Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine.

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.).

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

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