1996
7. Burr H, Coyne M, Gay C, et al: Duration of lmmunity in Companion Animals after Natural Infection and Vaccination. Research Report. Pfizer Animal Health, Exton, PA, 1998, pp 1-21
8. Burtonboy S: Performance of a high titre attenuated canine parvovirus vaccine I in pups with maternally derived antibody. Vet Rec 128:377-381, 1991
9. Carmichael LE: Canine viral vaccines at a turning point-a personal perspective. In Schultz RD (ed): Veterinary Vaccines and Diagnostics. San Diego, Academic Press, 1999, pp 289-307
10. Carmichael LE: Vaccines for dogs. In Pastoret PP (ed): Veterinary Vaccinology. Amsterdam, Elsevier, 1997, pp 327-331
11 . Donnelly JJ: DNA vaccines. Annu Rev lmmunol 15:617-M8, 1997 12. Duval D, Giger U: Vaccine-induced immune-mediated hemolytic anemia in the dog. j
Vet Intern Med 10:290-295, 1996 13. Ford RB, Vaden SL: Canine infectious tracheobronchitis. In Greene CE (ed): Infectious
Disease of the Dog and Cat, ed 2. Philadelphia, WB Saunders, 1998, pp 33--38 14. Hartman EG, Van Houten M, Frik JF, et al: Humoral immune response of dogs after
vaccination against Leptospirosis measured by an IgM and IgE specific ELISA. Vet lmmunollmmunopathol 7:245-254, 1984
15. Hogenesch H, Azcona-Olivera J, Scotte-Moncrieff C, et al: Vaccine-induced autoimmunity in the dog. Adv Vet Med 41:733--747, 1999
16. lida H, Fukuda S, Kawashima N, et al: Effect of maternally derived antibody levels on antibody responses to canine parvovirus, canine distemper virus and infectious canine hepatitis virus after vaccinations in beagle puppies. Exp Anim 39:9-19, 1990
17. Kontor Ej, Wegrzyn Rj, Goodnow RA: Canine infectious tracheobronchitis: Effects of an intranasal live canine parainfluenza-Bordetella bronchiseptica vaccine on viral shedding and clinical tracheobronchitis (kennel cough). Am j Vet Res 42:1694-1698, 1981
18. Larson Lj, Schultz RD: Comparison of selected canine vaccines for their ability to induce protective immunity against canine parvovirus infection. Am j Vet Res 58:360-363, 1997
19. Larson Lj, Schultz RD: Efficacy of immunity induced by canine coronavirus (CCV) vaccines compared against immunity after natural infection with CCV [abstract]. Conference for Research Workers in Animal Disease 77:64, 1996
".!: .. _ .
492 GREENEet~
20. Larson LJ, Schultz RD: High-titer canine parvovirus vaccine: Serologic response and challenge-of-immunity study. Vet Me<;l (Praha) 91:210-218, 1996
21. Liang FT, Jacobson RH, Straubinger RK, et al:-Characterization of a Borrelia burgdorferi VlsE invariable region useful in canine Lyme disease serodiagnosis by enzyme-linked immunosorbent assay. J Clin Microbiol 38:41~166, 2000
22. Morgan JIi, Cooper J: State of the art: Bacterial vaccines. [abstract]. In Proceedings of the Second International Veterinary Vaccines and Diagnostics Conference, Oxford, 2000, p 19
23. Pardo MC, Bauman JE, Mackowiak M: Protection of dogs against canine distemper by vaccination with a canary pox virus recombinant expressing virus fusion and hemagglutinin glycoproteins. Am J Vet Res 58:833-836, 1997
24. Pastoret PP: State of the · art: Viral vaccines [abstract]. In Proceedings of the Second International Veterinary Vaccines and Diagnostics Conference, Oxford, 2000, p 17
25. Povey RC, Carman PS, Ewert E: The duration of immunity to an inactivated adjuvanted canine parvovirus vaccine. Can Vet J 24:245-248, 1983
26. Rice Conlon JA, Mather TN, Tanner P, et al: Efficacy of a nonadjuvanted, outer surface protein A recombinant vaccine in dogs after challenge by ticks naturally infected with Borrelia burgdorferi. Veterinary Therapeutics 1:96-107, 2000
27. Richards J, Rodan I, Elston T, et al : 2000 Report of the American Association of Feline Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vaccines, Nashville, 2000
28. Schultz RD: Current and future canine and feline vaccination programs. Vet Med (Praha) 3:233-254, 1998
29. Schultz RD: Duration of immunity to canine vaccines: What we know and don't know. In Proceedings for the Canine lnfectious Diseases Workshop: From Clinics to Molecular Pathogenesis, James A. Baker Institute, August 1999(Available on-line: www.ivis.org / proceedings/Baker_Can_lnf_Dis / )
30. Sikes RK, Peacock GV, Acha P, et al: Rabies vaccines: Duration of immunity study in dogs. JAVMA 159:1491-1499, 1971
31. Van Kampen KR: Rabies vaccines. In Rabies: Guidelines for Medical Professionals. Trenton, NJ, Veterinary Learning Systems, 1999, pp 67-71
32. Weiner DB, Kennedy RC: Genetic vaccines. Sci Am 282:50-57, 1999 33. Wohl JS: Canine leptospirosis. Compend Contin Educ Pract Vet 11:1215-1241, 1996
Address reprint requests to
Richard B. Ford, DVM, MS Professor of Medicine
Department of Clinical Sciences College of Veterinary Medicine
North Carolina State University Raleigh, NC 27605
e-mail: [email protected]
VACCINES AND VACCINATIONS 0195-5616/ 01 $15.00 + .00
VACCINE-ASSOCIATED ADVERSE EVENTS
E. Kathryn Meyer, VMD
Widespread vaccination of pets against commonly encountered pathogens is credited with greatly reducing the morbidity and mortality previously associated with infectious diseases.3, 18, 21 , 35 Likewise, successful control of human public health threats such as rabies would not be possible without vaccination programs for domestic animals.28 As with any medical procedure, however, the benefits of vaccination are accompanied by risks.3, 35
Recent concerns regarding serious adverse events that may be associated with vaccination such as feline sarcomas14, 17, 22, 23 and autoimmune disorders7, 9, 18 have stimulated the veterinary profession to re-examine existing vaccination protocols with an increased sensitivity to potential risks. Because patient characteristics such as age, breed, immune status, and state of health may affect the risks and benefits of vaccination, veterinarians are beginning to view vaccination as an individualized medical procedure rather than a standard protocol applicable to all animals of a given species.7, 10, 18, 25 As such, the risks and benefits for the individual animal should be considered before vaccination recommendations are made. Veterinarians should keep in mind, however, that outbreaks of previously controlled but endemic diseases may occur if the number of vaccinated animais in a given population falls below a certain threshold. 38
Although this article focuses on adverse events associated with
From the United States Pharmacopeia Veterinary Practitioners' Reporting Program, United States Pharmacopeia, Rockville, Maryland
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE
VOLUME 3] • NUMBER 3 • MAY 200] 493
494 MEYER
vaccination (e.g., risks), a balanced discussion cannot be presented without examination of the benefits associ'ated with vaccination as well. Consequently, vaccine benefits are addr886ed first to properly orient the reader for subsequent discussion of risks.
BENEFITS OF VACCINATION
The projected benefits of vaccination for the individual animal are based on the efficacy of the specific vaccine in preventing clinical disease.32 Other factors that may affect the projected benefits of vaccination include the likelihood of exposure and infection as well as the severity of health consequences if infection does occur. 10 For example, the benefit of vaccinating an animal with an efficacious vaccine is limited if the potential for exposure is low and the clinical disease is mild. Consideration of projected benefits supports the philosophy of customizing vaccine recommendations for the individual animal provided that population immunity is not jeopardized.
Vaccine efficacy, which is the reduction in disease risk that results from an animal's having been vaccinated, can be estimated in manufacturer-generated prelicense challenge studies. Subsequent validation may be achieved through postmarketing monitoring and independent clinical or epidemiologic evaluations.
Prelicense Efficacy Studies
Under the 1913 Virus-Serum-Toxin Act, further amended by the 1985 Food Security Act, the United States Department of Agriculture's (USDA's) Animal and Plant Health Inspection Service (APHIS) is responsible for ensuring that veterinary biolOgics are pure, safe, potent, and effective. To this end, all veterinary biologics are licensed through the USDA APHIS Service Center for Veterinary Biologics (CVB)Y The results of vaccine efficacy studies required for USDA CVB licensure dictate the wording that appears on the product's labelingY For example, "For prevention of disease due to (a certain microorganism)" requires 80% efficacy in prevention of clinical disease in vaccinated and challenged animalsY "As an aid in the prevention" or "as an aid in the reduction of" requires that the product produce a significant effect, although the type and level of effect are not stipulated and may not be related or relevant to the clinical condition of the animals.20• 41
Most prelicense vaccine efficacy trials involve a small number of animals. For example, USDA-defined efficacy studies for canine distemper and hepatitis (adenovirus) vaccines require the inclusion of 20 vacci-
VACCINE-ASSOCIATED ADVERSE EVENTS 495
nates and 5 unvaccinated controls. 49. 50 For modified-live Chlamydia psittaci vaccines for cats, 20 vaccinates and 10 controls are required to establish efficacy.53 Subsequent to licensing, challenge studies are periodically performed to provide in vitro potency testing standards. Potency testing is performed by the manufacturer before the release of each batch. 51. 52
The interval for revaccination is ideally based on duration of immunity studies. Minimum duration of immunity studies are required for rabies vaccines and products containing "new product fractions."41 A "new product fraction" is an antigen that was not commercially available at the time the efficacy guidelines were published on May 12, 1995. Duration of immunity studies are not required to support label revaccination recommendations for all current and future vaccine products containing many commonly used canine and feline antigens, including rhinotracheitis/ calicivirus/panleukopenia (FVRCP) , chlamydia, and feline leukemia virus (FeLV) for cats and distemper, adenovirus (canine hepatitis), leptospira, parainfluenza, parvovirus, and coronavirus for dogsY
Postlicensure Measurement of Vaccine Efficacy
Postmarketing vaccine efficacy can be estimated through epidemiologic studies and clinical efficacy studies; however, such studies are not plentiful in the veterinary medical1iterature. The monitoring of. disease incidence over time relative to vaccinption practices can also prOvide information to support the effectiveness of vaccine programs; however, systematic monitoring of canine and feline infectious disease, with the exception of rabies, is not routinely performed.
Because rigorous independent scientific evidence documenting vaccine efficacy is not readily available for all commonly used canine and feline vaccines, veterinarians must rely on other sources of information. These sources include the licensing status of a vaccine, manufacturergenerated product information, and clinical impression of vaccine performance . Postmarketing surveillance systems can serve to collect reports on suspected lack of efficacy concerns as well. Despite the paucity of hard scientific evidence, clinical experience supports the impression that widespread vaccination has decreased the incidence of many potentially fatal canine and feline infectious diseases.3• 19. 21 . 35 The continued control of these infectious diseases is dependent on continued protection of the animal population through appropriate vaccination with effective products. l o• 38
., 496 MEYER
RISKS OF VACCINATION .,
The risks of vaccination are describeQ..as the potential adverse effects that may occur as a result of vaccine administration.32 The risk posed to an individual is based on the frequency of adverse reactions occurring after vaccination in the general population of similar animals as well on as host and environmental risk factors Y Ideally, reliable information regarding the likelihood and severity of potential adverse reactions or effects should be readily available to veterinarians so that appropriate vaccination recommendations can be made. Of equal importance is the communication of vaccination risk information to owners.!3 If risk information is shared, the owner can take part in the decision-making process and is better equipped to properly monitor the animal for potential adverse events associated with vaccination.
Prelicensing Measurement of Risk
As part of the licensing procedure, applicants for a veterinary product license are required to conduct field tests, especially to confirm product safety.42 Prelicensing field tests may involve several hundred or thousand animals at three geographic sites (Steve Karli, Director, USDA Center for Veterinary Biologies [CVB] Unit of Inspection and Compliance, personal communication, January 2000) Although the group is larger and usually more diverse than that involved in the efficacy studies, certain types of reactions may not be detected. These include rare events, events that occur after repeated exposure, and events that occur in a subgroup (e.g., specific breed, age) .13.32 For vaccines used in people, the nature and frequency of adverse events encountered during field trials are included on vaccine labeling.32 In contrast, adverse event information collected through field trials is not routinely required to appear on veterinary vaccine labeling, although a statement regarding the potential for anaphylactic reactions and the use of epinephrine as "antidotal" is required for all parenterally administered vaccines.
Postmarketing Measurement of Risk (Surveillance)
Continual evaluation of adverse events associated with medical products once they are available for widespread use is critical to safety monitoring.32 Postmarketing surveillance is particularly important for biologics, where changes in cultured organisms used to produce the product can affect the safety of the product by altering its virulence or immunogenicity. Similarly, mutations in field pathogens can cause
VACCINE-ASSOCIATED ADVERSE EVENTS 497
changes in a product's effectiveness, which may only be recognized on a clinical level. Furthermore, practitioner reporting can playa vital role in identifying potentially dangerous lapses in product quality such as contamination or Inisbranding, allowing the situation to be investigated and rectified.
Postmarketing surveillance can provide an excellent tool to identify rare reactions not discovered during prelicensing studies, monitor recognized reactions, characterize potential risk factors or conditions that may predispose to reactions, and detect particular product lots with unusual reporting patterns (e.g., increased number of reported reactions or unusual types of events}.32 For human vaccines, adverse event information collected through postmarketing surveillance is used to update existing label infonnation.32 In veterinary medicine, adverse event information derived from postmarketing surveillance is not routinely required on the product's label,38 although "special additional requirements" to specific product labels can be made.48 For example, the statement "Occasionally, transient corneal opacity may occur following the administration of this product" is a label requirement for vaccines containing modified-live canine adenovirus-I .
Although individual manufacturers may voluntarily include reported adverse events on labeling, there is a disincentive for companies to do SO.20 A vaccine with adverse events voluntarily listed on its label may be perceived as more dangerous than a comparable vaccine that does not include this label information. Unfortunately, veterinarians may erroneously believe that no adverse events are associated with the comparable product because none are listed on the label.
Two general types of surveillance mechanism exist-active and passive.32 For active surveillance, the vaccination status of all patients in a specified population is correlated with clinical outcomes. Because an active reporting program is designed so that all adverse events for the given population are reported, underreporting is theoretically eliminated. Although the data provided are comprehensive, the system is expensive. Active reporting systems usually include only a small number of participants and, as a result, may be unable to detect rare events. It has been suggested that large corporate veterinary practices could provide the framework for an active reporting systemY Patients could be monitored prospectively to estimate the incidence of specific vaccine reactions.
·In contrast to active systems, passive surveillance systems are based on the voluntary reporting of adverse events.32 Passive systems are simpler and less expensive. Because the population is not limited, passive systems offer the potential for detecting rare or unusual events. Limitations for passive surveillance systems include variable reporting standards, underreporting, and bias of reporters. Various stimuli to
498 MEYER
passive reporting can make analysis of data challenging. For example, a spike in reports involving a certain type of reaction or product may truly reflect an increased incidence or 1nay simply reflect increased awareness and reporting of that type of event, the incidence of which is actually remaining constant.
Surveillance is a form of descriptive epidemiology; thus, the frequency and distribution of reported adverse reactions are recorded without regard to predetermined causal relations.32 As such, surveillance data lack specificity, and causal relations cannot be definitively established.32,38 Because of the lack of specificity, passive reporting programs are best used to identify potential associations between products and adverse events.32• 38 Once the potential association or trend is identified, more rigorous controlled mechanisms can be used to better clarify the possible relation.13, 32. 38
Vaccine-associated feline sarcomas provide an example of how passive surveillance has been used to identify a potential association, with subsequent research supporting the associationY A trend of increasing vaccine site sarcomas submitted to a veterinary pathology laboratory was first identified.15 Further study demonstrated that vaccine site sarcomas differed morphologically, biologically, and histochemically from sarcomas occurring at nonvaccine sites.s, 14, 17 Epidemiologic studies have also demonstrated an association between vaccination and sarcoma development in cats.22• 23 The results of a prospective controlled epidemiologic study (Philip Kass, DVM, PhD, North American Multicenter Study of Determinants of Feline Vaccine-Associated Sarcomas) funded by the Vaccine-Associated Feline Sarcoma Task Force (VAFSTF) and conducted in 1998 and 1999 are expected to provide more insight iflto the risk factors involved with the development of vaccine-associated feline sarcomas (VAFSs).
POSTMARKETING SURVEILLANCE SYSTEM FOR HUMAN VACCINES
The Vaccine Adverse Event Reporting System (VAERS) provides a centralized surveillance system through which vaccine manufacturers, health care professionals, and consumers report adverse events after the administration of any vaccine licensed for use in human beings in the United States.32 The VAERS is coadministered by the Department of Health and Human Services, US Food and Drug Administration (FDA), and the Centers for Disease Control (CDC). This surveillance system was established to manage the adverse event reporting that is mandated in the National Childhood Vaccine Injury Act (NCYIA). The NCVIA, passed in 1986, requires health professionals and vaccine manufacturers
VACCINE-ASSOCIATED ADVERSE EVENTS 499
to report adverse events associated with vaccine administration in people. Approximately 12,000 reports are submitted to the VAERS annually, of which an estimated 40% are provided by manufacturers, 25% are generated by healtJ:1. care providers, and 33%' are from public health departments (Marcel Salive, MD, MPH, Chief, Epidemiology Branch, FDA, Center for Biologics Evaluation and Research, Division of Biostatistics and Epidemiology, personal communication, October 1999). Direct consumer reports comprise approximately 2% of the reports.
Because the V AERS system is a passive surveillance program, acknowledged limitations include underreporting, deficient data quality, simultaneous administration of multiple vaccine antigens, reporting bias, inclusion of events not causally related to vaccination, lack of control group, and lack of information on the number of vaccines given.32 The strengths of the system include the fact that it is the only system covering the entire US population, includes the largest number of case reports, and can assess the safety of specific vaccine lots. The VAERS provides timely availability of data from a geographically diverse population; is able to detect possible new, unusual, or rare adverse events; and can generate hypotheses that may be tested in other databases.
The CDC and FDA evaluate information from the VAERS database. The CDC focuses on aggregate information so as to detect unusual epidemiologic trends and associations.43 The FDA reviews individual reports, assessing whether a reported event is represented in product labeling and monitoring the system for trends involving individual vaccine manufacturers and vaccine lots. Various actions can be initiated by the FDA based on VAERS data, including labeling changes, postmarketing epidemiologic investigations, safety alerts or "Dear Health Professional" letters, inspections of the manufacturing facility, or market withdrawal of the vaccine. Adverse event information included on vaccine labels is periodically updated with VAERS information.33 Safety-related information directed to health care professionals is actively disseminated by the VAERS, and information collected in its database is available to the public through the National Technical Information Services (telephone: 703-487-4650) or through the Freedom of Information staff (telephone: 301-827-2000).32
VETERINARY VACCINE POSTMARKETING SURVEILLANCE
In 1998, the American Veterinary Medicine Association (AVMA) Executive Board approved the following recommendation, submitted by the AVMA Committee on Biologic and Therapeutic Agents:
500 MEYER ,
l'
The AVMA supports vaccinovigilance, which is monitoring of vaccines and other immunobiologics via a publicly available central
reporting system. The system showd include reports of adverse reactions or the failure of biologics to pilJtect animals from disease. We recommend that these reports follow a standardized, systematic template. Any compilation or interpretation of these reports should
be provided in a form that is useful to biological firms and veterinarians. Such reporting is not currently a function of the
United States Department of Agriculture (USDA) APHIS Center for Veterinary Biologics, but should be. The need for vaccinovigilance
is significant and urgent. Animal health, public health, and food safety are protected by credible reporting. Additional funding is
required to support adequate vaccinovigilance.·
Unlike the situation in human medicine, there is no regulation analogous to the NCVIA that mandates veterinary reporting of vaccineassociated adverse events. As regulations currently exist, vaccine manufacturers are not required to record adverse event reports that they receive from veterinarians and consumers. 20, 21 Furthermore, vaccine manufacturers are not currently required to routinely submit adverse event reports to the USDA, although USDA personnel may request adverse event records for review during manufacturer site inspections,
In contrast, manufacturers of veterinary drugs and pesticides are subject to mandatory reporting of adverse events, Veterinary drug manufacturers are required to forward adverse event reports regarding new animal drugs to the FDA Center for Veterinary Medicine (CVM), where they are entered into the FDA CVM Adverse Drug Event Reporting System for monitoring and analysis.54 Label changes that describe reported reactions Lan be required based on adverse event reporting, Summaries of adverse event reports are available on the FDA CVM website (www.fda.gov / cvm/ fda/TOCs/ adetoc.htrnl). Adverse events associated with pesticides used in animals are also subject to mandatory manufacturer reportingY Product registrants are required to submit to the US Environmental Protection Agency a summary of all adverse events received during a 90-day period within 60 days of the end of the collection period,55
Although the USDA CVB does not systematically receive reports of all adverse reactions reported to vaccine manufacturers, it does accept reports directly from practitioners and consumers through its Unit of Inspection and Compliance. This unit also accepts copies of reports involving veterinary biologics received by the United States Pharmacopeia (USP) Veterinary Practitioners' Reporting (VPR) Program. The VPR Program is a voluntary reporting program provided by the USP, in cooperation with the AVMA, as a service to the veterinary community (see page 511 for additional information about the USP VPR Program.)
'Proceedings of the 136th Annual Session of the American Veterinary Medical Association House of Delegates, New Orleans, LA, July 10-14, 1999; P 122.
VACCINE-ASSOCIATED ADVERSE EVENTS 501
The USDA CVB reviews adverse event data and takes action on a case-by-case basis. Unfortunately, the number of practitioners reporting to the USDA, either directly or through the USP, is small when compared with those who report directly to the manufacturer. In a survey of 266 veterinarians, 97% of respondents who reported problems did so directly to the manufacturer, although only 8% reported to the regulatory agency or the USP (USP Survey of Veterinarians' Attitudes and Behaviors Regarding Reporting, unpublished data collected at the North American Veterinary Conference, Orlando, FL, 1998). This reporting trend was supported by USP interviews with industry liaisons, who estimated that 95% of the reports they received from veterinarians were submitted directly to the company, with only 5% of the reports coming in through the USP. The USDA CVB receives approximately 100 reports a year directly from veterinarians and ' consumers,38 but a growing number of reports are submitted to the USDA through the USP VPR Program. During 1999 alone, the USP VPR Program shared 981 biologic reports with the USDA CVB. This number pales, however, when compared with the estimated 10,000 adverse events that are reported annually to animal vaccine manufacturers.38 Consequently, the data available to the USDA CVB for vaccine safety monitoring would increase substantially if manufacturers were required to submit their adverse event information to a centralized surveillance program.
The USDA CVB has a draft regulation, which is in its final stages of program comment and review, for mandatory industry reporting of adverse events related to biologics (Steven A. Karli, Director, CVB Division of Inspection and Compliance, personal communication, December 1999). The CVB plans to publish the proposed rule in the fiscal year 2001.
ADVERSE EVENTS ASSOCIATED WITH VACCINATION
Adverse events associated with vaccination have been well described and are categorized in various ways.3. 7. 35 For purposes of this discussion, adverse events associated with vaccines are classified as systemic or local reactions. Unless otherwise noted, the USP data presented in the following sections reflect information from the 1719 biologic reports submitted to the VPR Program between August 1, 1995 and September 30, 1999.
Systemic Reactions
Nonspecific Systemic Reactions
Clinical signs such as anorexia, lethargy, fever, and soreness beginning a few hours after vaccination and persisting for 24 to 36 hours are
502 MEYER
reported in association with vaccination.34• 39 The causes of these nonspecific reactions may include vaccine orgaQism replication of modified-live vaccines, exposure to endotoxins, adjuvtnt toxicity, or immune system responsiveness.24
• 34 Most reactions are mild, but in some cases, the animals are so severely affected that supportive care may be required. Because vaccines are designed to stimulate an immune response, these kinds of reactions are to be expected and have even been referred to as "normal toxicity" associated with vaccination.34• 35. 40 In a clinical study involving 2288 routinely vaccinated cats and kittens, nonspecific systemic signs were reported at a rate of 1.2%.39 This study also showed that reactions were more likely to occur when multiple vaccines were administered and that cats older than 1 year of age were more likely to experience reactions than younger animals. Most systemic vaccine reactions reported to the USP VPR Program involve nonspecific reactions that are presumed to be the result of the animal's immune response to the vaccine.
Type I Hypersensitivity (Anaphylaxis)
Type I hypersensitivity, or anaphylaxis, is a well-characterized adverse event associated with vaccine administration.3• 4O It is mediated by IgE and predominantly involves lymphoid tissues associated with body surfaces such as the skin, intestines, and lungs. In the classic type I reaction, interaction between the antigen and mast cell or basophilbound IgE causes degranulation, releasing vasoactive amines and initiating production of inflammatory mediators and cytokines.3• 35. 40 The clinical signs associated with anaphylaxis vary with species, although the most severe anaphylactic reaction in all species involves cardiovascular collapse, or anaphylactic shock.
Because anaphylactic reactions can persist for 24 to 48 hours, prolonged monitoring and multiple doses of corticosteroids, antihistamines, or epinephrine may be required. Four reports made to the USP VPR Program involved animals (three dogs, one cat) that were successfully treated for anaphylactic reactions occurring immediately after vaccination but died at home several hours later.
