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Immunization, Vaccines and Biologicals

The Immunological Basis

for Immunization Series

Module 17:

Rabies

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Immunization, Vaccines and Biologicals

The Immunological Basis

for Immunization Series

Module 17:

Rabies

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WHO Library Cataloguing-in-Publication Data

The immunological basis or immunization series: module 17: rabies.

(Immunological basis or immunization series ; module 17)

1.Rabies - immunology. 2.Rabies virus - immunology. 3.Rabies vaccines - therapeutic use. 4.Immunization. I.World Health Organization.

II.Series.

ISBN 978 92 4 150108 8 (NLM classifcation: WC 550)

World Health Organization 2011All rights reserved. Publications o the World Health Organization can be obtained rom WHO Press, World Health Organization, 20 Avenue Appia,1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; ax: +41 22 791 4857; e-mail: [email protected]). Requests or permission to repro-duce or translate WHO publications whether or sale or or noncommercial distribution should be addressed to WHO Press, at the aboveaddress (ax: +41 22 791 4806; e-mail: [email protected]).The designations employed and the presentation o the material in this publication do not imply the expression o any opinion whatsoever onthe part o the World Health Organization concerning the legal status o any country, territory, city or area or o its authorities, or concerningthe delimitation o its rontiers or boundaries. Dotted lines on maps represent approximate border lines or which there may not yet be ullagreement.The mention o specifc companies or o certain manuacturers products does not imply that they are endorsed or recommended by the World

Health Organization in preerence to others o a similar nature that are not mentioned. Errors and omissions excepted, the names o proprietaryproducts are distinguished by initial capital letters.

All reasonable precautions have been taken by the World Health Organization to veriy the inormation contained in this publication. However,the published material is being distributed without warranty o any kind, either expressed or implied. The responsibility or the interpretation

and use o the material lies with the reader. In no event shall the World Health Organization be liable or damages arising rom its use.

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The Department o Immunization, Vaccines and Biologicalsthanks the donors whose unspecifed fnancial support

has made the production o this document possible.

This module was produced or Immunization, Vaccines and Biologicals, WHO, by:

Dr Deborah J Briggs, Executive DirectorGlobal Alliance or Rabies Control

Manhattan Kansas, USA.

The Department o Immunization, Vaccines and Biologicals, WHO, also grateullyacknowledges the kind assistance and contribution o the Department o Control o

Neglected Tropical Diseases in the preparation and review o this module.

Printed in February 2011

Copies o this publication as well as additional materialson immunization, vaccines and biological may be requested rom:

World Health OrganizationDepartment o Immunization, Vaccines and Biologicals

CH-1211 Geneva 27, Switzerland Fax: + 41 22 791 4227 Email: [email protected]

World Health Organization 2010

All rights reserved. Publications o the World Health Organization can be obtained rom WHO Press,World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: +41 22 791 3264;ax: +41 22 791 4857; email: [email protected]). Requests or permission to reproduce or translateWHO publications whether or sale or or noncommercial distribution should be addressed toWHO Press, at the above address (ax: +41 22 791 4806; email: [email protected]).

The designations employed and the presentation o the material in this publication do not imply theexpression o any opinion whatsoever on the part o the World Health Organization concerning thelegal status o any country, territory, city or area or o its authorities, or concerning the delimitation o itsrontiers or boundaries. Dotted lines on maps represent approximate border lines or which there maynot yet be ull agreement.

The mention o specic companies or o certain manuacturers products does not imply that they areendorsed or recommended by the World Health Organization in preerence to others o a similar naturethat are not mentioned. Errors and omissions excepted, the names o proprietary products are distinguishedby initial capital letters.

All reasonable precautions have been taken by the World Health Organization to veriy the inormationcontained in this publication. However, the published material is being distributed without warranty oany kind, either expressed or implied. The responsibility or the interpretation and use o the materiallies with the reader. In no event shall the World Health Organization be liable or damages arising romits use.

The named authors alone are responsible or the views expressed in this publication.

Printed by the WHO Document Production Services, Geneva, Switzerland

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Contents

Abbreviations and acronyms .............................................................................................v

Preface .............................................................................................................................. vii

1. Rabies virus and disease .........................................................................................1

1.1 Structure of the virus ...................................................................................1

1.2 Classication ................................................................................................1

1.3 Pathology......................................................................................................2

1.4 Epidemiology................................................................................................2

2. Immunity to rabies.................................................................................................3

2.1. Preventing clinical disease...........................................................................3

2.2 Rabies vaccines .............................................................................................4

2.3 Response to immunization ..........................................................................4

2.4 Role of passive immunity ............................................................................5

2.5 Routes of active immunization...................................................................6

2.6 Immune response in different populations.................................................6

3. Duration o immunity ater immunization .......................................................8

3.1 Development of immunity..........................................................................8

3.2 Duration of rabies virus-neutralizing antibody.......................................8

3.3 Anamnestic response..................................................................................10

3.4 Timeliness of routine booster vaccination................................................11

4. Techniques to measure the immune response .................................................12

4.1 Choosing the test to t the purpose...........................................................12

4.2 Virus neutralization assays........................................................................12

4.3 Binding assays ............................................................................................134.4 Measuring cell-mediated immunity .........................................................13

5. Innocuity and efcacy o rabies biologicals ......................................................14

6. Future prospects ...................................................................................................15

Reerences ........................................................................................................................16

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iv

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v

Abbreviations andacronyms

ABLV Australian bat lyssavirus

ARAV Aravan virus

CCV cell culture rabies vaccine

CNS central nervous system

dRIT direct rapid immunohistochemical test

DTP-IPV combined diphtheria, tetanus, whole cell pertussis and inactivatedpoliomyelitis vaccine

DUVV Duvenhage virus

EBLV-1 European bat lyssavirus type 1

EBLV-2 European bat lyssavirus type 2

ELISA enzyme-linked immunosorbent assay

ERIG equine rabies immune globulin

FAT fuorescent antibody test

FAVN fuorescent antibody virus neutralization

GBS Guillain-Barr syndrome

HAART highly active antiretroviral therapy

HDCV human diploid cell vaccine

HIV human immunodeciency virus

HRIG human rabies immune globulin

ICTC International Committee on Taxonomy o Viruses

ID intradermal

Ig immunoglobulin

IM intramuscular

IRKV Irkut virus

JEV Japanese encephalitis vaccine

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KHUV Khujand virus

LBV Lagos bat virus

MHCII major histocompatibility complex class II

MNT mouse neutralization test

MOKV Mokola virus

NTV nerve tissue vaccines

PCECV puried chick embryo cell vaccine

PCR polymerase chain reaction

PDEV puried duck embryo cell vaccine

PEP post-exposure prophylaxis

PrEP pre-exposure vaccination

PVRV puried Vero cell rabies vaccine

RABV rabies virus

RFFIT rapid fuorescent ocus inhibition test

RIDT rapid immunodiagnostic test

RIG rabies immune globulin

RNA ribonucleic acid

RTCIT rabies tissue culture inection test

RT-PCR reverse transcription-polymerase chain reaction

RVNA rabies virus-neutralizing antibody

SHIBV Shimoni bat virus

WCBV West Caucasian bat virus

WHO World Health Organization

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vii

Preace

This module is part o the series The Immunological Basis for Immunization,which was initially developed in 1993 as a set o eight modules ocusing on the vaccinesincluded in the Expanded Programme on Immunization (EPI)1. In addition to a generalimmunology module, each o the seven other modules covered one o the vaccinesrecommended as part o the EPI programme diphtheria, measles, pertussis, polio,

tetanus, tuberculosis and yellow ever. The modules have become some o the mostwidely used documents in the eld o immunization.

With the development o the Global Immunization Vision and Strategy (GIVS)(20052015) (http://www.who.int/vaccines-documents/DocsPDF05/GIVS_Final_EN.pd) and the expansion o immunization programmes in general, as well as thelarge accumulation o new knowledge since 1993, the decision was taken to updateand extend this series.

The main purpose o the modules which are published as separate disease/vaccine-specic modules is to give immunization managers and vaccination proessionals

a brie and easily-understood overview o the scientic basis o vaccination, and alsoo the immunological basis or the World Health Organization (WHO) recommendationson vaccine use that, since 1998, have been published in the Vaccine Position Papers(http://www.who.int/immunization/documents/positionpapers_intro/en/index.html).

