Vaccine Safety - A pediatrician perspective
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Vaccine Safety – Case Scenario from a Pediatric
perspective !
Dr. Gaurav Gupta (Pediatrician),Charak Clinics
Overview Importance of vaccines safety About VAE Case studies – Rotavirus & MMR How to improve communication regarding
vaccine safety
IMPORTANCE OF VACCINATION
Vaccines help healthy people stay healthy Vaccines are used universally, especially in
children Relatively easy to deliver, and in most cases
provide lifelong protection. Boost development through direct medical
savings and indirect economic benefits too. Immunization - even with the addition of the new,
more costly vaccines - remains one of the most cost-effective health interventions. 1
GAVI's programme to expand vaccine coverage in eligible countries would deliver a rate of return of 18% by 2020 2 - higher than most other health interventions, and similar to primary education.
1. WHO State of the World's Vaccines and Immunization 2009 report2. Harvard School of Public Health study 2005
20th CenturyAnnual Morbidity
2000(Provisional)
PercentDecrease
Comparison of 20th Century Annual Morbidity and Current Morbidity, Vaccine-Preventable Diseases
Diphtheria
Measles
Mumps
Pertussis
Polio (paralytic)
Rubella
Congenital Rubella Syndrome
Tetanus
H. influenzae, type b and unknown (<5 yrs)
175,885
503,282
152,209
147,271
16,316
47,745
823
1,314
20,000
4
81
323
6,755
0
152
7
26
167
99.9
99.9
99.8
95.4
100
99.7
99.1
98.0
99.1
Source: CDC
“The Cow Pock – or – the Wonderful Effects of the New Inoculation!”J. Gillray, 1802
Vaccine Concerns: As Old As Vaccines Themselves
Medline Search: “Vaccine Safety”1980-2000
0
50
100
150
200
250
300
350
19
80
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19
82
19
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19
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20
00
Num
ber o
f arti
cles
Need for vaccine safety study ?
VaccineNo of child vaccinated,
1985(%)
No of child vaccinated,
2010(%)
Percent increas
eMeasles 1 74 98.7%Polio 14 70 85.2%BCG 8 87 91.6%Hib No inf.Hepatitis B 0 37 100%Diphtheria 18 72 80%
Immunization coverage among 1-year-olds (%) in India
Ref: WHO. Available at URL: http://apps.who.int/ghodata/?vid=80100.
Higher standard of safety is generally expected of
vaccines than of other medical interventions because, in
contrast to most pharmaceutical products, vaccines are
generally given to healthy people to prevent disease
Widespread use/ universal use of vaccines may make
even unrelated events appear causal (like infant deaths)
Public intolerance of adverse reactions related to
products given to healthy people, especially healthy babies.
This leads to increased chances of reporting / investigations
for even rare potential side-effects.
Unlike many classes of drugs, vaccines generally have few
alternative strains or types to chose from.
An erroneous association or attributable risk can undermine confidence in a
vaccine and have disastrous consequences for vaccine acceptance and
disease incidence.
Research in vaccine safety can help to distinguish true vaccine reactions
from coincidental unrelated events and help maintain public confidence &
credibility in immunizations programs
Temporal vs. Causal Associations:Is Sequence Consequence?
A Exposure(Vaccine, Drug,Diet, OccupationOthers)?
B Disease
Time
•Direct and only cause?•One of multiple potential causes?•Co-factor/indirect cause, trigger?•Coincidental?
Vaccine ASSOCIATED adverse events (VAE) ?
What is AEFI/ VAE ?
Untoward (temporally associated) event
following immunization that might or might
not be caused by the vaccine or the
immunization process.
Example: Intussusception following rotavirus
vaccine, febrile seizures following MMRV
vaccine etc.
1. Adverse vaccine reaction (vaccine induced): Causally related, e.g. VAPP due to Oral Polio Vaccine, anaphylaxis
2. Trigger reaction (vaccine potentiated): Reaction triggered by vaccine e.g. febrile seizure following vaccination in a predisposed child
3. Programmatic errors: Most common cause for serious adverse events and death, e.g. deaths following Measles vaccination due to toxic shock syndrome resulting from improper reconstitution and storage
4. Injection reaction: Not specific to vaccine, e.g. Syncope in adolescents, injection site abscesses, sciatic nerve damage due to gluteal injection & transmission of blood borne pathogens such as HIV/HBV/HCV
Classification
Methods of monitoring vaccine safetyPre-licensure
To identify potential safety problems, vaccines go through pre-release lot testing for safety and potency, occurs parallel to the clinical trials prior to vaccine licensure
Post licensure
Vaccine Adverse Event Reporting System (VAERS) and ad hoc epidemiologic studies. More recently, Phase IV trials and pre-established large linked databases (LLDBs) to study rare risks
Vaccine associated adverse event reporting system (VAERS)
VAERS is a passive surveillance system
because it depends on health care providers
and/or patients
Crucial to pick up previously unrecognized
adverse effects and generate further data on
vaccine safety
A robust system for reporting VAE exists in most
developed countries including the US.
