Full papers: Nishiura H, Schwehm M, Eichner M. Epidemiology 2006; 17(5): 576-81

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

2. Background 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 CDSR, WHO. WHO Fact Sheet on Smallpox. 2001 CDC. Smallpox Response Program & Guidelines. 2003

3. Are we still protected against smallpox? 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 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. Smallpox outbreak in Bombay (1969) Vaccinated Unvaccinated Elevated age at infection Suggesting the duration of vaccine-induced immunity 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. Observed number of vaccinated cases in age group a Poisson probability Expected number of vaccinated cases in age group a Vaccinatedcases Unvaccinatedcases Observed number of unvaccinated cases in age group a Poisson probability Expected number of unvaccinated cases in age group a 9

7. Vaccinatedcases Unvaccinatedcases 9

8. Vaccinatedcases Unvaccinatedcases odds of being vaccinated probability of still being protected 9 model for loss of protection

9. searching the parameter valueswhich maximize the likelihood Vaccinatedcases Unvaccinatedcases odds of being vaccinated probability of still being protected 9 maximum likelihood estimation model for loss of protection

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 1870s n = 9 761 B. Sheffield 1887-8 n = 6 088 C. London 1893 n = 2 101 D. Liverpool 1902-3 n = 1 163 E. Dewsbury 1904 n = 625 Variola minor F. London 1929-30 n = 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 Observed total number of unvaccinated cases in age group a Probability that an unvaccinated develops severe disease binomial probability Observed number of unvaccinated severe cases in age group a Observed total number of vaccinated cases in age group a Probability that an vaccinated develops severe disease binomial probability 5

13. Are we protected against severe disease? 5

14. Are we protected against severe disease? 5

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

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

17. Protection against severe disease Variola major C. London 1893 n = 2101 D. Liverpool 1902-3 n = 1163 E. Dewsbury 1904 n = 625 Combining both probabilities Partial protection against fatality decays very slowly(sometimes lifelong protection) The majority of vaccinees may still retain partial protection against severe and fatal smallpox 4

18. Heterogeneous populations 3

19. Heterogeneous populations Vaccination coverage 80% Heterogeneity parameter q =0.3 Forces of infectionl1=0.02/year, l2=0.08/year (R01=1.4; R02=5.6 for L=70 years) 3

20. Heterogeneous populations 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 tm and p. 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 diseaseBad news: mild disease may allow higher mobility, may not be easily recognized and, therefore, may increase spread 2

22. Outlook: simulation studies 1