Dogs. For acute anaphylactic reactions in dogs, as reported to the USP VPR Program, clinical signs were most often reported in the skin (51 %; most often manifested as urticaria usually involving the face and ears), in the gastrointestinal tract (40%; vomiting with or without diarrhea), and less frequently, in the respiratory tract (6%; respiratory distress). Fifty-nine reports of anaphylactic shock in dogs were reported to the USP, with 10 involving fatal outcomes. Four of the dogs reported to develop anaphylactic shock were vaccinated by their nonveterinarian owners. Two of these dogs did not survive. Thirty-eight different brands
VACcrNE-ASSOClATED ADVERSE EVENTS 503
were represented, including various combinations of distemper, adenovirus, leptospira, parainfluenza, and parvovirus antigens as well as rabies, coronavirus, Bordetella bronchisepticum, Borrelia burgdorferi, and Giardia lamblia'. No trend suggesting an association between anaphylaxis and a particular brand or type of vaccine was found.
Cats. The clinical signs of anaphylaxis in cats that were reported to the USP VPR Program showed a different pattern than those reported in dogs, with 66% involving the gastrointestinal tract (usually vomiting with or without diarrhea), 22% involving the respiratory tract, and 12% involving the skin. Thirty-nine cases of anaphylactic shock in cats were reported, with nine fatal outcomes. None of these animals had been vaccinated by nonveterinarian owners. Twenty-six different brands of vaccines were listed as suspected products, including rabies, FVRCP with or without a chlamydia fra~tion, FeLV, and feline infectious' peritonitis vaccines. As with dogs, no particular trend suggesting an association between anaphylaxis and a particular brand or type of vaccine was evident. In a published field study tracking adverse reactions in 2288 routinely vaccinated cats and kittens, the reported rate of anaphylaxis (repeated vomiting, diarrhea, or respiratory signs) was 0.26%.39
Ferrets. The USP VPR Program received 83 reports involving 130 ferrets that developed anaphylaxis subsequent to routine vaccination with one brand of canine distemper vaccine (Fervac-D; United Vaccines, Madison, WI) and one brand of rabies vaccine (Imrab; Merial Limited, Athens, GA). These brands are the only vaccines licensed in the United States for use in ferrets. Fifty-four of the 83 reports involved administration of the distemper vaccine alone, although 20 involved concomitant administration of distemper and rabies vaccines. Nine reports involved the rabies vaccine only. These reports of vaccine-associated anaphylaxis account for 99.8% of all reports in the USP VPR Program database involving ferrets.
The reported clinical signs for the ferrets were remarkably similar, with nearly all affected animals developing vomiting and diarrhea, usually hemorrhagic, within minutes of vaccination. Respiratory distress and derma to logic manifestations were also reported but less commonly. In one report, 4 of 5 unrelated ferrets in one household vaccinated at the same time experienced anaphylactic reactions. Similarly, 3 of 4 ferrets in another household suffered anaphylaxis when they were vaccinated as a group. One veterinarian reported six cases of anaphylaxis in the last 26 ferrets vaccinated at his clinic.
Of the 83 cases of anaphylaxis in ferrets, 49 involved cardiovascular collapse. All but 8 of the ferrets . recovered from the reaction with treatment, which usually included corticosteroids, antihistamines, and occasionally epinephrine. Because the information was gathered through a passive surveillance system, it does not prove causality or provide information on the reaction rate. Anaphylaxis is a well-documented
504 MEYER
reaction to vaccination, however, and the uniform description of the nature and tirrllng of the ferrets ' reactions is consistent with vaccineinduced anaphylaxis. More rigorous me~ds such as controlled experimental or clinical studies to estimate the reaction rate are required to better quantify the situation. If the reaction rate is considered unacceptable, reformulation of the vaccine may be considered to reduce the risks asso,ciated with vaccination. Additional label information describing the rate and type of reaction, with treatment recommendations, would prove helpful.
Type /I Hypersensitivity (Cytotoxic Type)
Type IT hypersensitivity involves cell destruction mediated by antibodies.34
•4O Examples of this type of reaction include phagocytic removal
of platelet-bound antigen when opsonized by antibody. This may account for the transient thrombocytopenia found in some studies after modified-live canine distemper virus vaccination of dogs.34 If a vaccine contains normal cell antigens such as erythrocyte antigens, it may induce antierythrocyte antibodies, which can lead to immune-mediated hemolytic anemia.35 No adverse events identified by the author as type II hypersensitivity to a vaccine have been received by the USP VPR Program.
Type 11/ Hypersensitivity (Immune Complex-Mediated)
Type III hypersensitivity involves the formation of antigen-antibody immune complexes. This initiates a number of biologic processes, of which the most significant is the complement cascade.4O An example of type III hypersensitivity in dogs is the condition referred to as blue eye.5
• 34. 40 Blue eye describes the corneal edema associated with antigenantibody complexes in the cornea that can occur after administration of adenovirus-l modified-live virus vaccine or infection with the wild virus. The USP VPR Program has received one report of blue eye in a dog that was vaccinated by its owner with an over-the-counter distemper combination vaccine. Although modem vaccines generally used by veterinarians contain an adenovirus-2 fraction that is not associated with the development of blue eye, vaccines containing adenovirus-l fractions are still available in the United States to consumers as over-the-counter products. The statement "Occasionally, transient corneal opacity may occur following the administration of this product" is required on the label,48 In contrast to the situation in the United States, blue eye is no longer encountered as a vaccine complication in Australia, because only canine adenovirus-2 is used in modified-live canine adenovirus vaccines.3 Corneal edema of undefined cause, which can clinically mimic
VACCINE-AS5CX:IATED ADVERSE EVENrS 505
adenovirus-I-associated blue eye, is reported rarely in various species after vaccination with a variety of different vaccine types (Dave Hustead, DVM; Fort Dodge Laboratories, Overland Park, KS; personal communication, March 2000).
Autoimmune Disease
There is some concern that vaccination may trigger autoimmune disease/' 9 In a controlled retrospective clinical study, a temporal association was made between vaccine administration in dogs and the clinical onset of immune-mediated hemolytic anemia.9 An experimental study evaluated the immune response of puppies routinely vaccinated with commercially available distemper, adenovirus, leptospira, parainfluenza, and parvovirus plus coronavinis and rabies vaccines. IS The results demonstrated that autoantibodies, particularly against fibronectin and laminin, developed after vaccination in these animals. The clinical significance of these findings has not yet been determined. Eight reports of suspected autoimmune hemolytic anemia in dogs developing within 2 to 14 days of vaccination have been submitted to the USP VPR Program.
Immunosuppression
Whether vaccination can cause clinically relevant immunosuppression in animals (and under what circumstances) has not been clearly established. One experimental study showed a decrease in lymphocyte numbers and response to mitogens in dogs vaccinated concomitantly with a Rockborn strain of canine distemper and adenovirus-lor adenovirus-2.33 In the same study, similar changes were not noted when dogs were vaccinated with a Snyder Hill strain of canine distemper and adenovirus-lor adenovirus-2. Other studies involving puppies receiving a series of routine vaccines did not demonstrate lymphopenia or a decrease in lymphocyte blastogenesis test results; however, the strain of canine distemper used was not indicated. IS. 27 It is difficult to draw general conclusions from these studies, because different brands of vaccines can differ in their effects. Furthermore, the clinical significance of decreased lymphocyte counts and decreased lymphocyte blastogenesis is not entirely clear. It has been suggested that these changes may reflect changes in lymphocyte trafficking between blood and lymphatics rather than true immunosuppression.35
In cats, the authors of a published case report suggest that vaccination with an intranasal modified-live panleukopenia virus vaccine may have contributed to immunosuppression in five kittens that resided in the same cattery.12 This immunosuppression may have allowed fatal overwhelming systemic infection with Salmonella typhimurium organ-
506 MEYER
isms, which were harbored in the kittens' gastroint~stinal tracts. No vaccine-associated adverse events described by the authors as immunosuppression have been submitted to tUe USP VPR Program.
Vaccine Virulence
Residual virulence of modified-live vaccines can cause adverse events in vaccinated animalS.3, 34 Causes can be associated with the product or the animals to which it is administered. Modified-live calicivirus and herpes virus vaccines can be associated with sneezing and nasal discharge 4 to 9 days after vaccination, even in healthy cats appropriately vaccinated, simply because of the residual virulence of the attenuated organisms.34,39 Likewise, a polyarthropathy has been associated with calicivirus, with antigens detected in synovial macrophages of cats either vaccinated with a modified-live vaccine or exposed to the field virus. 2,6 Reactions occurring 7 to 21 days after vaccination in cats, characterized by fever, anorexia, and lethargy and occasionally accompanied by joint, spinal, or generalized pain, have been associated with vaccines containing modified-live C. psittaci.39 Increased reaction rates were associated with increasing antigenic content of the chlamydia fraction of the vaccine.
The characteristics of the vaccinated animal can affect the manifestation of residual virulence. For example, attenuated microorganisms that are considered safe to use in healthy adult animals may cause disease when neonates are exposed to them, either directly through vaccination or through organisms shed by a recently vaccinated animaP6 Vaccination of pregnant animals with modified-live vaccines can result in fetal abnormalities such as cerebellar hypoplasia in kittens associated with feline parvovirus virus3, 37 and myocardial disease in puppies associated with canine parvovirus.34 Immunocompromised dogs vaccinated with modified-live canine distemper vaccines have been reported to develop postvaccinal encephalitis.35 Vaccination of an inappropriate species with modified-live vaccines has also been reported to result in virulence,35 Erroneous route of administration of a vaccine can contribute to the development of vaccine induced disease as a result of residual virulence. Parenteral feline herpes and calicivirus vaccines have been reported to cause clinical disease if aerosolized and inhaled by the cat.3, 34, 35
Inadequate inactivation of killed products or reversion to virulence in modified-live products can result in severe vaccine-induced disease. Modified-live rabies vaccines have been reported to produce clinical rabies in vaccinated dogs and cats.u,44 Postvaccinal encephalitis in dogs, believed to be associated with reversion to virulence of vaccine distemper virus, has been reported in the literature.4
VACCINE-ASSOCIATED ADVERSE EVENTS 507
Adverse Events Associated with Product Contamination
Systemic adverse events can be associated with contamination of vacc~es with viruses, fungi, mycoplasma, or bacteria.24 Contamination can occur during vaccine production as well as in the hands of the individual administering the product. Contamination with fungi and bacteria are generally easily seen and detected, because the appearance of the product is changed. Although vaccine contamination has been reported rarely, it can be associated with serious outcomes. The most dramatic cases of contamination are often seen with viruses. The contamination of a canine modified-live vaccine with bluetongue virus was associated with death and abortion in pregnant dogs. 1. 45
In an effort to minimize the release of contaminated products, each batch of animal vaccines is tested for purity by the manufacturer, and the test results are reviewed by the USDA before batch release.51• 52
Testing for extraneous bacteria, mycoplasma, and fungi is included. The USDA validates manufacturer-generated test results through check testing on selected serials. In 1999, the USDA CVB took regulatory action four times to address issues involving product sterility (Steven A. Karli, Director, CVB Division of Inspection and Compliance, personal communication, March 1999). Nevertheless, postmarketing surveillance remains an important tool in identifying potentially contaminated products that manage to enter the marketplace. Four cases of suspected vaccine contamination involving four different products have been submitted to the USP VPR Program.
Lack of Efficacy
Lack of efficacy is considered to be an adverse event by the Pharmaco vigilance Working Group of the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products and can be monitored through postmarketing surveillance systems. Because no vaccine can claim 100% efficacy, sporadic reports of a vaccine's failure to protect are likely to be encountered. When numerous reports of efficacy concerns regarding the same product are detected through a surveillance system, investigation of the situation may be warranted. The USP VPR Program has received 13 reports of suspected lack of efficacy for veterinary vaccines. Of these 13 reports, 8 involved distemper outbreaks in mink herds that were vaccinated per label instruction. Two reports involved clinical distemper in dogs despite vaccination with a canine distemper combination vaccine, and 1 report involved a dog that was not protected from clinical Lyme disease after vaccination against B. burgdorferi. The final 2 reports involved a cat vaccinated with an FVRCP vaccine that subsequently developed panleu-
508 MEYER
kopenia and a horse that became infected with rabies, despif~ vaccination.
Local Vaccine Reactions
Pain
It is not uncommon for animals to experience pain during or subsequent to vaccination. Immediate pain can be caused by vaccine administration' near a nerve, the vaccine's osmolality or pH, or the temperature of the vaccine when it is administered.34 Localized pain after vaccination is often related to the body's inflammatory response at the site of vaccine administration. Reports of lameness in cats vaccinated in the hind limbs, in accordance with the VAFSTF guidelines, have been received by the USP VPR Program. Many cats described in the reports experienced severe pain and became completely nonambulatory, particularly when vaccines were administered in both hind limbs on the same day. Lameness has been reported to persist for days to weeks after vaccination.
Benign Swelling, Nodules, and Masses
Immediate swelling at the injection site can be caused by the actual volume of the vaccine that is deposited subcutaneously or intramuscularly in small animals.34 Later, swelling can be related to influx of interstitial fluid and inflammatory cells. A local reaction of some type is an expected resl,llt of immunologically stimulating the vaccinated animal and is not considered an adverse event by some authors.35• 4O
Palpable nodules or masses often occur at vaccination sites. Causes can be related to hypersensitivity reactions or general inflammatory reactions. Local hypersensitivity reactions can be stimulated by the antigens, diluent, adjuvants, contamination, or endotoxins. Type I (immediate), type III (immune-complex), and type IV (delayed) hypersensitivity reactions can be involved in local reactions.24, 34, 35 Granulomas can occur locally and are frequently associated with adjuvant products, particularly depot adjuvants.3, 34 Granulomas are often sterile and painless, and they resolve over weeks to months. Focal necrotizing granulomatous panniculitis associated with rabies vaccination has been described in cats and dogs. 16
It is difficult to clinically differentiate benign vaccine site reactions based on causation, particularly if histopathologic testing is not performed on affected tissues. Consequently, the USP VPR Program data for all local swelling and benign nodules and masses occurring at injection sites are grouped together. Ninety-nine such reports involving dogs
VACCINE-ASSOCIATED ADVERSE EVENTS 509
were submitted to USP VPR Program. The products most frequently associated with the local reactions were either rabies vaccines or distemper combination vaccines. For cats, USP data include 110 reports of benign lumps developing at the site of vaccination. Rabies vaccines were most frequently associated with non-neoplastic masses in cats, accounting for 72% of all products reported. This trend is supported in a small experimental trial, where nine cats were vaccinated with rabies, FVRCP, and FeLV vaccines.36 All cats developed a palpable inflammatory lesion at the site of rabies vaccination. In contrast, a palpable lesion was found at the FVRCP vaccination site in only one cat, and FeLV vaccination did not result in any palpable lesions.
Vaccine-Associated Feline Sarcomas
The VAFSTF (www.avrna.org/ vafstf) was formed in response to the increased incidence of soft tissue sarcomas occurring at vaccine sites. The goals of the VAFSTF are to facilitate investigation of the epidemiology, etiopathogenesis, treatment, and prevention of these malignancies as well as to disseminate information to veterinarians and the cat-owning public. The VAFSTF has formally recommended that practitioners report VAFSs to the manufacturer and the USP VPR Program. The USP has collaborated in VAFSTF-funded epidemiologic research to define risk factors for VAFS development and has supplied data that were reviewed during the development of VAFSTF guidelines for the diagnosis and management of VAFSs. The USP provides the only centralized national repository of VAFS reports. A total of 506 reports of VAFSs resided in the USP VPR Program database as of December 31, 1999. A detailed discussion of vaccine-associated sarcomas is provided elsewhere in this issue.
Vaccine Site Alopecia
Localized alopecia after vaccination with inactivated rabies vaccine has been reported and is believed to be the result of vasculitis caused by antigen-antibody complexing.34
•46 In one published report, 10 of 13
affected dogs were Poodles.46 The USP VPR Program has received six reports of small-breed dogs (Chihuahua, Pomeranian, Bichon Frise, Maltese mixed breed, Shih Tzu, and Papillon) that developed thin skin and hair loss at the site of vaccination. Five of the reports involved a rabies or rabies combination vaccine, although one report involved a distemper combination vaccine.
510 MEYER
" Abscesses
Vaccine site abscesses can occur as a result of bacterial or fungal contamination of the product or conta1'nination introduced at the time of administration.34 Only four reports of abscesses after vaccinations in dogs or cats have been reported to the USP VPR Program. Two reports described cats that developed abscesses at the site of Microsporum canis vaccine administration. Two reports involved dogs with reported vaccine site abscesses. One abscess developed subsequent to rabies vaccination, although the other developed after the administration of a distemper combination vaccine.
Local Reactions Associated with Intranasal Vaccines
An intranasal FVRCP vaccine that is applied to the nostrils and eyes of the cat has been available since the late 1970s but has recently increased in popularity as a result of efforts to minimize injectable vaccine use. Over a 3-year period, the USP VPR Program received 72 reports from practitioners regarding intranasal FVRCP vaccines. Reported local reactions include nasal ulcers, oral ulcers, and conjunctivitis. The causes of these adverse events have not been determined.
OPTIONS FOR REPORTING
Postmarketing surveillance plays a vital role in identifying and monitoring potential risks associated with vaccine administration as well as with product efficacy. The depth of the surveillance system's database, however, is dependent on active reporting by practicing veterinarians. Observations on product performance in the clinical setting are valuable but must be shared with the manufacturer, the USDA, and the veterinary community to have maximal impact on product safety. Veterinarians wishing to report adverse events or quality concerns associated with vaccines may contact any or all of the following: the product manufacturer/labeler, the USDA CVB, or the USP VPR Program. The differences among these reporting options are outlined below.
Product Manufacturer
When veterinarians do report adverse events, they usually report them directly to the manufacturer. It is particularly important for veterinarians to contact the manufacturer in cases of death or serious injury; at that time, the manufacturer may provide assistance regarding diag-
VACCINE-ASSOCIATED ADVERSE EVENTS 511
nostics and therapy. Additionally, the manufacturer may require detailed information regarding the incident. The telephone number for the manufacturer's technical support division is often available on the package labeling, in veterinary reference texts, in the telephone directory, or through the Internet. The USP VPR Program (telephone: 800-487-7776) can provide company contact information to veterinarians upon request.
Vaccine manufacturers are not required to record postvaccinal adverse event reports that they receive from veterinarians.22 Although reports recorded by the manufacturer can be requested for review during USDA facility inspections, which can occur every 18 to 24 months, manufacturers are not required to systematically forward these reports to the USDA eVB at regular intervals. Information submitted directly to manufacturers is not entered into the USP's electronic database of veterinary reports nor is it shared with the AVMA.
United States Department of Agriculture Center for Veterinary Biologics
Veterinarians may report adverse events to the USDA eVB by telephone or by completing a paper reporting form (telephone: 800-752-6255; wwww.aphis.usda.gov/vs/cvb/ic/index.htm). Because the USDA eVB does not currently collect adverse event reports from industry, all information is submitted directly to the USDA by consumers and veterinarians or through the USP VPR Program. Adverse event report information received by the USDA is not published. Information submitted directly to the USDA is not entered into the USP VPR Program database of veterinary reports nor is it routinely shared with the AVMA.
United States Pharmacopeia Veterinary Practitioners' Reporting Program
The USP is a private, not-for-profit organization dedicated to the public health. The USP VPR Program, presented in cooperation with the AVMA, accepts reports on any type of problem experienced with any product, including vaccines, drugs, and pesticides, used in any species of animal. Reports are accepted by telephone, fax, mail, or through the Internet (telephone: 800-487-7776 / 800-4USP-PRN; www.usp.org). The USP forwards information from each report to the manufacturer Ilabeler of the product, the regulatory agency responsible for regulating that particular type of product, and the AVMA. The information is also entered into the USP's national repository of veterinary reports.
Information received through the USP VPR Program is made avail-
512 MEYER " ,
~1irI
able to the veterinary community in a variety of ways. If requested, the VPR Program can provide veterinarians ... submitting a report with general information regarding similar reports in the VPR Program database. More detailed printed information can ~e obtained by individuals or organizations pursuant to the USP's Document Disclosure Policy. Information from the database is also presented in scientific articles such as the Journal of the American Veterinary Medicine Association's feature "USP-Reporting Back to You"29-31 and lectures at veterinary continuing education meetings. Information from the USP's database has been reviewed by the VAFSTF in the development of its guidelines and has been used to identify issues for discussion by the AVMA's Committee on Biologic and Therapeutic Agents.
CONCLUSIONS
Although vaccination plays a vital role in maintaining animal health, there are risks associated with this medical procedure. Veterinarians are beginning to re-examine dogmatic vaccine protocols and consider risks and benefits before making vaccine recommendations. Risks should be effectively communicated to pet owners so that informed consent can be obtained and the animal can be properly monitored and promptly treated for vaccine-associated adverse events.
Unfortunately, veterinarians are hindered in this important task because of a lack of evidence-based information regarding vaccine risks. Prelicensing safety testing of vaccines involves a relatively small number of animals, and the results are not routinely required on product labeling. Postmarketing surveillance of vaccine safety is carried out by the USDA CVB; however, the data available for analysis are limited because manufacturers are not currently required to systematically forward adverse event information that is reported to them by veterinarians. Veterinarians' clinical observations of product performance are important; however, unless they are shared, they are of reduced value. By reporting their pertinent observations, veterinarians can take an active role in postmarketing surveillance of vaccine safety. Using a system that shares data with all involved parties and maintains the information in a centralized database, where it can be easily accessed for appropriate analysis, benefits the veterinary profession and the patients it serves.
References
1. Akita GY, Ianconescu M, MacLachlan NJ, et al: Bluetongue disease in dogs associated with contaminated vaccine [letter]. Vet Rec 134:283-284, 1994
VACCINE-ASSOCIATED ADVERSE EVENTS 513
2. Bennett D, Gaskell RM, Mills A, et al: Detection of feline calicivirus antigens in the joints of infected cats. Vet Rec 124:329-332, 1989
3. Brooks R: Adverse reactions to canine and feline vaccines. Aust Vet J 68:342-344, 1991 4. Cornwell HJ, Thompson H, McCandlish IA, et al: Encephalitis in dogs associated with
a batch of canine distemper (Rockborn) vaccine. Vet Rec 122:54-59, 1988 5. Curtis R, Barnett KC: The "blue eye" phenomenon. Vet Rec 112:347-353, 1983 6. Dawson S, McArdle F, Bennett D, et al: Investigation of vaccine reactions and break
downs after feline calicivirus vaccinations. Vet Rec 132:346-350, 1993 7. Dodds WJ: More bumps on the vaccine road. Adv Vet Med 41:7l5-732, 1999 8. Doddy FD, Glickman LT, Glickman NW, et al: Feline fibrosarcomas at vaccination sites
and non-vaccination sites. J Comp Pathol 114:165-174, 1996 9. Duval D, Giger U: Vaccine-associated immune-mediated hemolytic anemia in the dog.
