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. 2010 Mar 23:9:82.
doi: 10.1186/1475-2875-9-82.

Heterogeneity in malaria exposure and vaccine response: implications for the interpretation of vaccine efficacy trials

Michael T White  1 , Jamie T Griffin, Chris J Drakeley, Azra C Ghani
Affiliations

Heterogeneity in malaria exposure and vaccine response: implications for the interpretation of vaccine efficacy trials

Michael T White et al. Malar J. .

Abstract

Background: Phase III trials of the malaria vaccine, RTS, S, are now underway across multiple sites of varying transmission intensity in Africa. Heterogeneity in exposure, vaccine response and waning of efficacy may bias estimates of vaccine efficacy.

Methods: Theoretical arguments are used to identify the expected effects of a) heterogeneity in exposure to infectious bites; b) heterogeneity in individual's response to the vaccine; and c) waning efficacy on measures of vaccine efficacy from clinical trials for an infection-blocking vaccine.

Results: Heterogeneity in exposure and vaccine response leads to a smaller proportion of trial participants becoming infected than one would expect in a homogeneous setting. This causes estimates of vaccine efficacy from clinical trials to be underestimated if transmission heterogeneity is ignored, and overestimated if heterogeneity in vaccine response is ignored. Waning of vaccine efficacy can bias estimates of vaccine efficacy in both directions.

Conclusions: Failure to account for heterogeneities in exposure and response, and waning of efficacy in clinical trials can lead to biased estimates of malaria vaccine efficacy. Appropriate methods to reduce these biases need to be used to ensure accurate interpretation and comparability between trial sites of results from the upcoming Phase III clinical trials of RTS, S.

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Figures

Figure 1
Figure 1
Cumulative proportion of infected trial participants for an infection-blocking vaccine with an average individual efficacy of 45.0% based on RTS,S, and in a similar setting to the Mozambique trial site described by Alonso et al [5]. (A) Cumulative proportion of unvaccinated trial participants infected under a range of transmission heterogeneities. (B) Cumulative proportion of vaccinated trial participants infected for a range of vaccine types. The proportion infected for an all-or-nothing vaccine can never cross the dashed line marked 1-V = 0.55 as the 45% of vaccinees with total protection will never become infected. Note that the 4 vaccines each have the same individual efficacy but different heterogeneities in vaccine efficacy.
Figure 2
Figure 2
(A) Risk-based infection-blocking efficacy for a vaccine under the range of transmission heterogeneities in Table 2. (B) Risk-based infection-blocking efficacy for the four vaccines described in Table 3 with the same individual efficacy. (C) Rate-based infection-blocking efficacy under different transmission heterogeneities. (D) Rate-based infection-blocking efficacy for the four vaccines.
Figure 3
Figure 3
(A) Cumulative proportion of vaccinated trial participants infected for leaky and all-or-nothing vaccines. The dashed lines represent the infected proportion when vaccine efficacy wanes with a half-life of 1 year. (B) Rate-based efficacy for leaky and all-or-nothing vaccines. The dashed lines represent the expected rate-based efficacy with a waning vaccine.
See this image and copyright information in PMC

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