Confronting controversy – Combating confusion. Immunization Today

1. Confronting controversy – Combating confusion.Immunization Today DR S G KASI Consultant pediatrician, Bengaluru Member IAPCOI, 2011-12

2. Ten Great Public Health Achievements-United States • 1900-1999 • Vaccination • Motor-vehicle safety • Safer workplaces • Control of infectious diseases • Decline in deaths from coronary heart disease and stroke • Safer and healthier foods • Healthier mothers and babies • Family planning • Fluoridation of drinking water • Recognition of tobacco use as health hazard

3. Comparison of 20th Century Annual Morbidity and Current Morbidity, Vaccine-Preventable Diseases 20th Century Annual Morbidity 2000 (Provisional) Percent Decrease 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

4. Immunization coverage among 1-year-olds (%) in India Ref: WHO. Available at URL: http://apps.who.int/ghodata/?vid=80100.

5. 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

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

7. Arthritis Asthma ADD Autism Brain Damage Cancer Chronic Fatigue Syndrome Diabetes Gulf War Syndrome Infantile Spasms Inflammatory Bowel Disease Multiple Sclerosis Neuroimmune Dysfunction Sudden Infant Death Syndrome Temporal Associations Between Vaccinations and Serious Illnesses Cause Public Concern

8. Vaccines are generally given to healthy people to prevent disease • Higher standard of safety is generally expected of vaccines than of other medical interventions • Public are intolerant to even minor of adverse reactions related to products given to healthy people, especially healthy babies. • An erroneous association or attributable risk can undermine confidence in a vaccineand have disastrous consequences for vaccine acceptance and disease incidence.

9. The Vaccine safety balance

10. VACCINES HAVE TO BE SAFE

11. Prelicensure Vaccine Safety Studies • Vaccine research and development is a carefully controlled and very lengthy process • Vaccines are rigorously tested to ensure quality, safety and efficacy at ALL stages of development • Preclinical animal studies: immunogenicity and SAFETY • Phase I: assess SAFETY and obtain limited immunogenicity and dosing data, adults, n= 10-50 • Phase II: assess COMMON REACTIONS and obtain immunogenicity data in infants, n= 100-200 • Phase III: assess protective efficacy, identify laboratory correlates of protection, ASSESS RARER REACTIONS, n depends on disease.

12. Phase IV surveillance: post licensure • Studies of new vaccines do not stop at point of licensure • -The number of subjects in Phase I-III is too small to detect rare events • Even once a vaccine is in use, ongoing studies are needed to detect RARER ADVERSE EVENTS

13. AEFI surveillance in USA:

14. Vaccine Adverse Event Reporting System (VAERS) • Passive National reporting system • Jointly administered by CDC and FDA • Receives ~15,000 reports per year • Detects • new or rare events • increases in rates of known side effects • patient risk factors • Additional studies required to confirm VAERS signals • Does not assess causality

15. Large Linked Databases • VSD: VSD is a network of 9 managed care organizations across the United States. The combined population of these organizations is more than 9.8 million people. • Look back in medical records to see if a particular adverse event is more common among people who have received a particular vaccine • Rapid Cycle Analysis (RCA) to continuously look at information coming into VSD to see if the rate of certain health conditions is higher among vaccinated people

16. Clinical Immunization Safety Assessment Network • CDC’s Clinical Immunization Safety Assessment (CISA) Project was established in 2001 to address the unmet vaccine safety clinical research needs of the United States. • CISA is a national network of vaccine safety experts from the CDC’s Immunization Safety Office (ISO), seven medical research centers, and other partners, which provides a comprehensive vaccine safety public health service to the nation. •  CISA addresses vaccine safety issues, conducts high quality clinical research, and assesses complex clinical adverse events following vaccination.

17. AEFI:

18. Definition : AEFI • Any untoward medical occurrence which follows immunization and which does not necessarily have a causal relationship with the usage of the vaccine. • The adverse event may be any unfavourable or unintended sign, abnormal laboratory finding, symptom or disease • Causality assessment of adverse event following immunization (AEFI): user manual for the revised WHO classification.2013 • What are Serious AEFIs? Any AEFI that has caused or has the potential to cause • Death, Hospitalization, Disability, Cluster (>2 or more cases) or where the Vaccine quality is suspicious

19. The private practitioners (including pediatricians) should use the ‘First Information Report’ (FIR) form for reporting serious AEFI cases to the district officials. • The pediatricians should help the investigation team in collection of all the related information. • Once an AEFI is reported from private sector, the DIO and district AEFI committee members would then investigate the reported AEFI case (PIR) • After all investigations are done and a conclusion arrived , the DIR is made.

21. Vaccine AEFI Causality • Causality is the relationship between two events (the cause and the effect), where the second event is a consequence of the first • Causality assessment is the systematic review of data about an AEFI case; it aims to determine the likelihood of a causal association between the event and the vaccine(s) received.