J Vet Intern Med 10:290-295, 1996 10. Elston T, Rodan H, Flemming D, et al: 1998 Report of the American Association of
Feline Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vaccines. JAVMA 212:227-241, 1998
11. Esh ]B, Cunningham JG, Wiktor TJ: Vaccine-induced rabies in four cats. JAVMA 180:1336-1339,1982
12. Foley jE, Orgad U, Hirsch DC, et al: Outbreak of fatal salmonellosis in cats following use of a high-titer modified-live panleukopenia virus vaccine. JAVMA 214:67-70, 1999
13. Glickman LT: Weighing . the risks and benefits of vaccination. Adv Vet Med 41:701-7l3,1999
14. Hendrick MJ: Feline vaccine-associated sarcomas. Cancer Invest 17:273-277, 1999 15. Hendrick MJ, Goldschmidt MH: Do injection site reactions induce fibrosarcomas in
cats? [letter) JAVMA 199:968, 1991 16. Hendrick MJ' Dunagan CA: Focal necrotizing granulomatous panniculitis associated
with subcutaneous injection of rabies vaccine in cats and dogs: 10 cases (198s--B9). JAVMA 198:304-305, 1991
17. Hendrick MJ, Shofer FS, Goldschmidt MH, et al: Comparison of fibrosarcomas that developed at vaccination sites and at nonvaccination sites in cats: 239 cases (1991-92). JAVMA 205:1425-1429, 1994
. 18. Hogenesch H, Azcona-Olivera J, Scott-Moncrieff C, et al: Vaccine-induced autoimmunity in the dog. Adv Vet Med 41:733-747, 1999
19. Horzinek M: Vaccination: A philosophical view. Adv Vet Med 41:1-7, 1999 20. Hustead DR: Why do vaccine labels say the funny things they do? Adv Vet Med
41:633-641, 1999 21. Hustead DR, Carpenter T, Sawyer DC, et al: Vaccination issues of concern to prac
titioners. JAVMA 214:1000-1002, 1999 22. Kass PH, Barnes WG, Jr, Spangler WI, et al: Epidemiologic evidence for a causal
relation between vaccination and fibrosarcoma tumorigenesis in cats. JAVMA 203:396-405,1993
23. Lester S, Clemett T, Burt A: Vaccine site-associated sarcomas in cats: Clinical experience and a laboratory review (1982-1993). J Am Anim Hosp Assoc 32:91-95, 1996
24. Martinod S: Adverse effects of vaccination. In Pastoret P-P (ed): Veterinary Vaccinology. New York, Elsevier, 1997, pp 574-580
25. Martinod S: Vaccination practices in veterinary medicine: Standardization versus tailored to needs? Adv Vet Med 41:657-{i68, 1999
26. McCandlish IA, Cornwell HJ, Thompson H, et al: Distemper encephalitis in pups after vaccination of the darn. Vet Rec 130:27-30, 1992
27. McMillen GL, Briggs DJ, McVey DS, et al: Vaccination of racing greyhounds: Effects on humoral and cellular immunity. Vet Imrnunol ImrnunopathoI49:101-13, 1995
28. Meltzer Ml, Rupprecht CEo A review of the economics of the prevention and control of rabies. Part 1: Global impact and rabies in humans. Pharrnacoeconornics 14:365-383, 1998
29. Meyer EK: Adverse events associated with albendazole and other products used for treatment of giardiasis in dogs. JAVMA 213:44-46, 1998
30. Meyer EK: Rare, idiosyncratic reaction to acepromazine in dogs. JAVMA 210:1114-1115, 1997
514 MEYER
31. Meyer EK: Toxicosis in cats erroneously treated with 45 to 65% p~rmethrin products. JAVMA 215:198--203, 1999
32. Niu MT, Salive ME, Ellenberg SS: Post-marketing surveillance for adverse events after vaccination: The National Vaccine Adve.Lse Event Reporting System (VAERS). A MEDWATCH Continuing Education Article. Bethesda, National lnstitutes of Health / Foundation for Advanced Education in Science (NlH/ FAES), and Rockville, US Food and Drug Administration (FDA), 1998
33. Phillips T, Jensen JL, Rubino M], et al: Effects of vaccination on the canine immune system. Can J Vet Res 53:154-160, 1989
34. Povey RC, Carman PS: Risks of vaccination. In Pastoret P-P (ed): Veterinary Vaccinology. New York, Elsevier, 1997, pp 546-551
35. Roth JA: Mechanistic bases for adverse vaccine reactions and vaccine failures . Adv Vet Med 41:681-700, 1999
36. Schultze AE, Frank LA, Hahn KA: Repeated physical and cytologic characterizations of subcutaneous postvaccinal reactions in cat. Am J Vet Res 58:719-724, 1997
37. Sharp NJ, Davis BI, Guy JS, et al: Hydranencephaly and cerebellar hypoplasia in two kittens attributed to intrauterine p.arvovirus infection. J Comp PathoI121:39-53, 1999
38. Siev 0: An introduction to analytical methods for the postmarketing surveillance of veterinary vaccines. Adv Vet Med 41:749-775, 1999
39. Starr RM: Reaction rate in cats vaccinated with a new controlled-titer feline panleukopen.ia-rhinotracheitis-calicivirus-Chlamydia psittaci vaccine. Cornell Vet 83:311-323, 1993
40. Tlzard IR: Veterinary Immunology: An Introduction, ed 5. Philadelphia, WB Saunders, 1996
41. United States Department of Agriculture: USDA Veterinary Services Memorandum No 800.200, Veterinary Biologics General Licensing Considerations, Subject: Efficacy Studies. May 12, 1995
42. United States Department of Agriculture: USDA Veterinary Services Memorandum No 800.50, Basic License Requirements for Applicants. September 7, 1999
43. USFDA VAERS: How are VAERS reports analyzed? VAERS Frequently Asked Questions. [FDA VAERS Web site] Available at: http: //www.fda.gov / cber/ vaers/ faq.htm. Accessed September 16, 1999
44. Whetstone CA, Bunn TO, Emmons RW, et al: Use of monoclonal antibodies to confirm vaccine-induced rabies in ten dogs, two cats, and one fox. JAVMA 185:285-288, 1984
45. Wilbur LA, Evermann ]F, Levings RL, et al: Abortion and death in pregnant bitches associated with the canine vaccine contaminated with bluetongue virus. JAVMA 204:1762-1765, 1994
46. Wilcock BP, Yager J: Focal cutaneous vasculitis and alopecia at sites of rabies vaccina-tion in dogs. JAVMA 88:1174-1177, 1986
47. 7 USC Subsection 136-136y. 48. 9 Code of Federal Regulations, Part 112.7. 49. 9 Code of Federal Regulations, Part 113.201. 50. 9 Code of Federal Regulations, Part 113.202. 51. 9 Code of Federal Regulations, Part 113.5. 52. 9 Code of Federal Regulations, Part 113.6. 53. 9 Code of Federal Regulations, Part 113.7l. 54. 21 Code of Federal Regulations, Part 510.300, 510.301, and 510.302. 55. 40 Code of Federal Regulations, Part 159.184(d}.
Address reprint requests to
United States Pharmacopeia 12601 Twinbrook Parkway
Rockville, MD 20852
Attn: David Nash, DVM
VACCINES AND VACCINATIONS 0195-5616/ 01 $15.00 + .00
THE POTENTIAL FOR LIABILITY IN THE USE AND MISUSE OF
VETERINARY VACCINES
Duane Flemming, DVM, JD
Historically, most veterinarians have not paid much attention to the regulations regarding vaccines. Familiarity with the vaccine laws was not,really necessary, because by relying on the label instructions, veterinarians could, in most cases, shift the focus of any wrongdoing from themselves to the vaccine manufacturers. As it was fairly difficult to get reliable expert testimony against veterinarians, and because most of the vaccine manufacturers had fairly deep pockets, there was not much opposition to this strategy or much reason to change it. Recent developments in the law and in the practice of veterinary medicine have forced veterinarians to take a new look at their use of vaccines and to reevaluate their liability in using them.
UNITED STATES DEPARTMENT OF AGRICULTURE OR FOOD AND DRUG ADMINISTRATION
Many veterinarians still believe that their use of animal vaccines is highly regulated by the United States government through the Food and Drug Administration. They could not be more wrong. Through a combination of court decisions, regulatory changes, and interagency agreements, the government has effectively established that the Virus-
From the Contra Costa Animal Eye Clinic, Pleasant Hill, California
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE
VOLUME 31 ' NUMBER 3 · MAY 2001 515
516 FLEMMING
Serum-Toxin Act (VSTA) administered by the US Department of Agriculture and not the Food, Drug, and CosIIl£tic Act administered by the US Food and Drug Administration has iuwdiction over licensed animal "biologics" (vaccines) in the United States.a• b Because VSTA contains no reference to the use of animal biologics after their sale to the end user, federal control effectively ends with their sale.< Although there are usage guidelines within specific state or federal eradication/control programs, and perhaps as isolated rules within some state practice acts, there are no overarching federal regulations concerning the use of licensed animal
'The Code of Federal Regulations (9 CFR Part 101.2 (w)) defines biologics as "all viruses. serums, toxins, and analogous products of natural or synthetic origin, such as diagnostics, antitoxins, vaccines, live microorganisms, killed microorganisms, and the antigenic or immunizing components of microorganisms intended for use in the diagnosis, treatment, or prevention of diseases of animals."
bBefore 1900, there was no effective regulation of the production of drugs or vaccines in the United State. In 1906, the Federal Food and Drug Act (Chapter 3915, 34 Stat 768) prohibited the interstate shipment of adulterated food, drinks, and drugs. This act was administered by the Department of Chemistry, a division of the USDA. This did not provide adequate protection, so in 1913, the VirusSerum-Toxin Act (VSTA) (21 USC Part 151-158) was created to give the government regulatory control over the manufacture of biologics intended for interstate shipment. This act was administered by the Bureau of Animal Industry. In 1927, food and drug regulation was shifted from the USDA's Bureau of Chemistry to a new USDA subdivision, the Food, Drug, and Insecticide Administration, later to become the Food and Drug Administration (FDA)(44 Stat 515 and 44 Stat 1002). In 1938, the Federal Food, Drug. and Cosmetic Act (FOCA) (21 USC 321) extended federal regulatory control to cover any "article intended to diagnose, mitigate, treat or prevent disease in . . . animals" or "articles (other than food) intended to affect the structure or function of the body of ... animals." In 1940, the FDA was transferred from the USDA to a new agency, the Federal Security Agency, which, in tum, became a part of the Department of Health, Education, and Welfare. This series of transfers resulted in federal regulatory control of animal biolOgiCS by two separate federal agencies: the FDA and the USDA. In 1968, Congress attempted to direct supervision of animal biologics back to the USDA by amending the FOCA (21 USC Part 392[b]) to state that "Nothing in this chapter shall be construed as in any way affecting, modifying, repealing. or superseding the virus, serum, toxin, and analogous product provisiOns, applicable to domestic animals in the Act of Congress approved March 4, 1913 (VSTA)." In 1978 and 1980, in two lawsuits (Animal Health Institute vs USDA, 487 F supp 376, and Grand Laboratories vs Harris, 488 F supp 618), the courts re-established a dichotomy of jurisdiction by holding that the FDA had jurisdiction over the intrastate and the USDA over the interstate manufacture and sale of animal biologiCS. In 1982, the USDA and FDA attempted to resolve the issue in a memorandum of understanding (47 Fed Reg 28458{1982]). This agreement specified that the FDA would regulate animal biolOgiCS only where the VsTA did not apply or where the VsTA offered no remedy at law. This, in effect, limited the FDA to regulatory control only over unlicensed biologics entered into interstate commerce. Finally, in 1991, another attempt was made to solve the jurisdictional dispute by modifying the federal regulations (21 CFR 510.4) to provide that "an animal drug produced and distributed in full conformance with the animal virus, serum, and toxin law of March 14,1913 (VsTAj and any regulation issued thereunder shall not be deemed to be subject to section 512 of the Federal Food, Drug. and Cosmetic Act." This regulation was upheld by the Eighth Circuit Court of Appeals (US vs Pro-A Incorporated, 968 F2d 681) thus leaving as current law that licensed "animal viruses, serums, toxins, and analogous products of natural or synthetic origin, such as diagnostics, antitoxins, vaccines, live microorganisms, killed microorganisms and the antigenic or immunizing components of microorganisms intended for use in diagnosis, treatment, or prevention of diseases of animals" are subject to VSTA and thereby USDA regulation and that any regulations generated under the FOCA do not apply to animal vaccines.
'The Virus, Serum, and Toxin Act of 1913 (21 USC Part 151-158) in part provides that " it shall be unlawful for any person, firm, or corporation to prepare, sell, barter, or exchange in any place under the jurisdiction of the United States, or to ship or deliver for shipment from one State or Territory or the District of Columbia, any worthless, contaminated, dangerous, or harmful virus, serum, toxin, or analogous product intended for use in the treatment of domestic animals, and that no person, firm or corporation shall prepare, sell, barter, exchange, or ship as aforesaid any virus, serum, toxin, or analogous product manufactured within the United States and intended for use in the treatment of domestic animals, unless and until the said virus, serum, toxin, or analogous product shall have been prepared, under, and in compliance with, regulations prescribed by the Secretary of Agricuiture, at an establishment holding an unsuspended and unrevoked license issued by the Secretary of Agriculture as hereinafter authorized."
THE POTENTIAL FOR LLABfLITY IN THE USE AND MISUSE OF VACClNES 517
vaccines in the United States. These laws and regulations, in effect, have created a void in which a veterinarian's use of an animal vaccine is largely uncontrolled.
FEDERAL PREEMPTION
To complicate matters further for the veterinarian, in 1996, the United States Supreme Court refused to review the Seventh Circuit Court's decision in Lynbrook Farms versus SmithKline Beecham Corporation.d In that decision, the Seventh Circuit Court upheld the contention that VSTA preempted all state court tort remedies, which would have the effect of imposing requirements that were different from or in addition to those imposed by the US Department of Agriculture regarding the safety, efficacy, potency, or purity of a product. This action, in effect, eliminated vaccine manufacturers as defendants in all vaccine tort cases not alleging that the vaccine was improperly manufactured. Allegations regarding the use or misuse of the vaccine product after sale were not preempted." This ruling left the veterinarian pretty much alone and vulnerable to a client upset by any bad outcome perceived by the client or his or her attorney as vaccine related.
As a result, new claims not related to manufacturing defects are now likely to be centered around malpractice and the failure of the veterinarian to adhere to the prevailing standards of practice in maintaining, selecting, or administering the vaccines as well as around allegations that the vaccines were administered without obtaining the proper informed consent. In addition, breach of warranty is also likely to become a more frequently litigated issue.
STANDARD OF CARE
If something goes terribly wrong, and the quality of care provided by a veterinarian is called into question in a court of law, the practitioner's actions are compared with the prevailing standard of care. Standard of care is a legal term that may be simply defined as the care a practitioner of similar knowledge, experience, and training would deliver under the same or similar circumstances. Stated another way, would another veterinarian have done what I did in the same circumstances?
d79 F3d 620. <The issue of preemption has been well covered in American Veterinary Medical Law
Association Proceedings. See: Veterinarian and Vaccine Manufacturer Liability After SmithKline: Implications for Both Sectors (A Panel Presentation), 1997 and Federal Preemption of Vaccine Product Liability Litigation-Rationale and Result, 1998.
518 FLEMMING
The label instructions provide a fairly clear standard of care for the storage and handling of most vaccines. To preclude liability, the veterinarian would only have to show <that he or she maintained the vaccine according to those label instructions.
The prevailing standard of care for the use of, or even the basic need for, a particular vaccine is, however, in a state of flux. This is exemplified by comments from an increasing number of veterinary virologists, veterinary colleges, professional organizations, and practitioners regarding the revaccination interval for certain vaccine antigens.3. 5• 7 By themselves, a few published articles or stated opinions of recognized experts do not define a new standard of care; rather, it is their adoption and use by a substantial portion of the veterinary community that is significant. Vigorous debate within the profession is undoubtedly going to result in a new standard of care in the selection and use of vaccines.
Although many veterinarians may resist and delay the adoption of new protocols because of financial considerations or more simply because "we have always done it this way," they should consider that adherence to the old ways as the established standard of care may, in the light of new knowledge, not protect them, because " ... conformity to custom is not in itself an exercise of care as a matter of law."13
The veterinarian's exposure to liability starts with the issue of whether there is a need to vaccinate at all and, if so, the choice of the agent to vaccinate against. To which infectious diseases is this animal likely to be exposed? Is this cat, for example, going to be exposed to feline leukemia virus or herpes? How about chlamydia or coronavirus? What are the short- and long-term risks in vaccinating or not vaccinating this animal for a particular disease? Was there a risk-benefit analysis, and what was its outcome? Was it reasonable to vaccinate this animal for this disease? In some situations, the answers are simple. In others, they are complex and fraught with potential error. In Caran Versus the United States, the case centered around the standard of care. 14 The government was found liable for injuries to a 4-month-old child resulting from the inoculation of an adult dose of typhoid inoculum. The practice of using adult doses in children was outside the standard practice unless a taken history revealed that the child was going to travel in a typhoidendemic country. In this case, negligence was proved, because no history was taken and the doctor could not establish that the child was even going to be exposed to typhoid.
INFORMED CONSENT
A large part of the standard of care involves the issue of informed consent. Some veterinarians seem to believe that their clients are incapable of understanding complex medical issues and that it is the veterinari-
mE POTENTIAL FOR LIABILITY IN 1HE USE AND MISUSE OF VACCINES 519
an's responsibility to decide for them the appropriate medical careY By not obtaining truly informed consent, these veterinarians are simply inviting legal action. In fact, courts have long held that a physician cannot, without first obtaining their consent, inoculate or vaccinate persons, even those exposed to the risk and dangers of a contagious disease, to protect them from contracting such a disease.4
, 9 This ruling also applies to veterinarians, who should not inoculate animals, even those with known exposure to disease, without obtaining the owner 's informed consent.
In Harries versus the United States, the issue was, in part, informed consent.1S The plaintiff developed encephalitis after a smallpox vaccination. Liability was predicated on the asserted failure of the physician to advise the plaintiff that the vaccination could cause encephalitis. Judgment was for the defendant but only because the plaintiff failed to prove that the smallpox vaccination was the proximate cause of the encephalitis. Veterinarians should advise their clients of any known and significant potential adverse consequence that could result from the proposed vaccination.
In Hitchcock versus the United States, another case dealing with informed consent, the government was found negligent, in part, for not disclosing that the vaccination was not required or recommended, that the vaccination had limited and undetermined benefits, and that the possibility of injury through allergic reaction existed.16 The factors discussed in that case all apply, at one time or another and in one form or another, to the veterinary use of vaccines.
The current informed consent standard is the "reasonable patient standard." Under this standard, the scope of disclosure is measured not by the physician's standards but by the patient's needs and whether the information is material to the patient's decision.8
As a broad general statement, material information is information that a reasonable person in the client's position would use to make an intelligent decision whether to accept or reject a recommended medical procedure. Under this standard, the veterinarian should disclose the nature of the condition and the proposed treatment plus any reasonable dangers in the veterinarian's knowledge that are incident to or may result from the treatment. When a procedure inherently involves a known risk of death or serious harm to the animal, it is the veterinarian's duty to disclose to the client the possibility of such an outcome and to explain in lay terms any significant potential complications that might occur.
For any consent to be valid, it must be based on a clear understanding of the information presented. Veterinarians must remember that to be understood, the information must be effectively communicated. Detailed technical expositions of fact are not legally required and usually are not
520 FLENflMmNG
desired. Most clients are overwhelmed with masses of unintelligible technical data that they are ill equipped" to comprehend or use in reaching a health care decision. Conversely, a blunt and insensitive recitation of the facts can also impede the process ~f client understanding:
In providing the necessary information, the veterinarian should take into account the experience, education, and linguistic abilities of the client. First-time pet owners may require more information from the veterinarian to make a valid decision about their animal than breeders with much greater experience. A foreign language-speaking client may not understand the risks involved in vaccination when the necessary information is provided in English. Similarly, a person with limited education may not comprehend technical information suitable for a college graduate with advanced training in science or medicine. Although the veterinarian is not expected to do a complete background check on his clients, he or she is expected to use his or her senses to evaluate a client and to tailor the presentation to that individual's particular needs.
Under the informed consent doctrine, the veterinarian is not expected to be the client's financial advisor, nor is it the veterinarian's duty to save the client money. The veterinarian is expected to provide information to th~ client regarding all the reasonable alternatives available for vaccination. It is up to the client and not the veterinarian to approve or disapprove the expenditure.
Once the veterinarian has provided the appropriate information and effectively communicated it to the client, he or she should, as a separate act, specifically ask for and obtain the client's consent to the proposed procedure. In fact, the failure to specifically obtain the client's informed consent after appropriate disclosure could itself be construed as negligence and result in legal liability for veterinary malpractice. The consent does not necessarily have to be in writing, although that is the best way to legally establish the granting of informed consent.
It is unwise for any veterinarian to pursue vaccination or any course of treatment that is hazardous or capable of producing a harmful effect without first securing the client's specific statement of understanding and consent.
WARRANTY
In seeking compensation for their losses, unhappy clients may also look to issues of warranty and the breach thereof. In a 1996 California case, Shelby/Fullerton versus Grand Labs/Veterinary Pharmaceuticals / Thomas Worthington/Chino Veterinary Services, the jury found for the plaintiffs in the amount of $1,541,948 for losses resulting from the negli-
THE POTENTIAL FOR LIABILITY IN THE USE AND MlSUSE OF VACCINES 521
gent use of a vaccine.17 The decision was based, in part, on a warranty from the veterinarian that the vaccine was safe for use in calves under 3 months of age. Veterinarians should remember that few, if any, vaccines are 100% free of adverse effects or are 100% certain to prevent the indicated disease. In this context, the veterinarian's words to the client are particularly important. If a veterinarian guarantees that a particular vaccine product is absolutely safe or that it is going to prevent disease and it either is not or does not, he or she may be liable not for malpractice but for breach of warranty. Important to the veterinarian, this cause of action may not be covered by veterinary malpractice insurance.
VETERINARIAN'S CHOICE
Assuming that the veterinarian and the client have made a proper, informed, and joint judgment about the need for vaccination against a particular disease, the veterinarian alone must still choose the proper vaccine to use. With the myriad of vaccine types currently available and soon to be available, a veterinarian has a plethora of choices as to type: live virus; modified-live, attenuated, or killed virus; and monovalent or multivalent vaccine. Did a wrong choice injure the animal directly, or did it result in failure to provide the promised immunity? In Anderson versus Blackfoot Livestock Commission Company, selection of the proper vehicle for conveying immunity was exactly the issue.ls In that case, the plaintiff sued a veterinarian and others for, in part, the veterinarian's negligence in the inoculation and vaccination of swine. The plaintiff purchased hogs that had been represented as vaccinated for hog cholera by the defendant veterinarian from the Blackfoot Commission Company. Shortly after the purchase and transportation to his farm, 241 hogs died from what was determined later to be hog cholera. The State of Idaho testified that it required the use of serum in hog sales yards because serum provided immediate protection against hog cholera and sales yards are "exposed places." The defendant veterinarian used modified-live virus alone. Testimony was taken about the type of immunity attained with serum verus that obtained with modified-live virus. Judgment was, as relates to this issue, against the veterinarian.
Having selected the appropriate vaccine and presumably cared for it in the proper manner, the veterinarian must select the proper route of administration. There are now a variety of routes available: nasal, ocular, subcutaneous, intramuscular, and intravenous. What is the effect of choosing the wrong route? Did the veterinarian's choice injure the animal or adversely affect the desired immunity? In Philips versus Leuth, the plaintiff appealed from a directed verdict for the defendant veterinarian.19 The veterinarian was charged with negligence in the vaccination
522 FLEMMING
of hogs. This time the allegation was based, in part, on an improper method of performing the vaccination. At trial, evidence was entered as to the usual location for vaccination ~d the proper sterilization of needles. The plaintiff contended that the defendant veterinarian did not place the hogs in the proper position, that he did not use proper restraint for the insertion of needles, and that the injections were not made into the proper parts of the body. Not surprisingly, the "expert" testifying in this case was a competing veterinary surgeon. ' The Court denied the appeal and noted, among other things, that the plaintiffs case had a lot of "dead wood" in it, including interrogatories relating to whether the hogs were standing or sitting when vaccinated and how many there were of each. Regardless of the outcome of this particular case, it is illustrative of the kinds of claims veterinarians have faced and may face again. Certainly, questions are currently being asked within the profession about the appropriate routes and sites for vaccination, especially in cats.6• 10
SUMMARY
The lack of specific rules regarding the use of animal vaccines by veterinarians leaves them vulnerable to legal action for negligence or breach of warranty. A veterinarian's liability may depend on the answers to the questions asked previously in this article. The answers ultimately depend on the specific circumstances of the case. Although no one can ensure that he or she is never going to be sued, veterinarians can go a long way in defending themselves against these kinds of allegations by conforming to the standards of practice as they apply to the care and use of vaccines; by adhering closely to the doctrines of informed consent; and by not providing undue warranty to the vaccine product he or she sells.
References
1. American Veterinary Medical Law Association: Veterinarian and vaccine manufacturer liability after Smith-Kline: Implications for both sectors [panel presentation]. In Proceedings of the American Veterinary Medical Law Association, 1997
2. American Veterinary Medical Law Association: Federal preemption of vaccine product liability litigation: Rationale and result. In Proceedings of the American Veterinary Medical Law Association, 1998
3. Philips TR, Schultz RD: Canine and feline vaccines. In Bonagura JD (ed): Kirk's Current Veterinary Therapy XI. Philadelphia, WB Saunders, 1992, p 205
4. Davis v. Rodman 227 SW 612, ]921. 5. Elston T, Rodan 1, Flemming D, et al: 1998 Report of the American Association of
THE POTENTIAL FOR LIABlUTY IN THE USE AND MISUSE OF VACCINES 523
Feline Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vaccines. JAVMA 212:227-241, 1998
6. Hershey AE, Soreruno KU, Hendrick M], et ale Prognosis for presumed feline vaccineassociated sarcoma after excision: 61 cases (1986-1996). JAVMA 216:58-64, 2000
7. Hu&tead DR, Carpenter T, Sawyer DC, et ale Commentary: Vaccination issues of concern to practitioners. JAVMA 214:1000--1002, 1999
8. Flemming 0: The informed consent doctrine: What you should tell your clients. California Veterinarian 51:12-13, 1997
9. O'Brien v. Cunard SS Company, Ltd. 28 NE 266, 1891. 10. Weigand CM, Brewer WG: Vaccination-site sarcomas in cats. Compend Contin Educ
Pract Vet 18:869-875, 1996 11. Whitford RE: Doctor to doctor practice tips. DVM Magazine April 12, 2000 12. 117 S Ct 178, 1996 13. 30 Am Jur 2nd, Evidence Part 1123 14. 548 F2d 366, 1976 15. 350 F2d 231, 1965 16. 665 F2nd 354, 1981 17. RCV 65023 consolidated with RCV 01521 18. 375 P2d 704, 1962 19. 204 NW 301, 1925
Address reprint requests to
Duane Flemming, DVM, JD Contra Costa Animal Eye Clinic
2100 Monument Boulevard, Suite 7 Pleasant Hill, CA 94523-3440
e-mail: animaleyedoctor®mindspring.com
VACCINES AND VACCINATIONS 0195-5616/ 01 $15.00 + .00
RECENT ADVANCES IN THE TREATMENT OF VACCINE
ASSOCIATED SARCOMAS
Gregory K. Ogilvie, DVM
Soft tissue sarcomas have been difficult tumors to treat in feline oncology, because it is difficult to estimate the extent of the margins of tumor. l • 3. 5-8. 10 This results in many patients that do not receIve appropriate therapy, which, in turn, means a high recurrence rate. This problem has grown steadily in the last decade since vaccine-associated sarcomas were first recognized. Indeed, the increasing prevalence of this malignant condition has eroded the trust that exists between clients and their family veterinarian. The profession has had to respond quickly to determine how to treat and prevent this devastating disease. In essence, this is a critical care concern for the health and well-being of the profession as much as it is for our feline patients and the clients that entrust us with their care.
The purpose of this article is to briefly review background information about vaccine-associated sarcomas followed by diagnostic procedures essential to understand how to determine the extent of the primary and metastatic tumor as well as to understand the general health of the patient. Finally, and just as importantly, this article addresses the importance of understanding the nonmedical needs of the client who is faced with this perplexing problem.
