A novel CSP C-terminal epitope targeted by an antibody with protective activity against Plasmodium falciparum
Potent and durable vaccine responses will be required for control of malaria caused by Plasmodium falciparum (Pf). RTS,S/AS01 is the first, and to date, the only vaccine that has demonstrated significant reduction of clinical and severe malaria in endemic cohorts in Phase 3 trials. Although the vacc...
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Published in | PLoS pathogens Vol. 18; no. 3; p. e1010409 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Public Library of Science
01.03.2022
Public Library of Science (PLoS) |
Subjects | |
Online Access | Get full text |
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Summary: | Potent and durable vaccine responses will be required for control of malaria caused by Plasmodium falciparum (Pf). RTS,S/AS01 is the first, and to date, the only vaccine that has demonstrated significant reduction of clinical and severe malaria in endemic cohorts in Phase 3 trials. Although the vaccine is protective, efficacy declines over time with kinetics paralleling the decline in antibody responses to the Pf circumsporozoite protein (PfCSP). Although most attention has focused on antibodies to repeat motifs on PfCSP, antibodies to other regions may play a role in protection. Here, we expressed and characterized seven monoclonal antibodies to the C-terminal domain of CSP (ctCSP) from volunteers immunized with RTS,S/AS01. Competition and crystal structure studies indicated that the antibodies target two different sites on opposite faces of ctCSP. One site contains a polymorphic region (denoted α-ctCSP) and has been previously characterized, whereas the second is a previously undescribed site on the conserved β-sheet face of the ctCSP (denoted β-ctCSP). Antibodies to the β-ctCSP site exhibited broad reactivity with a diverse panel of ctCSP peptides whose sequences were derived from field isolates of P. falciparum whereas antibodies to the α-ctCSP site showed very limited cross reactivity. Importantly, an antibody to the β-site demonstrated inhibition activity against malaria infection in a murine model. This study identifies a previously unidentified conserved epitope on CSP that could be targeted by prophylactic antibodies and exploited in structure-based vaccine design. |
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Bibliography: | new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current address: Bluestar Genomics, San Mateo, California, United States of America. Current address: Pfizer Inc., San Diego, California, United States of America. We have read the journal’s policy and the authors of this manuscript have the following competing interests. The authors N.B., T.P., D.O., Y.F.G., R.S.M., E.G., J.C., M.P., L.Y., E.L., J.A.R., S.D., A.M.E., D.E.N., E.W., C.R.K., F.Z., D.R.B., I.A.W., and T.F.R. declare that they have no competing interests. W.V., D.E. were or are employees of Atreca, Inc. and own equity in Atreca, Inc. Current address: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. |
ISSN: | 1553-7374 1553-7366 1553-7374 |
DOI: | 10.1371/journal.ppat.1010409 |