Anti-malaria RTS,S/AS01 vaccine generates a limited pool of memory B cells expressing specificities associated with protection

RTS,S/AS01, an adjuvanted subunit malaria vaccine, induces protective but short-lived anti-Plasmodium falciparum circumsporozoite protein (CSP) antibody titers. To better understand the lack of sustained protection post-vaccination, we analyzed CSP-specific B cells over time in malaria-naive individuals following immunization with RTS,S/AS01 followed by controlled malaria infection. Longitudinal analyses revealed a shift in the repertoire and regional protein specificity of CSP-specific B cells over time. Early post-vaccine responses were dominated by class-switched memory B cells (MBCs) specific for the NANP-repeat region of CSP, epitopes associated with protective antibodies. However, the frequency of NANP-repeat-specific MBCs declines, while longer-term memory responses, including responses both before and after a malaria challenge, had increased frequencies of MBCs specific for the C-terminus of CSP. Despite class-switching and affinity maturation, C-term monoclonal antibodies derived from these MBCs failed to protect mice against a transgenic parasite challenge. Taken together, these findings suggest that RTS,S/AS01 induces a transient, protective NANP-repeat-specific B cell response that is subsequently replaced by B cells with non-protective reactivities, potentially explaining its limited long-term efficacy.