Repertoire, function, and structure of serological antibodies induced by the R21/Matrix-M malaria vaccine

The World Health Organization recently recommended the programmatic use of R21/Matrix-M vaccine forPlasmodium falciparummalaria prevention in children living in malaria-endemic areas. To determine its effects on humoral immunity, we conducted a proteomic analysis of polyclonal IgG antibodies directed against the NANP tetrapeptide of the circumsporozoite protein (CSP) which comprises the vaccine’s core immunogen. In ten malaria-naïve adult volunteers, R21/Matrix-M induced polarized IgG anti-NANP repertoires, heavily skewed forIGHV3-30/3-33genes bearing minimal somatic mutation, which remained static in composition following a controlled human malaria infection challenge. Notably, these vaccine-generated antibodies cross-reacted with another protective CSP epitope, the N-terminal junction region, despite its absence from the R21 construct. NANP-specificIGHV3-30/3-33monoclonal antibodies mined from polyclonal IgG repertoires blocked sporozoite invasionin vitroand prevented parasitemiain vivo. Overall, R21/Matrix-M elicits polarized, minimally mutated, polyclonal IgG responses that can target multiple protective CSP epitopes, offering molecular insight into the serological basis for its demonstrated efficacy againstP. falciparummalaria.