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

Abstract

BackgroundPhase 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.MethodsTheoretical 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.ResultsHeterogeneity 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.ConclusionsFailure 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.

A Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Infants

“…This could be due to waning vaccine efficacy, differential acquisition of natural immunity, or other factors that may influence the model, 28 such as heterogeneity of exposure, the vaccine effect at the individual level, or both. 29,30 If vaccine efficacy does wane, this might contribute to the lower observed efficacy among infants than among older children, especially because young infants may be less susceptible to malaria in the immediate postvaccination period owing to maternally acquired immunity, fetal hemoglobin, lower exposure, and other factors. 31 The 11 sites of the phase 3 trial cover a wide range of malaria-transmission intensity.…”

First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Children

“…7,[21][22][23][24][25] Decreasing protection over time could reflect waning immunity, acquisition of natural immunity in the control group, or heterogeneity of exposure. 26 Further follow-up and evaluation of the effect of a booster dose will provide a better understanding of the relative contribution of these factors.…”

Heterogeneity in disease risk induces falling vaccine protection with rising disease incidence

“…Although both distributions are likely to affect current measures of vaccine efficacy [16], we wanted to counter a perceived tendency in the research community to explain the observations entirely in light of the latter. Meanwhile, the full parameterisation of vaccine efficacy models remains an important subject for future research.…”