October 11, 2005 Walter A. Orenstein, M.D. Professor of Medicine and Pediatrics Director, Emory Vaccine Policy and Devel

1. Vaccine Safety Controversies AAP – General Session October 11, 2005 Walter A. Orenstein, M.D. Professor of Medicine and Pediatrics Director, Emory Vaccine Policy and Development Associate Director, Emory Vaccine Center

3. Physician Reports of Parental Vaccine Safety Concerns in 2000- Results of a National Survey of Pediatricians+ + Freed GL et al. Am J Prev Med 2004;26:11-14 ++ Response from pediatricians and family physicians combined

4. Major Vaccine Safety Concerns Autism and thimerosal Autism and MMR Multiple immunizations and Diabetes Asthma Heterologous infections MCV4 and GBS

5. 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

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

7. All Mercury is Not the Same • Major toxicity – methyl Hg • Ethyl mercury – shorter ½ life • Less associated with neurotoxicity

8. Blood Mercury Concentrations in Infants Aged 2 Months (diamonds) and 6 Months (squares) by Time of Sampling All values <29 nMOL/L safety limit Lancet 2002; 360: 1737-1741

9. Incidence Rate of Autism in Sweden & Cumulative Thimerosal in Vaccines From Stehr-Green P et al. Am J Prev Med 2003; 25:101-106

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

11. 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. † Immunization Safety Review Committee, Institute of Medicine, National Academies Press, 2004

12. Institute of MedicineImmunization Safety Review Vaccines 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

13. 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 7/6/05

14. Children Receiving Autism Services by Quarter, California, 2002-2005 California Department of Developmental Services From Steve Cochi, MD, acting director, NIP/CDC provided for the National Immunization Awareness Month press briefing held at the National Press Club on July 26, 2005

15. Linking Autism and MMR* — I • Report of 12 cases of autism and bowel disease, 8 after MMR • Ileal-lymphonodular hyperplasia • Speculated measles-caused bowel disease • Leak of toxins *Lancet 1998;351:637-41

16. Linking Autism and MMR* — II • Other information used to support link of autism and MMR • Detection of measles virus in bowel (Molecular Pathology 2002; 55: 84-90) • Detection of measles virus in lymphocytes* • Statistical correlation of natural measles† and mumps infections in same year *Digestive Diseases and Sciences 2000;45:723-729 †Gastroenterology 1999;118:796-803

17. Studies Against MMR and Autism Link • Ecologic – no clustering of onset or diagnosis around vaccination† • Regressive evaluated separately • No relationship to inflammatory bowel disease‡ • Studies failing to detect measles virus in bowel (in IBD cases) †BMJ 2002; 324: 393-6 ‡Archives Pediatr Adolesc Med 2001; 155: 354-9

18. Danish MMR/Autism Study Results – Adjusted RR (95% CI)* Aut DisOther Spect Dis Overall 0.92 (.68-1.24) 0.83 (.63-1.07) Age at vac 0.56-1.20 0.62-1.09 Time from vac 0.39-1.38 0.31-1.18 Yr of vac 0.73-1.35 0.71-1.13 * age, sex, calendar period, bw, gest age, mat educ, family SES N Engl J Med 2002; 347: 1477-82

19. Percentage of Children Receiving MMR in Second Year of Life and Caseload of Children With Autism, by Year of Birth,California, 1980-1994* *JAMA 2001, 285: 1183 - 1185

20. Number of Immunogenic Proteins and Polysaccharides in Vaccines Since 1960† TOTAL †From Pediatrics 2002; 109: 124-129

21. Theoretical Calculation of Number of Antigens an Infant can Respond to at One Time† • 10,000 vaccines • Assuming 107 B cells/ul • And 103 epitopes per vaccine †From Pediatrics 2002; 109: 124-129

22. IOM Conclusions on Multiple Antigens† • Evidence favored rejection of a causal relationship between multiple immunizations and increased risk for infections and type 1 diabetes • Evidence insufficient to accept or reject a causal relationship for allergic disorders including asthma • Did not recommend a policy review of current recommendations † Institute of Medicine – Immunization Safety Review: multiple immunizations and immune dysfunction. 2/20/02

23. Relative Risk of Developing Asthma by Immunizations Received and Correcting for Medical Care Utilization† †Pediatr Infect Dis J 2002; 21: 498-509 Also see Pediatrics 2003; 111: 653-659 2 HMOs

24. Meningococcal Conjugate Vaccine and Guillain Barré Syndrome (GBS) - I† • Incidence of meningococcal disease ~1/100,000 • 5 cases of GBS in 17-18 year olds within 2-5 weeks post vaccination reported to VAERS • 2.5 million doses distributed to date • According to CDC, rate similar to what might be expected by coincidence, within 6 weeks of vaccination. However, timing of concern. †Source: MMWR Dispatch Vol. 54, October 6, 2005. Available at www.cdc.gov

25. Meningococcal Conjugate Vaccine and Guillain Barré Syndrome (GBS) - II† • No cases of GBS in 110,000 MCV4 recipients in VSD • According to CDC, no changes in vaccine recommendations at present • Please report any cases of GBS or other neurologic illnesses that follow MCV4 to VAERS • Please inform adolescents and caregivers of ongoing investigation into this issue. †Source: MMWR Dispatch Vol. 54, October 6, 2005. Available at www.cdc.gov

26. Conclusions • The best available evidence does not support a role for thimerosal or MMR in causing autism • The infant immune system should be able to respond to many vaccines simultaneously • Epidemiologic studies have not found a relationship between multiple immunizations and other infections, type 1 diabetes, and asthma • Ongoing studies to evaluate MCV4 and GBS

27. Extra Slides

28. Danish Immunization and Diabetes Study† † N Engl J Med 2004; 350: 1398-04

29. Biological Mechanisms Supporting a Role for Vaccines in Causing Heterologous Infections+ Immune interference T-cell cross reactivity Carrier induced epitope suppression Competition for antigen presentation (peptide competition for binding to MHC molecules or competition between T cells for the same antigen presenting cells) + Stratton K, Wilson CB, McCormick MC, editors. Immunization Safety Review. Multiple Immunizations and Immune Dysfunction. Institute of Medicine www.iom.edu/imsafety

30. Study of Heterologous Infectious Disease Hospitalizations and Vaccines, Denmark+ • 2,900,464 person years of follow-up; 83,317 cases identified • 42 possible associations (6 vaccines and 7 infectious disease categories) • Only 1 positive association – Hib and URI RR 1.05 95% CI (1.01-1.08) • Within positive associations expected by chance + Hviid A et al. JAMA 2005; 294:699-705

31. Useful Websites with Information on Vaccine Safety I National Immunization Program www.cdc.gov/nip American Academy of Pediatrics www.aap.org Immunization Action Coalition www.immunize.org Children’s Hospital of Philadelphia Vaccine Education Center www.chop.edu/vaccine

32. Useful Websites with Information on Vaccine Safety II Institute of Medicine www.IOM.edu/imsafety National Partnership for Immunization www.partnersforimmunization.org National Network for Immunization Information www.immunizationinfo.org Institute for Vaccine Safety www.vaccinesafety.edu