From the Department of Oncology and Internal Medicine, Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Department of Clinical Sciences, Veterinary Teaching Hospital, Colorado State University, Fort Collins, Colorado
VETERINARY CLINICS OF NORTH AMERlCA: SMALL ANIMAL PRACTICE
VOLUME 31 • NUMBER 3 • MAY 2001 525
526 OGILVIE
Table 1. SITES AT WHICH SOFT TISSUE SARCOMAS OCCURRED IN 170 CATS
Location
Vaccination Sites Interscapular / scapular Flank/ paral urnbar Dorsolateral thorax Dorsal area of back or neck Femoral region
Nonvaccination Sites Head (including oral cavity) Limbs (including scapular and inner thigh) Bone Tail Other
Dubious Vaccination Site Ventrolateral neck
TOTAL
Number (%)
30 (17.6) 27 (15.9) 19 (11.2) 17 (10.0) 11 (6.5)
31 (18.2) 13 (7.6) 3 (1.8) 4 (2.4)
10 (5.9)
5 (2.9) 170 (100)
From Doddy FD, Glickman LT, Glickman NW, et al: Feline fibrosarcomas at vaccination sites and nonvaccination sites. J Comp Pathol 114:165-174, 1996, with permission.
DIAGNOSIS
Signalment
Vaccine-associated sarcomas have been identified in middle-aged to older cats of either gender and any breed.1, 5. 7, 10 It should be recognized, however, that vaccine-associated sarcomas are most often documented in cats that are younger than cats with other sarcomas of a similar histologic type not associated with vaccines (Tables 1 and 2). The more often a cat is vaccinated, the higher is the risk of vaccine-associated sarcomas. Vaccine- and injection-associated malignancies have been reported to develop within weeks to years after injection.
Physical Examination Findings
A vaccine-associated sarcoma is noted as a firm swelling at or near a site of previous vaccination. Note that this lump or thickening may
Table 2. SARCOMAS AS A RATIO OF TOTAL FELINE ACCESSIONS AND RATIO OF INJECTION SITE SARCOMAS (IS) TO NON-INJECTION SITE SARCOMAS (NIS)
1989 1990 1991 1992 1993 1994
Total cat accessions 1855 1244 1314 1215 1184 1129 FSAtotal ratio 1.13 1.69 2.97 1.65 3.04 2.92 lS:N1S 0.54 1.00 1.47 1.86 2.6 4.33
From Doody FD, Glickman LT, Glickman NW, et al: Feline fibrosarcomas at vaccination sites and nonvaccination sites. J Comp Pathol 114:165-174, 1996, with permission.
ADVANCES IN TREATMENT OF VACCINE-ASSOCIATED SARCOMAS 527
appear days to years after vaccination. Occasionally, the lump may occur in sites ventral to the site of vaccination, presumably as a result of ventral migration of the causative agent. Metastatic disease, although relatively rare, can result in regional lymphadenopathy or respiratory signs such as tachypnea or dyspnea secondary to pulmonary metastases.
Clinical Evaluation Procedures
A definitive procedure cannot be planned and the client cannot be informed of the potential risks and benefits of these procedures unless the identity of the tumor is obtained, the extent of the primary or metastatic disease is elucidated, and the condition of the patient is documented.
The first step is to obtain a tissue sample either by fine-needle aspiration or biopsy. Fine-needle aspirate cytology can be helpful in eliminating other causes of a mass such as an abscess, granuloma, foreign body, or persistent vaccine- or injection-associated "reaction." Note that some vaccine granulomas can have "reactive" fibroblasts, which may have characteristics that can be confused with a malignant process. These changes include multiple nucleoli and mitotic figures, for example. When there is any doubt, a histologic biopsy of these lesions is imperative. This preoperative incisional biopsy is often viewed as a vital prelude to definitive treatment of this highly invasive malignancy. Regardless of whether a biopsy or aspirate is performed, these procedures should be done such that the biopsy tract can be completely surgically excised or included in the radiation therapy field . Vaccineand injection-associated sarcomas can fall under a number of histologic diagnoses, including fibrosarcoma, neurofibrosarcoma, nerve sheath tumor, hemangiopericytoma, malignant fibrous histiocytoma, schwannoma, leiomyosarcoma, and rhabdomyosarcoma.6, 7, 10
Although obtaining a diagnosis of the cause of the primary tumor is of immense importance, so is determining the presence of metastatic disease. Chest and regional (tumor) radiographs are essential to identify metastatic disease or the extent of the primary neoplasia, or to evaluate the patient for underlying disease. Palpation and an aspirate or biopsy of enlarged lymph nodes is vital to document any metastatic disease to the regional lymph nodes. Computerized tomography (CT), magnetic resonance (MR) imaging, or diagnostic ultrasonography is ideal to determine the extent of the primary tumor,
Although it is critical to obtain an initial diagnosis and to search for metastatic disease, it is also important to assess the general condition of the patient. A hemogram, platelet count, biochemical profile, and urinalysis as well as T4, feline leukemia virus, and feline immunodeficiency
528 OGTLVIE
virus tests are often helpful to document malignancy-relafed disorders or problems unrelated to the cancer that Viould potentially affect treatment decisions and prognosis. ..
No one test can definitively distinguish a vaccine- or injectionassociated sarcoma from a sarcoma of unrelated origin. Histopathologic evaluation may provide indirect evidence that the sarcoma in question may be vaccine associated. Regardless, the treatment is the same. Differential diagnoses include but are not limited to primary tumor, metastatic tumor, abscess, granuloma, foreign body, and postvaccinal reaction.
Client Support
Vaccine-associated sarcomas result in a unique situation for most veterinarians, because this disease is likely induced. Clients with cats with vaccine- or injection-associated malignancies are often scared and overwhelmed. They may be angry with the vaccine manufacturers and the veterinarian or feel guilty for authorizing a preventative procedure that resulted in harm to their cat. Clients often believe that cancer is an evil, frightening, and threatening disease which is emotionally overwhelming. These feelings of vulnerability and lack of control need be acknowledged as the truth about this disease and the treatment options are carefully explained. Because of the emotional nature of this disease, clients with cats with these malignancies are often initially unable to process information and make decisions. All explanations, facts, figures, and decisions should be written or recorded fpr subsequent review. Although the disease may be perceived as an emergency, decisions regarding treatment need not be made quickly. These significant decisions may best be made after the client has had time to thoughtfully and rationally consider the treatment options and all the information presented.
Because cancer steals power and control from the client, the results of diagnostic tests not only direct therapy and allow the clinician to provide a prognosis but empower a client with information, thus allowing that individual to make intelligent and appropriate decisions in this stressful setting. Clients usually appreciate being educated about the individual risks and benefits of each diagnostic test. By including them as a member of the veterinary health care team, most clients take an active roll to benefit the patient and. the veterinary health care team.
TREATMENT
Therapy is divided into treatment of the primary tumor and metastatic disease and support of the patient.
ADVANCES IN TREATMENT OF VACCINE-ASSOCIATED SARCOMAS 529
Primary Tumor
Treatment of the primary tumor is best divided into two categories: cats With small- to medium-sized tumors and cats with large bulky tumors that cannot be comfortably removed with a definitive surgical procedure. Regardless the size of the tumor, cure is most likely with the first procedure.3 "Salvage" procedures are often palliative and expensive.
Small- to Medium-Sized Tumors
Wide and deep surgical excision taking the tumor and a "cuff" of normal tissue around these highly locally invasive tumors is essential. Removing the tumor with 2-cm margins laterally and one fascial layer deep to the tumor is indicated. CT or MR imaging is often a valuable tool to help direct the tumor excision. Adjunctive therapy with radiation and chemotherapy is often recommended. Radiation therapy is initiated at suture removal, and chemotherapy is initiated approximately 2 weeks after the completion of radiation therapy. Concurrent supportive, nutritional, and pain management is essential for these patients.
The use of therapies to enhance tumor control via modulation of the immune system remains largely unproved. Nonspecific immunomodulation using a mixed bacterial vaccine, or levamisole, had no obvious effect on recurrence rates or survival after surgical excision.2 Acemannan is a nonspecific immunomodulator that has been evaluated in a small number of cats with fibrosarcoma. Cats were injected with 2 mg/kg intralesionally weekly for 6 weeks before surgery and megavoltage radiation therapy (60 Gy). The cats then received 1 mg/kg intraperitoneally weekly for 6 weeks and then monthly. Of four cats treated this way, one had tumor recurrence 8 months after surgery and the other three had no recurrence between 14 and 19 months after surgery.11 The true contribution of acemannan to survival in these cats is difficult to evaluate.
Tenogeneic cells (Vero hIL-2) that secrete human recombinant interleukin-2 were infiltrated peritumorally at the time of surgical resection and implantation of iridium-192 seeds for brachyradiotherapyY This infiltration was repeated 5 days later and five times again over the next 2 months. Of 16 cats treated by this protocol, 2 had local recurrence and 3 had metastases for an overall median survival of 16 months. In comparison, 11 of 16 cats that did not receive Vero hIL-2 cells had tumor recurrence and a median survival of 8 months. Antibodies to the cells were detected after 5 days of treatment, and most cats had a local inflammatory reaction to injection. One cat developed anaphylaxis. l3 As a result, this treatment modality is not openly recommended.
530 OGILVIE
Large Unresectable Tumors
Tumors that cannot be comfortably excised with one definitive procedure may be "downsized", or cytoreduced, with radiation therapy or, in some cases, chemotherapy using doxorubicin or carboplatin, for example. These tumors can sometimes be surgically removed subsequently. If radiation is used initially followed by surgery, chemotherapy is recommended at the time of suture removal. Radiation therapy doses are determined with CT- or MR-guided two- or three-dimensional radiation planning and frequently involve 3 to 6 weeks of therapy using 18 to 30 daily doses of 2- to 3.3-Gy fractions to a total dose of 54 to 64 Gy.' Bolus equivalent material is often needed, especially when treating a previous incision or biopsy site that may be contaminated with cancer cells. Chemotherapy is as listed below. Concurrent supportive, nutritional, nausea, and pain management is often essential for these patients.
Possible Microscopic Metastatic Disease
There is little information regarding chemotherapy in the treatment of soft tissue sarcomas in cats. The higher metastatic rates now reported and the reduction in the rate of local recurrence after the use of surgery and radiation therapy mean that chemotherapy may have an increasing role in the management of soft tissue sarcomas in cats. Drugs that anecdotally seem to have no efficacy are vincristine, methotrexate, and cyclophosphamide. Doxorubicin has been used to treat cats with local recurrence after surgery with apparent success. The use of carboplatin chemotherapy did not seem to improve survival rates in another study.n In one study, seven cats that had recurrence of sarcoma after surgery and radiation received either doxorubicin, mitoxantrone, or carboplatin.4
The two chemotherapy agents that have been most often recommended for the treatment of vaccine-associated sarcomas are doxorubicin and carboplatin.
Until more information is known, many recommend the use of doxorubicin (25 mg per square meter of body surface area or 1 mg/ kg every 3 weeks administered intravenously slowly over 20 minutes in cats with normal renal and cardiac function) or carboplatin (200-220 mg per square meter of body surface area every 4 weeks administered intravenously slowly over 20 minutes in cats with normal renal function) therapy, which is initiated after surgery and radiation therapy. Before either drug is administered, a hemogram should be evaluated to ensure that there are at least 3000 neutrophils per microliter. Metocloprarnide is often helpful for reducing anorexia, nausea, and vomiting.
ADVANC~ IN TREATMENT OF VACCINE-ASSOCIATED SARCOMAS 531
Client
The goals, risk, and benefits of each treatment must be carefully outlined, recognizing that the only words more frightening than cancer are chemotherapy and radiation therapy. Clients must be empowered with the ability to intervene on behalf of their cat to support, nurture, and prevent any adverse effects associated with surgery (e.g., to control pain, a 2.5-mg fentanyl transdermal patch may be administered every 72 hours as needed or acupuncture may be used), chemotherapy (to control nausea, 0.4 mg/ kg of metoclopramide may be given orally every 6-8 hours), and radiation (to control pain, a 2.5-mg fentanyl transdermal patch may be administered every 72 hours as needed or acupuncture may be used). The common goal of compassionate care must be carefully reviewed.
Adjunctive Treatments
Palliative radiation therapy (3-8 Gy fractions as needed or on days 0, 7, and 21) may be helpful in some cases for reducing inflammation and discomfort.
Supportive Treatment
Three of the many goals of compassionate care are to ensure that the patients do not have discomfort, that they are not nauseated, and that they have adequate nutritional support. Discomfort can be treated with nonsteroidal analgesics such as feldine (0.3 mg/ kg administered orally every 48 hours), opiates such as a 2.5-mg fentanyl transdermal patch administered every 72 hours as needed, or acupuncture. Mild to moderate cases of nausea can be prevented or treated with 2.5 mg of metoclopramide administered orally every 8 hours as needed, whereas moderate to Significant nausea and vomiting may be best treated with parenteral metocloprarnide (1-2 mg/ kg/ d constant rate infusion [CRID, dolasetron mesylate (0.6-1 mg/ kg administered intravenously slowly every 24 hours), or ondansetron hydrochloride (0.1-0.3 mg/ kg administered intravenously or orally every 12 hours) . Adequate hydration can be treated with analgesics, antiemetics, pain relievers, comfortable surroundings, and appetite stimulants such as 2 mg of cyproheptadine administered orally every 12 to 24 hours or 0.25 to 5 mg/ kg of megestrol acetate administered orally daily for 3 days and then every 48 to 72 hours as needed for anorexia.
532 OGILVIE
Patient Management "
Postoperative analgesics are essentIal as is a common plan with the client to monitor the patient's comfort l~el. The incision must be kept clean and dry. The client should be given oral and written instructions to monitor his or her cat to ensure that the incision is not hot or swollen. Sutures should be watched to make sure that the patient does not remove them. Information about how to contact the veterinary staff and a strategy for after-hours care should be provided before discharging the patient.
The most common adverse effects associated with radiation therapy include (but are not limited to) hair loss, skin color change, and altered hair color regrowth as well as moist or dry desquamation requiring cleansing with mild soap and water. Petroleum-based oils or creams are contraindicated in the management of these cases.
Chemotherapy can be a frightening concept to most clients who care for their cat with a vaccine-associated sarcoma. As mentioned earlier, nausea should be prevented, and the client should be carefully instructed to monitor for an elevated body temperature, especially at the time of chemotherapy nadir (7-10 days for doxorubicin; day 21 for carboplatin).
PROGNOSIS
Favorable prognostic indicators include small size, lack of metastatic disease, and tumor-free margins. Similarly, unfavorable prognostic indicators include large tumor, presence of metastatic disease, prior unsuccessful surgery, and tumor at surgical margins suggesting that recurrence is likely.
A recent study was completed documenting the prognostic significance of the skill of the surgeon.9 In that study, cats that had surgery for a vaccine-associated sarcoma by a surgeon at a referral institution had dramatically longer tumor-free time compared with those cats that were operated on by less skilled surgeons. Overall survival curves and tumor control were determined.
The median time of tumor control was 94 days. Median tumor control for tumors treated with excision performed at a referral institution (274 days) was significantly longer than that for tumors excised by a referring veterinarian (66 days) . A radical first excision yielded significantly longer median tumor control (325 days) than did a marginal first excision (79 days). Cats with tumors located on the limbs had longer median tumor control (325 days) than cats with tumors located at other sites (66 days). The median overall survival time was 576 days. Signifi-
ADVANCES IN TREATMENT OF VACCINE-ASSOCIATED SARCOMAS 533
cant differences in survival times between groups were not detected. Few cats (13.8%) receiving only surgical treatment had long-term (>2 years) survival, suggesting that radiation and chemotherapy are highly indicated as adjunctive therapies.
References
1. Bergman PJ: Etiology of feline vaccine-associated sarcomas: History and update. JAVMA 213:1424-1425, 1998
2. Brown NO, Patnaik AK, Mooney SC, et al: Soft tissue sarcomas in the cat. JAVMA 173:744-779, 1978
3. Couto CG, Macy DW: Review of treatment options for vaccine-associated feline sarcoma. JAVMA 213:1426-1427, 1998
4. Cronin K, Page RL, Spodnick G, et al: Radiation therapy and surgery for fibrosarcoma in 33 cats. Vet Radiol U1trasound 39:51-56, 1998
5. Doddy FD, Glickman LT, Glickman NW, et al: Feline fibrosarcomas at vaccination sites and non-vaccination sites. J Comp Pathol 114:165-174, 1996
6. Esplin DG, McGill LD, Meninger AG, et al: Postvaccinal sarcomas in cats. JAVMA 202:1245-1247, 1993
7. Hendrick MJ: Historical review and current knowledge of risk factors involved in feline vaccine-associated sarcomas. JAVMA 213:1422-1423, 1998
8. Hendrick MJ, Brooks JJ: Postvaccinal sarcomas in the cat: Histology and immunohistochemistry. Vet Pathol 31:126-129, 1994
9. Hershey AE, Sorenmo KU, Hendrick MJ, et al: Prognosis for presumed feline vaccineassociated sarcoma after excision: 61 Cases (1986-1996). JAVMA 216:5~1, 2000
10. Kass PH, Barnes WG, Spangler WL, et al: Epidemiologic evidence for a causal relation between vaccination and fibrosarcoma tumorigenesis in cats. JAVMA 203:396-405, 1993
11. King GK, Yates KM, Greenlee PG, et al: The effect of acernannan irnrnunostirnulant in combination with surgery and radiation therapy on spontaneous canine and feline fibrosarcomas. J Am Anim Hosp Assoc 31:439--447, 1995
12. Kleiter M, Leschnik M: Postoperative chemotherapie zur behandlung eines zweifach rezidivierten vakzine-assoziierten fibrosarkoffiS. Kleintierpraxis 43:295-302, 1998
13. Quintin-Colonna F, Devauchelle P, Fradelizi D, et al: Gene therapy of spontaneous canine melanoma and feline fibrosarcoma by intra tumoral administration of histoincompatible cells expressing human interleukin-2. Gene Ther 3:1104-1112, 1996
Address reprint requests to
Gregory K. Ogilvie, DVM Animal Cancer Center
DepartrnentofClUUcai Sciences Veterinary Teaching Hospital
Colorado State University Fort Collins, CO 80523
e-mail: gogilvie®[email protected]
VACCINES AND VACCINATIONS 0195--5616/ 01 $15.00 + .00
RECOMBINANT VACCINE TECHNOLOGY IN VETERINARY
MEDICINE
Kent R. Van Kampen, DVM, PhD
Vaccines are an integral part of the practice of veterinary medicine. The oldest types of vaccines are made from whole pathogens, viral or bacterial, that have been treated with chemicals or heat to render them inactive. These antigens are combined with antibiotics, adjuvants, and other substances in a suspension that is used for injection. Pathogens have also been attenuated by subjecting them to abnormal growth conditions, multiple passages, and selection for various characteristics of reduced virulence or pathogenicity. After this attenuation, the modified pathogen is used as a live vaccine.
Inactivated vaccines almost always required the addition of adjuvants. The duration of immunity is often 1 year or less. There may be reactions at the site of administration that include swelling, redness, and some pain. Residual lumps at the site of injection are common with the use of these vaccines.
Live attenuated vaccines usually impart a strong immunity. Because of their live nature, the vaccines may be subject to contamination during manufacturing. There is also a danger of reversion to virulence as the organisms replicate in the body of the vaccinated animal.
An ideal vaccine should meet certain criteria of safety and efficacy. The immunity induced should be strong and prolonged. The vaccine should be free of significant adverse side effects. The antigen(s) should be stable under a variety of conditions of handling. If possible, the profile of immunization should be different from that of an active infection. The
From the Van Kampen Group, Inc., Hoover, Alabama
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE
VOLUME 31 • NUMBER 3 • MAY 200]
536 RECOMBINANT VACCINE TECHNOLOGY
route of administration of the vaccine should be easy for the veterinarian to administer.
NEW TECHNOLOGY
A new range of vaccines using a technology distinctly different from the inactivated or live attenuated vaccines has been developed. This technology has been labeled "recombinant" and has been implemented by the revolution of genetic engineering that allows genetic material to be exchanged between various organisms. With recombinant technology, these new vaccines focus the immune response to specific antigens known to be associated with protection against disease. It is not necessary to expose the immune system to dozens of antigens found in whole pathogens. Since these vaccines do not contain pathogens, there is little chance for in vivo recombination and return to virulence of the pathogen. Some of these recombinant vaccines also allow for multiple routes of administration.
METHODOLOGIES
Genetic engineering allows microorganisms to have their genetic material segmented into sequences that are complete or incomplete genes. These genetic sequences can be re-arranged and inserted into alternate organisms for the purpose of producing proteins, encoding other antigens, producing substances that induce physiologic or desired immune responses. This technology can also be used to insert specific genes into cells that are congenitally devoid of these genes. This is called gene therapy.
In making vaccines using recombinant technology, the pathogen's genetic material is subjected to enzymatic action that results in segmentation. The resultant RNA or DNA is identified as to its function, if known. The desired genetic material is selected. If the genetic material is RNA, it is incubated with reverse transcriptase and cDNA is obtained. DNA or cDNA is then inserted into a recipient host that is usually a yeast, a bacterium, or a virus. One or more genetic segments may be inserted by recombination into the recipient organism. In order to produce a good vaccine, knowledge of specific antigens associated with immunologic protection is required.
For purposes of regulating the use of recombinant vaccines, the United States Department of Agriculture has classified these new vaccines into three categories. They are
Type I Recombinant - subunit vaccines Type IT Recombinant - gene-deleted vaccines Type III Recombinants - vectored vaccines
VAN KAMPEN 537
TYPE I RECOMBINANT SUBUNIT VACCINES
In this technology, an antigen is produced during the culture of the synthetic, recombinant organism. A gene encoding a particular antigen, the product of which confers protection, is selected from the pathogen. This gene is inserted into another host organism such as a yeast, bacterium, or virus. The modified host organism is cultured (propagated) during which time the product of the inserted gene is produced. The gene product is then isolated, purified, and used as the antigen in the vaccine. This antigen mayor may not be adjuvanted for use as a vaccine.
One such vaccine in veterinary medicine is a recombinant Lyme disease vaccine, licensed for use in dogs. This vaccine protects against the organism Borrelia burgdorfi that is transmitted by ticks. A single gene encoding the outer surface protein A (OspA) is taken from the Borrelia organism and inserted into a nonpathogenic E. coli. The E. coli is then cultured, the gene product produced in the cytoplasm, the organism lysed, and the OspA purified. The purified protein is then suspended without adjuvant and administered to the dog by injection. The resultant immune profile will be distinctly different from that of an infected animal.
TYPE II RECOMBINANT GENE-DELETED VACCINES
In this classification, a pathogen is subjected to genetic manipulation that results in the removal of one or more genes. This actioQ reduces the pathogenicity and the virulence of the pathogen. The gene-deleted pathogen is then replicated and used as the vaccine. The immune system reacts to the type IT recombinant in such a manner that the serologic profile will not contain an antibody to the deleted gene products. That means that the immune profile of an infected animal will differ from that' of the vaccinated animal.
The gene-deleted vaccine used most commonly in veterinary medicine is against the viral infection, pseudorabies. The difference in the immune profiles of the vaccinated and the infected animals allows vaccination in the face of an outbreak of disease and subsequent culling of infected animals from the herd. This has resulted in significant control of pseudorabies.
TYPE III RECOMBINANTS: VECTORED VACCINES
This process begins by isolating gene(s) from the pathogen that are associated with protection against disease. These genes are then inserted
538 RECOMBINANT VACCINE TECHNOLOGY
into a gene-deleted vector that may be a bacterium' or a virus. The synthetically modified organism is then proliferated or replicated. The organism is then purified, suspended, and used as the vaccine. These vaccines are activated when adrninis~red by a variety of routes. The inserted gene(s) product(s) is/are produced when the synthetic organism enters the cells of the vaccinate. The antigen is taken up by antigen presenting cells (APCs) and the immune system produces an antibody or cellular immune response.
Licensed veterinary vaccines using recombinant vectored technology are primarily poxvirus based. The poxviruses are large, stable, and can be made nonreplicating for use as va.ccine vectors. A vaccinia vectored rabies vaccine containing the genetic insert encoding the rabies glycoprotein has been licensed by the USDA for controlling rabies in raccoons. Canarypox vectored vaccines, including rabies and canine distemper, are licensed for use in cats and dogs, respectively. In the disteII).per vaccine, two genes, the hemagglutinin and the fusion genes, were inserted. A fowl pox vector is also the vehicle for delivering genes that protect against Newcastle disease and avian influenza. This vector is a replication competent recombinant and research has demonstrated that as few as five viral particles inoculated as the vaccine can provide protection against a specific disease.
Other viral vectors that have been used experimentally in veterinary medicine include adenovirus and retroviruses. Bacterial vectors such as Salmonella, Shigella, and Mycobacterium have also been researched. None of these vectors have been licensed for use in the veterinary field.
Additional Readings
1. Babiuk LA, Lewis J. Van Den Hurk S, et al; DNA imrmmization; Present and future . III Schultz RD (ed); Veterinary Vaccines and Diagnostics. Advances in Veterinary Medicine. 41:163-179, 1999
2. Horzinek MC: Vaccination; A philosophical view. III RD Schultz (ed); Veterinary Vaccines and Diagnostics. Advances in Veterinary Medicine. 41;1~, 1999
3. Adams LG, Ford RB, Gershwin LJ. et al; Recombinant vaccine technology. Veterinary Exchange. Compendium Cont Ed Pract Vet (sup pi). 19;5-16, 1997
4. Pastoret PP, Brochier B; The development and use of a vaccinia-rabies recombinant oral vaccine for the control of wildlife rabies; a link between Jenner and Pasteur. Epidemiol Infect 116(3);235-240, 1996
5. Pastoret PP, Brochier B, Languet B, et al ; Stability of recombinant vaccinia-rabies vaccine in veterinary use. Dev Bioi Stand 87;245-249, 1996
6. Paoletti E; Application of pox virus vectors to vaccination; An update. Proc Natl Acad Sci USA 93(21);11349-11353, 1996
Address reprint requests to Kent R. Van Kampen, DVM, PhD
The Van Kampen Group, Inc. 1008 Lake Winds Drive
Hoover, AL 35244
VACCINES AND VACCINATIONS 0195-5616/ 01 $15.00 + .00
WHAT YOU CAN AND CANNOT LEARN FROM READING A
VACCINE LABEL
David R. Hustead, DVM
Although most veterinarians look at vaccine labels each day, they rarely see them. When practitioners sense a need. to read labels, they find that the labeling answers some of their basic questions but that these labels often fail to address many relevant issues. In addition, veterinarians find that the issues addressed are often presented Simplistically and that labels are sometimes just wrong. This article addresses how and why we have come to this point in our profession and what practitioners need to do to better understand the products most of them use on a daily basis.
