Derek A.T. Cummings University of Pittsburgh Graduate School of Public Health and Johns Hopkins Bloomberg School of P

1. Models of New Vaccines for Measles Derek A.T. Cummings University of Pittsburgh Graduate School of Public Health and Johns Hopkins Bloomberg School of Public Health

2. Measles Virus • Major cause of child morbidity and mortality • Causes ~500,000 deaths each year

3. Distribution of Global Mortality 2003 282,000 183,000 57,000 8,000 530,000 1999 519,000 263,000 77,000 14,000 873,000 Region Africa South Asia East Asia and Pacific Other Total MMWR, 2005

4. Current measles vaccine • Current vaccine is a live attenuated vaccine derived from passage in chick embryo cells • Targeted age of delivery is 9-12 months • Induces immunity in 85% of recipients at 9 months of age and 90-95% of recipients at 12 months of age • Immunogenicity in early infancy is limited by relative immaturity of the immune system and the presence of maternal antibodies

5. Can we eliminate/eradicate measles using this vaccine? The experience in the Americas suggests we can

6. Some of the Largest Challenges lie ahead for Measles Control Strebel, Nature, 2001

7. Vaccine Candidates • Several candidates are under development • Aerosol delivered vaccines that could minimize interference with maternal antibody and ease delivery • DNA vaccines encoding particular measles virus proteins with the potential to be immunogenic at ages as early as 2 months • One design goal is to be able to target earlier ages in the EPI schedule

8. Long history of work in measles on disease dynamics Data (red circles) and Model (blue line) of weekly measles incidence in London, 1944-1965 Grenfell et al, 2001

9. RAS model of measles transmission Mi Si Ei Ii Ri i denotes age cohorts

10. Cohorts age together • Schenzle’s approach used to reduce system of partial differential equations to a system of ordinary differential equations • Age groups all age at the same time

12. Force of Infection • As a first step, I’ve used age specific forces of infection from the literature estimated using age stratified serological data in the UK and in Senegal

13. WAIFW Matrix β1β1β1β1 β1β2β2β2 β1β2β3β3 β1β2 β3β4 β1β1β1β1 β1β2β1β1 β1β1β3β1 β1β1 β1β4 … … … …

14. Age Structure of the Population Need to incorporate younger age groups than previous models (0-1 months, 1-2 months,2-3 months, 3-4 months, 4-5 months, 5-6 months,6-9 months, 9-12 months, 1-2 years, 2-3 years…, 5-10 years, 10 and older Uniformly distribute age specific force of infection of larger age classes to smaller age classes Used data on the age structure of the population in Cameroon from a Demographics and Health Survey Set derivatives with respect to time to zero and solved for birth rate and age specific deaths rates that would match age distribution

15. Comparing different age cohort structures (red, 13 age classes, agregatedyellow, 7 age classes,

16. Vaccination • Vaccination moves some portion of susceptible or those with maternal immunity into the removed class • Vaccination is done during the age cohort transitions into targeted age groups • As simplest case I assume new vaccine is delivered at 4th month (third dose of DPT) • Vaccination rates are higher at 4 months than 9 months

17. Results using a vaccine given at 4 months w/ 65% efficacy (irrespective of presence of maternal immunity compared to current vaccine delivered at 9 months with reduced efficacy in those with maternal immunity Equivalent vaccine efficacy is 78% With extreme empirical estimate of increase in vaccination, 71%

18. Extensions • Multiphase strategy • Incorporate vaccine efficacy at three doses • Incorporate empirical data on association of timeliness of vaccines on age of delivery • Create analogous stochastic model to explore elimination

19. Is the birth cohort large enough in these cities so that the number of children not targeted by the vaccine is greater than the critical community size

20. Monthly measles incidence in Cameroon, 1997-2001 Cummings et al, IJID, 2006

21. Incidence in Northern Region Incidence in Southern Region

22. An aside: one lesson from Cameroon experience • The number of cases is not the best indicator of the state of population immunity. Susceptible fractions can slowly increase and lead to large outbreaks. • Public health systems should anticipate post-honeymoon outbreaks

25. The experience in the Americas is the standard. Would models predict the elimination of measles transmission in this region given the vaccination coverage attained The experience in the Americas suggests we can

26. Estimates of transmissibility of measles from Africa are rare Number of reported cases of measles in the urban community of Niamey, 1 November 2003 to 6 June 2004. Grais, Trans. Roy. Soc. of Trop. Med. and Hyg. (2006)

27. Recent data suggest R0 is slightly lower in some parts of Africa than historic estimates from the UK and the US Estimates of R0 from Niger (Grais et al)

28. Question for the audience- How many think the elimination campaign in southern Africa will maintain low numbers of cases? Do you think we can eliminate measles with the current vaccine?