October 11, 2007 Walter A. Orenstein, M.D. Professor of Medicine and Pediatrics Director, Emory Vaccine Policy and Devel

1. A Tale of Two Vaccine Safety Concerns • Rotashield • (Original Rotavirus Vaccine) • Thimerosal American Medical Writers Association Meeting October 11, 2007 Walter A. Orenstein, M.D. Professor of Medicine and Pediatrics Director, Emory Vaccine Policy and Development Associate Director, Emory Vaccine Center

2. From: MMWR 2006; 55 (RR-12) 1-13

3. Rhesus Rotavirus Vaccine† • Licensed in 1998 • Contained 4 vaccine viruses (RRV-TV) • 1 derived from a virus isolated in Rhesus monkeys • 3 reassortant viruses with 1 human gene and 10 rhesus genes • 3 doses, 50-60% effective against all disease, 80-90% against severe disease From: Clark HF, et al. Chapter 51, Rotavirus Vaccines, Vaccines 4th edition, eds. Plotkin SA and Orenstein WA, 2004 pp 1327-1345

4. Prelicensure Evaluation of RRV-TV • 11,000 children evaluated • Adverse events 15% fever attributable to vaccine, 3-5 days post dose 1, 2% post dose 2 • Intussusception noted in 5 of 11,000 vaccinees, 1 of 4500 placebo recipients (difference not significant) • ACIP and AAP warned intussusception might be an adverse event and encouraged reporting From: Clark HF, et al. Chapter 51, Rotavirus Vaccines, Vaccines 4th edition, eds. Plotkin SA and Orenstein WA, 2004 pp 1327-1345

5. Intussusception and RRV-TV† • 9/1/98 – 7/7/99 – 15 cases reported • 13/15 after dose 1 • 12/15 within 1 week of any dose • 11/15 onset 3 – 5 days post vaccination Preliminary studies in one HMO and one State suggested an increased risk although the numbers were too small to reach significance CDC recommends postponing vaccination until more data available † MMWR 1999; 48:577-81

6. From: Murphy TV, et al. N Engl J Med 2001; 344(8):564-573

7. From: Kramarz P, et al. Pediatr Infect Dis J 2001; 20(4):410-416

8. Withdrawing of Rotavirus Vaccine Recommendation† • ACIP votes on October 22, 1998 to withdraw recommendation for routine use † MMWR 1999; 48:1007

9. Summary of Deliberations on Intussusception - I • Possibility of intussusception noted in pre-licensure trials. Physicians warned of possible adverse events and encouraged to report • Reports of 15 cases were unusual – clustered 3 – 5 days post dose 1 • Preliminary data in HMO and one State also raised concerns • CDC recommended stopping vaccination until more data were available

10. Summary of Deliberations on Intussusception - II • Extensive studies conducted which confirmed causal association • Recommendation withdrawn • Standards for evaluating new rotavirus vaccines changed • Current vaccine evaluated in 72,325 infants to detect intussusception

11. Exposure to Mercury from Vaccines in US Infants (<6months) at the Time of Review Pediatrics 2001; 107: 1147-1154

12. Government Actions on Thimerosal† - I • Significant safety margin in mercury exposure limits • Exposure for ethyl mercury in vaccines could exceed limits for methyl mercury for EPA but not ATSDR or FDA • No known harms from thimerosal in vaccines • Known harms from failure to vaccinate † MMWR 1999; 48:563-564

13. Government Actions on Thimerosal† - II • Remove thimerosal-containing vaccines as soon as possible • Continue to vaccinate with any available vaccine • Potentially alter the hepatitis B schedule † MMWR 1999; 48:563-564

14. 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

15. Thimerosal and AutismCharacteristic findings in Autism and in Mercury Poisoning† † Nelson KB, Bauman ML. Pediatrics 2003; 111: 674-679

16. 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

17. Epidemiologic Studies of Autism and Vaccines Ecologic • Compare secular trends over time with trends in vaccine coverage rates, thimerosal exposure, etc. • Weakest kind of study Case-Control • Select cases, determine vaccine and/or thimerosal exposure • Select controls and compare exposures in cases and controls • Measure odds ratio which approximates relative risk Cohort • Compares rates of autism in children exposed and not exposed to vaccines • Can look for a dose-response effect • Measure relative risk

18. Selected Strengths and Weaknesses of Epidemiologic Studies Strengths • Measure disease in human populations • Measure under conditions of actual product use • Best able to detect relationships if factor of concern accounts for large proportion of total cases Weaknesses • Potential for biases in case ascertainment, case definition, and confounding

19. Figure 2. Birth cohort prevalence rates and ethyl mercury exposure. Dotted lines take Into account the additional ethyl mercury exposure because of mass vaccination Campaign against meningitis. From: Fombonne E, et al. Pediatrics 2006; 118:e139-e150

20. Rate Ratio of Autism and Autism Spectrum Disorders (ASD) by Exposure to Thimerosal in Vaccines† †JAMA 2003; 290: 1763-1766 Schedule 5 weeks, 9 weeks, 10 months, in Denmark

21. Criteria for Evaluating the Quality of Cohort Studies of Autism and Thimerosal Exposure† • Cohort inclusion/exclusion criteria precisely described • Outcome measures (diagnoses) precisely described • Outcome measures validated at least for a sample • Methods to calculate Thimerosal exposure described and appropriate • Basis for sample size described &/or power discussed • Study controls for bias and confounding • Potential impact of bias on results • Other study limitations discussed † Parker SK et al. Pediatrics 2004; 114:793-804

22. Methodologic Evaluation of Studies Addressing Link of Autism and Thimerosal† † Parker SK et al. Pediatrics 2004; 114:793-804

23. 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

24. Maximum Content of Mercury in Vaccines Children Receive Through 6 months of Age † Ball LK et al. Pediatrics 2001; 107:1147-1154 †† www.fda.gov/cber/vaccine/thimerosal.htm, accessed 4/24/06

25. Children Receiving Autism Services by Quarter, California, 2002-2006 California Department of Developmental Services From Wharton M via email 4/19/06

26. Thimerosal and Adverse Neurologic Outcomes† • 1047 children studied with standard assessment • 42 outcomes evaluated • Among girls, 2 significant associations with better performance • Among boys, 1 significant better performance and 2 significant negative associations • Conclusion – study does not support a link between thimerosal and neurodevelopment disorders • Autism was not studied † Thompson WW, et al. N Engl J Med 2007; 357:1281-92

27. Comparison of Actions on Rotashield (RRV-TV) and Thimerosal