First, what is a vaccine label? A product label is normally defined as the written information that is furnished with the product at its time of sale. Per federal regulations, this written information must be approved by the relevant federal authority, and it must accompany the product at the time of sale (9 Code of Federal Regulations [CFR] Part 101.4)." This written information normally includes the text found
'The federal government regulations are published in the Code of Federal Regulations (CFR). Section 9 of the CFR contains the regulations written by the United States Department of Agriculture (USDA) that deal with animals and animal products. Subchapter E of Section 9 of the CFR contains the regulations dealing with vaccine manufacture and distribution. Subchapter E contains parts 100 through 124. The written reference to 9 CFR Part 101.4 is a commonly used shorthand abbreviation to refer to Section 9 of the CFR Subchapter E Part 101.4.
From Fort Dodge Animal Health, Overland Park, Kansas
VETERINARY CLINlCS OF NORTH AMERICA: SMALL ANIMAL PRACTICE
VOLUME 3} • NUMBER 3 • MAY 2oo} 539
540 HUSTEAD
attached to the bottles or boxes of the product. If a "package insert" is included with the product, this woul ... d be part of the approved label. Separate package inserts are often not included with vaccines, because the information provided on the botttes or boxes is considered to be sufficient by the manufacturer, and it fulfills all federal regulations. This is in stark contrast to pharmaceutical products, where a package insert would almost always be provided because of the amount of text normally provided with these types of products. At its broadest definition, a vaccine label would include any and all written information a company might produce that is likely to be seen by customers and that mentions attributes or characteristics of the product. Examples of a label by this definition would include advertisements in magazines or journals, sales bulletins, and technical monographs. For the purposes of this article, the term vaccine label is used for the more narrow definition to include just those materials provided with the product at the time of sale.
USERS' EXPECTATIONS
Veterinarians and all vaccine users expect to be able to read a vaccine's label to gain understanding about the characteristics of the product in addition to how it is best used in animals. At one level, these expectations are entirely reasonable. A label must provide identification of the product and provide the reader with important information about the product. A vaccine's label use directions should be clear, easy to follow, and realistic to implement the given realities of animal husbandry practices. Because these are products steeped in the scientific process, the directions for use should be based on the data that are collected to support the vaccine's licensing. At another level, these expectations are incredibly naIve. The effective use of a vaccine requires at least a working knowledge of the diseases of concern, practical immunology, preventive medicine theory and application, applied clinical medicine, and animal husbandry. That is a tall order for college curricula, let alone a vaccine package label.
VACCINE LABEL REALITY
The information that appears on a vaccine label is greatly influenced by the scientific process and the regulatory process that licenses the vaccine for sale. Because the reader has learned the science elsewhere, this article looks at regulatory issues that most veterinarians were never exposed to in school. To understand what is and what is not on a vaccine's label, one must have a practical understanding of the regula-
READING A VACCINE LABEL 541
tory process. Most veterinarians know that the drugs they use in the United States must be approved by the Food and Drug Administration (FDA) (21 CFR Part 510). These same veterinarians are often surprised to find out that animal vaccines are licensed by the United States Department of Agriculture (USDA) (9 CFR Part 101). This dichotomous approval process is unusual in human medicine, where a single regulatory agency would handle both types of products. This dichotomy is also unusual in most of the world for animal health drugs and vaccines. The USDA and FDA approach product regulation from two different points of view. To practitioners, this difference means that their understanding of the approval process for drugs cannot be generalized toward an understanding of the vaccine licensing process.
The USDA was given authority over animal vaccine sales by the .Virus-Serum and Toxin Act of 1913 as amended in 1985 (9 CFR Part 101). This means that the USDA has been approving the text of vaccine labels for a considerable period of time. Many labeling practices have slowly evolved over this period. Like most complex bureaucratic processes, vaccine labeling procedures change slowly, because inadequacies are found in the current system. Changes are then instituted to better fit the current view of reality. Rarely are changes in labeling practices forced on products that are already licensed unless the manufacturer attempts to license a "new" product based on the "old" product or the USDA reviews the product because of concerns about the product's suitability for sale. Changes in product labeling tend not to occur after a product has been licensed. New USDA regulations are normally applied to products that have not yet been licensed and not to products already licensed and available. To practitioners, this means several things. First, some vaccine labels are quite old, containing text that has been in place for decades without modification. Second, similar vaccines for the same disease could have different label texts, and, at the same time, relatively different vaccines could have similar label texts. It is unlikely that the reader can determine whether these similarities or differences in label text are the result of differing biologic behaviors of the products or are the result of the rules in place at the time each product was licensed. This process also means that the text found on a vaccine label is almost always behind the profession's current expectations and, rarely, if ever, leads vaccine users toward better product understanding. Any reading of a current vaccine label must be viewed within the context of the rules that existed when it was licensed.
The USDA exerts its Virus-Serum and Toxin Act authority by requiring that vaccines be licensed by the USDA before their sale (9 CFR Part 102). To obtain a vaccine license, the manufacturer must provide the USDA with sufficient information so that the USDA can determine whether the product is pure, potent, safe, and effective (9 CFR Part 102).
542 HUSTEAD
A vaccine's potency and purity rarely affect the information found on its labeling; thus, they are ignored in tbis article. The reader is cautioned that the approval process for purity and potency has a dramatic impact on the products that are used. The criteria for purity and potency testing and assessment are beyond the scope of this discussion.
WHAT A VACCINE LABEL CAN TELL YOU
Type of United States Department of Agriculture License
Products that have been routinely licensed by the USDA do not have a statement on the label that the product is approved by the USDA This is in contrast to FDA-approved products, where the label states "approved by FDA" A vaccine approved by the USDA has a notation on the label that provides the USDA license number. This notation looks something like "U.s. Vet. License No. XXX." This license number is for the establishment that produces the vaccine and is not unique to the product. The presence of the USDA license number does inform the reader that the product has been approved by the USDA This vague licensure statement is in contrast to tl).e text found on products that are conditionally licensed by the USDA If a product has a USDA conditional license, this status is directly stated on the label. Most readers are not aware that the USDA has two different licenses for vaccines. The form of approval that most users are familiar with is often referred to as a full license. The other is a conditional license (9 CFR Part 102). Conditional licenses for vaccines are intended to be used when there is a special circumstance that creates medical need for a vaccine, but for reasons of expediency or technical limitations, the vaccine has not undergone the protocols normally expected for a full license. To obtain a conditional license, a vaccine must demonstrate purity, potency, and safety in the same manner as a full license. The difference is only in efficacy determinations. For a conditional license, a vaccine must demonstrate an "expectation of efficacy" instead of a "demonstration of efficacy." Conditional licenses are temporary and are generally reviewed every year. The USDA expects the manufacturer to collect additional information to either continue the conditional license or to work toward a full license. Failure to collect additional data appropriate for licensure could result in loss of the conditional license. It is important that practitioners understand that conditionally licensed products normally do not have the same level of effectiveness data as fully licensed products. In addition, a conditionally licensed product could lose its license and be removed from the marketplace before becoming fully licensed. The
READING A VACCINE LABEL 543
conditional licensure statement is thus an important part of a vaccine label.
True Name
Readers of a vaccine label can learn the identification of each antigenic component of the product by reading its true name. The true name is the most prominent printed information found on the label. By regulation (9 CFR Part 112 and Veterinary Services Memorandum 800.54), the true name of the product can not be overshadowed by any other lab"el text. The text on the label with the largest print is thus the true name of the product. The federally mandated true name lists the antigenic fractions contained in the product. The order of listing is regulated. At the end of the antigenic listing are indications as to whether the fractions are "live" or "killed" and the type of organism (i.e., viral, bacterial, fungal, protozoan). An example of a true name is "Feline Leukemia Vaccine killed ViruS."b In some ways, the true name is similar to a generic name for a drug in that it identifies active fractions of the product. On the other hand, the true name is not similar to a generic name because it does not uniquely identify the active ingredients of the product to the user. Some basic user questions about the antigenic constituents in the vaccine should be resolved by reading the true name of the prod~ct.
Trade Name
The trade name of a product is the name the manufacturer gives the product. This name can be almost anything and is optional. Trade names are used to help users remember products or easily identify them. For example, if a company makes a canine vaccine called "Puppyshot," this trade name does not necessarily mean the vaccine can only be used in puppies. Normally, this trade name only informs readers about the contents of the product if they already know what the trade name describes. Vaccines that are conditionally licensed do not have a trade name on the label.
Effectiveness Claims
All vaccines make claims about their effectiveness on the label. A vaccine label contains a statement similar to the following: "For vaccina-
bFel-O-Vax LvK (Fort Dodge Animal Health, Overland Park, KS).
544 HUSTEAD ... ,
tion of healthy dogs to prevent signs of disease associated with Wection of canine distemper virus." This statement is much more important than most users are aware. The intended animal species is listed here. In this example, dogs are the only intended species for this vaccine. In addition, part of the statement is to use the vaccine in healthy animals. This is important, because animals that are unhealthy may not mount an adequate immune response.4 The label informs readers that only healthy animals should be vaccinated. This statement also addresses the common desire of veterinarians to use vaccines in a therapeutic manner. Because animals that need therapy are not healthy, the healthy animal statement tells readers that therapeutic use is outside the product's intended uses.
A second important area of the effectiveness claim is the phrase "to prevent signs of disease." To most readers, these words seem obvious. Most users believe that is exactly what vaccines are supposed to do. It is important to note that this phrase is a level of effectiveness claim. To better understand the issue of level of expected claims, a short explanation of how effectiveness claims are determined follows.
Efficacy testing to support a license is normally a laboratory-based in vivo assessment of the product's ability to stimulate an immune response that is anticipated to confer protection to an individual on subsequent natural challenge (9 CFR Part 113). Initial efficacy studies are almost always based on challenge studies, comparing the clinical disease observed in vaccinates with the disease observed in nonvaccinates after challenge. Although the law would allow efficacy determinations to be based on serologic responses observed in vaccinates after vaccination, such a practice for initial vaccine approval would be unusual. Normally, these' challenge studies are conducted in the target species, but laboratory animal substitutes are allowed occaSionally. All laboratory-based methods of vaccine study are only approximations of the real world. Some of these approximations better simulate clinical reality than do others. Just a few factors that would affect the laboratorybased challenge so that it more accurately reflects clinical reality would include the animals selected (mongrels versus purebreds or multiple purebreds), the similarity of the challenge virus to clinical isolates, the dose of challenge administered (approximating real challenge situations), a route of inoculation similar to that of clinical settings, and a clinical scoring system that accurately reflects the clinical disease that is seen. Using the species of interest in these studies should more accurately estimate clinical reality than if a surrogate species were used.
It is difficult to precisely describe the efficacy testing that is conducted for vaccines, because there are a large number of antigens tested, each antigen has unique testing issues, and each antigen can have multiple test procedures. With this said, there are some elements common to most efficacy determinations that can be described. The potency
READING A VACCINE LABEL 545
of the test vaccine used in efficacy studies is normally at the lowest level anticipated to be used in the field. Doing so is intended to provide a reasonable level of assurance that the vaccine efficacy shown in these studies is the least likely to be seen by routine users because they use vaccines with higher levels of antigenic components. The number of animals in an efficacy study is somewhat variable, but 20 vaccinates is a common number. For a challenge study to support a "prevention .of disease" label claim, 80% of the vaccinates should be free of infection or disease in contrast to the nonvaccinated controls, which would be expected to demonstrate a reasonable amount of disease (9 CFR Part 113 and Veterinary Services Memorandum 800.200). It is the relative difference between the disease observed in the nonvaccinated controls and the vaccinates that is the descriptor of vaccine effectiveness. The reader should note that this standard is achieved with less than 100% of vaccinated animals expected to demonstrate an adequate response to vaccine administration. It is a universally recognized fact that essentially all biologic responses, including immune responses to vaccines, are not uniform in a population of animals.4 Because of the random variability of animals (a result of genetic and environmental factors), the immune responses of most individuals are close to the average response, but some responses are greater and some are less. (This is immediately obvious after viewing student examination scores or athletic performances as long as there are a large number of participants.) This distribution of biologic responses ensures that not all animals respond to vaccine administration. The federal requirement for adequate vaccine efficacy to be defined at less than 100% is a demonstration of this immovable fact.
The efficacy testing procedures for some antigens are precisely described in the federal regulations (9 CFR Part 113). If a disease efficacy study procedure is described in the USDA regulations, that ' codified study procedure must be used to establish a product's efficacy. There are many antigens that do not have codified efficacy procedures. When this occurs, the manufacturer wanting to develop a product for a specific disease must develop a method of assessing the product's efficacy. Before this method can be used by a manufacturer, the method must be approved by the USDA (Veterinary Services Memorandum 800.200). As a work product of a commercial organization, the noncodified procedure is not normally disclosed to others by the USDA.
As previously described, products that demonstrate efficacy by reducing disease in 80% of the vaccinates as compared with the nonvaccinated controls after challenge are permitted to make the label claim "to prevent disease or to prevent signs of disease." This wording is in contrast to the text "to aid in the prevention of disease," which is commonly found on vaccine labels. Although these two statements look similar, each describes a differing claim of effectiveness. Products whose
546 HUSTEAD "
labels claim that the product serves "as ~ aid in prevention" do not have to demonstrate efficacy at the levels previously described (Veterinary Services Memorandum 800.200). The requirement for this claim is to demonstrate that after challenge, the vaccinates are less sick than the controls. For diseases where the challenge produces a mild disease with a wide range of signs, it is not uncommon for the challenge to only demonstrate vaccine effectiveness that supports the "aid in prevention" claim. Vaccine labels containing the phrase "as an aid in prevention" are informing the reader that the level of effectiveness demonstrated by this product may be less than that of a similar product with the claim "to prevent." On the other hand, the claim difference may be the result of inadequacies in laboratory-based challenge evaluations for clinical efficacy. The reader of the label is expected to understand the significance of the difference in wording.
Use Directions
The product's use directions normally tell the reader how to administer the product in the average animal. A typical use direction is to "administer one 1 mL dose subcutaneously. Repeat in 3 weeks." These directions should be followed, because they are likely to be the only protocol that was used in the safety and efficacy studies for the product's licensure. There is also a statement on essentially all animal vaccines that says "annual revaccination is recommended." This set of directions is a historically accepted repeat vaccination interval for essentially all domestic animal vaccines.
Safety Information
All vaccines must provide a warning about the potential for anaphylaxis and the need to treat it with epinephrine (9 CFR Part 112). The amount of additional safety information on an animal vaccine is sparse and somewhat variable. Some products carry additional safety information that is viewed as necessary by the manufacturer or the USDA.
Dose Volume
The volume to be administered is stated on the label. For companion animals, the standard is 1 mL, but there are other doses. The dose volume that is stated is the one dose volume that was tested by the manufacturer during the licensing process.
READING A VACCINE LABEL 547
Storage Conditions
Vaccine labels contain storage directions (9 CFR Part 112.6), for example, "Store in the dark at 2°_7', do not freeze." Like most biologic specimens, vaccines are adversely affected by storage in light and heat. The label recommendation is a reflection of this concern, because longterm storage is enhanced by storage in the dark at low temperatures. The effect of freezing on most vaccines is poorly understood. Although freezing does prolong the storage of many biologic specimens, it does induce changes in biologic materials.3 These changes may have effects on vaccine antigenicity or immunogenicity. In addition, adjuvant systems common in many vaccines can be affected by freezing and thawing. 2
The biologic impact of these changes is normally not well understood; thus, the recommendation is not to freeze the product.
Preservatives
If a vaccine contains nonimmunologic agents or chemicals, they are identified on the label (9 CFR Part 112). The most common items listed here are residual amounts of inactivating agents, antibiotics, or antifungal agents.
WHAT A VACCINE LABEL DOES NOT TELL YOU
United States Department of Agriculture Licensure Statement
There are vaccine products that are sold in the United States that are not licensed by the USDA. These products are sold in the state where they are made. These intrastate products are not directly licensed by the USDA, but the USDA does approve the state regulations that license the products (9 CFR Part 107.2). At the time of this writing, California is the only state to have such intrastate vaccine products (D. Siev, DVM, personal communication, 2000).
True Name
There are many limitations of the true name found on vaccine labels. The true name fails to uniquely identify a product, it fails to inform the reader about the precise identification of the "strain" of organism used in the product, it often fails to mention if vaccine organ-
548 HUSTEAD
isms are whole organisms or subunits, and it ignores' completely the presence or absence of an adjuvant. Fo,r a single-antigen product, a true name informs the reader about the anti~enic component in the product, but after that, the true name system tends to confuse more than it informs. For a combination product (one that contains more than one disease antigen), especially where some fractions are live and some are killed or contain different sources of organisms (e.g., bacterial and viral antigens), the true name often confuses users about the identity of the organisms contained in the product. This is because all the information about the antigens follows the listing of the antigens, often without regard to the order in which the antigens are listed. It can be difficult or even impossible to tell which antigens are "live" and which are "killed." For example, the true name of a licensed vaccinee is "Bovine Rhinotracheitis-Bovine Virus Diarrhea-Parainfluenza-3--Respiratory Syncytial Virus Vaccine, Modified-Live and Killed Virus." In this example, some of the fractions are live and some are killed. Which is which? The true name does not say. Products that are dissimilar can have the same true name. This occurs when two combination products have the same antigen listings but diffel' in which antigens are live and which are dead. The true names for these products can be identical. An example would be when the true names of two licensed vaccines are identical to the true name just given; however, when these two products are compared, each has different live and killed antigenic fractions.d• e This ability of the true name to confuse rather than to inform is unfortunate, because these issues can make differences in users' understanding, uses, and expectations for efficacy and safety of vaccines.
Limitations of Efficacy Claims
There are many limitations to the efficacy claims found on vaccine labels. First and foremost is the level of expectations that many users have concerning the effectiveness of vaccines. Vaccine labels inform readers that the products can prevent disease; thus, it is not unreasonable for practitioners and lay users of vaccines to have expectations that most vaccines can essentially protect all animals from disease if challenged. Although this may seem to be true from clinical experience with some vaccines, the reality of immune responses and the licensing process is that vaccines tend to work at levels that are considerably less than 100%. Second, users of vaccine expect to be able to read a product's label to
'Prism 4 (Fort Dodge Animal Health, Overland Park, KS). dFusion 4 (Merial, Iselin, NJ) . ' IBR-Plus 4-Way (Merial, Iselin, NJ).
READING A VACCINE LABEL 549
gain an understanding about the product's clinical efficacy. If products are not tested under clinical conditions, the clinical effectiveness is likely unknown. The efficacy that is stated on the label is a function of the labonitory-based approximation of clinical conditions. Third, practitioners often desire to use vaccine labels to compare products they may purchase so that they may select the ones with the highest levels of effectiveness. Such comparisons between products may be possible . if each vaccine has a similar label claim and if they were licensed using a codified efficacy test system. In reality, differences between even codified protocols may make direct comparison difficult. If two vaccine products use different noncodified systems, especially if the details of those procedures are not well known (except to the manufacturer and the USDA), any meaningful comparison is likely impossible, regardless of what is said on the label. Two similar 'vaccines can have differing claims. The two common efficacy claims have been described. For products with the "aid in prevention" claim, do they have real lower levels of efficacy, or are these claim differences the result of low levels of disease in the nonvaccinates, small reductions in disease in the vaccinates as compared to the controls, or just regulatory "red tape"? Finally, what can the reader infer when two products have label claims for different syndromes of the same disease? Is the vaccine with more claims the better vaccine? As an example, most feline leukemia vaccines claim to prevent persistent viremia. Some feline leukemia vaccines also contain claims to prevent transient or latent viremia. Because feline leukemia efficacy studies are still noncodified by the USDA, manufacturers use several methods to demonstrate efficacy. They are free to adapt their studies to obtain data not collected by other manufacturers. This allows for data collection to support additional claims. Do these additional label claims imply additional efficacy or just a reflection of the study conducted? Do these additional claims have clinical relevancy to the patient? It is clear that vaccine label efficacy claims must be read carefully for them to have any relevant meaning to the user.
Optimal or Acceptable Initial Revaccination Interval
The initial revaccination interval on the vaccine's label is most likely the one interval that was studied. If no other data are collected for the product's license, no alternative uses are discussed on the label. In addition, there is no requirement for the manufacturer to determine if this interval is the most optimal. Neither does the label tell the reader about less than optimal but still acceptable intervals. What is the longest interval between initial vaccinations that can still stimulate an appropriate response? What is the practitioner to say to the kitten owner who
550 HUSTEAD
. returns 10 weeks after the kitten's initial vaccination? Do you start over? Does it make a difference if you are using a killed or live vaccine? The label does not address these common questions.
Annual Revaccination Recommendations for All
Essentially all vaccine labels say that annual revaccination is recommended. The annual revaccination recommendation that is found on essentially all current USDA vaccine labels is a historically accepted practice. To make this claim on a vaccine label, the USDA does not require manufactures to prove that their vaccine provides immunity for a year or that this annual period is biologically important. There is a USDA policy (Veterinary Services Memorandum 800.200) requiring that new and novel vaccine antigens (antigens for which a vaccine does not already exist) have duration of immunity data collected before that product receives a license. This duration information is then presented as a recommended revaccination interval that is as long as the tested interval. Even this regulation does not require that this demonstration of duration of immunity be relevant to the animal's biology. Unfortunately, there may be considerable difference between a demonstrated interval of efficacy and an optimal revaccination interval. If a vaccine demonstrates protection from disease at 1 year after vaccination, it only makes sense that the revaccination interval is not 1 year but some time longer than 1 year. In addition, the new USDA standard still does not address the question of the optimal or acceptable revaccination intervals that would be needed to maintain lifetime immunity. To further complicate this issue, the new regulation gives us two kinds of products with the same annual revaccination label claim. One set is the old products with a historic claim, and one set is the new products, where the manufacturer has demonstrated that immunity conferred by the vaccine is present 1 year after vaccination. From a reader's perspective, this becomes quite confusing. Essentially all vaccine labels say to vaccinate annually, but some can show this annual claim has support and some cannot. In neither case has the biologic necessity of the practice been demonstrated, and all this is a long way from determining the optimal revaccination interval of individuals in the population.
Use in Animals That Are Not Average Adults
For many years vaccine labels did not indicate the minimum age of administration. This was assumed to be a matter of veterinary practitioner discretion. Today, newly licensed vaccines say to use in animals
READING A VACCINE LABEL 551
older than a specified age as a result of a new USDA policy (Veterinary Services Memorandum 800.200). This is helpful for the label readers, because the USDA requires demonstration of efficacy and safety in the age of animal noted on the label, but the vaccine user is again confronted by similar vaccines that have dissimilar use directions. How is the user to know if this labeling difference is important biologically or just a regulatory issue? There are other examples of differing label texts abQut use in animals that are not average adults that are based on important biologic differences, but this importance becomes confused in labeling text. As an example, a modified live virus panleukemia vaccine label says not to administer the product to pregnant cats. This is because the statement is required (9 CFR Part 112.7) for this product, but this requirement is based on real safety concerns in the unborn kitten with the live virus growing in its · brain and causing disease. This same concern is not addressed on killed vaccine labels, because reversion to virulence of the killed organism is not possible; hence, no regulation requires a statement. Does that absence of a precaution mean that it is a good idea to vaccinate pregnant cats with a killed vaccine? Rarely does a vaccine label address expected responses in older animals, because there is a dearth of information about the vaccine needs of older animals
. and the responses that vaccines are likely to induce. Some labels' text about uses in animals that are not average adults can be driven by regulations or biologic factors. The reader has problems knowing which is which. In addition, practitioners are cautioned that the lack of information about a particular use on labels should not be viewed, by default, as a tacit recommendation for that use.
Administration by an Alternate Route
Vaccine labels do not discuss use by alternate routes, because manufacturers rarely gather data on other possible routes. There can be differences in the immune responses observed after administration of vaccines by different routes.! Whether these differences have a clinical impact on animals is not normally known. There can be important safety concerns about giving vaccines by alternate routes. As an example, injectable modified live virus vaccines for feline herpe~ can revert to virulence if they gain access to mucous membranes as a result of accidental aerosols or if the cat licks at vaccine that contaminates an injection site.' These issues are commonly ignored on vaccine labels. Vaccine users should only administer vaccine by the routes indicated on the vaccine's label, and practitioners are cautioned that the lack of information about a particular use on labels should not be viewed, by default, as a tacit recommendation for that use.
552 HUSTEAD :
' . Limitations of Safety Information
... The minimalistic approach to safeQ4. information on vaccine labels
was described previously. Vaccines must be determined to be safe by the USDA for licensure (9 CRF Part 113). It is the reality of the biologic process that vaccine administration is associated with adverse responses in some animals.' A vaccine is considered safe by the USDA if it does not cause undue local or systemic responses (9 CFR Part 101.5). There is no regulatory definition of undue responses, and different groups of vaccine users would probably define undue responses quite differently. To better explain the limitations on the safety information provided on vaccine labels, a short explanation of how these undue responses are characterized and how their absence is demonstrated is in order.
