Presented at the International conference for Patient safety in NIPER, Chandigarh, India on 20th March 2012

1. Vaccine Safety – Case Scenario
from a Pediatric perspective !
D r. G au rav G u p ta (P e d iatrician),
C h arak C linics

2. Overview
 Importance of vaccines safety
 About VAE
 Case studies – Rotavirus & MMR
 How to improve communication regarding vaccine safety

3. IM P O R TAN C E O F VAC C IN ATIO N

4. 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 report
2. Harvard School of Public Health study 2005

5. Comparison of 20th Century Annual Morbidity and
Current Morbidity, Vaccine-Preventable Diseases
20th Century 2000 Percent
Annual Morbidity (Provisional) Decrease
Diphtheria 175,885 4 99.9
Measles 503,282 81 99.9
Mumps 152,209 323 99.8
Pertussis 147,271 6,755 95.4
Polio (paralytic) 16,316 0 100
Rubella 47,745 152 99.7
Congenital Rubella Syndrome 823 7 99.1
Tetanus 1,314 26 98.0
H. influenzae,
type b and unknown (<5 yrs) 20,000 167 99.1
Source: CDC

6. Vaccine Concerns:
As Old As Vaccines Themselves
“The Cow Pock – or – the Wonderful Effects of the New Inoculation!”
J. Gillray, 1802

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Medline Search: “Vaccine Safety”

10. Need for vaccine safety study ?

11. Immunization coverage among 1-year-olds
( %) in India
Vaccine No of child vaccinated, No of child vaccinated, Percent
1 985(% ) 201 0(% ) increase
Measles 1 74 98.7%
Polio 14 70 85.2%
BCG 8 87 91 .6%
Hib No inf.
Hepatitis B 0 37 1 00%
Diphtheria 18 72 80%
Ref: WHO. Available at URL: http://apps.who.int/ghodata/?vid=80100.

12.  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.

13.  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

14. Temporal vs. Causal Associations:
Is Sequence Consequence?
A B
Exposure Disease
(Vaccine, Drug,
Diet, Time
Occupation
Others)? •Direct and only cause?
•One of multiple potential causes?
•Co-factor/indirect cause, trigger?
•Coincidental?

15. Vaccine ASSOCIATED adverse
events (VAE) ?

16. 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.

17. Classification
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

18. Methods of monitoring vaccine safety
Pre-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

19. 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

20. 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
21

22. Case Study 1 (cont.)
• 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
22

23. Case Study 1 (cont.)
 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
23

24. How did this impact next rotavirus vaccine?
 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
24
1. N Engl J Med 2011; 364:2283-2292

25. Case Study – 2
MMR vaccine & Autism

26. 13
12

27. Wakefield’s “Study”
 Findings not reproducible
 10/13 authors retract their findings (2004)
 London Times investigation (2009)

28. The “Denmark” 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
Madsen KM, et al. N Engl J Med 2002;347:1477- 1482

29. The Science
 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

30. “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”

31. S ome rarely occurring A DR’s due
to vaccination

32. 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 Not Known
(Hib)
Pneumococcal conjugate, (PCV-7), Not Known
(PCV-10)
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/inde
. Accessed on 13 March 2012.

33. 2000- July 2009: At Least 13 cVDPV Outbreaks in 12
Countries Caused et Least of 300 Paralytic Polio cases CHINA
2004
VDPV 1
2 cases
MYANMAR
2006-07
VDPV 1
ETHIOPIA 5 cases
NIGER 2008-09
2006 VDPV 2
VDPV 2 4 cases CAMBODIA
2 cases 2005-06
VDPV 3
DOR / HAITI 2 cases
INDIA
2000-01
2009
VDPV 1
NIGERIA VDPV 1, 2
21 cases PHILIPPINES
2005-08 2 & 18
VDPV 2 cases 2001
148 cases VDPV 1
3 cases
MADAGASCAR
VDPV 2 INDONESIA
DR CONGO 2001-02 2005
2008 5 cases VDPV 1
VDPV 2 2005 46 cases
11 cases 3 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”
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

34. Disproven link between vaccine and Adverse effects

35. Vaccine as s ociation and p u b lic conce rn

36. 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.

37. Reasons Parents Refuse Vaccines for Their Children
• 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

38. Do Vaccines “Overwhelm” the Immune System?
1900 1960 1980 2000
Vaccine Proteins Vaccine Proteins Vaccine Proteins Vaccine Proteins
smallpox ~200 smallpox ~200 diphtheria 1 diphtheria 1
diphtheria 1 tetanus 1 tetanus 1
tetanus 1 wc-pertussis ac-pertussis 2-5
wc-pertussis ~3000 polio 15
~3000 polio 15 measles 10
polio 15 measles 10 mumps 9
mumps 9 rubella 5
rubella 5 Hib conj. 2
varicella 69
pneumo conj. 8
TOTALS: hepatitis B 1
1 ~200 5 ~3217 7 ~3041 11 123-126
dified from Offit PA, et al. Pediatrics January 2002

39. 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

40. 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

41. 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 Economist
February 14, 2002

42. 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.”

43. Immunization Resources
 www.immunizationinfo.org
 www.vaccine.gov
 www.iapcoi.com
 Resource Kit: Communication with Patients About
Immunizations
 Immunization Newsbriefs