Currently not available in India
Pediatricians are encouraged to report VAE to
the IAP immunization website www.iapcoi.com
Case Study – 1 Rotavirus Vaccine and
Intussusception
21
First rotavirus vaccine (Rotashield) licensed by FDA in August 1998 for prevention of rotavirus gastroenteritis in infants Pre-licensure data for Intussusception (IS)
5 cases in 10,054 vaccines 1 cases in 4633 placebo recipients Difference in rates not statistically significant Lack of apparent association between IS and wild-type
rotavirus infection Phase 4 study commitment at licensure Package insert: IS included as potential AE IS prospectively added as term in VAERS
database
Case Study 1 (cont.)
22
• VAERS reports 9/1/98 – 6/2/99: 10 IS cases, temporal clustering after 1st dose and within 7 days after vaccination provided signal
• July 1999*– 15 IS cases reported to VAERS, 12 within 7 days
after vaccination• ~1.5 million doses administered 8/98-6/1/99• 14-16 cases would be expected in week after vaccination
by chance alone – Population-based studies suggested higher IS rates
after vaccination (not statistically significant) – CDC and AAP recommended temporary suspension
of use
*MMWR July 16, 1999; 48:577-581
Case Study 1 (cont.)
23
October 1999 Population-based studies: elevated risk of IS after
vaccination* ACIP withdrew its recommendation for vaccination Wyeth voluntarily withdrew vaccine
What was attributable risk? Initial estimate 1/2500 to1/5000 Consensus estimate ~1/10,000**
Did vaccine “trigger IS but result in no net increase?***
*MMWR September 3, 2004;53:786-789 **Pediatrics 2002;110:e67-73 ***Lancet 2004;363:1547-50
How did this impact next rotavirus vaccine?
24
Second rotavirus vaccine (Rotateq) licensed by FDA in February 2006 Pre-licensure: very large safety study (70,000 infants,
1:1 vaccine to placebo), no increased risk of IS Post-licensure surveillance: VAERS, manufacturer’s
phase 4 study (44,000 infants) and CDC’s VSD study (90,000 infants)
Very slight increase in risk of IS in some post licensure studies, however significant cost benefit ratio in favor. Combined annual excess of 96 cases of intussusception in Mexico (1 per 51,000 infants) & Brazil (1 per 68,000 infants) and 5 deaths due to intussusception was attributable to RV1. However, RV1 prevented approximately 80,000 hospitalizations and 1300 deaths from diarrhea each year in these two countries. 1
1. N Engl J Med 2011; 364:2283-2292
Case Study – 2MMR vaccine & Autism
12
13
Findings not reproducible
10/13 authors retract their findings (2004)
London Times investigation (2009)
Wakefield’s “Study”
Retrospective cohort study of all children born in Denmark
between 1991 and 1998
537,303 children, 82% vaccinated with MMR vaccine
Same incidence of autism
No clustering of cases related to vaccine
The “Denmark” Study
Madsen KM, et al. N Engl J Med 2002;347:1477- 1482
After review of multiple studies (~18)
Institute of Medicine (2004) – no link between autism and
MMR vaccine
Feb, 2009, the U.S. Court of Federal Claims dismissed
~4,900 cases involved the National Vaccine Injury
Compensation Program
The Science
“Then we’ve agreed that all of the evidence isn’t in, and that even if all of the evidence were in, it still wouldn’t be definitive”
Some rarely occurring ADR’s due to vaccination
Vaccine Rare ADRs
Oral polio vaccine (OPV) VAPP very rare (0.0002% – 0.0004% or 2 – 4/1,000,000)
Measales Febrile seizure (uncommon at 0.3% or 1/3000)Thrombocytopenic purpura(very rare at 0.03% or 1/30,000)
BCG Fatal dissemination of BCG infection (very rare at 0.000019% – 0.000159% or 0.19 – 1.56/1,000,000)
IPV Not Known
Haemophilus influenzatype b conjugate (Hib)
Not Known
Pneumococcal conjugate, (PCV-7), (PCV-10)
Not Known
Hepatitis B (HepB) Not Known
Inactivated polio vaccine (IPV) Not Known
Rotavirus Rare Intussusception risk (1:50-60,000)
Vaccine safety . Safety profile of vaccine. https://extranet.who.int/vaccsafety/en/vaccine/learning/learning/module1/index.html. Accessed on 13 March 2012.