Product safety is generally demonstrated in a field trial (9 CFR Parts 103 and 113). There are no precise safety determination procedures in the USDA regulations. As a result, safety testing can be even more varied than the previously described efficacy testing. On the other hand, there are common elements to most safety test procedures. A safety study is generally performed by private practice veterinarians in multiple geographic locations. The veterinarians use the test product in patients as part of a preventive medicine program. The product used in the test is said to be representative of the product that is going to be sold commercially. The number of animals involved in the trial is not codified in the regulations, but, normally, at least 300 and, commonly, 500 to 1000 animals are used. The general protocol for these studies involves informing the animal's owner about the study, administering the test vaccine, observing the animal for a short period of time (i.e., 30 minutes), instructing the owner to observe the animal for adverse ,responses until it is presented to the veterinarian again, instructing the owner to report any adverse responses observed, representing the animal for a booster vaccination a few weeks later, and then repeating this procedure. All responses that are considered adverse are recorded. The responses that are recorded are then categorized as vaccine-mediated or non-vaccine-mediated responses.
The USDA approach to safety implies that vaccines can be categorized as safe or unsafe and that only the safe ones get to the marketplace. If these safe products have a small amount of safety text on the label, this would imply that the USDA and the manufacturer have determined that the safety information provided on the label is sufficient for the product's use. Does this amount of safety information adequately inform vaccine users? What can be said with certainty is that the quality and quantity of safety information on an animal vaccine label is much less than that found on the labels of common human vaccines. As an example, a currently approved human vaccine for diphtheria, tetanus, and
READLNG A VACCINE LABEL 553
pertussis has 49 column inches of text on its approved package insert about safety concerns associated with vaccine administration (Diphtheria and Tetanus Toxins and Pertussis Vaccine USP; Pasteur Merieux Connaught, Swiftwater, PA, 1999 package insert). The label lists many adverse responses with estimates of their frequency. Tl)ere are also guidelines as to which responses parents should pay more attention to and advice on when to call a health care provider if adverse responses are observed. It could be argued that this amount of text is overkill; at the same time, it is obvious that the average physician has access to considerably more information about vaccine safety than the average veterinarian. In contrast, it is not unusual for an animal vaccine label to essentially ignore the safety concerns of vaccine administration, with the exception of anaphylaxis. Anticipated USDA regulations are likely to result in more safety information being placed on the label by requiring significant responses seen in the safety studies to be noted on the product's label, but these rules are not in place at the time of this writing (USDA reviewer, personal communication, 1999).
What should practitioners take home from these safety issues? First, safety studies look for clinically obvious problems that are readily associated with vaccine administration and are seen within a short period after vaccination. An adverse consequence of vaccine administration that does not have a clinically obvious sign is not likely to be seen. Second, these studies are designed to demonstrate responses that are fairly common. If an adverse consequence is seen in 1 of 1000 vaccinates, a study that includes 500 animals has essentially a 50:50 chance of seeing the adverse response. Many practitioners vaccinate more than 1000 animals per year; thus, they would be expected to see things not described in these studies. As adverse responses become less frequent, these studies become less likely to evaluate the response. Third, these studies are highly subjective and require considerable interpretation on the part of the people involved. These studies depend on the people conducting the observations to be able to effectively observe responses in animals. They must then accurately describe the observation and its proposed association with vaccination in the study papers. As the study is interpreted, the observations must be accurately categorized, or their significance may be lost. Any breakdown in the process of communication makes the information less applicable to practitioners. Fourth, if the observers of the animals in the study are less observant than the average veterinarian or animal owner, significant responses may be ignored. This is a common problem with studies conducted in commercial kennels or herds. On the other hand, a single practitioner in a safety study may be overly responsive to animals' postvaccination responses. All these factors may change the way these data are collected and analyzed. For the vaccine label, all these factors eventually get distilled down to a few
554 HUSTEAD
short safety statements that in all probability do not accurately reflect the clinical safety of the product as ob.served by all users.
In the same manner as efficacy claims, differences in safety claims between similar products are hard to understand. Comparing two similar products may reveal differences in the safety information provided. Is the product with more detailed safety information on its label less safe? Maybe that is true, but maybe the manufacturer of one product has decided to more fully describe the adverse responses that are actually seen with this product or with similar products. Maybe the manufacturer simply wants to limit its liability by more fully describing safety concerns inherent in all vaccines. As a result, vaccines with the same safety text on their labels may behave differently in animals, and, at the same time, vaccines with differing label texts may behave the same. Differing claims for safety and efficacy on vaccine labels may be clinically important, or they may not. How is the reader to know?
Dose Volume
Beyond the single dose volume recommended on the label, vaccine labels tell nothing about the biologic issues associated with dose volume. The most common question from practitioners about this label direction is "Why does a Toy Poodle get the same dose as a Great Dane?" The only real answer is that no one knows for sure. The dose volume that is stated is the one dose volume that was tested in the licensing process. During the preceding discussion on safety and efficacy testing, the issue of breed was ignored. There are no regulated standards for the testing of breeds in animals. As a result, testing might be done in a single breed (i.e., Beagle or purposefully bred mongrels). From a regulatory perspective, the immune responses of all animals in the species get lumped into a single group. Although this is an open question, there is no information available to this author demonstrating that from an efficacy perspective, vaccine dose would be expected to be smaller for smaller animals. On the other hand, it is generally believed that the number of immune-sensitive cells in a species is fixed by the species and not the size of the individual animal.s In addition, vaccine effectiveness as demonstrated in a laboratory has been shown to be related to dose for some vaccines. 2 It is not known if this reduction in laboratory efficacy translates into less clinical efficacy, but that remains a concern. Using a smaller than directed dose volume could have reduced effectiveness in some animals. From a safety perspective, it is commonly argued from a clinical perspective that smaller animals are less likely to suffer adverse responses if they are given smaller doses of vaccine. This author .is unaware of any controlled data that support this claim. Until further
READING A VACCINE LABEL 555
work is done to define the safety or efficacy implications on breed or size of animals, the answer that is standard in the vaccine industry is that one size fits all.
Storage Conditions
Vaccine labels ignore all vaccine storage issues except storage at the recommended temperature range. They tell you little about what to do if the vaccine is stored outside these storage limits. It is well known that vaccines, like most biologic specimens, are negatively affected by storage in light and heat. Just how much heat and light negatively affect the product is not precisely known. Vaccine manufacturers are required to provide assurances that products are acceptable for use for the time period shown by the expiration date on the label (9 CFR Part 112). It is common in the vaccine industry for these expiration dates to be 2 to 3 years after the manufacture date. Vaccine labels have adopted storage condition recommendations that are most advantageous to the longterm storage of the product. There is a dearth of research on what happens to vaccines stored outside their label storage conditions. It is common biolOgic knowledge that small excursions from the label storage directions would be expected to have a small impact on the product. On the other hand, these excursions would be expected to be cumulative over the life of the product. At a practical level, storage of many vaccines at room temperature for a couple of hours is of little significance, but what if that storage occurs every day for a few days or weeks? What if that storage occurs over the weekend on the receiving dock? If vaccine users want the manufacturer's assurance that the product they use can be expected to perform like the product used in the safety and efficacy testing performed for the product's licensing, their only recourse is to store it per the directions on the label. The actual biologic impact of storage under any other environmental conditions is probably unknown.
CONCLUSIONS
Vaccine labels have important functions and can provide excellent service if they are read. On the other hand, current vaccine labels reflect specific word selection, or the absence of text, unique to the manufacturer or the USDA and are not always correctly understood by veterinarians. These characteristics of vaccine labels can make a user's effective information gathering difficult. Understanding the USDA labeling regulations and how vaccine labels evolved may resolve some of the user 's confusion regarding the use of a particular product. It is clear
556 HUSTEAD .,.
that there is ample scope for improvements in USDA reg'Uiations, which have a direct impact on vaccine labels.,. A few higher priority improvements would include a system of identification that informs users about a vaccine's unique antigenic components and identifies the presence of nonantigenic but immunogenic components (adjuvants), increased use of codified efficacy testing procedures that accurately reflect clinical reality, improved use directions that effectively deal with the classes of animals that all practitioners may need to vaccinate, and improved information on the actual clinical safety of vaccines. When users desire product information that they cannot locate on the product's label, an excellent resource is the technical staff of the manufacturer. These individuals should be able to discuss why the label does not adequately address a specific question and should be able to provide additional information. Be a well-informed vaccine user. It is important to you, your client, and your patient.
References
1. Greene C: Infectious Diseases of the Dog and Cat. Philadelphia, WB Saunders, 1998, p 104
2. Nervig MN, Gough PM, Kaeberle ML, et al: Advances in Carriers and Adjuvants for Veterinary Biologics. Ames, lA, Iowa State University Press, 1986, pp 55, 115-120
3. Runnels RA, Monlux WS, Monlux AW, et al: Principles of Veterinary Pathology. Ames, lA, Iowa State University Press, 1965, pp 80-81
4. Tizard IR: Veterinary lrrununology. An Introduction. Philadelphia, WB Saunders, 2000, pp 244, 247-251
Address reprint requests to David R. Hustead, DVM
International Technical Director Fort Dodge Animal Health
Overland Park, KS 66225
e-mail: [email protected]
VACCINES AND VACCINATIONS 0195-5616/ 01 $15.00 + .00
RABIES POSTEXPOSURE PROPHYLAXIS
Human and Domestic Animal Considerati011.8
M. Gayne Fearneyhough, BS, DVM
Since the middle of this century, an average of one or two human rabies cases has been reported annually in the United States. The 1996 estimated cost for rabies biologic agents required for postexposure prophylaxis (PEP) for people exposed to a rabid or potentially rabid animal was between $26.5 and $65.3 million.s In three studies conducted since 1980, the total annual expenditure to prevent rabies in the United States was found to be at least $230 million, and it may be as much as $1 billion annually.7 A cursory analysis of the public health significance of rabies in the United States could easily result in the conclusion that a disproportionate number of resources are allocated to the disease, especially when the numbers of cases of human rabies and rabies in domestic animals have declined over the last 50 years. A more detailed examination of the epidemiologic nature of rabies reveals a valid cause for concern, however, with rapidly expanding epizootics of wildlife rabies in raccoons in the eastern United States, in foxes in Texas and the northeastern United States, and in coyotes in Texas. An additional cause for concern is the identification of a viral variant transmitted by bats, which may represent an increased public health threat. That threat has caused modification to the Centers for Disease Control and Prevention (CDC) recommendations for PEP in people experiencing potential exposure to a bat. 4
Prior Director, Oral Rabies Vaccination Program, Texas Department of Health, Zoonosis Control Division, Austin, Texas from 1993-2000
VETERINARY CLINICS OF NORTIl AMERJCA: SMALL ANIMAL PRACTICE
VOLUME 31 • NUMBER 3 • MAY 2001 557
558 FEARNEYHOUGH
Although rabies causes only one ortwo human deaths annually in the United States, it is important to UI1derstand an estimated 40,000 to 100,000 human deaths result worldwide from rabies each yearY Consequently, as a society, we tend to have a strong and sometimes unreasonable fear of exposure to the rabies virus. That fearful response may be attributed in part to the graphic depiction of the disease by the entertainment industry in motion pictures such as "Old Yeller" and "Cujo." Fear of rabies may stimulate someone with a potential exposure to rabies to seek medical intervention and thereby save a human life. Conversely, fear also causes patients to demand treatment when a threat does not exist and may result in the inappropriate use of valuable medical resources. Practicing veterinarians, medical professionals, or public health workers may find that they are the most informed participants in a risk analysis process after a potential human or animal exposure to rabies. When administered according to recommendations provided by the Advisory Committee on Immunization Practices (ACIP), PEP has been shown to be essentially 100% effective. Given that rabies is universally fatal, it is essential that accurate and timely decisions be made concerning the administration of PEP.
A 1946 report by the Committee on Animal Health of the National Research Council determined that rabies was a preventable disease and proposed that a coordinated effort to achieve that goal be developed under the leadership of the United States Department of Agriculture (USDA) and individual state veterinarians.lJ Control measures that focused on domestic animal vaccination, local animal control programs, public education, and wildlife depopulation were proposed. In 1938, there were 9412 cases of rabies reported in animals (mostly in domestic species) and 47 human deathsY As late as 1960, most rabies cases were still reported in domestic species. Beginning in 1990, however, there was a dramatic increase in reported cases of wildlife rabies, primarily attributed to the raccoon rabies epizootic in the eastern United States. From 1990 to 1993, a 225% increase was reported in raccoon rabies cases (from 1812 to 5885) in the mid-Atlantic and northeastern states. By 1996, more than 90% of the 7124 animal rabies cases reported in the United States to the CDC were in wildlife species.s, 13
Although a coordinated national program did not develop, some or all of the principles for rabies control that were proposed in 1946 were employed at the state and local levels. It is reasonable to assume that those measures have had a favorable impact on the reduction of human and domestic animal rabies cases over the last 50 years. Nevertheless, the changing face of rabies with the identification of new animal reservoirs and new viral variants has necessitated that rabies control and PEP recommendations constantly evolve. That evolutionary process should
RABfES POSTEXPOSURE PROPHYLAXIS 559
employ the application of new technology to continue to prevent human deaths through the appropriate application of PEP and the development of ~ovative programs to reduce the presence of rabies in wildlife.
RABIES RISK ASSESSMENT
The evaluation process to ascertain an individual's risk of exposure to rabies first involves the determination of whether a bite or nonbite exposure may have occurred. If an exposure has occurred that could result in rabies virus transmission, it is critical that proper wound management techniques be used immediately. The simple process of proper wound cleansing and irrigation with adequate soap and water can reduce the potential for rabies. 2 Assessment of the wound and appropriate use of antibiotic therapy and tetanus prophylaxis should also be considered. .
The end result of what can be a complicated risk assessment process is the decision of whether to initiate PEP. A decision to withhold PEP while awaiting the outcome of a laboratory test or the outcome of a quarantine period for the biting domestic animal constitutes a decision to not treat the patient at that time. If a patient has been exposed to rabies, the greatest chance for survival may depend on prompt initiation of PEP. The process of reaching a risk assessment decision can be complicated and clouded by emotional and legal considerations. The following summary of risk assessment considerations is taken from the recommendations of the ACIP and the National Association of State. Public Health Veterinarians (NASPHV) as published in the Morbidity and Mortality Weekly ReporU· 10 These recommendations constitute the minimum criteria that should be considered in evaluating a patient's risk for rabies exposure. Figure 1 represents a rabies PEP decision tree.
Type of Exposure
The primary mechanism of rabies transmission involves a bite wound, which allows the passage of virus-containing saliva across a previously intact skin barrier. Bites to the face and hands carry the highest risk, but the site of the bite should not influence the decision to begin PEP. Nonbite exposure by means of scratches, abrasions, open wounds, or mucous membranes that are exposed to saliva or other infective material (i.e., brain tissue, cerebrospinal fluid) may also constitute an exposure. Petting a rabid animal; exposure of intact skin to blood, urine, or feces of a rabid animal; or contact with fluids that may
560 FEARNEYHOUGH
Figure 1. Rabies postexposure prophylaxis decision trae.
have been infective but have dried does not constitute an exposure. Nonbite exposure from aerosolized rabies virus in caves, laboratory settings, or organ transplants (i.e., corneas) has occurred but represents unlikely an exposure situation.
RABIES POSTEXPOSURE PROPHYLAXIS 561
Exposing Animal
Wild Animal Bites
Bites by wild carnivores and bats should be considered an exposure to rabies and require initiation of PEP for the patient. The biting animal should be humanely killed immediately, and the brain should be tested for rabies, especially in species that may be defined as high risk for rabies exposure such as raccoons, skunks, foxes, and bats. The recent epizootic of canine rabies in coyotes along the Texas-Mexico border and the practice of translocating coyotes for hunting purposes may make it prudent to also consider them a high-risk species. PEP may be delayed if the bite occurs in a geographic area of the United States that is free of terrestrial rabies and if the results of immunofluorescence testing are available within 48 hours. If treatment is initiated and the biting animal is shown not to be rabid, treatment may be discontinued. Exotic animals and valuable specimens that have been confined and have been determined by public health authorities to represent a limited risk may be quarantined for 30 days in lieu of testing. Rodent and lagomorph species are almost never found to be infected with rabies, and local health departments should be consulted concerning bites by those animal groups. Rabies in groundhogs accounted for 70% of the 179 cases among rodents reported to the CDC from 1971 through 1988, however.2 An analysis of data reported by Krebs and associates9 from 1991 through 1996 indicates an annual average of 52 cases of rabies in groundhogs, with most of those cases attributed to the raccoon variant of the rabies virus. The Conference of State and Territorial Epidemiologists and the NASPHV consider exotic pets and domestic animals crossbred with wild animals to be wild animals.10 A bite by any of those animals should be handled as an exposure to a wild animal.
Modifications to PEP recommendations were presented to the ACIP in 1996, because data indicated that bats were associated with an increasing number of human rabies cases. From 1990 through 1996, bat rabies variants were associated with 15 of 17 indigenously acquired cases of human rabies. An identifiable bite was reported in only 1 of those cases, suggesting that minimal or unnoticed physical contact with bats may result in viral transmission.8 In situations in which a bat is physically present and the person(s) cannot reasonably exclude the possibility of a bite exposure, PEP should be given unless prompt capture and testing of the bat have excluded rabies virus infection.3 This recommendation has particular significance for children, mentally challenged adults, and intoxicated individuals, who may be unable to responsibly assess whether contact with a bat has occurred. If a bat is found in a room with an unattended child or is found present in a room in which a child
562 FEARNEYHOUGH
or adult was sleeping and physical contact cannot be excluded, PEP should be initiated immediately, and, it available, the bat should be tested for rabies. Negative immunofluorescence antibody testing results from a certified laboratory are justification for discontinuing PEP.
Domestic Animal Bites
The NASPHV makes recommendations to be used in the management of animals that bite human beings (Ref. la, p 83) .10
Circumstances of the Bite
An unprovoked bite by a domestic animal may constitute an increased risk for rabies in the biting animal and contributes to a decision to initiate PEP for the patient. People fear being bitten by an animal; thus, it is reasonable to assume that most bites inflicted on human beings by domestic animals are not intentionally provoked. It is important to emphasize that the human definition of provocation may not be consistent with conditions that elicit aggressive or ·defensive behavior in a domestic species. Although not often seen as provocative behavior by people, actions such as invading the ill-defined physical territory of an animal, disturbing an animal during eating, staring into the eyes of a dominant animal, playing by children that may attempt to force an animal to the ground, and blowing into the face of an animal are but a few examples of human behavior that may produce an aggressive response in a normal animal.
Vaccination Status of the Exposing Animal
Knowledge that a biting domestic animal is currently vaccinated with a vaccine licensed for that species does not remove all concern for involvement of rabies, because no vaccine can be considered to be 100% effective. Animal vaccines licensed for use in the United States have achieved a high level.of immunogenicity, however, and their use in a domestic species for which a license has been approved markedly reduces the potential for rabies involvement. Knowledge of a current vaccination in the biting animal, when combined with a lack of epidemiologic evidence of terrestrial rabies in the geographic area and reduced risk associated with conditions of the bite, may allow for justification of a la-day quarantine period for a biting animal. Employing a la-day quarantine period has obvious benefits to the owner of a valuable animal compared with euthanizing the animal and testing the brain. If the
RABIES POSTEXPOSURE PROPHYLAXlS 563
animal is available for quarantine and the risk assessment process indicates a low probability for rabies, PEP can be delayed for the patient; however, PEP should be initiated immediately at the first sign of rabies in the' quarantined animal (Table 1).
RABIES IMMUNIZING PRODUCTS FOR USE IN HUMAN BEINGS
There are two types of immunizing products for use in human beings: immune globulins that provide rapid passive immune protection for a short time (half-life of about 21 days) and vaccines that induce an active immune response (requires about 7-10 days to develop, but immunity may persist for at least 1 year). Both types of products should be used concurrently for rabies PEP in those persons who have never received prior immunization against rabies. It is recommended that the package insert be consulted before any of these products is used.14
Table 1. CURRENT ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES RABIES POSTEXPOSURE HUMAN PROPHYLAXIS GUIDE
Animal Type
Dogs and cats
Skunks, raccoons, bats, foxes, and most other carnivores; groundhogs
Uvestock, rodents, and lagomorphs (rabbits and hares)
Evaluation and Disposition of Animal
Healthy and available for 10 days
Rabid or suspect rabid Unknown or escaped Regarded as rabid tmless
geographic area is known to be free of rabies or until animal is proved negative by laboratory testt
Consider individually
Postexposure Prophylaxis Recommendations
Should not begin PEP unless animal develops clinical signs of rabies'
Immediate PEP Consult public health officials Immediate PEP
Consult public health officials; bites of squirrels, hamsters, guinea pigs, gerbils, chipmunks, rats, mice, other rodents, rabbits, and hares almost never require antirabies treatment
'During the 10-day holding period, begin treatment with human rabies inunune globulin and human diplOid cell vaccine or purified chick embryo cell culture at first sign of rabies in a dog or cat that has bitten someone. The animal with clinical signs should be euthanized inunediately and tested.
tThe animal should be euthanized and tested as soon as possible. Holding for observation is not recommended. Discontinue vaccine if inununofluorescence test nesults of the animal are negative.
PEP = postexposure prophylaxis. From Centers for Disease Control and Prevention: Rabies prevention-United States, 1991, recom
mendations of the lmmunization Practices Advisory Committee (ACIP). MMWR Morb Mortal WkIy Rep 4O(RR-3):1-19, 1991.
564 FEARNEYHOUGH
Table 2. POSTEXPOSURE TREATMENT PRODUCTS-HUMAN RABIES IMMUNE GLOBULlN*
Product Name • Manufacturer ...
Irnogam BayRab
Pasteur Merieux Connaught Laboratories (Swiftwater, PAl Bayer Laboratories (Pittsburgh, PAl
• Administered at time of first dose of vaccine only. Patient weight is needed to determine dose. Dose is 20 lU / kg (2 mL per 33 Ib).
Rabies Immune Globulin
Human rabies immune globulin (HRIG) (Irnogam Rabies-HT, Pasteur Merieux Connaught, Swiftwater, PA; and BayRab, Bayer Laboratories, Pittsburgh, PA) is antirabies ·gamma globulin concentrated by cold ethanol fractionation from the plasma of immunized human donors. Rabies neutralizing antibody content is standardized to contain 150 IU / mL. It is supplied in 2-mL (300 IU) and 10-mL (1500 IU) vials for pediatric and adult use, respectively (Table 2). Irnogam Rabies-ill has received an additional heat treatment step to further reduce the risk of the transmission of known or unknown blood-borne viruses.
Vaccines
Human Diploid Cell Vaccine
Human diploid cell vaccine (HDCV) is an inactivated virus vaccine prepared from rabies virus grown in human diploid cell culture and then inactivated (Table 3) . Vaccine is supplied as 1-mL single-dose vials of freeze-dried vaccine with accompanying diluent for intramuscular (1M) injection (Irnovax Rabies Vaccine, Pasteur Merieux Connaught) and O.l-mL single-dose syringes of freeze-dried vaccine with accompanying diluent for pre-exposure intradermal use (Irnovax Rabies LD., Pasteur Merieux Connaught). Both formulations must be used immediately after reconstitution.
Table 3. POSTEXPOSURE TREATMENT PRODUCTS-HUMAN RABIES VACCINES
Product Name Manufacturer
Irnovax: human diploid cell vaccine Pasteur Merieux Connaught Laboratories (Swiftwater, PAl
RabAvert: purified chick embryo cell culture Chiron Behring GrnhH & Company (Hessen, Germany)
RABIES POSTEXPOSURE PROPHYLAXIS 565
Purified Chick Embryo Cell Culture
Purified chick embryo cell (PCEC) culture is a sterile freeze-dried vaccine obtained by growing the Flury-fixed virus strain, low-egg passage 'in primary cultures of chicken fibroblasts (see Table 3). PCEC culture (RabAvert, ChiTon Behring GmbH & Company, Hessen, Germany) is licensed in the United States for IM use in pre-exposure immllllization and PEP. The schedules and dosage for PCEC culture are the same as for HDCY. It may be used as a booster dose even if another rabies vaccine was used for the primary series.
Serious adverse reactions associated with some rabies vaccines include systemic, anaphylactic, and neuroparalytic reactions. Serious adverse reactions occur at lower rates with HDCV or PCEC vaccines than with previously available types of rabies vaccine.
POSTEXPOSURE PROPHYLAXIS IMMUNIZATION PROTOCOL
Postexposure antirabies immllllization should include administration of rabies antibody (HRJG) and vaccine (HDCV or PCEC culture). An exception to this guideline is made for exposed persons who have been previously immunized with the recommended pre-exposure or postexposure regimens of HDCV or PCEC culture (or who have been immllllized with other types of vaccines and have documented an adequate rabies antibody titer). In those cases, HRJG would not be given, and only two doses of vaccine would be given on day 0 and day 3 (Table 4).
The combination of immune globulin and vaccine is recommended for persons not previously immllllized for bite exposures and nonbite exposures, regardless of the interval between exposure and treatment. The sooner treatment is begun after exposure, the better is the chance of effectiveness. If there was a delay in recognizing a rabies exposure, treatment may be started even months after that exposure occurred.
Five 1-mL doses of HDCV or PCEC culture should be given IM in the deltoid region in adults or on the anterolateral thigh in infants. The intradermal route should not be used for PEP. The first dose should be given as soon as possible after exposure; additional doses should be given on days 3, 7, 14, and 28 after the first dose. Antibody response after the recommended vaccination regimen has been uniformly satisfactory; thus, routine postvaccination serologic testing is not normally recommended. In unusual instances, however, such as when the patient is immunodeficient or immunosuppressed, serologic testing (rapid fluorescent focus inhibition test) is indicated. This test is available with fast
566 FEARNEYHOUGH .. ,
Table 4. RABIES POSTEXPOSURE PROPHYLAXIS SCHEDULE IN THE UNITED STATES
Patient Vaccination Status Treatment ..
