1. Full papers:Nishiura H, Schwehm M, Eichner M. Epidemiology 2006; 17(5): 576-81 Nishiura H, Eichner M. Infection 2006; 34: in press. Learning about long-term vaccination effects from outbreak data Martin Eichner, Markus Schwehm & Hiroshi Nishiura 19 September 2006 14

2. Background CDSR, WHO. WHO Fact Sheet on Smallpox. 2001 CDC. Smallpox Response Program & Guidelines. 2003 Since World Health Organization announced the total eradication of smallpox in 1979, routine vaccination was ceased worldwide The potential for bioterrorism has led to intensive discussions on the durability of vaccine-induced immunity Mass vaccination prior to an attack is currently not recommended CDC suggests vaccine-induced immunity lasts more or less for 3-5 years 13

3. Epidemiologic evidence: vaccinated cases tended to be much older than unvaccinated ones. Text book statements: protection lasts 20 years Experimental evidence: more than 90% of previously vaccinated individuals hold either cellular or humoral immunity Are we still protected against smallpox? Elkington JSC, Outbreak of smallpox in Launceston, 1904 Iguchi J. A report on prevention of smallpox, 1929 Dixon CW. Smallpox. London, 1962. Eichner M. Am J Epidemiol 2003; 158: 717-723. Gallwitz S et al. Clin Microbiol 2003;41:4069-70. Hammarlund E et al. Nat Med 2003;9:1131-7. Amara RR et al. J Virol 2004;78:3811-6. Crotty S et al. J Immunol 2003;171:4969-73. 12

4. Elevated age at infection Suggesting the duration of vaccine-induced immunity Unvaccinated Vaccinated Smallpox outbreak in Bombay (1969) 11

5. Statistical analysis Historical records on epidemic of smallpox Criteria for inclusion: (1) Epidemic caused by variola major (not variola minor) (2) Age-specific incidence with vaccination history (3) No revaccination. No post-exposure vaccination (-> UK during the late 19th century) Key assumptions for a statistical model: (1) Vaccination took place shortly after birth (within 3 months) (2) Primary vaccination failure neglected (3) Booster effects can be adjusted by using age-specific force of infection among unvaccinated (4) Force of infection, probability of case detection, and natural mortality are identical for vaccinated and unvaccinated people 10

6. Unvaccinated cases Vaccinated cases Observed number of unvaccinated cases in age group a Poisson probability Expected number of unvaccinated cases in age group a Observed number of vaccinated cases in age group a Poisson probability Expected number of vaccinated cases in age group a 9

7. Unvaccinated cases Vaccinated cases 9

8. Unvaccinated cases Vaccinated cases odds of being vaccinated probability of still being protected model for loss of protection 9

9. Unvaccinated cases Vaccinated cases odds of being vaccinated probability of still being protected model for loss of protection searching the parameter values which maximize the likelihood 9 maximum likelihood estimation

10. Estimated duration of vaccine-induced immunity against smallpox Gompertz curve Median CI based on the profile likelihood 8

11. Conclusions Variola major A. London 1870sn = 9 761 B. Sheffield1887-8 n = 6 088 C. London1893 n = 2 101 D. Liverpool1902-3n = 1 163 E. Dewsbury1904n = 625 Variola minor F. London1929-30n = 3 023 Result: Protection against smallpox lasts for 15 to 35 years Conclusion: Our present population may not hold residual protection against smallpox infection 6

12. Are we protected against severe disease? Observed number of unvaccinated severe cases in age group a binomial probability Probability that an unvaccinated develops severe disease binomial probability 5 Observed total number of unvaccinated cases in age group a Observed number of unvaccinated severe cases in age group a Probability that an vaccinated develops severe disease Observed total number of vaccinated cases in age group a

13. Are we protected against severe disease? 5

14. 5

15. probability of still being protected model for loss of protection Are we protected against severe disease? 5

16. probability of still being protected model for loss of protection searching the parameter values which maximize the likelihood Are we protected against severe disease? 5 maximum likelihood estimation

17. Variola major C. London1893 n = 2101 D. Liverpool1902-3n = 1163 E. Dewsbury1904n = 625 Partial protection against fatality decays very slowly (sometimes lifelong protection) The majority of vaccinees may still retain partial protection against severe and fatal smallpox Combining both probabilities Protection against severe disease 4

18. Heterogeneous populations 3

19. Vaccination coverage 80% Heterogeneity parameter q =0.3 Forces of infection 1 =0.02/year, 2 =0.08/year (R 01 =1.4; R 02 =5.6 for L=70 years) 3

20. For small q, our estimates appropriately reflect the true duration of immunity and the true vaccination coverage. For larger values of q, we slightly overestimate t m and p. Heterogeneous populations 2

21. Final conclusions Are we still protected against smallpox? Bad news: protection against infection and disease should mostly be lost by now Good news: infected individuals may still be protected against life-threatening disease Bad news: mild disease may allow higher mobility, may not be easily recognized and, therefore, may increase spread 2

22. Outlook: simulation studies 1