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

26. NATIONAL AEFI GUIDELINES IN INDIA

27. Some Case Studies….. • RotaShield and Intussusception • MMR and Autism • Thiomersal in vaccines and adverse neurodevelopmental outcome • Multiple vaccines and overload of immune system • DTwP and encephalopathy • Pentavalent vaccine in India

28. Case Study – 1 Rotavirus Vaccine and Intussusception

29. 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

30. Case Study 1 (cont.) • VAERS reports Sept 98 – Feb 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

31. 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? • 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

32. How did this impact next rotavirus vaccine? • To evaluate an IS risk of 1/10000, study size had to be atleast 40000 • Both Rotateq and Rotarix had study sizes of 60000-70000 • Pre-licensure studies: 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)

33. 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 IS 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

34. Case Study – 2 MMR vaccine & Autism

35. The origin of the controversy !

36. Wakefield’s theory was supported by studies that identified measles virus nucleic acid sequences in the blood cells and intestinal tissue of some children who had experienced severe behavioral regression • A similar investigation with a larger sample failed to reveal persistence of measles virus nucleic acids in the peripheral blood of children with autism-spectrum disorder • Results of several large population and ecologic-based studies have failed to provide any support for Wakefield’s theory

37. 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

38. The Science ………….. • After a review of multiple ( 18) well conducted studies • The Institute of Medicine (IOM) in a report on vaccine safety has stated that “the committee concludes that the evidence favors rejection of a causal relationship between MMR vaccine and autism” • Feb, 2009, the U.S. Court of Federal Claims dismissed ~4,900 cases involved the National Vaccine Injury Compensation Program

40. Thiomersal and Vaccines:

41. Thiomersal and Vaccines: • Thimerosal has been used as a preservative in vaccines since the 1930s • Some concern regarding mercury exposure and adverse neurodevelopmental outcome • In 1999, the US FDA estimated that infants who were immunized according to the recommended schedule might have received amounts of ethylmercury that exceed EPA limits for exposure to methylmercury. • The US PHA and AAP urged vaccine manufacturers to remove thimerosal from all infant vaccines as soon as practical • Almost all childhood vaccines in USA, Europe and Australia are thimerosal free.

42. California Estimated Prevalence of Autism and Estimated Mercury Exposure in Vaccines From Stehr-Green P et al. Am J Prev Med 2003; 25:101-106

43. All Mercury is Not the Same • Mercury in any form has not been linked to autism • Major toxicity – methyl Hg • Ethyl mercury – shorter ½ life • Less associated with neurotoxicity

44. CDC sponsored studies:

45. Children who were enrolled in an efficacy trial of pertussis vaccines in 1992–1993 were contacted in 2003. • N= 1043, 2 groups, Gp1: TM= 62.5mcg, Gp2: TM= 137.5mcg • Results: Among the 24 neuropsychological outcomes that were evaluated, only 2 were significantly associated with thimerosal exposure. • Conclusion: The few associations found between thimerosal exposure and neuropsychological development might be attributable to chance. The associations found were based on small differences in mean test scores, and their clinical relevance remains to be determined. • Alberto Eugenio Tozzi, MD at al. Pediatrics 2009;123:475–482

46. A case-control study was conducted in 3 managed care organizations (MCOs) of 256 children with ASD and 752 controls matched by birth year, gender, and MCO. • Adjusted OR Prenatal: 1.12 (0.83–1.51) • Birth-1 month: 0.88 (0.62–1.26) • Birth- 7 months: 0.60 (0.36–0.99) • Birth- 20 months: 0.60 (0.32– 0.97) • Conclusion: Prenatal and early-life exposure to ethylmercury from thimerosal-containing vaccines and immunoglobulin preparations was not related to increased risk of ASDs. • Cristofer S. Price, ScM et al. Pediatrics 2010;126:656–664

47. 1047 children enrolled,7 - 10 years age and administered standardized tests assessing 42 neuropsychological outcomes.( ASD excluded) • Association between current neuropsychological performance and exposure to mercury during the prenatal period, the neonatal period , and the first 7 months of life. • Among the 42 neuropsychological outcomes, we detected only a few significant associations with exposure to mercury from thimerosal. The detected associations were small and almost equally divided between positive and negative effects.

48. Conclusion…… • Our study does not support a causal association between early exposure to mercury from thimerosal-containing vaccines and immune globulins and deficits in neuropsychological functioning at the age of 7 to 10 years. • William W. Thompson et al. n engl j med 357;13 september 27, 2007

49. Institute of MedicineImmunization Safety Review Vaccines and Autism† • The Committee concludes that the evidence favors rejection of a causal relationship between 1) thimerosal-containing vaccines and autism and 2) MMR vaccine and autism • In the absence of experimental or human evidence that vaccination (either the MMR vaccine or the preservative thimerosal) affects metabolic, developmental, immune, or other physiological or molecular mechanisms that are causally related to the development of autism, the Committee concludes that the hypotheses generated to date are theoretical only † Immunization Safety Review Committee, Institute of Medicine, National Academies Press, 2004

50. Thiomersal and Vaccines: WHO-GAVACS • Upon review of the current epidemiologic evidence and phamacokinetic profile of thiomersal, the Global Advisory Committee on Vaccine Safety concluded that there is currently no evidence of mercury toxicity in infants, children, or adults exposed to thiomersal in vaccines.