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

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; Dyann F Wirth

doi:10.1056/NEJMoa1505819

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

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 ConnollyUmberto 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, Dyann F Wirth

Centre for Medical Parasitology

176 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	New England Journal of Medicine
Vol/bind	373
Udgave nummer	21
Sider (fra-til)	2025-37
Antal sider	13
ISSN	0028-4793
DOI	https://doi.org/10.1056/NEJMoa1505819
Status	Udgivet - 19 nov. 2015

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Neafsey, D. E., Juraska, M., Bedford, T., Benkeser, D., Valim, C., Griggs, A., Lievens, M., Abdulla, S., Adjei, S., Agbenyega, T., Agnandji, S. T., Aide, P., Anderson, S., Ansong, D., Aponte, J. J., Asante, K. P., Bejon, P., Birkett, A. J., Bruls, M., ... Wirth, D. F. (2015). Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine. New England Journal of Medicine, 373(21), 2025-37. https://doi.org/10.1056/NEJMoa1505819

Neafsey, DE, Juraska, M, Bedford, T, Benkeser, D, Valim, C, Griggs, A, Lievens, M, Abdulla, S, Adjei, S, Agbenyega, T, Agnandji, ST, Aide, P, Anderson, S, Ansong, D, Aponte, JJ, Asante, KP, Bejon, P, Birkett, AJ, Bruls, M, Connolly, KM, D'Alessandro, U, Dobaño, C, Gesase, S, Greenwood, B, Grimsby, J, Tinto, H, Hamel, MJ, Hoffman, I, Kamthunzi, P, Kariuki, S, Kremsner, PG, Leach, A, Lell, B, Lennon, NJ, Lusingu, J, Marsh, K, Martinson, F, Molel, JT, Moss, EL, Njuguna, P, Ockenhouse, CF, Ogutu, BR, Otieno, W, Otieno, L, Otieno, K, Owusu-Agyei, S, Park, DJ, Pellé, K, Robbins, D, Russ, C, Ryan, EM, Sacarlal, J, Sogoloff, B, Sorgho, H, Tanner, M, Theander, T, Valea, I, Volkman, SK, Yu, Q, Lapierre, D, Birren, BW, Gilbert, PB & Wirth, DF 2015, 'Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine', New England Journal of Medicine, bind 373, nr. 21, s. 2025-37. https://doi.org/10.1056/NEJMoa1505819

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title = "Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine",

abstract = "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.",

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

year = "2015",

month = nov,

day = "19",

doi = "10.1056/NEJMoa1505819",

language = "English",

volume = "373",

pages = "2025--37",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "21",

}

TY - JOUR

T1 - Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine

AU - Neafsey, Daniel E

AU - Juraska, Michal

AU - Bedford, Trevor

AU - Benkeser, David

AU - Valim, Clarissa

AU - Griggs, Allison

AU - Lievens, Marc

AU - Abdulla, Salim

AU - Adjei, Samuel

AU - Agbenyega, Tsiri

AU - Agnandji, Selidji T

AU - Aide, Pedro

AU - Anderson, Scott

AU - Ansong, Daniel

AU - Aponte, John J

AU - Asante, Kwaku Poku

AU - Bejon, Philip

AU - Birkett, Ashley J

AU - Bruls, Myriam

AU - Connolly, Kristen M

AU - D'Alessandro, Umberto

AU - Dobaño, Carlota

AU - Gesase, Samwel

AU - Greenwood, Brian

AU - Grimsby, Jonna

AU - Tinto, Halidou

AU - Hamel, Mary J

AU - Hoffman, Irving

AU - Kamthunzi, Portia

AU - Kariuki, Simon

AU - Kremsner, Peter G

AU - Leach, Amanda

AU - Lell, Bertrand

AU - Lennon, Niall J

AU - Lusingu, John

AU - Marsh, Kevin

AU - Martinson, Francis

AU - Molel, Jackson T

AU - Moss, Eli L

AU - Njuguna, Patricia

AU - Ockenhouse, Christian F

AU - Ogutu, Bernhards Ragama

AU - Otieno, Walter

AU - Otieno, Lucas

AU - Otieno, Kephas

AU - Owusu-Agyei, Seth

AU - Park, Daniel J

AU - Pellé, Karell

AU - Robbins, Dana

AU - Russ, Carsten

AU - Ryan, Elizabeth M

AU - Sacarlal, Jahit

AU - Sogoloff, Brian

AU - Sorgho, Hermann

AU - Tanner, Marcel

AU - Theander, Thor

AU - Valea, Innocent

AU - Volkman, Sarah K

AU - Yu, Qing

AU - Lapierre, Didier

AU - Birren, Bruce W

AU - Gilbert, Peter B

AU - Wirth, Dyann F

PY - 2015/11/19

Y1 - 2015/11/19

N2 - 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.

AB - 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.

U2 - 10.1056/NEJMoa1505819

DO - 10.1056/NEJMoa1505819

M3 - Journal article

C2 - 26488565

SN - 0028-4793

VL - 373

SP - 2025

EP - 2037

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 21

ER -

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

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