• Daniel E Neafsey, Michal Juraska, Trevor Bedford, David Benkeser, Clarissa Valim, Allison Griggs, Marc Lievens, Salim Abdulla, Samuel Adjei, Tsiri Agbenyega, Selidji T Agnandji, Pedro Aide, Scott Anderson, Daniel Ansong, John J Aponte, Kwaku Poku Asante, Philip Bejon, Ashley J Birkett, Myriam Bruls, Kristen M Connolly, Umberto D'Alessandro, Carlota Dobaño, Samwel Gesase, Brian Greenwood, Jonna Grimsby, Halidou Tinto, Mary J Hamel, Irving Hoffman, Portia Kamthunzi, Simon Kariuki, Peter G Kremsner, Amanda Leach, Bertrand Lell, Niall J Lennon, John Lusingu, Kevin Marsh, Francis Martinson, Jackson T Molel, Eli L Moss, Patricia Njuguna, Christian F Ockenhouse, Bernhards Ragama Ogutu, Walter Otieno, Lucas Otieno, Kephas Otieno, Seth Owusu-Agyei, Daniel J Park, Karell Pellé, Dana Robbins, Carsten Russ, Elizabeth M Ryan, Jahit Sacarlal, Brian Sogoloff, Hermann Sorgho, Marcel Tanner, Thor Theander, Innocent Valea, Sarah K Volkman, Qing Yu, Didier Lapierre, Bruce W Birren, Peter B Gilbert, and Dyann F Wirth.
• From the Broad Institute of Massachusetts Institute of Technology and Harvard (D.E.N., C.V., A.G., S. Anderson, K.M.C., J.G., N.J.L., E.L.M., D.J.P., K.P., D.R., C.R., E.M.R., B.S., S.K.V., Q.Y., B.W.B.), Cambridge, and Harvard T.H. Chan School of Public Health (C.V., K.P., S.K.V., D.F.W.) and Simmons College School of Nursing and Health Sciences (S.K.V.), Boston - all in Massachusetts; Fred Hutchinson Cancer Research Center (M.J., T.B., D.B., C.V., P.B.G.) and University of Washington (D.B., P.B.G.), Seattle; GlaxoSmithKline Vaccines, Rixensart, Belgium (M.L., M.B., A.L., D.L.); Ifakara Health Institute, Bagamoyo (S. Abdulla, J.T.M.), and National Institute for Medical Research, Korogwe (S.G., J.L.) - both in Tanzania; School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi (S. Adjei, T.A.), and Kintampo Health Research Centre, Kintampo (K.P.A., B.G., S.O.-A.) - both in Ghana; Albert Schweitzer Hospital, Lambaréné, Gabon (S.T.A., D.A., P.G.K., B.L.); Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany (S.T.A., P.G.K., B.L.); Centro de Investigaçåo em Saúde de Manhiça, Manhiça, Mozambique (P.A., J.J.A., C.D., J.S.); ISGlobal, Barcelona Center for International Health Research, Hospital Clinic-Universitat de Barcelona, Barcelona (P.A., J.J.A., C.D.); PATH Malaria Vaccine Initiative, Washington, DC (A.J.B., C.F.O.); Medical Research Council Unit, Banjul, Gambia (U.D.); London School of Hygiene and Tropical Medicine, London (B.G.); Institut de Recherche en Sciences de la Santé, Nanoro, Burkina Faso (H.T., H.S., I.V.); Centers for Disease Control and Prevention (CDC), Atlanta (M.J.H.); University of North Carolina (UNC), Chapel Hill (I.H.); UNC Project, Lilongwe, Malawi (P.K., F.M.); Kenya Medical Research Institute (KEMRI)-Wellcome Trust Research Program, Kilifi (P.B., K.M., P.N.), KEMRI-CDC Research and Public Health Collaboration, Kisumu (S.K., K.O.), and KEMRI-Walter Reed Project, Kombewa (B.R.O., W.O.,
• N. Engl. J. Med. 2015 Nov 19;373(21):2025-37.

BackgroundThe RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus.MethodsWe used polymerase chain reaction-based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination.ResultsIn the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine efficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P=0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy.ConclusionsThese results suggest that among children 5 to 17 months of age, the RTS,S vaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles. (Funded by the National Institutes of Health and others.).

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