The public health impact of malaria vaccine RTS,S in malaria endemic Africa: country-specific predictions using 18 month follow-up Phase III data and simulation models

Abstract

BackgroundThe RTS,S/AS01 malaria vaccine candidate recently completed Phase III trials in 11 African sites. Recommendations for its deployment will partly depend on predictions of public health impact in endemic countries. Previous predictions of these used only limited information on underlying vaccine properties and have not considered country-specific contextual data.MethodsEach Phase III trial cohort was simulated explicitly using an ensemble of individual-based stochastic models, and many hypothetical vaccine profiles. The true profile was estimated by Bayesian fitting of these models to the site- and time-specific incidence of clinical malaria in both trial arms over 18 months of follow-up. Health impacts of implementation via two vaccine schedules in 43 endemic sub-Saharan African countries, using country-specific prevalence, access to care, immunisation coverage and demography data, were predicted via weighted averaging over many simulations.ResultsThe efficacy against infection of three doses of vaccine was initially approximately 65 % (when immunising 6–12 week old infants) and 80 % (children 5–17 months old), with a 1 year half-life (exponential decay). Either schedule will avert substantial disease, but predicted impact strongly depends on the decay rate of vaccine effects and average transmission intensity.ConclusionsFor the first time Phase III site- and time-specific data were available to estimate both the underlying profile of RTS,S/AS01 and likely country-specific health impacts. Initial efficacy will probably be high, but decay rapidly. Adding RTS,S to existing control programs, assuming continuation of current levels of malaria exposure and of health system performance, will potentially avert 100–580 malaria deaths and 45,000 to 80,000 clinical episodes per 100,000 fully vaccinated children over an initial 10-year phase.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0408-2) contains supplementary material, which is available to authorized users.

Incidence and admission rates for severe malaria and their impact on mortality in Africa

“…In addition, not explicitly accounting for the fate of severe malaria cases that do not make it to health facilities implies that national level burden of disease statistics for P. falciparum malaria, such as WMR, are also highly uncertain. Recently, several geography-specific predictions of malaria intervention impact and cost-effectiveness from OpenMalaria have allowed for national levels of effective treatment for uncomplicated disease [30, 31], but so far not for variations in access to in-patient care. It is not clear whether even these analyses accurately capture the quantitative impact of access to effective of treatment on subsequent burden, since the strength of this relationship is not well calibrated against field data, which is also lacking.…”

Malaria Modeling in the Era of Eradication

“…The availability of massive amounts of geolocation data means that modeling of the likely impacts of specific intervention programs (like RTS,S vaccination) in specific places and times has become feasible (Penny et al 2015a), and these profuse data are available for calibration and validation of models. This sets a high bar for malaria modeling: Fitting complex models to multiple types of data is challenging, and model predictions are always likely to be unreliable at very high spatial resolution.…”

Breadth of humoral response and antigenic targets of sporozoite-inhibitory antibodies associated with sterile protection induced by controlled human malaria infection

“…The circumsporozoite protein (CSP), a major sporozoite surface protein, has been identified as the antigen to which the antibody response is dominant humans and animals immunized with irradiated sporozoites (Nussenzweig and Nussenzweig, 1984;Zavala et al, 1986), making it a leading vaccine candidate (Herrington et al, 1990). The most advanced formulation (RTS,S) has now been extensively tested in Phase III trials, where it was shown to help diminish clinical cases, but not to prevent infection (Bejon et al, 2013;Penny et al, 2015;Stoute et al, 1997). It is likely that other, as yet unidentified antigens are implicated in the sterile immunity induced by irradiated sporozoites (Gruner et al, 2007;Kumar et al, 2006;Mauduit et al, 2010) (Chia et al, 2014;Longley et al, 2015).…”