In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 18, No. 3 ( 2022-3-28), p. e1010409-
Abstract:
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 ( Pf CSP). Although most attention has focused on antibodies to repeat motifs on Pf CSP, 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.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1010409
DOI:
10.1371/journal.ppat.1010409.g001
DOI:
10.1371/journal.ppat.1010409.g002
DOI:
10.1371/journal.ppat.1010409.g003
DOI:
10.1371/journal.ppat.1010409.g004
DOI:
10.1371/journal.ppat.1010409.g005
DOI:
10.1371/journal.ppat.1010409.s001
DOI:
10.1371/journal.ppat.1010409.s002
DOI:
10.1371/journal.ppat.1010409.s003
DOI:
10.1371/journal.ppat.1010409.s004
DOI:
10.1371/journal.ppat.1010409.s005
DOI:
10.1371/journal.ppat.1010409.s006
DOI:
10.1371/journal.ppat.1010409.s007
DOI:
10.1371/journal.ppat.1010409.s008
DOI:
10.1371/journal.ppat.1010409.s009
DOI:
10.1371/journal.ppat.1010409.s010
DOI:
10.1371/journal.ppat.1010409.s011
DOI:
10.1371/journal.ppat.1010409.s012
DOI:
10.1371/journal.ppat.1010409.s013
DOI:
10.1371/journal.ppat.1010409.r001
DOI:
10.1371/journal.ppat.1010409.r002
DOI:
10.1371/journal.ppat.1010409.r003
DOI:
10.1371/journal.ppat.1010409.r004
DOI:
10.1371/journal.ppat.1010409.r005
DOI:
10.1371/journal.ppat.1010409.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2205412-1
Permalink