Vaccine-Induced Antibodies to a C-Terminal Plasmodium falciparum Circumsporozoite Protein Epitope Associated With Protection Against Malaria Challenge

Background Plasmodium falciparum circumsporozoite protein (CSP) is the target of multiple malaria vaccines that include only a part of the protein, such as RTS,S and R21. The monoclonal antibodies L9 and CIS43 are directed against key CSP junctional region epitopes not included in RTS,S and R21, and next-generation vaccine candidates attempt to elicit similar antibodies. Understanding the effectiveness of multiple antibody responses against CSP peptides will inform next-generation vaccines. Methods Using serum samples collected during controlled human malaria infection experiments that evaluated vaccine efficacy, we used a peptide array inclusive of CSP genetic variants to quantify anti-CSP antibody responses in unprotected adults who received a full-length recombinant CSP vaccine (rCSP), protected adults who received RTS,S, and unprotected adults who received RTS,S. We compared the breadth and intensity of responses to CSP variants between groups. Results Overall, rCSP recipients had lower CSP antibody responses compared with the protected RTS,S group. Compared with the unprotected groups, protected RTS,S vaccinees had higher breadth of responses to peptides in the junctional region, central repeat region, and C-terminal region. The protected RTS,S group also had higher intensity of responses to 2 C-terminal peptides, including part of Th3R. In addition, protected RTS,S recipients had higher breadth of immunoglobulin A responses to variants of the C-terminal epitope PNDPNRNV, identified as a dominant motif by motif recognition software, and to similar sequences in the junctional region. Conclusions Protection-associated antibody responses to the junctional region not contained in RTS,S suggest a cross-reactive, vaccine-induced response that provides additional benefit beyond antibodies targeting vaccine peptides.