Not previously vaccinated Local wound cleansing
HRIG
Vaccine
Previously vaccinated:j: Local wound cleansing
HRIG
Vaccine
Regimen·
All postexposure treatment should begin with immediate thorough cleansing of all wounds with soap and water
20 IV/kg of body weight; as much as possible of the full dose should be infiltrated into and around the wound(s), and the remainder should be administered 1M at an anatomic site distant from vaccine administration; HRIG should not be administered in the same syringe as vaccine; Because HRIG may partially suppress active production of antibody, no more than the recommended dose should be given
1 mL of HDCV or PCEC culture 1M (deltoid areat) on days 0, 3, 7, 14 and 28
All postexposure treatment should begin with immediate thorough cleansing of all wounds with soap and water
HRIG should not be administered
1 mL of HDCV or PCEC culture IM (deltoid areat) on days 0 and 3
'These regimens are applicable lor all age groups, including children. tThe deltoid area is the only acceptable site 01 vaccination lor adults and older children. For
younger children, the outer aspect 01 the thigh may b~ used. Vaccine should never be administered in the gluteal area. .
:j:Any person with a history 01 pre-exposure vaccination with HDCV or PCEC, prior postexposure prophylaxis with HDCV or PCEC, or previous vaccination with any other type 01 rabies vaccine and documented history 01 antibody response to the prior vaccination.
HRJG = human rabies immune globulin; 1M = intramuscularly; HDCV = human diploid cell vaccine; PCEC = purified chick embryo cell
From Texas Department of Health: Rabies Prevention in Texas 1997. Austin, DC, Texas Department of Public Health stock no 6-108, 1997; with permission.
turnaround through the Department of Veterinary Diagnostics, Veterinary Medical Center, Kansas State University, Manhattan, Kansas 66506 (telephone: 785-532-5650).
The selection of sites for IM injections of vaccine seems to be critical
RABrES POSTEXPOSURE PROPHYLAXIS 567
for vaccine efficacy. In adults and larger children, HDCV or PCEC culture should be given in the deltoid area. In infants and small children, the anterolateral thigh should be used. In the two laboratory-confirmed cases · of human rabies after postexposure treatment with HDCV and HRlG within 24 hours, the HDCV was administered in the gluteal area. Presumably, subcutaneous fat in the gluteal area may interfere with proper 1M administration of the vaccine and thus reduces the immunogenicity of the vaccine.
HRlG is administered only once at the beginning of antirabies prophylaxis to provide immediate antibodies until the patient responds to vaccination with active production of antibodies. If HRlG was not given at the initiation of vaccination, it can be given up to the eighth day after the first dose of vaccine. From the eighth day on, HRIG is not indicated, because an antibody response to the vaccine is presumed to have occurred.
The recommended dose of HRlG is 20 IU /kg or approximately 9 IU/lb (2 mL per 33 lb) of body weight. As much of the full dose of HRlG as possible should be thoroughly infiltrated into and around the wound(s). Any remaining volume should be administered 1M at a site distant from vaccine inoculation. No more than the recommended dose of HRlG should be given because it may partially suppress active production of antibody.
POSTEXPOSURE PROPHYLAXIS TREATMENT OUTSIDE THE UNITED STATES
If PEP treatment is begun outside the United States with locally produced biologic agents, it may be desirable to provide additional treatment when the patient reaches the United States. For specific advice in such cases, contact the local health department.
POSTEXPOSURE THERAPY OF PREVIOUSLY IMMUNIZED PERSONS
Pre-exposure immunization does not remove the need for PEP; it merely reduces the extent of treatment. On exposure to rabies, an immunized person who was vaccinated with the recommended regimen of HDCV or PCEC culture or who has previously demonstrated rabies antibody should receive two 1M doses (1 mL each) of HDCV or PCEC culture, one immediately and one 3 days later (see Table 4). HRlG should not be given in these cases. Full primary postexposure antirabies treatment (HRlG plus five doses of HDCV or PCEC culture) may be
568 FEARNEYHOUGH ..
necessary in the case of unknown immune status in a previously vaccinated person who did not receive the recommended HDCV or PCEC regimen. In such cases, if antibody can be demonstrated in a serum sample collected before vaccine is given, treatment can be discontinued after at least two doses of HDCV or PCEC culture.
ACCIDENTAL HUMAN EXPOSURE TO ANIMAL RABIES VACCINE
Accidental inoculation or vaccine contact with mucous membranes may occur in human beings during administration of rabies vaccines to animals. Such exposure to inactivated rabies vaccine constitutes no known rabies hazard.
PRECAUTIONS AND CONTRAINDICATIONS
Immunosuppression
Corticosteroids and other immunosuppressive agents, antimalarials, and immunosuppressive illnesses (such as HIV infection) can interfere with the development of active immunity and predispose the patient to the development of rabies. Immunosuppressive agents should not be administered during postexposure therapy unless they are essential for the treatment of other conditions. When rabies PEP is administered to persons receiving corticosteroids or other immunosuppressive therapy or to persons having an immunosuppressive illness, it is especially important that the patient be tested for rabies antibody to ensure that an adequate response has developed.
Pregnancy
Because of the potential consequences of an inadequately treated rabies exposure and limited data indicating that fetal abnormalities have been associated with rabies vaccination, pregnancy is not considered a contraindication to PEP. If a substantial unavoidable risk of exposure to rabies exists, pre-exposure prophylaxis may also be indicated during pregnancy.
RABIES POSTEXPOSURE PROPHYLAXIS 569
Allergies
Persons with histories of hypersensitivity should be gjven rabies vaccines with caution. When a patient with a history suggesting hypersensitivity to HDCV or PCEC culture must be gjven that vaccine, antihistamines can be provided; epinephrine should be readily available to counteract anaphylactic reactions, and the person should be carefully observed.
MANAGEMENT OF PETS EXPOSED TO RABID ANIMALS
The management of cases of domestic animals exposed to rabies can be difficult because of the lack of an immediate perceived threat to human life. The exposure incident obviously could later result in human exposure if the domestic animal should develop rabies. As a result, the recommendation normally has been to sacrifice the exposed animal. Management of these cases may also be further complicated by the emotional value of the animal as well as conflict over the rights of ownership of private property and disposition of that property when little or no human health risk exists. The NASPHV recommends postexposure management for animals exposed to a rabid animaLB
Confusion has occurred with respect to (1) . the la-day observation period for a dog, cat, or ferret that has bitten or scratched a human being and (2) the period of strict isolation required for an unvaccinated dog, cat, or ferret that has been exposed to a rabid animal. Generally, when clinical symptoms of rabies are first evident, the rabies virus also becomes present in the saliva, and a dog, cat, or ferret survives no longer than 3 to 5 days. If the animal is clinically normal 10 days after the biting incident, it is not considered likely for rabies virus to have been present in its saliva at the time of the bite. As a result, exposure to rabies virus could not have resulted from the bite, and PEP is not indicated. A dog, cat, or ferret may develop rabies more than 10 days after having bitten a person, but the animal would not be considered to have been infective at the time of the bite.
The la-day observation period is not applicable for a dog, cat, or ferret exposed to a rabid animal. The average incubation time for rabies in those species is generally 3 to 8 weeks; thus, an observation period of 45 days for vaccinated animals and 180 days for unvaccinated animals is recommended. Consequently, the la-day observation period is useful in ensuring that a dog, cat, or ferret was not able to transmit rabies at the time of a biting incident, but it is not applicable for those species under observation after an exposure to a rabid animal.
570 FEARNEYHOUGH
POSTEXPOSURE PROPHYLAXIS JUSTIFICATION FOR DOMESTIC ANIMALS
The primary concern of the risk -assessment process to determine the appropriateness of PEP for a human patient must be the patient's safety. Rabies is universally fatal; thus, there is a tendency to administer PEP to the human patient when there may be even a limited potential for rabies exposure. That conservative approach to management of the human patient has also resulted in recommendations for sacrificing an animal exposed to or potentially exposed to rabies. Such recommendations are not usually based on a callous approach to the value of the animal but rather on a concern that the exposed animal might later develop rabies and represent a serious public health threat. The reluctance to advocate the use of PEP in animals is also complicated by the fact that there are limited scientific data published to demonstrate the effectiveness of PEP when administered to domestic animals.
A 1996 study by Clark and Wilson5 does provide data to demonstrate the effectiveness of PEP in unvaccinated domestic animals. This retrospective study was conducted using two PEP protocols on 1345 unvaccinated domestic animals that were exposed to rabies and reported to the Texas Department of Health over a 16-year period. The first PEP protocol was used from 1979 through 1987 and involved 713 animals (440 dogs; 57 cats; 145 cattle; 53 horses; and 18 sheep, goats, and pigs). The exposed animals were immediately vaccinated and revaccinated 1 month before release from a 6-month period of isolation (there is no USDA~licensed vaccine for goats and pigs). The second protocol was used from 1988 through 1994 and involved 632 animals (406 dogs; 106 cats; 69 cattle; 43 horses; 7 sheep, pigs, and goats; and 1 llama). In the second protocol, the exposed animals were vaccinated immediately and given booster vaccinations during the third and eighth weeks of a 90-day isolation period (there is no USDA-licensed vaccine for llamas). This study determined that 711 of 713 animals (99.7%) given PEP using the first protocol and 629 of 632 animals (99.5%) given the second protocol survived.
Another study in ' 1991 conducted by Blancou and associates! to determine the efficacy of the human PEP protocol used 68 sheep experimentally infected with fox rabies virus. The infected sheep were divided into three groups and were given cell culture vaccine on days 0, 3, 7, and 14; HRlG at 26 IU/ kg on day 0; or a combination of vaccine and immune globulin. Seventy-one percent of the controls died; the treatment protocol using a combination of vaccine and immune globulin was found to be 100% effective. These results seem to indicate that there may be justification for PEP for domestic animals. Additional studies are needed to identify animal PEP protocols capable of producing a high
RABIES POST EXPOSURE PROPHYLAXIS 571
level of survivability, conforming to public health concerns, and yet being economically applicable to domestic animals.
SUMMARY
The emphasis on rabies control and prevention in the United States seems to be a function of our perception of proximity of the threat. Wildlife rabies epizootics within a state may be of little concern to the uninformed urban dweller. Additionally, many parts of the western United States are free of terrestrial rabies; were it not for the presence of bat rabies, people in those areas would likely interpret rabies control as a minor public health concern. It is essential that federal, state, and local public health programs emphasize the importance of rabies control through activities that include rabies education, sponsorship of legislated requirements for domestic animal vaccination, support for local animal control programs, and the promotion of recommendations that encourage the appropriate use of PEP. We are almost guaranteed that rabies is going to remain a major public health issue well into the next century because of expanding wildlife rabies epizootics, identification of new rabies viral variants with increased public health concern, emotional and legal concerns associated with rabies exposure, and increasing national cost associated with rabies control and prevention. Nevertheless, the development of new laboratory technology that allows an understanding of the epidemi9logic nature of the rabies virus based on an evolving genetic history and the interrelationship with wildlife reservoirs should allow access to valuable tools for rabies control. When combined with programs using new developments in oral rabies vaccine that can immunize whole populations of wildlife reservoirs, that technology offers encouragement in our effort to control one of the diseases of antiquity.6
ACKNOWLEDGMENTS
The author thanks Dr. Erik Svenkerud and Pamela J. Wilson of the Texas Department of Health for their assistance and editorial comments.
References
1. Blancou J, Baltazar RS, Molli I: Effective postexposure treatment of rabies-infected sheep with rabies immune globulin and vaccine. Vaccine 9:432-437, 1991
2. Centers for Disease Control and Prevention: Rabies prevention-Urtited States, 1991, recommendations of the immunization Practices Advisory Comrrtittee(ACIP). MMWR Morb Mortal Wkly Rep 40(RR-3):1-19, 1991
3. Centers for Disease Control and Prevention: Rabies prevention. MMWR Morb Mortal Wkly Rep 445:209, 1996
572 FEARNEYHOUGH
4. Childs JE, Krebs JW, Rupprecht CE: Epidemiology of bat rabies in the VSA. Presented at the Eighth Annual International Meeting of Rabies in the Americas, Kingston, Ontario, Canada, November 2-6, 1997
5. Clark KA, Wilson PI: Postexposure rabies prophylaxis and preexposure rabies vaccination failure in domestic animals. JAVMA 208:182~830, 1996
6. Feameyhough MG, Wilson PI. Clark KA, et al: Results of an oral rabies vaccination program for coyotes. JAVMA 212:498-502, 1998
7. Fishbein DB, Robinson LE: Rabies. N Engl I Med 329:1632-1638, 1993 8. Krebs JW, Long-Marin SC, Childs JE: Causes, cost, and estimates of rabies postexposure
prophylaxis treatment in the United States. Journal of Public Health Management and Practice 4:56-62, 1998
9. Krebs JW, Smith JS, Rupprecht CE, et al: Rabies surveillance in the United States during 1996. JAVMA 211:1525-1539, 1997
10. National Association of State Public Health Veterinarians: Compendium of animal rabies control, 1998. MMWR Morb Mortal Wkiy Rep 47(RR-9):1-9, 1998
11. National Research Council: Committee on Animal Health report: Rabies and its control. JAVMA 108:293-302, 1946
12. Rupprecht CE, Smith JS, Fekadu M, et al: The ascension of wildlife rabies: A cause for public health concern or intervention? Ernerg Infect Dis 1:107-113, 1995
13. Rupprecht CE, Smith JS, Krebs I. et al: Current issues in rabies prevention in the United States, health dilemmas, public coffers, private interests. Public Health Rep 111:400-407, 1996
14. Texas Department of Health: Rabies Prevention in Texas 1997. Austin, TX, Texas Department of Public Health, stock no 6-108, 1997
Address reprint requests to M. Gayne Fearneyhough, BS, DVM
516 Lariat Lane Dripping Springs, TX 78620
e-mail: [email protected]
VACCINES AND VACCINATIONS 0195-5616/01 $15.00 + .00
IMPORTATION OF DOGS AND CATS TO RABIES-FREE AREAS
OF THE WORLD
Deborah J. Briggs, MS, PhD, and Kristen Schweitzer, BS
The World Health Organization (WHO) defines a rabies-free area as "one in which an effective import policy is implemented and, in the presence of adequate disease surveillance, no case of indigenously acquired rabies infection has been confirmed in humans or any animal species at any time during the previous two years."6 The presence or absence of rabies virus in the indigenous bat population is not induded in the WHO definition. Countries and areas where no rabies was reported in 1997 are published at the WHO world wide web site and include but are not limited to: Australia, Bahamas, Fiji, Finland, Guam, Hawaii, Hong Kong, Iceland, Japan, New Zealand, Papua New Guinea, Portugal, St. Kitts and Nevis, Singapore, Sweden, and the United Kingdom.6
Prior to the advent of highly efficacious killed rabies vaccines, lengthy quarantine laws for dogs and cats entering rabies-free areas were used as a means to prevent the introduction or reintroduction of rabies. However, quarantine periods of 4 to 6 months have become increasingly unacceptable to many people relocating to rabies-free areas that wish to take their family pet with them. Resulting public pressure from a very mobile society has caused the governments of many rabies-
From the Rabies Laboratory, Kansas State University, College of Veterinary Medicine, Manhattan, Kansas
VETERINARY CLINlCS OF NORTH AMERICA: SMALL ANIMAL PRACTICE
VOLUME 31 • NUMBER 3 • MAY 2001 573
574 BRlGGS & SCHWEITZER
free areas to re-evaluate their quarantine system. In the Eighth Report of the WHO Expert Committee on Rabies alternate recommendations to lengthy quarantine requirements were mad~to ensure the protection of rabies-free areas while simultaneously reducing the length of time required for a dog or cat to be held in a quarantine facility.6 Several rabiesfree areas have embraced all or part of the WHO recommendations while others are in the process of reviewing or updating their import requirements for dogs and cats from countries in which rabies is absent or well controlled. Rabies-free areas that have replaced their lengthy quarantine periods for dogs and cats being imported from the continental United States with alternate measures include Australia, New Zealand, St. Kitts and Nevis, St. Vincent and the Grenadines, Malta, Guam, and Hawaii. Between 1995 and 2000, more than 15,000 dogs and cats have been imported into these areas with no reports of rabies being introduced or reintroduced.
When preparing to move to a rabies-free area that has strict importation regulations regarding dogs and cats, meeting the criteria to qualify for a reduced quarantine program requires time, patience, and advanced preparation. There are several commercial companies that specialize in pet moving services, relieving the owner of the tedious and often complicated preparation that is necessary to fulfill governmental requirements. If a pet relocation specialist is chosen by the owner to help with the move, the specialist should be reputable and preferably belong to the Independent Pet and Animal Transport Association International, Inc. (!PATA). Members of the !PATA are registered or licensed by the USDA (in the United States) and form a network of pet shippers throughout the world. If the pet owner decides to forego the services of a pet relocation service, they should contact the consulate of the destination country to determine the regulations required for importing their animal.
REQUIREMENTS
The requirements for importing dogs and cats can generally be obtained through the department of agriculture in the country in question or through their governmental consulate in Washington, D.C. Most countries require an import permit at some point in the application process. Also, some countries prohibit the importation of certain breeds of dogs and cats. If, upon arrival, an animal has not fulfilled the prearrival requirements or is a prohibited breed, the owner is usually responsible for removing the animal from the country. Alternatively, the animal could be placed in extended quarantine or in the worst case scenario, euthanized.
IMPORTATION TO RABIES-FREE AREAS 575
Rabies-free areas depend on their import regulations to prevent the introduction or reintroduction of rabies virus. The countries listed in Table 1 have implemented rigid rabies vaccination and antibody testing schedUles to reduce the length of time dogs and cats must remain in quarantine. It is critical to review and understand these regulations with a veterinarian knowledgeable in vaccination and transportation policies well in advance of anticipated departure. For example, to meet the qualifications for the minimum 30-day quarantine in Australia, a dog or cat must be vaccinated against rabies and have blood withdrawn for a rabies neutralizing antibody titer test (RNATT) 150 days prior to export.
All blood samples for RNATT must be sent to a laboratory approved by the government of the destination area. If an identifying microchip or tattoo is required, it must be in place prior to having the blood withdrawn. In addition, the blood sample and the accompanying paperwork must be labeled with the draw date and identifying microchip or tattoo number. Currently, Hawaii regulations state that only animals identified with AVID (Norco, CA) or Home Again (Schering Plough Animal Health, Kenilworth, NJ) microchips are valid for entry. Australia and New Zealand regulations require the signature of an official USDA area veterinarian on all paperwork prior to the animal leaving the country of export. The regulations in Hawaii, Guam, St. Kitts and Nevis, and St. Vincent and the Grenadines require the official RNATT testing laboratory to send the results directly to the governmental office in their country. Some regions have special provisions for certified service dogs that allow the dog to bypass quarantine if additional required testing, permits and vaccinations have been completed in advance.
Two RNATT are recognized by the Office des International Epizooties (OIE),1 the World Organization for Animal Health: the rapid fluorescent focus inhibition test (RFFIT) and the fluorescent antibody virus neutralization test (FAVN). In general, most rabies-free areas will accept the results from either test; however, some areas may only accept the results from serum tested by one methodology (Table 1). Rabies-free areas may require more than one serologic test to be performed prior to entry and some areas require an additional test to be performed after the animal has arrived. The consulate of the respective rabies-free area should be contacted for specific requirements. The RFFIT and the FAVN are based on the same principle and have been proven to produce similar results on duplicate serum samples.4
Rabies virus neutralization assays measure the animal's humoral immune response after vaccination. When an RNATT is required, the results must be equal to or greater than 0.5 International Units of rabies neutralizing antibody per mL of serum (IU/mL). The level of 0.5 IUI mL was originally selected as the value at or above which inhibition of rabies virus could not be attributed to nonspecific interference factors
<.n
"I '"
Tab
le 1
. R
AB
IES
SE
RO
LO
GY
AN
D A
NIM
AL
TR
AN
SP
OR
T T
O R
AB
IES
-FR
EE
AR
EA
S·
RN
AT
Tt
Des
tin
atio
n
Iden
tifi
cati
on
R
abie
s V
acci
nat
ion
R
equ
ired
Aus
tral
ia
Mic
roch
ip
2 re
quir
ed,
last
wit
hin
RF
FIT
or
FAV
N
12 m
on
ths
of
expo
rt.
New
Zea
land
T
atto
o o
r m
icro
chip
1
vacc
ina
tio
n b
etw
een
RFF
IT o
r FA
VN
1
and
6 m
on
ths
of
expo
rt.
Haw
aii
AV
ID o
r H
ome
Aga
in
2 re
quir
ed,
last
FA
VN
onl
y br
and
mic
roch
ip
vacc
inat
ion
betw
een
12 a
nd 3
m
onth
s of
exp
ort
St.
Kit
ts &
A
VID
mic
roch
ip
2 re
qu ir
ed,
last
at
RFF
IT o
r FA
VN
N
evis
le
ast
30 d
ays
prio
r to
, b
ut
wit
hin
12
mo
nth
s of
exp
ort.
St
. V
ince
nt &
M
icro
chip
2
requ
ired
, la
st a
t R
FFIT
or
FAV
N
Gre
nadi
nes
leas
t 30
day
s p
rio
r to
, b
ut
wit
hin
12
mo
nth
s of
exp
ort.
Tim
ing
of
RN
AT
T
Po
st-A
rriv
al Q
uara
nti
ne
On
e ti
ter
dra
wn
at l
east
60
Min
imum
30
days
. 18
0 da
ys
days
, b
ut
no
mor
e th
an 1
2 fr
om
dra
w o
f fi
rst
mo
nth
s p
rio
r to
exp
ort
(150
se
rolo
gy s
amp
le m
ust
d
ays
idea
l). S
econ
d ti
ter
pass
bef
ore
rele
ase
from
u
po
n ar
riva
l. qu
aran
tine
. T
wo
tite
rs r
equi
red.
On
e pr
ior
Min
imum
of
30 d
ays.
180
to
app
lica
tion
for
im
port
da
ys i
f la
st R
NA
TT
was
pe
r mit
at
leas
t 6
mon
ths
not
pass
ed.
befo
re e
xpor
t. S
econ
d ti
ter
wit
hin
30 d
ays
of e
xpor
t.
May
be
rete
sted
aga
in w
hile
t
in q
uara
ntin
e.
One
tit
er r
ecei
ved
by t
esti
ng
30 d
ays
if a
U q
uali
fica
tion
s la
b at
lea
st 9
0 d
ays
prio
r to
ar
e m
et.
Fai
lure
of
seco
nd
expo
rt.
Sec
ond
tite
r ti
ter
resu
lts i
n 12
0 da
y pe
rfo
rmed
whi
le i
n qu
aran
tine
. q
uar
anti
ne.
Tw
o tit
ers
requ
ired
, d
raw
n a
t 30
day
in
hom
e qu
ara
nti
ne.
le
ast
4 w
eeks
ap
art.
May
T
wo
vacc
inat
ions
req
l\iT
ed
dep
art
30 d
ays
afte
r la
st
wit
hin
firs
t 30
day
s of
d
raw
dat
e.
arri
val.
T
wo
tite
rs r
equi
red
, d
raw
n a
t 30
day
in
hom
e q
uara
ntin
e.
leas
t 4
wee
ks a
part
. M
ay
Tw
o va
ccin
atio
ns r
equi
red
dep
art
30
day
s af
ter
last
w
ithi
n fi
rst
30 d
ays
of
dra
w d
ate
arri
val.
1.11 ::j
Bri
tish
Vir
gin
Isla
nds
Gu
am
Mal
ta
Tri
nida
d &
T
obag
o
Uni
ted
Kin
gdom
Non
e
Mic
roch
ip
Mic
roch
ip
Mic
roch
ip
Mic
roch
ip
2 re
quir
ed,
last
va
ccin
atio
n at
lea
st
1 m
onth
pri
or t
o se
rolo
gy &
w /
in 1
2 m
onth
s of
exp
ort.
2
requ
ired
, la
st
vacc
inat
ion
betw
een
12 a
nd
3
mon
ths
of
expo
rt.
1 w
ithi
n 1
year
of
expo
rt.
1 va
ccin
atio
n be
twee
n 6
& 1
2 m
ontl
,s o
f en
try.
1 re
quir
ed.
RFF
IT o
nly
FAV
N o
nly
RFF
IT o
r FA
VN
RFF
IT o
r FA
VN
RFF
lT o
r FA
VN
, b
ut
by
MA
FF
t ap
pro
ved
la
bora
tory
.
On
e ti
ter
com
plet
ed b
efor
e ex
port
wit
h n
o w
ait
befo
re
trav
el.
Mu
st w
ait
at l
east
o
ne
mon
th a
fter
las
t va
ccin
atio
n to
dra
w s
ampl
e.
On
e ti
ter
rece
ived
by
test
ing
lab
at l
east
90
days
pri
or t
o ex
port
. S
econ
d ti
ter
perf
orm
ed w
hile
in
quar
anti
ne.
On
e ti
ter
com
plet
ed b
etw
een
3 an
d 6
mo
nth
s of
dep
artu
re.
Sec
ond
tite
r w
hile
in
quar
anti
ne.
On
e ti
ter
dra
wn
at
leas
t 60
da
ys,
bu
t no
mor
e th
an 1
2 m
onth
s pr
ior
to e
xpor
t (1
50
day
s id
eal)
. S
econ
d ti
ter
up
on
arr
ival
. A
nim
als
from
Haw
aU &
oth
er
rabi
es-f
ree
area
s m
ayb
e im
po
rted
6 m
onth
s fr
om
seru
m d
raw
dat
e. Q
uali
fyin
g ti
ter
not
acce
pted
fro
m
cont
inen
tal
U.S
.