WHO would like to thank all the people who were involved in the development othe initial Immunological Basis for Immunization series, as well as those involved inits updating, and the development o new modules.

1 This programme was established in 1974 with the main aim o providing immunization or childrenin developing countries.

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1.1 Structure o the virus

Rabies virus is an enveloped, rod-shaped virus containing a single-strand negative-sensenon-segmental ribonucleic acid (RNA) genome. It has a simple genome organizationthat encodes ve structural proteins: RNA polymerase (L); nucleocapsid protein

(N); phosphoprotein (P); matrix protein (M), and a surace glycoprotein (G). It is theG that induces the production o rabies virus-neutralizing antibodies (RVNA) thatare the major immune eectors in protecting against inection with rabies virus (1,2).The ribonucleoprotein complex consisting o the N, P, L, and negative-strand genomicRNA has been reported to potentially play a role in the establishment o immunologicmemory and long-lasting immunity (3).

1.2 Classifcation

Rabies virus belongs to the genus Lyssavirus in the amily Rhabdoviridae (1).According to the International Committee on Taxonomy o Viruses (ICTV), as o

2009, 11 species were classied under the Lyssavirus genus (http://www.ictvonline.org).The 11 species include: rabies virus (RABV), Lagos bat virus (LBV), Mokola virus(MOKV), Duvenhage virus (DUVV), European bat lyssavirus type 1 (EBLV-1),European bat lyssavirus type 2 (EBLV-2) and Australian bat lyssavirus (ABLV) (4,5),Aravan virus (ARAV), Khujand virus (KHUV), Irkut virus (IRKV) and West Caucasianbat virus (WCBV) (610). In addition, a new virus, Shimoni bat virus (SHIBV) wasreported in 2010, and needs urther classication (11).

Besides rabies virus, viruses belonging to all other known lyssavirus genotypes havebeen demonstrated (i.e. ABLV, DUVV, EBLV, MOKV), or can all be expected(ARAV, KHUV, IRKV, WCBV and SHIBV) to cause a rabies-like lethal encephalitisin humans.

Reports available on genetic classication o seven lyssavirus species/genotypes(i.e. RABV, LBV, MOKV, DUVV, EBLV-1, EBLV-2 and ABLV) suggest that theyare divided into two phylogroups according to dierences in genetic makeup,serologic cross-reactivity and animal pathogenesis. Phylogroup I includes RABV,DUVV, EBLV-1, EBLV-2 and ABLV, while phylogroup II includes LBV and MOKV(6). The level o immunity against phylogroup II viruses induced by administeringthe currently licensed rabies vaccines is dependent on how ar the genetic makeup othese viruses converges or diverges rom that o RABV (7). The level o protectionprovided against newly identied lyssaviruses by the currently available rabies vaccinesor immunoglobulins has, as yet, not been completely evaluated, and they may provide

reduced or no protection.

1. Rabies virus and disease

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WHO immunological basis for immunization series - Module 17: Rabies2

1.3 Pathology

Human rabies as a disease has the highest case-atality rate ever reported (12).Rabies virus inection can cause an acute progressive encephalopathy in a wide varietyo mammals, including humans, in which the disease almost invariably results in thedeath o the host (12,13). Ater an exposure occurs, generally through inltration ovirus-contaminated saliva rom a rabid animal into a bite wound, or contact with mucousmembrane, the highly neurotropic rabies virus replicates in muscle tissue and entersperipheral nerves, spreads by way o the peripheral nervous system to the spinal cordand ascends to the brain. Ater dissemination within the central nervous system (CNS),the virus spreads centriugally rom the CNS back along the nerves to various organs,including the salivary glands, where it is emitted into the saliva and passed on to thenext victim, again usually through a bite wound or contamination o virus-carryingsaliva on to a mucous membrane (14).

1.4 Epidemiology

Rabies is an underreported disease that is present on every continent, except Antarctica,with more than 55 000 human deaths occurring annually (15,16). Most human deathsoccur in Arica and Asia (1518). Although all mammals are, to varying degrees,susceptible to rabies, the primary reservoirs o the disease belong to the OrdersCarnivora and Chiroptera (i.e. dogs, oxes, jackals, coyotes, raccoon dogs, skunks,raccoons, mongoose and bats) (13,19). Globally, over 98% o all human rabies deathsoccur ollowing exposures to inected dogs. Millions o exposures to dogs occurannually, with tens o thousands o human deaths resulting rom cases o untreatedexposures (12,13,15). Human rabies, especially paralytic rabies (which may representas much as 30% o total clinical rabies presentations), is oten misdiagnosed as other

encephalitic diseases, such as malaria or Guillain-Barr syndrome (GBS), thus maskingthe true global burden o the disease (20,21,22).

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2.1. Preventing clinical disease

Rabies is almost unique compared to other inections in that the development oclinical disease ollowing exposure to the virus is preventable, even in patients thathave not been previously vaccinated, through timely administration o post-exposure

prophylaxis (PEP). PEP, as recommended by WHO, comprises three components:(a) wound treatment with cleansing, fushing and disinection; (b) vaccine administrationover 28 to 90 days, depending on regimens and route o administration; (c) administrationo rabies immune globulin (RIG) with, or within the week which ollows administrationo the rst dose o vaccine in all category III (severe1) exposures (13,23). The outcomeo an exposure to rabies depends on many actors, including: the site and severity othe exposure; the dose and variant (genotype or biotype) o virus inoculated into thewound(s), and the timeliness o administering and adherence to WHO recommendationsor PEP (12,13,23). Both the innate (basic immune system inducing non-specicresistance to disease) and adaptive (highly specialized, systemic cells and processes)immune responses o a patient, are involved in securing protection against developingrabies (24,25).

Besides wound treatment, whose action is mechanical and chemical, the primaryimmunological objective o PEP is to neutralize and destroy rabies virus that wasinoculated into a victims body at the time o exposure. This needs to be achieved asquickly as possible by increasing the amount o rabies virus neutralizing antibody(RVNA) available to complete the task. Thus, it is critical or a protective immuneresponse to ensure that RVNA directed against the G o the virus is produced as soonas possible (3,24). The level o RVNA is almost always high enough to be detectedbetween 7 to 14 days ater primary vaccination (adaptive or active immunity) (41,42,43).However, because human rabies is invariably atal, the administration o rabies immuneglobulin (RIG) (passive immunity) early in the vaccination regimen aims at providing

additional protection, especially or patients with severe and/or multiple wounds(13,23,26,27,28).

2. Immunity to rabies

1

Severe exposure is dened by WHO as single or multiple transdermal bites or scratches and lickson broken skin, and contamination o mucous membrane with saliva.

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2.2 Rabies vaccines

Since their development over three decades ago, cell culture- and embryonatedegg-based rabies vaccines (CCVs) have proved to be highly eective in preventinghuman rabies, both when administered as pre-exposure vaccination (PrEP) and whenused in association with RIG or PEP (29). The production o CCVs represented asignicant advance, particularly over the rst crude nerve tissue vaccines (NTV) orrabies manuactured over a century ago using the brain material o inected animals (29).It should be noted that all NTVs are reactogenic and the WHO has recommendedthat they be replaced with CCVs (13). Several dierent cell substrates have been usedor the production o rabies vaccines, including Syrian baby hamster kidney cells,human diploid cells, primary cell lines produced rom embryonated chicken and duckeggs, and continuous cell lines produced rom Vero cells (29). Rabies vaccines producedon Vero cells and primary cell lines originating rom embryonated eggs have expandedthe sae use and availability o CCVs throughout the world. CCVs have also allowed abroader use o vaccines or PrEP, so protecting those at constant risk o exposure (13,23).

Over the past two decades numerous data have been published proving the ecacyand saety o CCVs (7,23,3033). The cost o administering a 5-dose intramuscular (IM)PEP regimen using CCVs is oten beyond the nancial capability o many personsliving in developing countries. Thereore, where budgetary limitations may deter theuse o CCVs or PEP, the WHO has recommended the administration o intradermal(ID) PEP using CCVs that meet specic potency and immunological criteria (13).Ongoing research specically aimed at developing new, low cost and eective rabiesvaccines, could eventually reduce the global cost o preventing rabies (26).

