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Vaccine Safety - A pediatrician perspective


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

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

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  • 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
  • 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 GAVIs 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 Worlds Vaccines and Immunization 2009 report 2. Harvard School of Public Health study 2005
  • 5. Comparison of 20th Century Annual Morbidity andCurrent 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 99.1Source: CDC
  • 6.  Vaccine Concerns:As Old As Vaccines Themselves“The Cow Pock – or – the Wonderful Effects of the New Inoculation!”J. Gillray, 1802
  • 7. Number of articles 50 0 100 150 200 250 300 350089189128913891489158916891789189189109191291391 1980-20004915916917918919102 Medline Search: “Vaccine Safety”
  • 8. Need for vaccine safety study ?
  • 9. Immunization coverage among 1-year-olds ( %) in IndiaVaccine No of child vaccinated, No of child vaccinated, Percent 1 985(% ) 201 0(% ) increaseMeasles 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:
  • 10.  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.
  • 11.  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
  • 12. Temporal vs. Causal Associations: Is Sequence Consequence? A BExposure Disease(Vaccine, Drug,Diet, TimeOccupationOthers)? •Direct and only cause? •One of multiple potential causes? •Co-factor/indirect cause, trigger? •Coincidental?
  • 13. Vaccine ASSOCIATED adverseevents (VAE) ?
  • 14. 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.
  • 15. Classification1. Adverse vaccine reaction (vaccine induced): Causally related, e.g. VAPP due to Oral Polio Vaccine, anaphylaxis2. Trigger reaction (vaccine potentiated): Reaction triggered byvaccine e.g. febrile seizure following vaccination in a predisposed child3. Programmatic errors: Most common cause for seriousadverse events and death, e.g. deaths following Measles vaccination dueto toxic shock syndrome resulting from improper reconstitution andstorage4. Injection reaction: Not specific to vaccine, e.g. Syncope inadolescents, injection site abscesses, sciatic nerve damage due to glutealinjection & transmission of blood borne pathogens such asHIV/HBV/HCV
  • 16. Methods of monitoring vaccine safetyPre-licensureTo identify potential safety problems, vaccines go through pre-release lot testing for safety and potency, occurs parallel to theclinical trials prior to vaccine licensurePost licensureVaccine Adverse Event Reporting System (VAERS) and ad hocepidemiologic studies. More recently, Phase IV trials and pre-established large linked databases (LLDBs) to study rare risks
  • 17. 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
  • 18. Case Study – 1Rotavirus Vaccine and Intussusception
  • 19.  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
  • 20. 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
  • 21. 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
  • 22. 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
  • 23. Case Study – 2MMR vaccine & Autism
  • 24. 1312
  • 25. Wakefield’s “Study”  Findings not reproducible 10/13 authors retract their findings (2004)  London Times investigation (2009)
  • 26. 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 vaccineMadsen KM, et al. N Engl J Med 2002;347:1477- 1482
  • 27. 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
  • 28. “Then we’ve agreed that all of the evidence isn’t in, and thateven if all of the evidence were in, it still wouldn’t bedefinitive”
  • 29. S ome rarely occurring A DR’s due to vaccination
  • 30. Vaccine Rare ADRsOral 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 KnownHaemophilus influenzatype b conjugate Not Known(Hib)Pneumococcal conjugate, (PCV-7), Not Known(PCV-10)Hepatitis B (HepB) Not KnownInactivated polio vaccine (IPV) Not KnownRotavirus Rare Intussusception risk (1:50-60,000)Vaccine safety . Safety profile of vaccine. Accessed on 13 March 2012.
  • 31. 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:, 2009 GPEI.Strategic Plan 2009-2013. Available at:,2009 Wringe et al. Plos One, 2008
  • 32. Disproven link between vaccine and Adverse effects
  • 33. Vaccine as s ociation and p u b lic conce rn
  • 34. It’s no longer enough tosay, “Trust us, we’re theexperts.”Physicians and healtheducators must deal fullyand respectfully with thevaccine safety concernsof parents and patients.
  • 35. 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
  • 36. Do Vaccines “Overwhelm” the Immune System? 1900 1960 1980 2000Vaccine 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. 8TOTALS: hepatitis B 1 1 ~200 5 ~3217 7 ~3041 11 123-126dified from Offit PA, et al. Pediatrics January 2002
  • 37. 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
  • 38. 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  diseaseSalmon DA.  Health consequences of religious and philosophical exemptions from immunization laws. JAMA 1999
  • 39. Improving theImmunization 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
  • 40. 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.”
  • 41. Immunization Resources Resource Kit: Communication with Patients About Immunizations Immunization Newsbriefs