2000- July 2009: At Least 13 cVDPV Outbreaks in 12 Countries Caused et Least of 300 Paralytic Polio cases
Particular concern: re-emergence of type 2 (as VDPV) whereas the wild type was declared eradicated in 2002 and reported in 5 independent cVDPV outbreaks since then
According to some experts: “more likely several million individuals were infected during these events, and many thousand more have been infected by VDPV lineages within outbreaks which have escape detection”
DOR / HAITI2000-01VDPV 121 cases
DOR / HAITI2000-01VDPV 121 cases
NIGER2006
VDPV 22 cases
NIGER2006
VDPV 22 cases
NIGERIA2005-08VDPV 2
148 cases
NIGERIA2005-08VDPV 2
148 cases
DR CONGO2008
VDPV 211 cases
DR CONGO2008
VDPV 211 cases
MADAGASCARVDPV 22001-025 cases
20053 cases
MADAGASCARVDPV 22001-025 cases
20053 cases
MYANMAR2006-07VDPV 15 cases
MYANMAR2006-07VDPV 15 cases
INDONESIA2005
VDPV 146 cases
INDONESIA2005
VDPV 146 cases
CHINA2004
VDPV 12 cases
CHINA2004
VDPV 12 cases
CAMBODIA2005-06VDPV 32 cases
CAMBODIA2005-06VDPV 32 cases
PHILIPPINES2001
VDPV 13 cases
PHILIPPINES2001
VDPV 13 cases
ETHIOPIA2008-09VDPV 24 cases
ETHIOPIA2008-09VDPV 24 cases
WHO. cVDPV 2000-2008. Available at: http://www.polioeradication.org/content/general/cvdpv_count.pdf, 2009
GPEI.Strategic Plan 2009-2013. Available at: http://www.polioeradication.org/content/publications/PolioStrategicPlan09-13_Framework.pdf,2009
Wringe et al. Plos One, 2008
INDIA2009
VDPV 1, 2 2 & 18 cases
INDIA2009
VDPV 1, 2 2 & 18 cases
Disproven link between vaccine and Adverse effects
Vaccine association and public concern
It’s no longer enough to say, “Trust us, we’re the experts.” Physicians and health educators must deal fully and respectfully with the vaccine safety concerns of parents and patients.
• Concerns about vaccine safety cause harm: 69% overload the immune system: 49%
• Child is not at risk for disease: 37%
• Disease is not dangerous: 21%
• Vaccine may not work: 13%
• Ethical or moral issues: 9%
• Religious beliefs: 9%
• Natural immunity better - ?
Arch Pediatr Adolesc Med 2005; 159:470-6
Reasons Parents Refuse Vaccines for Their Children
Do Vaccines “Overwhelm” the Immune System?
Vaccine Proteins Vaccine Proteins Vaccine Proteins Vaccine Proteins
1900 1960 1980 2000
TOTALS:
1 ~200 5 ~3217 7 ~3041 11 123-126
smallpox ~200 smallpox ~200diphtheria 1tetanus 1wc-pertussis~3000polio 15
diphtheria 1tetanus 1wc-pertussis~3000polio 15measles 10mumps 9rubella 5
diphtheria 1tetanus 1ac-pertussis 2-5polio 15measles 10mumps 9rubella 5Hib conj. 2varicella 69pneumo conj. 8hepatitis B 1
Modified from Offit PA, et al. Pediatrics January 2002
True: Vaccines are Not Without Risk
• No vaccine is 100% safe • No vaccine is 100% effective• All vaccines have possible side effects, most mild, rarely
severe • The risk of disease far outweighs the risk of vaccine
False: Avoiding Vaccines Would Be "Safer"
• By choosing not to vaccinate one takes on the risk of disease
• Both vaccinating and not vaccinating carry risks, and the risks are far higher for unvaccinated children (& their peers)
• Children unvaccinated against measles are 35 times more likely than immunized children to catch the disease
Salmon DA. Health consequences of religious and philosophical exemptions from immunization laws. JAMA 1999
Improving the Immunization Dialogue
All health-care workers, from general practitioners to midwives, need to be kept up to date with developments in the debate and learn how to discuss, rather than dismiss, parents' fears.
The EconomistFebruary 14, 2002
Presenting Risk Information: What’s Best?
1. “A serious reaction to this vaccine occurs about 1 to 3 times per 10,000 doses.”
2. “About 1 to 3 children out of 10,000 who receive this vaccine will experience a serious reaction.”
3. “This vaccine rarely causes serious reactions-- about 1 to 3 children out of 10,000 who receive it.”
4. “This vaccine is very safe-- 9,997 children out of 10,000 who receive it will experience no adverse reaction.”
Immunization Resources www.immunizationinfo.org www.vaccine.gov www.iapcoi.com Resource Kit: Communication with Patients
About Immunizations Immunization Newsbriefs
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