2.3 Response to immunization

Early experiments designed to identiy the components o the immune system responsibleor protection against rabies virus inection have proved that inactivated rabies vaccinescan induce the production o cytotoxic T-cells (34). Additional experimental evidenceinvestigating the role o cell-mediated immunity in mice conrmed the act thatcytotoxic T- cells alone do not protect against rabies, as the depletion o CD8+ T-cellshad no eect on the resistance to disease nor on the survival rate o vaccinated animals(3,24,35). Research indicates that inactivated rabies vaccines stimulate B-cells as wellas CD4+ cells using major histocompatibility complex class II (MHCII) mechanismsand coner protection through the induction o an immune response including theactivation o lymphocytes, CD4+ antibody-secreting plasmocytes and neutralizingantibodies that migrate into the nervous system parenchyma (3,24,35). The activationo CD4+ T-lymphocytes ultimately results in the production o RVNAs that target and

destroy rabies virus, thus playing a major role in protecting victims exposed to rabiesagainst developing the disease (24,35,36).

The immune characteristics o both the humoral and cellular immune responses aterrabies vaccination was recently studied in 17 healthy patients and in ve patients sueringrom a combined B- and T-cellular immunodeciency (37). In all healthy patients theenzyme-linked immunosorbent assay (ELISA) test results indicated that at one weekater primary vaccination there was a signicant rise in the level o immunoglobulin(Ig) M, and at two weeks ater primary vaccination there was a signicant rise in thelevel o IgG (IgG1 and IgG3) and IgA. In the same study, ater a booster vaccinationwas administered, the level o IgG increased signicantly aster (measured one week

ater the booster dose) than it did ater the primary series o doses was administered.

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Overall, IgG1 is the major IgG subclass present ater primary and booster rabiesvaccination. The ve patients with a combined immunodeciency, vaccinated usingthe same protocol, showed a number o abnormalities in their humoral and cellularimmune responses.

Following inoculation o virulent rabies virus into animal models, the virus may eitherreplicate at the site o inoculation (usually in muscle tissue) or enter directly into theperipheral nerves innervating the wound site without replication (38). Once rabies virusenters the neurons neutralization could potentially be possible, although, according toearlier research, it seems to be less likely (39). However, the pathogenesis o rabies is,as yet, not completely dened and, because the administration o PEP has been eectiveseveral days to months ater an exposure has occurred, it is possible that RVNA canoccasionally clear rabies virus rom the CNS.

Following administration o rabies vaccines, antibodies produced against other viralproteins besides the G (specically the N) have been detected in the sera o human

subjects. Published reports indicate that antibodies directed against the N do notneutralize rabies virus, and thereore these specic anti-N antibodies are unlikely toplay a major role in the development o protective humoral immunity. At present, therole o non-neutralizing viral antibodies in providing immunity against disease is notully understood (25,40). There is no specic level o RVNA that is recognized as beingprotective against rabies in humans, although WHO recommends an antibody level o0.5 IU/mL as being proo o an adequate immune response ater vaccination (13,23).

2.4 Role o passive immunity

Due to the critical role that RVNA plays in destroying by neutralizing rabies virus,

the level o protection against this disease can be enhanced through the immediateadministration o RIG into wounds inficted by a rabid animal. RIG administrationdelivers RVNA specically targeted against rabies virus to the anatomical regionwhere it was injected during the trauma o the exposure. Convincing clinical evidenceproving that the administration o anti-rabies antiserum (in conjunction with vaccine)into patients that were severely exposed to rabid animals reduced the risk o rabies,was collected during a eld study in Iran in 1954 (44). In this early study, dierentdoses o anti-rabies serum and/or vaccine were administered to 29 patients that hadreceived severe bite wounds rom one rabid wol. O the 29 bite victims, 17 that hadincurred severe head wounds were treated as ollows: ve patients received two doseso anti-rabies serum plus vaccine (all ve patients survived); seven patients receivedone dose o anti-rabies serum plus vaccine (one patient subsequently died o rabies),and ve patients received only vaccine (three patients subsequently died o rabies).One six-year old patient that had received exceptionally deep head wounds includinga crushed skull received six doses o serum over a six-day period, plus vaccine,and survived. The other patients involved in the exposure were bitten in the trunk andlegs and were administered either vaccine alone, or vaccine and serum. All o thesepatients survived.

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RIGs should be inltrated into and around the wound sites o patients bitten by rabidanimals in order to neutralize rabies virus that may have been deposited in tissuesduring an exposure (13). Human rabies immune globulin (HRIG) produced in humansubjects is administered at a dose o 20 IU/Kg o body weight, and equine rabiesimmune globulin (ERIG) produced in horses is administered at a dose o 40 IU/Kgo body weight. Unortunately, due to the expense and lack o availability o RIGs,not all patients that should receive passive immunity as part o PEP actually have accessto this lie-saving product (13,15,45). Although the administration o vaccine alone willsave most patients, some patients will need to receive passive immunity immediatelyin order to survive (46). Patients with bites into highly innervated regions such as thehead or hands, and those that have deep or multiple wounds, are the most vulnerableand most in need o RIG (46,47). Specic recommendations or administration o RIGas part o PEP is detailed elsewhere (http://www.who.int/rabies/human/en/index.html) (13,23).

2.5 Routes o active immunization

The rst CCVs, initially administered IM, were seen as the solution to replace earlyreactogenic nerve tissue vaccines (NTVs) that normally induced a low or moderateimmune response (48). However, the high cost o CCVs relative to the cost oNTVs, and the large number o patients that required PEP in canine rabies endemiccountries, initially curtailed the widespread use o CCVs. In an eort to alleviate thesituation by reducing the cost o CCVs without lowering the eciency o the vaccine,clinical trials were conducted to investigate the ecacy o ID regimens using a raction(60% to 80%) o the IM vaccine dose or PEP (49,50,51).

Over the past two decades, results published rom several clinical trials have conrmed

the immunogenicity and ecacy o the ID route or rabies PEP which is currentlybeing used eectively in many Asian countries, including India, the Philippines,Sri Lanka and Thailand (51,52,53). The ability o the ID route to induce an immunologicalresponse results rom the act that the skin is an eective immune organ and vaccineecacy is enhanced when antigens are presented into the dermal layer (54,55,56).Furthermore, the administration o antigens into the skin layer acilitatestheir exposureto the numerous antigen-presenting cells, such as macrophagesand dendritic cells, thatare present in higher numbers in skinthan in muscle.

2.6 Immune response in dierent populations

CCVs are among the most immunogenic vaccines in the world, as is evidenced bythe very ew reported human rabies deaths in patients that received prompt PEPaccording to the WHO recommendations (25,28,57). Rabies vaccines are highlyimmunogenic in almost every population, with perhaps the exception o patientshaving very low CD4+ cells (5861). In one study which investigated the immuneresponse o CCVs in selected populations o human immunodeciency virus (HIV)inected adults, only 57% o symptomatic HIV-inected patients with CD4+ countsbelow 400 developed a measurable RVNA response above 0.5 IU/mL ater receiving a5-dose regimen o PEP intramuscularly on days 0, 3, 7, 14 and 30 (58). In another study,10 HIV-inected adults with CD4+ counts between 25 and 472 were given a multi-sitePEP regimen whereby our doses o CCV were administered ID on days 0, 3 and 7, andtwo doses o CCV were administered ID on days 28 and 90 (4-4-4-0-2-2) (60).

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A lower than expected immune response was reported in all 10 patients; two othe patients did not develop RVNA titres above 0.5 IU/ml by day 14, and one othose patients did not develop RVNA above 0.5 IU/ml by day 30. In another study,the immune response to a three-dose IM PrEP regimen was examined in 13 HIV-inectedchildren with CD4+ counts that were below normal, and compared to the immuneresponse in nine uninected children (62). In this study, children that had ewer than15% o the normal CD4+ cells had signicantly lower RVNA titres when comparedwith the control group and our o the 13 HIV-inected children ailed to develop anymeasurable RVNA. In a more recent study that examined the immune response atervaccination with CCVs in HIV-inected patients receiving highly-active antiretroviraltherapy (HAART), slightly lower IgG and IgM titres were reported in older patientsinected with HIV (63). However, this study also reported that 63% o patients receivingHAART still had measurable antibody titres ve years ater primary vaccination.In another study evaluating more eective vaccination protocols in immunosuppressedpatients, two groups o HIV-positive subjects, one with CD4+ counts below 200 andthe other with CD4+ counts above 200, received a modied multiple eight-site series

o PEP consisting o eight intradermal injections on each o days 0, 3, 7, 14 and 30.All subjects responded with titres above 0.5 IU/mL (64). PEP administered to childrenthat were exposed to rabies while receiving immunosuppressive therapy ater solidorgan transplants, was also reported to be successul in all patients (65).

