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

19

81

19

82

19

83

19

84

19

85

19

86

19

87

19

88

19

89

19

90

19

91

19

92

19

93

19

94

19

95

19

96

19

97

19

98

19

99

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

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