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Fab236 in complex with the C-terminal alpha-TSR domain of P. falciparum
Structural highlights
Publication Abstract from PubMedPotent 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 alpha-ctCSP) and has been previously characterized, whereas the second is a previously undescribed site on the conserved beta-sheet face of the ctCSP (denoted beta-ctCSP). Antibodies to the beta-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 alpha-ctCSP site showed very limited cross reactivity. Importantly, an antibody to the beta-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. A novel CSP C-terminal epitope targeted by an antibody with protective activity against Plasmodium falciparum.,Beutler N, Pholcharee T, Oyen D, Flores-Garcia Y, MacGill RS, Garcia E, Calla J, Parren M, Yang L, Volkmuth W, Locke E, Regules JA, Dutta S, Emerling D, Early AM, Neafsey DE, Winzeler EA, King CR, Zavala F, Burton DR, Wilson IA, Rogers TF PLoS Pathog. 2022 Mar 28;18(3):e1010409. doi: 10.1371/journal.ppat.1010409. , eCollection 2022 Mar. PMID:35344575[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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