Inants and the elderly: The immune response to rabies vaccine in inants and theelderly, without specic immunosuppressive conditions, is reported to be adequate.In a report published that reviewed two studies examining the immune responses insubjects o various ages, a reduction was observed in the level o RVNA ater vaccinationin older individuals (66). In one o the reported studies, the immune response o260 subjects between the age o 11 to 25 that received a six-dose PEP regimen was

compared to patients receiving the same regimen that were above the age o 50. In thisstudy, 52% o the adults above 50 years o age had signicantly lower RVNA titres aterPEP compared to the younger cohort (67). In another study involving 875 patients agedbetween 274 years o age that received either PEP or PrEP, no signicant dierence inthe production o RVNA compared to either age or sex was reported (68). The immuneresponse to rabies PEP was also reported to be highly immunogenic in children withconrmed malnutrition, between Grade I and Grade IV (41).

Patients taking chloroquine or anti-malarial treatment: The administration orabies vaccine by the ID route has been reported to produce reduced titres in patientstaking chloroquine or anti-malarial treatment and, or this reason, vaccines should beadministered to this group o patients using the IM route (13,69,70).

Pregnant women: Rabies PEP is not counterindicated or pregnant women and isimmunogenic, sae and highly ecacious in this population (13). Rabies PEP shouldnever be withheld rom pregnant women as it is a lie-saving vaccine. No reported risko abortion, and no other harm to the etus, has been reported due to administrationo PEP with CCV in pregnant women (71,72).

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3.1 Development o immunity

The development o immunological memory ater immunization with CCVs is acritical component in the establishment o long-lasting immunity against rabies inhumans (3). O the millions o persons that have received CCVs, less than a handul o

vaccination ailures have been reported, all o which occurred in developing countries,and most o which involved deviations rom the WHO recommended PEP protocol(25,28). Although one human death has been reported in a person that was previouslyvaccinated with a CCV and subsequently exposed to a rabid puppy (70), this patientdid not seek, nor was she given the WHO recommended PEP booster series aterthe exposure occurred. The results o several clinical trials and retrospective studieshave been published providing evidence that CCVs provide long-lasting immunity torabies.

3.2 Duration o rabies virus-neutralizing antibody

The measurement o RVNAs is the most convenient method o conirming animmunological response ater rabies PrEP or PEP. The relationship between thenumber o doses a patient receives during the initial vaccination (PrEP or PEP) and thelongevity o circulating RVNA has been examined in several studies. In one retrospectivestudy, a Kaplan-Meier survival analysis was used to evaluate the longevity o antibodyin 875 patients that received either a primary three-dose (IM or ID) PrEP series ora ve-dose IM PEP series o human diploid cell vaccine (HDCV) (68). The studyreported no signicant dierence between the number o doses o vaccine a patientreceived and the length o time ater initial vaccination that RVNA could be detected.In this study, no booster dose o vaccine was administered ater the primary series,and blood samples rom patients were tested at various time intervals up to nine yearsater primary vaccination. Circulating RVNA was detectable or a longer period o time

in patients that were vaccinated IM as opposed to patients that had been vaccinated bythe ID route, with approximately 80% o patients that had received vaccination by theIM route still having detectable RVNA titres nine years ater primary vaccination.

3. Duration o immunity ater

immunization

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The longevity o the humoral immune response was also evaluated in 18 patients thathad received their primary series o PrEP or PEP using HDCV or puried chick embryocell vaccine (PCECV) rom two to 14 years previously (73). The patients in this studydid not receive a booster vaccination between their initial series and the subsequentdrawing o blood that was analyzed or the presence o RVNA. All patients in thestudy had detectable RVNA titres up to 14 years ater having received their initialvaccination. In another study, levels o RVNA were evaluated in 58 patients that received,more than ve years previously, PEP using HDCV, puried Vero cell rabies vaccine(PVRV), puriied duck embryo cell vaccine (PDEV) or PCECV by either theEssen IM or Thai Red Cross ID regimen (74). All patients had detectable RVNA at thetime their blood was drawn. In a more recent study examining the longevity o antibodyand the eect o booster vaccination in 118 patients aged 16 to 78 years and vaccinatedve to 21 years previously with either HDCV or PVRV, all patients had detectableantibody titres when they were tested prior to being given a booster dose o vaccine (75).Finally, a study conducted in 29 travellers who had received their initial PreP usingHDCV by the ID route reported long-lasting immunity in patients that had received

their primary vaccination between two and >10 years previously (76).

In addition to published data delineating the extended duration o circulating RVNAin patients that received only a primary PrEP or PEP vaccination series without anadditional booster vaccination at one year post-primary vaccination, studies havereported long-lasting RVNA in patients that have received a primary series o PrEPollowed by one booster one year later. In one study, 312 subjects were ollowed or10 years ater having received either a 2-dose or 3-dose PrEP regimen, with eitherHDCV or PVRV, and one booster dose o vaccine one year later (77). The resultsindicate that approximately 96% o all subjects that received the 3-dose PrEP regimenollowed by one dose o vaccine one year later still had measurable RVNA 10 years

ater having received their initial series. Similar results were reported in anotherstudy where 10 subjects that had received their initial PrEP series with PCECV14 years earlier were administered a booster dose one year later (78). In another studyconducted in 72 Vietnamese children, hal o the children received a 3-dose series o acombined diptheria, tetanus, whole cell pertussis and inactivated poliomyelitis vaccine(DTP-IPV) along with three doses o PVRV given at two and our months and one year,and the other hal o the children received only DTP-IPV (33). Results rom this studyindicate that rabies vaccines had no eect on the long-term antibody levels o diptheriaand poliomyelitis, and the majority o children continued to have measurable RVNAtitres throughout the ve-year ollow-up study. Similarly, a study was conducted in200 Thai children that were vaccinated with PCECV in either a 2- or 3-dose IM or IDPreP regimen concommitent with Japanese encephalitis vaccine (JEV), ollowed bya booster dose o PCECV either IM or ID (as per the original route o vaccination)one year later, and a booster dose o JEV (79). Three years ater primary vaccination,all children that received their initial PrEP series by the IM route or that received a3-dose PrEP ID regimen still had detectable RVNA.

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3.3 Anamnestic response

Two o the arguments in avour o administering PrEP to persons at risk o contractingrabies are that i these persons are subsequently exposed to rabies:

1) a short series o booster vaccinations will elicit a rapid anamnestic response thusreducing the number o doses o vaccine and visits required or a ull PEP;

2) RIG is not required (13).

Several published clinical trials provide data conrming that a previously vaccinatedperson will respond to one or more booster doses o rabies vaccine even i the initialseries o PrEP or PEP was administered several years previously; regardless o whetherthe initial vaccination regimen was administered IM or ID; regardless o whether theyare boosted using the ID or IM route, and independent o whether the previouslyvaccinated person has detectable RVNA or not (74,75,80,81,82). A three-year study

conducted in 194 subjects who initially received one, two, or three doses o HDCVadministered either by the IM or ID route, and were boosted six to 24 months laterwith one dose o HDCV administered by the ID or IM route, reported the highesttitres and longest lasting antibodies in the subjects that had received an initial 3-dosevaccination series (ID or IM) (80). All subjects in this study, regardless o whether theyhad received one additional dose o vaccine ID or IM, had an anamnestic response whenboosted 6, 12, or 24 months later.