Non
e
30 d
ays
if a
ll qu
alif
icat
ions
ar
e m
et.
Cur
rent
ly,
addi
tion
al 9
0 d
ay h
ome
quar
anti
ne f
ollo
win
g 30
da
ys q
uara
ntin
e.
Min
imum
of
30 d
ays.
180
da
ys i
f la
st R
NA
TT
was
n
ot
pass
ed.
180
days
fro
m d
raw
of
firs
t se
rolo
gy s
ampl
e,
min
imu
m 3
0 da
ys.
180
days
if
last
RN
AT
T w
as
not
pass
ed.
Cur
rent
ly,
anim
als
from
ti,
e co
ntin
enta
l U
.S.
MU
ST
be
quar
anti
ned
for
6 m
onth
s.
No
qua
rant
ine
for
anim
als
from
Haw
aU t
hat
have
met
qua
lifi
cati
ons.
-The
se r
equi
rem
ents
are
sub
ject
to
chan
ge,
othe
r re
quir
emen
ts m
ay a
pply
. S
peci
al p
rovi
sion
s fo
r ce
rtif
ied
serv
ice
dogs
may
app
ly.
Alw
ays
chec
k w
ith
gove
rnm
ent
auth
orit
y of
are
a of
im
port
tR
abie
s N
eutr
aliz
ing
Ant
ibod
y T
Itra
tion
Tes
t. :j:
Min
istr
y of
Agr
icul
ture
, F
ishe
ries
, an
d F
ood
.
~
578 BRIGGS & SCHWEITZER
Table 2. PRE-EXPORT CHECKLIST FOR DOGS AND CATS
r ,
' .
j Contact agriculture department of export destinaH"on to obtain written requirements, j Apply for importation permit. .. j Permanently identify the pet with a microchip, j Administer any necessary vaccinations, j Conduct all necessary laboratory tests, j Make airline reservations and obtain airline requirements, j Make reservations at the quarantine station at destination (if necessary) j Purchase an lATA approved animal carrier, j Obtain an approved veterinarian's signature on all necessary paperwork, including a
health certificate, j Treat the animal for internal and external parasites of concern,
present in some serum samples. Therefore, a rabies virus neutralizing antibody level of 0.5 IU/ mL or greater can be attributed to the presence of rabies virus neutralizing antibody present in the serum sample, presumably after the animal has been vaccinated. The level of rabies virus neutralizing antibody required to protect a dog or cat from a challenge of rabies virus has received much debate.2• 5 It is difficult to correlate rabies neutralizing antibody titers to protection because cellular immunity is also involved in successfully surviving a challenge with rabies virus, In addition, serologic titers may fall below 0.5 IU/ ml in animals considered to be 'current' in their rabies vaccination, Therefore, in the United States, there is no level of rabies neutralizing antibody that is considered 'protective.' Rabies virus neutralization assays are a valuable tool to measure whether an animal responded to a rabies vaccination and in some cases have identified animals that have an underlying immunosuppressive condition that may prevent them from responding adequately to rabies vaccines.3
In addition to RNATI, most rabies-free areas require other assays to be conducted, Generally, more tests are required for dogs than for cats (i.e., Brucella canis, Ehrlichia canis, Leptospira canicola, microfilaria, and others) . Most rabies-free areas have some required treatment or test for internal and external parasites as well. Once the date of importation is determined by the owner, a list of tasks and timelines should be devised (Table 2) . The schedule of specific laboratory tests, vaccinations, examinations, and other treatments differ for each country, and inadvertently missing one of the target dates can delay an animal from being allowed entry into the destination country.
SHIPPING REGULATIONS
When traveling from the mainland United States to a rabies-free area, the fastest and most humane method to transport animals long
rMPORTAll0 TO RABIES-FREE AREAS 579
distances is by air. Unfortunately not all airports in rabies-free areas have adequate facilities to accept animals. Therefore it is necessary to contact the consulate of the destination country for airport customs information. To ensure that the animal arrives safely in the destination country, several factors should be taken into consideration prior to booking the animal's flight.
The International Air Transport Association (lATA) Live Animals Regulations are recognized as the world standard for transporting animals by commercial airlines. However, some countries have more stringent standards than the lATA and should be contacted to clarify their requirements· for shipping live animals. Additionally, the USDA Animal Welfare Act has instituted standards governing the shipping of animals that could influence travel plans. There are temperature guidelines for shipping live animals that make it difficult to ship an animal in summer or winter. For example, the temperature in route must be between 45 and 85 degrees Fahrenheit or the airline may not accept the animal for transport. Some airlines will accept a statement signed by a veterinarian stating that the animal is acclimated to extreme temperatures. The breed of the animal should also be considered prior to shipment as snub-nosed dogs generally are intolerant to high temperatures. Additionally, the weather at all scheduled stopovers should be investigated prior to arriving at the airport to avoid extreme temperatures en route. Recent changes in the Federal Aviation Administration (FAA) guidelines regarding the transportation of dangerous goods have increased security measures for all cargo which may affect the shipment of a pet as the animal may have to be removed from the carrier for inspection.
The lATA Live Animals Regulations include detailed information for choosing an appropriate shipping container and for safeguarding the welfare of the animals during the shipping process. The container requirements mandated by the lATA are based on the species, number, and size of the animal(s) to be shipped. The size requirement for animal containers was carefully determined to prevent injury during travel while still allowing the animal to travel in comfort. When a shipping container is purchased, it should first be determined whether the pet will be shipped as cargo in a heated and ventilated hold or whether the pet will accompany the owner in the cabin. For small animals traveling in the cabin, a soft carrying bag is sufficient, but a small rigid carrier may also be used. For animals traveling in the hold, the container must be rigid and conform to the lATA Live Animals Regulations. It must be big enough for the animal to stand normally, tum around, and lie down. Kennels must have the correct amount of ventilation openings for good air circulation during all flights. Food and water dishes should be attached to the kennel, yet accessible from the outside. Additional dry food should be supplied. The container should be labeled "This Way
580 BRIGGS & SCHWEITZER -,,"
.'
Up" and "Live Animal" along with the name, address: and phone number of the owner as well as care instructions for the animal. In addition, any medication that has/is bein~given must be recorded with the name of the drug, route, and time of administration. Tranquilizers are not recommended for animals traveling by air. Drugs can have different reactions in animals at pressure above 8000 feet.
The USDA requires that no more than two live puppies or kittens, 8 weeks to 6 months in age, of comparable size, and weighing 20 pounds or less be transported in the same primary enclosure. Anytime multiple animals are to be shipped in the same container, the size, temperament, and type of animals should be considered as even animals that share the same household may become stressed and aggressive toward each other when traveling by air. To help eliminate stress it is also advisable to purchase the container ahead of time to allow ' the animal to become accustomed to it prior to travel. It is also a good idea to feed the animal inside the container so that it takes 'ownership' of the space.
It is the responsibility of the shipper to make sure that all of the required documentation has been obtained and is securely attached to the airway bill. The shipper must provide the airline with two copies of the Shipper's Certification for Live Animals. The number and species of animals must also be stated on the airway bill. A current health certificate signed by a veterinarian is usually necessary. The airline that has been chosen to transport the pet should be contacted to determine whether they would accept the pet on the selected day and flight. The airline must be contacted at least 48 hours in advance of departure to ensure that there is adequate space available for the animal.
Some airlines restrict the number of animals that they carry on any one flight. Therefore advance reservations are strongly recommended. The length of check-in time required for the pet should be determined. If the pet is traveling with the owner in the cabin and may become stressed in the airport crowds, this can be kept to a minimum by checking in as late as possible. If the animal will be traveling in the hold, the owner should check the pet in at least 2 hours in advance, but not more than 4 hours. The food, but not water, intake should be reduced the day prior to travel. Dogs should be taken for a walk prior to setting out for the airport and if possible again before checking in. This will allow the animal to urinate and defecate prior to boarding. A light meal 2 hours prior to departure may help calm the animal, but it is unwise to feed it a heavy meal. If the animal is being shipped as air freight, the shipper should confirm the operating hours of the air freight facility so that the animal may be claimed upon arrival. Weekdays are preferable to weekends for shipping because departments are generally working at full staff, and transfers are easier along the route.
Some airlines will not accept animals handled by anyone other than
IMPORTATION TO RABIES-FREE AREAS 581
a shipper, and therefore it may be necessary to hire an animal shipper who can make all of the necessary reservations and take full charge of the pet for the owner. Finally, prior to shipment, reservations at quarantine facilities (if quarantine is required) should be made, and the owner should have a clear understanding as to how and when the animal will be transported to these facilities.
FUTURE DIRECTIONS
A new era in rabies prevention was initiated in 1992 when the WHO Expert Committee on Rabies recommended alternate procedures to replace lengthy quarantine periods for dogs and cats entering rabiesfree areas. Australia and New Zealand were the first countries to implement reduced quarantine procedures followed a few years later by Hawaii and St. Kitts and Nevis. Recently, several other Caribbean islands have or are currently evaluating reduced quarantine policies. St. Vincent and the Grenadilles, Trinidad and Tobago are among those areas that have recently implemented new importation regulations. St. Lucia, Montserrat, the Cayman Islands, and the British Virgin Islands are in the process of reviewing their importation regulations. Although the reduced quarantine programs in these rabies-free areas are relatively new, they have received worldwide attention and to date have been very successful. The new quarantine programs depend on positive identification through microchips or tattoos, documented rabies vaccinations, serologic testing, and health certificates. If the programs instituted in . these countries continue to be successful, increased pressure will be put on other rabies-free areas to follow their example.
In 1998 a panel of experts headed by Professor Ian Kennedy met in Great Britain to reevaluate rabies and the quarantine regulations that had been in place ill that country for almost a century. The experts concluded that if dogs and cats were allowed to travel from Great Britain to the European Union (EU), European Economic Area (EEA) member states, or to rabies-free islands and back again, there would only be a marginal increase in risk of reintroducing rabies. In light of these findings, the Ministry of Agriculture, Fisheries and Food (MAFF) instituted a new policy called the Pet Travel Scheme (PETS) was first implemented early in 2000. This allows dogs and cats from approved areas in Europe to enter Great Britain without being held in quarantine for 6 months. Dogs and cats are required to be implanted with a microchip, vaccillated against rabies, and have a RNATT conducted by a MAFF approved laboratory. The owner must apply for a PETS certificate from an approved veterinarian. The PETS certificate is valid for travel to and from Great Britain begillning 6 months after the date of the blood sample for
582 BRIGGS & SCHWEITZER
Table 3. RABIES-FREE ISLANDS ELIGIBLE FOR PETS
Antigua and Barbuda Barbados Falkland Islands Guadaloupe Japan Mayotte New Zealand St. Kitts & Nevis Vanuatu
Ascension Isl!nd Bermuda Fiji Hawaii Marinique Montserrat Reunion St. Vincent Wallis and Futuna
.. Australia Cayman Islands French Polynesia Jamaica Mauritius New Caledonia St. Helena Singapore
the RNATI is withdrawn and expires on the date the animal is scheduled for a rabies vaccination booster (not more than a year later). An approved veterinarian must treat the dog or cat for internal and external parasites within 48 hours prior to travel. Using this system, eligible dogs and cats can bypass quarantine and enter Great Britain through an approved airline, rail, or ferry. As of January 31, 2001, dogs and cats from certain rabies-free islands (Table 3), considered "Long Haul" areas, were also eligible to enter Great Britain under PETS. These changes mark some of the most radical and sweeping changes that have ever occurred in Great Britain's quarantine laws.
The fqrecast for the future replacement of quarantine systems in many other countries is encouraging. Certainly when rabies-free areas relax their rigorous quarantine laws, they need to be replaced by vigilant importation requirements. Certified laboratories and federally licensed veterinarians need to continue to work closely with the government officials of rabies-free areas to ensure that documentation is accurate and that potentially rabies-infected dogs and cats are identified and prevented from entering the country. Only under these circumstances will the risk factors remain low and residents of rabies-free areas be assured that rabies will not be introduced to their country.
References
1. Anonymous: Rabies. In OIE Manual of Standards for Diagnostic Tests and Vaccines, ed 3. Office of International des Epizooties, Paris France, 1996, pp 211-213
2. Aubert MF: Can vaccination validated by the titration of rabies antibodies in serum of cats and dogs be an alternative to quarantine measures? Bureau Hyg Trop Med 68:R2-R22, l993
3. Briggs OJ: Kansas State University Rabies Laboratory. Unpublished data from laboratory submissions, 1998
4. Briggs, OJ, Smith, JS, Schweitzer K, et al: A comparison of two serological methods for detecting the immune response after rabies vaccination in dogs and cats being exported to rabies-free areas. Biologicals 26:347-355, 1998
IMPORTATION TO RABIES-FREE AREAS 583
5. Tizard I: Use of serologic testing to assess immune status of companion animals. J Am Vet Med Assoc 213:54-60, 1998
6. WHO Expert Committee on Rabies, 8th report. (WHO Technical Report Series, No. 824). World Health Organization, Geneva, Switzerland, 1992, p 41 or www.who.int/ emcdocuments / rabies/docs/ wsr97/ wsr97 _al.html
Address reprint requests to Kristen Schweitzer, BS
Kansas State University College of Veterinary Medicine Mosier 0-247
1800 Denison Avenue Manhattan, KS 66506-5612
e-mail: [email protected]
VACCINES AND VACCINATIONS
INDEX
Note: Page numbers of article titles are in boldface type.
Abscess(es), at site of vaccination, 510 Adenovirus-1, canine, vaccines containing,
481 Adenovirus-2, canine, vaccines containing,
481 Adenovirus infection, canine, 481-482 Adverse events, vaccine-associated,
493-514 Alopecia, at site of vaccination, 509 American Association of Feline
Practitioners, and Academy of Feline Medicine, Advisory Panel on Feline Vaccines, 455
Vaccine Panel, recommendations of, 458-461
American Veterinary Medicine Association, 499
Council on Biologic and Therapeutic agents, 440
Anaphylaxis, associated with vaccine adrnllUstration,502-504
Animal shelter(s), vaccination program for, assumptions in, 444
Darwinian approach to, 444 filtered approach to, 444 unlimited funds approach to, 444-445
Antibody titers, versus annual vaccinations, 442-443
Antigens, selection of, 443-445 in shelter environment, 443-445
vaccine, used in dogs, duration of immunity of, 488-489
Autoimmune disease, associated with vaccination, 505
Bordetella bronchiseptica, 482 Bordetella bronchispetica infection, in cats,
466-467 clinical signs of, 468 vaccine to prevent, 468
Borreliosis, Lyme, 486-487
Calcivirus infection, feline, 457-462 vaccination against, 462
adverse events associated with, 462-463
Canine adenovirus infection, 481-482 Canine corona viral infection, 484-485 Canine distemper, 480-481
modified live virus vaccines against, 480 Canine distemper vaccines, recombinant,
480 Canine infectious tracheobronchitis, 482
vaccination against, 483 viruses causing, 482
Canine leptospirosis, 485-486 Canine parvoviral enteritis, 483-484
recovery from, vaccination following, 484
Canine parvovirus-2 vaccines, 483 duration of immunity confe+red by, 484. recommendations for use of, 483-484
Canine vaccination, 473-492 recommendations for, revision of, 474
Cats. See also Dogs, and cats. anaphylactic reactions in, associated
with vaccines, 503 Bordetella bronchispetica infection in, 467-
468 dermatophytosis in, 466-467 giardiasis in, 468-469 vaccination guidelines for, 455-472 vaccination of, American Association of
Feline Practitioners and Academy of Feline Medicine on, 458-461
vaccine-associated fibrosarcoma in, 447-448
vaccine-associated sarcomas in, 463, 493, 498, 509
vaccines and vaccinations for, 439-440 Chlamydia psittaci, 465 Chlamydiosis, clinical signs of, 465
vaccination against, 465 Coronaviral infection, canine, 484-485
vaccines for, 484
585
586 INDEX
Corona viral infection (Continued) challenge immunity studies of, 485
Corona viruses, feline, 465 Cytotoxic hypersensitivity, associated with
vaccine administra tion, 504
Dermatophytosis; in cats, 466-467 . Distemper, canine, 480-481
modified live virus vaccines against, 480
Distemper-measles vaccine, combined, 480-481
Dogs, anaphylactic reactions in, associated with vaccines, 502-503
and cats, irnporta tion of, to rabies-free ar-eas of world, 573-583
future directions in, 581-582 requirements for, 574-578 shipping regulations for, 578-581
pre-export checklist for, 578 rabies vaccines for, 490 vaccination of, 473-492
Feline calcivirus infection, 457-462 Feline coronaviruses, 465 Feline infectious peritonitis, 465
vaccination in, benefit of, 466 Feline panleukopenia, 456 Feline parvovirus, cause of, 456
vaccination against, 456 Feline vaccination guidelines, 455-472 Feline viral rhinotracheitis, 457-462 Ferrets, anaphylactic reactions in,
associated with vaccines, 503-504 Fibrosarcoma, feline vaccine-associated,
447-448
Giardia lamblia, 487 disease caused by. See Giardiasis.
Giardiasis, 487-490 diagnosis of, 468 in cats, 468-469 transmission of, 468-469 treatment of, 468 vaccine licensed for, 469
HypersensitivLy, Type I, associated with vaccine administration, 502-504
Type II, 'associated with vaccine administra tion, 504
Type III, associated with vaccine administration, 504-505
Immune complex-mediated hypersensitivity, associated with
""vaccine administration, 504-505 ~osuppression, associated with
vaccination, 505-506 Infectious peritonitis, feline, 465
vaccination in, benefit of, 466 Informed consent, veterinarian and,
518-520 International Air Transport Association
Live Animals Regulations, 579
Kennel cough, 482 Killed virus vaccine, modified-live virus
versus, 443
Leptospira vaccines, 486 Leptospirosis, canine, 485-486 Leukemia virus infection, feline,
transmission of, 464 vaccination against, 464-465
Local reactions, to vaccinations, 508-510 Lyme borreliosis, 486-487
Measles-distemper vaccine, combined, 480-481
M icrosporu m ca 11 is, 466 vaccination against, 466-467
Modified-live virus vaccine(s), for cats, 462 for dogs, 483 versus killed virus vaccine, 443
"Naked" DNA vaccines, 450-451 National Childhood Vaccine Injury Act,
498-499 Nodules, and masses, in response to
vaccination, 508 Nosodes, 452 Nucleic acid vaccines, 450-451
Pain, in response to vaccination, 508 Panleukopenia, feline, 456 Panleukopenia virus vaccine, intranasal
modified-live, 505 Parvoviral enteritis, canine, 483-484
recovery from, vaccination following, 484
Parvovirus, feline, cause of, 456 vaccination against, 456-457
Pets, exposed to rabid animals, management of, 569
Rabid animals, pets exposed to, management of, 569
Rabies, as preventable disease, 558 reporting of, 463 risk of, assessment of, 559-563 transmission of, 463 type of exposure to, 559-560
Rabies-free area, WHO definition of, 573 Rabies immune globulin, 564 Rabies immunizing products, allergies
and,569 for use in human beings, 563--565 human diploid cell vaccine, 564 immunosuppression and, 568 pregnancy and, 568 purified chick embryo cell culture, 564,
565 Rabies neutralizing antibody titer test, 575 Rabies postexposure prophylaxis, 557-572
circumstances of bite and, 562 cost of, 557 decision tree, 560 for domestic animals, justification for,
570-571 in previously immunized persons, 567-
568 in wild animal bites, 561-562 lack of national program concerning, 558 mortality associated with, 558 outside of United States, 567 precautions in, and contraindications to,
568-569 protocol for, 565--567 vaccination status of exposing animal
and, 562-563 Rabies vaccines, administration of, statutes
governing, 463 for dogs, 490
Reovirus, 482 Rhinotracheitis, feline viral, 457-462
vaccination against, 462 adverse events associated with,
462-463
Sarcoma(s), feline, soft-tissue, sites of, 526 vaccine-associated, 463, 493, 498, 509
client support in, 528 clinical evaluation procedures in,
527 diagnosis of, 526-528 physical examination findings in,
526-527 treatment of, 529-530
adjunctive, 531 client management in, 531 in microscopic metastatic disease,
530 prognosis in, 532-533
INDEX 587
recent advances in, 525-533 supportive, 531-532
Standard of care, veterinarian and, 517-518 Swelling, benign, in response to
vaccination, 508 Systemic reactions, to vaccinations,
501-508
Tracheobronchitis, canine infectious, 482 vaccination against, 483 viruses causing, 482
United States Department of Agriculture, animal vaccines and, 515--517
Center for Veterinary Biologics, 511 vaccine labels and, 541, 542, 545, 547,
551, 552-553 United States Food and Drug
Administration, animal vaccines and, 515--517
United States Pharmacopeia Veterinary Practitioners' Reporting Program, 500, 511-512
Vaccination(s), adverse events associated with, 493-494, 501-510
reporting of, 500 against feline leukemia virus infection,
464 against feline parvovirus, 456-457 annual, 440-442
antibody titers versus, 442-443 benefits of, 494-495 canine, 473-492 health maintenance prior to, 455 local reactions to, 508-510 of cats, American Association of Feline
Practitioners and Academy of Feline Medicine on, 458-461
overall objectives of, 456 protocols for, for companion animals,
448 response to, environmental factors influ
encing, 449-450 risk(s) of, 496-498
postmarketing measurement of, 496-498
prelicensing measurement of, 496 surveillance of, 496-498
site of, abscesses at, 510 alopecia at, 509
systemic reactions to, 501-508 vaccines and, 439-583
importance of, 439
588 INDEX
Vaccination(s) (Ccmtinued) strategic issues concerning, 439-453
Vaccination guidelines, feline, 455-472 Vaccine(s), ability to respond to, factors
negatively affecting, 455 adverse event associated with, 445-447
causes of, 447 reporting criteria for, 446-447
and vaccinations, 439-583 importance of, 439 strategic issues concerning, 439-453
animal, Urtited States Department of Agriculture and, 515-517
Urtited States Food and Drug Administration and, 515-517
attentuated, 445, 451 canine, 473
administration of, recommended guidelines for, 475-479
labeling of, and product inserts for, 474
canine distemper, recombinant, 480 choice of, by veterinarian, 521-522 combined distemper-measles, 480-481 contamination of, adverse events associ-
ated with, 507 core, 443
deterrrtination of, 449 efficacy measurement of, postlicensure,
495 efficacy studies of, prelicense, 494-495 federal preemption and, 517 for rabies immunization, 564-565
accidental human exposure to, 568 immunity conferred by, 480 intranasal, local reactions associated
with,510 lack efficacy of, as adverse event, 507 liability associated with, 448 modified-live virus, for cats, 462
for dogs, 483 versus killed virus vaccines, 443
multidose vials of, 448, 456 noncore, 443 over-the-counter sales of, 451-452 polyvalent, 456
annual administration of, 474 postrnarketing surveillance of, 446, 498-
499 potential risks of, options for reporting,
510-512 rabies, for dogs, 490 recombinant, 450-451
in veterinary medicine, 535-538 methods of producing, 536 new technology in, 536 Type I subunit, 537
_--_~T.ype Il gene-deleted, 537-538
lJ\\llf.1t TAM, <.,~ ~. , ~
<;. -~
,. >'
Type III vectored,638 USDA classification of, 536-537
risk assessment associated with, 448-450 safety of, 445-448 s~on and administration of, 456-469 veterinary, postrnarketing surveillance
of,499-501 use and misuse of, potential for liabil
ity in, 515-523 Vaccine Adverse Event Reporting System,
498-499 Vaccine antigens, used in dogs, duration of
immunity of, 488-489 Vaccine-associated adverse events, 493-514 Vaccine label, alternate route of
administration on, 551 annual revaccination recommendations
on, 550 definition of, 539-540 dose volume on, 546, 554-555 efficacy claims of, 543-546
limitations of, 548-549 minimun age of administration on, 550-
551 preservatives listed on, 547 reading of, what can be and cannot be
learned from reading, 539-556 reality of, unaerstanding of regulatory
process and, 540-542 revaccination interval and, 549-550 safety information on, 546
limitations of, 552-554 storage conditions on, 555 ·storage directions on, 547 trade name of product and, 543 true name of product and, 543 true name on, 547-548 US Department of Agriculture and, 541,
542,545, 540551, 552-553 use directions on, 546 user 's expectations of, 540
Vaccine manufacturer, veterinarians reporting adverse events to, 510-511
Vaccine virulence, resid ual, 506 Veterinarians, choice of vaccines by,
521-522 informed consent and, 518-520 reporting of adverse events to vaccine
manufacturer, 510-511 standard of care and, 517-518
Warranty, and breach of, veterinary clients and, 520-521
World Health Organization, definition of rabies-free area of, 573
Changing Your Address?
Make sure your subscription changes too! When you notify us of your new address, you can help make our job easier by including an exact copy of your Clinics label number with your old address (see illustration below.) This number identifies you to our computer system and will speed the processing of your address change. Please be sure this label number accompanies your old address and your corrected address-you can send an old Clinics label with your number on it or just copy it exactly and send it to the address listed below.
\tVe appreciate your help in our attempt to give you continuous coverage. Thank you.
W. B. Saunders Company
151 BENIGNO BLVD
BELLMAWR, N J 08031
SECOND CLASS POSTAGE PAlO AT BELLMAWR. N.J.
,
This is your copy of the _ CLINICS OF NORTH AMERICA
Your Clinics Label Number
00503570 DOE-J32400
JOHN C DOE MD 324 SAMSON ST BERLIN NH 03570
XP-D11494
Copy it exactly or send your label along with your address to: W.B. Saunders Company, Customer Service Orlando, FL 32887-4800 Call Toll Free 1-800-654-2452
101 NH
Please allow four to six weeks for delivery of new subscriptions and for processing address changes .
8102
JAN ISSUE