Genetic diversity and protective efficacy of the RTS,S/AS01 malaria vaccine.

Authors: Neafsey, Daniel E and Juraska, Michal and Bedford, Trevor and Benkeser, David and Valim, Clarissa and Griggs, Allison and Lievens, Marc and Abdulla, Salim and Adjei, Samuel and Agbenyega, Tsiri and Agnandji, Selidji T and Aide, Pedro and Anderson, Scott and Ansong, Daniel and Aponte, John J and Asante, Kwaku Poku and Bejon, Philip and Birkett, Ashley J and Bruls, Myriam and Connolly, Kristen M and D'Alessandro, Umberto and Dobaño, Carlota and Gesase, Samwel and Greenwood, Brian and Grimsby, Jonna and Tinto, Halidou and Hamel, Mary J and Hoffman, Irving and Kamthunzi, Portia and Kariuki, Simon and Kremsner, Peter G and Leach, Amanda and Lell, Bertrand and Lennon, Niall J and Lusingu, John and Marsh, Kevin and Martinson, Francis and Molel, Jackson T and Moss, Eli L and Njuguna, Patricia and Ockenhouse, Christian F and Ogutu, Bernhards Ragama and Otieno, Walter and Otieno, Lucas and Otieno, Kephas and Owusu-Agyei, Seth and Park, Daniel J and Pellé, Karell and Robbins, Dana and Russ, Carsten and Ryan, Elizabeth M and Sacarlal, Jahit and Sogoloff, Brian and Sorgho, Hermann and Tanner, Marcel and Theander, Thor and Valea, Innocent and Volkman, Sarah K and Yu, Qing and Lapierre, Didier and Birren, Bruce W and Gilbert, Peter B and Wirth, Dyann F

The 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.We 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.In 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.These 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.).

Journal: The New England journal of medicine
DOI: 10.1056/NEJMoa1505819
Year: 2015

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