Another study reported that an anamnestic response occurred in 76 individualsinitially vaccinated with HDCV by the ID route and then boosted two years laterwith one ID dose o HDCV (81). The anamnestic response occurred in all individuals,regardless o whether the subjects had a detectable antibody titre just prior to the

administration o the booster, or not. Similar results were reported in a study where29 travellers were initially vaccinated with a 3-dose ID HDCV regimen and boosted withone IM dose o HDCV 12 to 14 months later (82). In this study, all persons developedan anamnestic response even though some did not have detectable titres at the time thatthey were boosted. In another study, the immune response o 57 patients vaccinatedor PEP, either by the 5-dose Essen IM regimen or the ID Thai Red Cross regimen,were evaluated or a subsequent anamnestic response ater receiving a booster vaccination(74). In this study, patients were vaccinated 510 years previously with HDCV,PCECV, PVRV or PDEV, and titres were evaluated ater patients were boosted withtwo ID doses o PDEV. All patients developed an anamnestic response ater boosterswere administered, and there was no signicant dierence in the antibody level in

patients that had received vaccination 510 years earlier and those that had beenvaccinated more than 10 years previously. In another study, the immunological responsewas examined in 118 patients that had received primary PEP or PrEP with HDCVor PVRV ve to 21 years earlier and were boosted with two ID doses o PVRV todetermine i they would mount an anamnestic response (75). In this study, all patientsvaccinated up to 21 years previously developed an immunological response with nosignicant dierence in the level o titres in patients that received PrEP or PEP, nor inthe length o time since their initial vaccination was administered.

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3.4 Timeliness o routine booster vaccination

Due to the act that rabies is virtually 100% atal once clinical symptoms areevident, and because until recently no long-term immunity studies were available,the recommendations or timely routine booster doses o rabies vaccine ater aprimary series has varied rom one to ve years. However, several recently-publishedclinical trials have shown that individuals that have received an initial 3- to 5-doseseries o rabies CCVs will have long-term immunity lasting or decades (74,75,76,82).These published data indicate that individuals that received their primary series up to21 years previously will elicit a good anamnestic response ater booster vaccination.

As mentioned earlier, individuals vaccinated with a CCV will respond to a boostervaccination regardless o whether the vaccinated individual had measurable antibodypresent or not at the time that the booster was administered (81,82,83). A recent survivalcase in which a human patient that had been unknowingly given a transplanted liverrom a donor that was later diagnosed as having rabies provides an indication as to the

ecacy o rabies vaccines (84). The patient that received the inected liver survived,whereas the recipients o the two kidneys and pancreas rom the inected donor diedo rabies encephalitis within three weeks ollowing transplant. Further investigationrevealed that the liver recipient had received rabies vaccination as a child.

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4.1 Choosing the test to ft the purpose

Numerous assays are available to test or the presence o rabies virus in the tissues oinected mammals, and to conrm evidence o a humoral or cellular immune responseater exposure to rabies viral antigens (8589,96). Ultimately, the intended purpose

o an assay and the precision o the data required should be the determining actorswhen choosing a testing procedure. For example, conrming herd immunity ateroral vaccination in animals generally does not require the same level o accuracy asdoes evaluating the immunogenicity o a new rabies vaccine or humans, or whenserology testing is employed as part o the diagnostic workup or human rabiespatients (90,91,92). The importance o the level o quality assurance associated withconducting any assay or evaluating an immune response or diagnoses o a patient,or ater immunization, or or identiying rabies antigen in tissue samples, cannot beoverstated, due to the consequences associated with a misdiagnosis (93). To summarize,the sensitivity and specicity o an assay, the accuracy and precision required by theinvestigator or clinician, the laboratory acilities that are available, and the purpose othe data to be collected all need to be critically evaluated beore testing o a samplesstatus is initiated (92).

4.2 Virus neutralization assays

Virus-neutralization assays are among the most widely-used methods to detectthe presence o antibody to the rabies virus. RVNAs are not only responsibleor protection against rabies, the presence o RVNA in serum is seen as a reliableindicator o active immunization ater vaccination (13,89). The rapid fuorescent ocusinhibition test (RFFIT) and the fuorescent antibody virus neutralization (FAVN) testare both in vitro virus-neutralization assays. Both the RFFIT and the FAVN test areequivalent when conducted under good laboratory practices and both are considered

to be the most ecient methods or accurate measurement o RVNA (13,90,94,95).A third virus-neutralization assay, the mouse neutralization test (MNT), is an in vivomethod to measure RVNA that is still utilized in some laboratories that lack the capacityto conduct in vitro tests (96). Methodologies or all three virus-neutralization assaysare published elsewhere (85,86,96,97,98). Virus-neutralization assays are valuable toolsthat can conrm the presence o protective antibodies specically targeted againstrabies virus, but they are also highly complex tests to perorm and must be conductedby experienced personnel in a high containment acility (92,93). It is advisable ordiagnostic laboratories perorming either one or both o these types o RVNA assaysto participate in an established quality assurance programme (92).

4. Techniques to measure the

immune response

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4.3 Binding assays

The ELISA is the most requently used binding assay available, with numerouspublished protocols and proessionally marketed ELISA kits available to detectrabies antibodies (99103). The specicity o the ELISA is dependent upon the choiceo the target antigen used in the test whole virus or puriied viral proteins.Antibodies detected in an ELISA do not necessarily have a neutralizing unction (92).Published reports indicate that cross-reactivity, potentially leading to alse positives,may increase in ELISA assays that employ whole virus rather than puried G as thetarget antigen (99,103). Several studies have been published comparing results romserum samples tested by various ELISA techniques, and by the RFFIT or FAVN test,with mixed results (89,102,104,105). Newer ELISA protocols and ELISA kits withincreased specicity, such as the PLATELLATM RABIES II, have been reported tohave better correlation with the RFFIT and FAVN test. For example, in comparativetesting with the RFFIT, the sensitivity and specicity o the PLATELLATM RABIESII ELISA kit was reported to be approximately 95% (102). Additionally, a competitive

ELISA has been developed, using highly-puried G as the target antigen, that reportedlywill bind neutralizing-related antibodies (103). In the development o this competitiveELISA, 4350 canine serum samples were tested in a comparative study using the FAVNtest where the results indicated that there were no alse positives or negatives and thatthere was a correlation between serological titre results as determined by the ELISAand FAVN test o 96.2% (103). The remaining 3.8% o serum samples tested had titresabove the level o 8.0 IU/mL when assayed by both testing methods, and the serologicaltitre results rom both tests were more divergent at high titre levels.

4.4 Measuring cell-mediated immunity

Assays to measure a cell-mediated immune response are usually used or researchpurposes only because they are more complicated to perorm on a routine basis thanserological assays. Detection o a cell-mediated immune response is commonly achievedby measuring an increase in lymphocyte prolieration using a [H3]thymidine assay.Methodologies or [H3]thymidine assays are published elsewhere (36,73). Newer assayshave been developed to measure cell-mediated immunity that utilize cell-tracking dyesin conjunction with fow cytometry and are able to quantiy the response o specictypes o lymphocytes to rabies antigen (36,106).

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The development and widespread use o rabies biologicals prepared on cell culturehave dramatically increased the saety and ecacy o PEP (23). Failures o rabies PEPhave been reported in some patients in developing countries, but in most o these casessome deviation was reported rom the WHO recommended PEP protocol (25,28,57).Generally, the reasons associated with treatment ailures (where there was a ailure

to ollow the correct PEP protocol) include: delays in seeking treatment; lack o,or improper primary wound care; lack o, or improper administration o RIG;suturing wounds without inltrating with RIG, or poor quality rabies vaccines(25,28,107). The number o true PEP ailures (where a patient died despite receiving thecorrect PEP protocol in a timely manner) are very low when compared to the millionso doses o CCVs administered globally each year (25,107). Short incubation periodso less than one week have been reported in patients that have severe head wounds,such as in patients that have sustained brachial-lexus injuries rom dog bites (20).In one paper that examined case records rom 15 human rabies patients reportedworldwide, it was concluded that seven patients received PEP in a timely and appropriatemanner, and still died o rabies (28). The paper discusses potential reasons or these

ailures, including the possibility that a small unidentied wound may have beenoverlooked, that perhaps one or more o the patients may have had an underlyingimmunosuppressive condition, that the biologicals used to treat these patients were olow potency, or perhaps that the treatment protocols were misrepresented. In any case,all o the treatment ailures occurred ater dog bites, and the paper stresses the act that,on rare occasions treatment ailures may occur, even with CCVs and RIGs.

Local and systemic reactions have been recorded ater the administration o CCVs inclinical trials (30,31,32,69). These studies generally reported local reactions, includingpain, itchiness, redness and/or swelling at the site o injection in 35% to 45% o theenrolled subjects. Common systemic reactions, which are usually reported in 10% to15% o subjects include ever, myalgia, malaise, headaches, dizziness, hives and rash

(108).

