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

Derek A.T. Cummings University of Pittsburgh

Graduate School of Public Health and Johns Hopkins Bloomberg School of Public Health

Models of New Vaccines for Measles

Measles Virus

• Major cause of child morbidity and mortality

• Causes ~500,000 deaths each year

Distribution of Global Mortality

Region

AfricaSouth Asia

East Asia and PacificOtherTotal

1999

519,000263,00077,00014,000

873,000

2003

282,000183,00057,0008,000

530,000

MMWR, 2005

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

Can we eliminate/eradicate measles using this vaccine?

The experience in the Americas suggests we can

New York

Buenos Aires

Sao Paulo

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Population Size in 2000 (millions)

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Some of the Largest Challenges lie ahead for Measles Control

Strebel, Nature, 2001

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

Data (red circles) and Model (blue line) of weekly measles incidence in London, 1944-1965

Grenfell et al, 2001

Long history of work in measles on disease dynamics

RAS model of measles transmission

Mi Si Ei Ii Ri

i denotes age cohorts

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

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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

WAIFW Matrix

β1 β1 β1 β1

β1 β2 β2 β2

β1 β2 β3 β3

β1 β2 β3 β4

β1 β1 β1 β1

β1 β2 β1 β1

β1 β1 β3 β1

β1 β1 β1 β4

…

…

……

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

Comparing different age cohort structures

(red, 13 age classes, agregatedyellow, 7 age classes,

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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

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

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Equivalent vaccine efficacy is 78%With extreme empirical estimate of increase in vaccination, 71%

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

New York

Buenos Aires

Sao Paulo

Mexico City

Tokyo

Mumbai

Lagos

Dhaka

Karachi

Jakarta

LA

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Population Size in 2000 (millions)

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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

Monthly measles incidence in Cameroon, 1997-2001

Cummings et al, IJID, 2006

Incidence in Northern Region

Incidence in Southern Region

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

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

Number of reported cases of measles in the urban community of Niamey, 1 November 2003

to 6 June 2004.

Estimates of transmissibility of measles from Africa are rare

Grais, Trans. Roy. Soc. of Trop. Med. and Hyg. (2006)

Estimates of R0 from Niger (Grais et al)

Recent data suggest R0 is slightly lower in some parts of Africa than historic estimates from the UK and the US

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?