5. Innocuity and ecacy o

rabies biologicals

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1. Wunner WH. Rabies virus. In: Jackson AC, Wunner WH, eds. Rabies,2nd ed.Amsterdam, Elsevier Academic Press, 2007:2368.

2. Wandeler AI. Rabies vaccinology and immunology.Developments in Biologicals,2006, 125:181184.

3. Dietzschold B et al. Concepts in the pathogenesis o rabies. Future Virology,2008, 3(5):481490.

4. Tordo N et al. Rhabdoviridae. In: Mayo CM et al., eds. Virus Taxonomy.London, Elsevier Academic Press, 2004:623644.

5. Tordo N et al. Rabies: Epidemiological tendencies and control tools.Developments in Biologicals, 2006, 125:313.

6. Badrane H et al. Evidence o two Lyssavirus phylogroups with distinctpathogenicity and immunogenicity. Journal of Virology, 2001, 75:32683276.

7. Hanlon CA et al. Ecacy o rabies biologics against new lyssaviruses romEurasia.2005, Virus Research, 111:4454.

8. Brooks SM et al. Rabies human diploid cell vaccine elicits cross-neutralizingand cross-protecting immune responses against European and Australian batlyssaviruses. Vaccine, 2005, 23: 41014109.

9. Kuzmin IV et al. Complete genomes o Aravan, Khujand, Irkut andWest Caucasian bat viruses, with special attention to the polymerase gene andnon-coding regions. Virus Research, 2008, 136:8190.

10. Nadin-Davis SA. Molecular epidemiology. In: Jackson AC, Wunner WH, eds.Rabies. 2nd ed. Amsterdam, Elsevier Academic Press, 2007:69122.

11. Kuzmin IV et al. Shimoni bat virus, a new representative o the Lyssavirus genus.Virus Research, 2010, 149:197210 [Epub. 6 February 2010].

12. Rupprecht CE.A tale o two worlds: public health management decisions inhuman rabies prevention. Clinical Infectious Diseases : an ofcial publicationof the Infectious Diseases Society of America, 2004, 39:281283.

13. WHO Expert Consultat ion on Rabies . F ir s t Report . Geneva ,World Health Organization, 2004 (WHO Technical Report Series, No. 931).

14. Jackson AC. Pathogenesis. In: Jackson AC, Wunner WH, eds. Rabies,2nd ed.Amsterdam, Elsevier Academic Press, 2007:341381.

15. Knobel DL et al. Re-evaluating the burden o rabies in Arica and Asia.Bulletin of the World Health Organization, 2005, 83:360368.

Reerences

8/7/2019 9789241501088_eng

27/34

17

16. Cleaveland S et al. A dog rabies vaccination campaign in rural Arica:impact on the incidence o dog rabies and human dog-bite injuries.Vaccine, 2003, 21:19651973.

17. Coleman PG, Fevre EM, Cleaveland S. Estimating the public health impact o

rabies. Emerging Infectious Diseases, 2004, 10:140142.18. Fevre EM et al.The epidemiology o animal bite injuries in Uganda and

projections o the burden o rabies.Tropical Medicine & International Health :TM & IH, 2005, 10:790798.

19. Rupprecht CE et al. Can rabies be eradicated? OIE. In: Dodet B et al., and theScientic and Technical Dept o the OIE, eds. Toward the elimination of rabiesin Eurasia. Basel, Karger, 2008, 131:95122.

20. Hemachudha T, Laothamatas J, Rupprecht CE. Human rabies: a diseaseo complex neuropathogenetic mechanisms and diagnostic challenges.Lancet Neurology, 2002, 1:101109.

21. Mallewa M et al. Rabies encephalitis in malaria-endemic area, Malawi, Arica.Emerging Infectious Diseases, 2007, 13:136139.

22. Hemachuda T et al.Immunologic study o human encephalitic and paralyticrabies. Preliminary report o 16 patients. The American Journal of Medicine,1988, 84: 673677.

23. WHO position paper on rabies vaccines. Weekly Epidemiological Record,2010, 85 (31):293308.

24. Laon M. Immunology. Jackson AC, Wunner WH, eds. Rabies, 2nd ed.Amsterdam, Elsevier Academic Press, 2007:489504.

25. Franka R et al. Rabies virus pathogenesis in relationship to intervention withinactivated and attenuated rabies vaccines. Vaccine, 2009, 27:71497155.

26. Ertl HC.Novel vaccines to human rabies. PLoS Neglected Tropical Diseases,2009, 3:e515.

27. Dodet B, AREB. Report o the Fith AREB Meeting Ho Chi Minh City,Viet Nam, 1720 November 2008. Vaccine, 2009, 27:24032407.

28. Wilde H. Failures o post-exposure rabies prophylaxis. Vaccine, 2007,25:76057609.

29. Briggs DJ. Human vaccines. In: Jackson AC, Wunner WH, eds. Rabies, 2nd ed.Amsterdam, Elsevier Academic Press, 2007:505516.

30. Briggs DJ et al. Antibody response o patients ater postexposure rabiesvaccination with small intradermal doses o puried chick embryo cell vaccineor puried Vero cell rabies vaccine. Bulletin of the World Health Organization,2000, 78:693698.

31. Quiambao BP et al. Reducing the cost o post-exposure rabies prophylaxis:ecacy o 0.1 ml PCEC rabies vaccine administered intradermally using theThai Red Cross post-exposure regimen in patients severely exposed to laboratory-conrmed rabid animals. Vaccine, 14, 2005, 23:17091714.

32. Chutivongse S et al. Postexposure rabies vaccination duringpregnancy: eect on 202 women and their inants.Clinical Infectious

Diseases : an ofcial publication of the Infectious Diseases Society ofAmerica, 1995, 20:818820.

8/7/2019 9789241501088_eng

28/34


33. Lang J, Feroldi E, Vien NC. Pre-exposure puried Vero cell rabies vaccineand concomitant routine childhood vaccinations: 5-year post-exposureollow-up study o an inant cohort in Vietnam.Journal of Tropical Pediatrics,2009, 55:2631.

34. Wiktor TJ, Doherty PC, Koprowski H. In vitro evidence o cell-mediatedimmunity ater exposure o mice to both live and inactivated rabies virus.Proceedings of the National Academy of Sciences of the United States of America,1977, 74:334338.

35. Hooper C et al. Collaboration o antibody and infammation in clearanceo rabies virus rom the central nervous system. Journal of Virology, 1998,72:37113719.

36. Moore SM et al.Detection o cellular immunity to rabies antigens in humanvaccines. Journal of Clinical Immunology, 2006, 26:533545.

37. Brinkman DM et al. Vaccination with rabies to study the humoral and

cellular immune response to a T-cell dependent neoantigen in man.Journal ofClinical Immunology, 2003, 23:528538.

38. Shankar V, Dietzschold B, Koprowski H.Direct entry o rabies virus into thecentral nervous system without prior local replication. Journal of Virology, 1991,65:27362738.

39. Dietzschold B et al.Mechanisms o rabies virus neutralization by glycoprotein-specic monoclonal antibodies. Virology, 1987, 161:2936.

40. Herzog M et al.Nucleocapsid specic T and B cell responses in humans aterrabies vaccination. Virus Research, 1992, 24:7789.

41. Sampath G et al.Rabies post-exposure in malnourished children exposed to

suspect rabid animals. Vaccine, 2005, 23:11021105.

42. Khawplod P et al. Revision o the Thai Red Cross intradermal rabiespost-exposure regimen by eliminating the 90-day booster injection.Vaccine, 2006, 24:30843086.

43. Vodopija I et al. Interaction o rabies vaccine with human rabies immunoglobulinand reliability o 2-1-1 schedule application or post-exposure treatment.Vaccine, 1988, 6:283286.

44. Baltazard M, Bahmanyar M. Essai pratique du srum antirabique chez lesmordus par loups enrags. Bulletin of the World Health Organization, 1955,13:747772.

45. Rupprecht CE, Hanlon CA, Hemachudha T.Rabies re-examined. The LancetInfectious Diseases, 2002, 2:327343.

46. Wilde H et al.Rabies update or travel medicine advisors. Clinical InfectiousDiseases : an ofcial publication of the Infectious Diseases Society of

America,2003, 37:96100.

47. Khawplod P et al. Prospective immunogenicity study o multipleintradermal injections o rabies vaccine in an eort to obtain an earlyimmune response without the use o immunoglobulin.Clinical InfectiousDiseases : an ofcial publication of the Infectious Diseases Society of

America, 2002, 35:15621565.

8/7/2019 9789241501088_eng

29/34

19

48. WHO Expert Committee on Rabies. Geneva, World Health Organization,1984 (WHO Technical Report Series No. 824:84).

49. Chutivongse S et al. Postexposure prophylaxis or rabies with antiserum andintradermal vaccination. Lancet, 1990, 335:896989.

50. Kamoltham T et al.Elimination o human rabies in a canine endemic provincein Thailand: ve-year programme. Bulletin of the World Health Organization,2003, 81:375381.

51. Wilde H, Tipkong P, Khawplod P. Economic issues in postexposure rabiestreatment. Journal of Travel Medicine, 1999, 6:2342.

52. Wasi C et al. Progress and achievement o rabies control in Thailand.Vaccine, 1997, 15:S711.

53. Sudarshan MK. Introducing intradermal rabies vaccination in India:paradigm shit or the better. Indian Journal of Public Health, 2006,50:209212.

54. Lambert PH, Laurent PE. Intradermal vaccine delivery: will new delivery systemstransorm vaccine administration? Vaccine, 2008, 26:31973208.

55. Intradermal delivery of vaccines. A review of the literature and potential for usein low income and developing countries. Seattle, World Health Organization,PATH, 2009 (http://www.path.org/les/TS_opt_idd_review.pd).

56. Picot V. Meeting Report Intradermal Immunization: an alternative route orvaccine administration. Vaccine, 2008, 26:S15.

57. Wilde H et al.Failure o postexposure treatment o rabies in children.Clinical Infectious Diseases : an ofcial publication of the Infectious Diseases

Society of America, 1996, 22:228232.58. Deshpande A, Briggs DJ. Rabies vaccination in immunosuppressed patients.

In: Dodet, B, Meslin F-X, eds. Rabies in Asia. Paris, John Libbey, 2001:5860.

59. Pancharoen C et al. Failure o pre- and post-exposure rabies vaccinationsin a child inected with HIV. Scandinavian Journal of Infectious Diseases,2001, 33:390391.

60. Tantawichien T et al. Failure o multiple-site intradermal postexposurerabies vaccination in patients with human immunodeiciency viruswith low CD4+ T lymphocyte counts. Clinical Infectious Diseases :an ofcial publication of the Infectious Diseases Society of America ,2001, 33:122124.

61. Thisyakorn U, Pancharoen C, Wilde H. Immunological and virologicalevaluation o HIV-1-inected children ater rabies vaccination. Vaccine,1112 2001, 19:15341537.

62. Thisyakorn U et al. Saety and immunogenicity o preexposure rabiesvaccine in children inected with human immunodeciency virus type 1.Clinical Infectious Diseases : an ofcial publication of the Infectious DiseasesSociety of America, 2000, 30:218.

63. Gelinck LB et al. Restoration o the antibody response upon rabies vaccinationin HIV-inected patients treated wtih HAART. AIDS (London, England), 2009,23:24512458.

8/7/2019 9789241501088_eng

30/34


64. Sirikwin S et al. Antibody response to an eight-site intradermal rabies vaccinationin patients inected with Human Immunodeiciency Virus. Vaccine, 2009,27:43504354.

65. Cramer CH et al. Immune response to rabies vaccination in pediatric transplant

patients. Pediatr Transplantation, 2008, 12:874877.66. Leder K, Weller P, Wilson ME. Travel vaccines and elderly persons:

review o vaccines available in the United States. Clinical InfectiousDiseases : an ofcial publication of the Infectious Diseases Society of America,2001, 33:15531566.

67. Mastroeni I et al. Immune response o the elderly to rabies vaccines.Vaccine, 1994, 12:518520.

68. Briggs DJ, Schwenke JR. Longevity o rabies antibody titre in recipients ohuman diploid cell rabies vaccine. Vaccine, 1992, 10:125129.

69. Pappaioanou M et al. Antibody response to preexposure human diploid-cell

rabies vaccine given concurrently with chloroquine. The New England Journalof Medicine, 1986, 314:280284.

70. Bernard KW et al. Pre-exposure rabies immunization with humandiploid cell vaccine: decreased antibody responses in persons immunized indeveloping countries. The American Journal of Tropical Medicine and Hygiene,1985, 34,:633647.

71. Abazeed ME, Cinti S. Rabies prophylaxis or pregnant women.Emerging Infectious Diseases, 2007, 13:19661967.

72. Sudarshan MK et al.Assessing the saety o post-exposure rabies immunizationin pregnancy. Human Vaccines, 2007, 3:8789.

73. Thraenhart O et al. Long-term humoral and cellular immunity atervaccination with cell culture rabies vaccines in man. Clinical Immunology andImmunopathology, 1994, 71:287292.

74. Naraporn N et al. Immune response to rabies booster vaccination insubjects who had postexposure treatment more than 5 years previously.

Journal of Travel Medicine, 1999, 6:134136.

75. Suwansrinon K et al.Survival o neutralizing antibody in previously rabiesvaccinated subjects: a prospective study showing long lasting immunity.Vaccine, 2006, 24:38783880.

76. Brown D et al. Intradermal pre-exposure rabies vaccine elicits long lastingimmunity. Vaccine, 2008, 26:39093912.

77. Strady A et al. Antibody persistence ollowing preexposure regimens ocell-culture rabies vaccines: 10-year ollow-up and proposal or a new boosterpolicy. The Journal of Infectious Diseases, 1998, 177:12901295.

78. Malerczyk C et al.Duration o immunity: An anamnestic response 14 yearsater rabies vaccination with puriied chick embryo cell rabies vaccine.

Journal of Travel Medicine, 2007, 14:6364.

8/7/2019 9789241501088_eng

31/34

21

79. Pengsaa K et al. A three-year clinical study on immunogenicity, saety, and boosterresponse o puried chick embryo cell rabies vaccine administered intramuscularyor intradermally to 12- to 18-month-old Thai children, concomitantly with

Japanese encephalitis vaccine. The Pediatric Infectious Disease Journal, 2009,28:335337.

80. Turner GS et al. Evaluation o a human diploid cell strain rabies vaccine:nal report o a three year study o pre-exposure immunization. The Journal of

Hygiene, 1982, 89:101109.

81. Horman JT et al. Antibody response ater a two-year intradermal booster orabies human diploid cell vaccine.Journal of the American Veterinary Medical

Association, 1987, 191:185187.

82. Gherardin AW et al. Early rabies antibody response to intramuscular booster inpreviously intradermally immunized travelers using human diploid cell rabiesvaccine.Journal of Travel Medicine, 2001, 8:122126.

83. Strady C et al.Immunogenicity and booster ecacy o pre-exposure rabiesvaccination. Transactions of the Royal Society of Tropical Medicine andHygiene, 2009, 103:11591164.

84. Bourhy H et al.Rabies in Europe in 2005.Euro Surveillance : bulletin europensur les maladies transmissibles = European communicable disease bulletin,2005, 10:575.

85. Smith JS, Yager PA, Baer GM. A rapid reproducible test or determiningrabies neutralizing antibody. Bulletin of the World Health Organization,1973, 48:535541.

86. Cliquet F, Aubert M, Sagne L.Development o a fuorescent antibody virus

neutralization test (FAVN test) or the quantitation o rabies-neutralisingantibody.Journal of Immunological Methods, 1998, 212:7987.

87. Kissling RE. The fuorescent antibody test in rabies. In: Baer GM, ed. The NaturalHistory of Rabies, 1st ed. Boca Raton, CDC Press, 1975, 1:401416.

88. Lembo T et al. Evaluation o a direct, rapid immunohistochemical test or rabiesdiagnosis. Emerging Infectious Diseases, 2006, 12:310313.

89. Feyssaguet M et al. Multicentre comparative study o a new ELISA,PLATELLA RABIES II, or the detection and titration o anti-rabies glycoproteinantibodies and comparison with the rapid fuorescent ocus inhibition test(RFFIT) on human samples rom vaccinated and non-vaccinated people.

Vaccine, 2007, 25:22442251.90. Smith JS. Rabies serology. In: Baer GM, ed.A natural history of rabies, 2nd ed.

Boca Raton, CDC Press, 1971:236290.

91. Gibbons RV, Rupprecht CE.Twelve common questions about human rabiesand its prevention. Infectious Diseases in Clinical Practice (Baltimore, Md.),2000, 9:202207.

92. Moore SM, Chandra CR, Briggs DJ. Rabies serology. In: Jackson AC,Wunner WH, eds. Rabies, 2nd ed. Amsterdam, Elsevier Academic Press,2007:471488.

93. Trimarchi CV, Nadin-Davis SA. Diagnostic evaluation. In: Jackson AC,

Wunner WH, eds. Rabies,2nd ed. Amsterdam, Elsevier, 2007:411469.

8/7/2019 9789241501088_eng

32/34


94. WHO Expert Committee on Biological Standardization. Fifty-sixth report.Geneva, World Health Organization, 2007, Annex 2.

95. Briggs DJ et al. A comparison o two serological methods or detecting theimmune response ater rabies vaccination in dogs and cats being exported to

rabies-ree areas.Biologicals : Journal of the International Association of BiologicalStandardization, 1998, 26:347355.

96. Meslin FX, Kaplan MM. An overview o laboratory techniques in the diagnosisand prevention o rabies and in rabies research. In: Meslin FX, Kaplan MM,Koprowski H, eds. Laboratory techniques in rabies, 4th ed. Geneva, World HealthOrganization, 1996:927.

97. Johnson HN. The virus neutralization index test in mice. In: Meslin FX,Kaplan MM, Koprowski H, eds. Laboratory techniques in rabies, 3rd ed.Geneva, World Health Organization, 1973:9497.

98. Trimarchi CV, Rudd RD, Saord M. An in vitro virus neutralization test or rabies

antibody. In: Meslin FX, Kaplan MM, Koprowski H, eds. Laboratory techniquesin rabies, 4th ed. Geneva, World Health Organization, 1996:193199.

99. Perrin P et al.The infuence o the type o immunosorbent on rabies antibodyEIA: advantages o puried glycoprotein over whole virus. Journal of BiologicalStandardization, 14:95102.

100. Elmgren LD, Wandeler AI. Competitive ELISA or the detection o rabiesvirus-neutralizing antibodies. Meslin FX, Kaplan MM, Koprowski H, eds.Laboratory techniques in rabies, 4th ed. Geneva, World Health Organization,1996:200208.

101. Cliquet F et al. ELISA test or rabies antibody titration in orally vaccinated oxes

sampled in the elds. Vaccine, 2000, 18:32723279.102. Welch RJ, Anderson BL, Litwin MW. An evaluation o two commercially

available ELISAs and one in-house reerence laboratory ELISA or thedetermination o human anti-rabies virus antibodies. Journal of MedicalMicrobiology, 2009, 58:806810.

103. Zhang S et al. Competitive ELISA using a rabies glycoprotein-transormedcell line to semi-quantiy rabies neutralizing-related antibodies in dogs.Vaccine, 2009, 27:21082113.

104. Servat A, Cliquet F. Collaborative study to evaluate a new ELISA test tomonitor the eectiveness o rabies vaccination in domestic carnivores.

Virus Research, 2006, 120:1727.105. Stanic-Pavlinic M et al. Vaccination against rabies and protective

antibodies comparison o ELISA and luorescent antibody virusneutralization assays. Veterinarski Arhiv, 2006, 76:281289.

106. Vengatesan D et al. Detection o rabies virus antigen or antibody using fowcytometry. Cytometry. Part B, Clinical Cytometry, 2006, 70B:335343.

107. Rupprecht CE et al. Evidence or a 4-dose vaccine schedule or humanrabies post-exposure prophylaxis in previously non-vaccinated individuals.Vaccine, 2009, 27:71417148.

8/7/2019 9789241501088_eng

33/34

23

108. Mahendra BJ, Briggs DJ. Public health management o humans at risk.In: Jackson AC, Wunner WH, eds. Rabies, 2nd ed. Amsterdam, Elsevier AcademicPress, 2007:545566.

109. Gautret P et al. Rabies post-exposure prophylaxis in travellers returning

rom Bali, Indonesia, November 2008March 2010. Clinical Microbiology andInfection : the ofcial publication of the European Society of Clinical Microbiologyand Infectious Diseases [Epub. 19 May 2010].

110. Hampson K et al. Rabies exposures, post-exposure prophylaxis and deathsin a region o endemic canine rabies. PLoS Neglected Tropical Diseases,2008, 2:e339.

111. Bakker AB et al. First administration to humans o a monoclonal antibodycocktail against rabies virus: saety, tolerability, and neutralizing activity.Vaccine, 2008, 26:59225927.

112. Muller T et al. Development o a mouse monoclonal antibody cocktail or

post-exposure rabies prophylaxis in humans. PLoS Neglected Tropical Diseases,2009, 3:e542.

113. Khawplod P et al. One or three intradermal injections within one weekor rabies pre-exposure immunization. Developments in Biologicals,2008, 131:393401.

114. Prapimporn S, Wilde H, Hemachuda T. Postexposure rabies prophylaxiscompleted in 1 week: preliminary study.Clinical Infectious Diseases : an ofcial

publication of the Infectious Diseases Society of America [in press 2009].

115. Faber M et al.Eective preexposure and postexposure prophylaxis o rabieswith a highly attenuated recombinant rabies virus. Proceedings of the National

Academy of Sciences of the United States of America, 2009, 106:1130011305.116. Wu X et al.Development o combined vaccines or rabies and immunocontraception.

Vaccine, 2009, 27:72027209.

117. Human and dog rabies prevention and control. Report o theWHO/Bill & Melinda Gates Foundation Consultation, Annecy,7 September 2009. WHO /HTM/NTD/NZD/2010.1, pp. 37.

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The World Health Organization has provided

technical support to its Member States in the

eld of vaccine-preventable diseases since

1975. The ofce carrying out this function

at WHO headquarters is the Department of

Immunization, Vaccines and Biologicals (IVB).

IVBs mission is the achievement of a world

in which all people at risk are protected

against vaccine-preventable diseases.

The Department covers a range of activities

including research and development,

standard-setting, vaccine regulation and

quality, vaccine supply and immunization

nancing, and immunization system

strengthening.

These activities are carried out by three

technical units: the Initiative for Vaccine

Research; the Quality, Safety and Standards

team; and the Expanded Programme on

Immunization.

The Initiative for Vaccine Research guides,

facilitates and provides a vision for worldwide

vaccine and immunization technology

research and development efforts. It focuses

on current and emerging diseases of global

public health importance, including pandemic

inuenza. Its main activities cover: i ) researchand development of key candidate vaccines;

ii ) implementation research to promote

evidence-based decision-making on the

early introduction of new vaccines; and iii )

promotion of the development, evaluation

and future availability of HIV, tuberculosis

and malaria vaccines.

The Quality, Safety and Standards team

focuses on supporting the use of vaccines,

other biological products and immunization-

related equipment that meet current inter-

national norms and standards of quality

and safety. Activities cover: i ) setting norms

and standards and establishing reference

preparation materials; ii ) ensuring the use of

quality vaccines and immunization equipment

through prequalication activities and

strengthening national regulatory authorities;

and iii ) monitoring, assessing and responding

to immunization safety issues of global

concern.

The Expanded Programme on Immunizationfocuses on maximizing access to high

quality immunization services, accelerating

disease control and linking to other health

interventions that can be delivered during

immunization contacts. Activities cover:

i ) immunization systems strengthening,

including expansion of immunization services

beyond the infant age group; ii ) accelerated

control of measles and maternal and

neonatal tetanus; iii ) introduction of new and

underutilized vaccines; iv ) vaccine supply

and immunization nancing; and v ) disease

surveillance and immunization coverage

monitoring for tracking global progress.

The Directors Ofce directs the work of

these units through oversight of immunization

programme policy, planning, coordination and

management. It also mobilizes resources and

carries out communication, advocacy and

media-related work.

Family and Community Health

World Health Organization

20, Avenue Appia

CH-1211 Geneva 27

Switzerland

E-mail: [email protected]

Web site: http://www.who.int/immunization/en/

Department of Immunization, Vaccines and Biologicals

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