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

Netland, J.; Thouvenel, C. D.; Gregory, S.; Adams, W. C.; Jongert, E.; Brunette, N.; King, N. P.; Kisalu, N. K.; King, C. R.; Rawlings, D. J.; Pepper, M.

doi:10.64898/2025.12.22.696031

bioRxiv · 10.64898/2025.12.22.696031

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

Netland, J.·Thouvenel, C. D.·Gregory, S.·Adams, W. C.·Jongert, E.·Brunette, N.·King, N. P.·Kisalu, N. K.·King, C. R.·Rawlings, D. J.·Pepper, M.

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Abstract

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. Longitudinal analyses of the cellular responses revealed a shift in the specificity of CSP-specific B cells over time. Early post- vaccine responses were dominated by plamsablasts and 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 specific for the C-terminus of CSP persists. Despite being class-switched and affinity matured, 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 memory B cells with non-protective reactivities, potentially explaining its limited long-term efficacy and limited response to subsequent challenges or boosters.

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Netland, J., Thouvenel, C. D., Gregory, S., Adams, W. C., Jongert, E., Brunette, N., King, N. P., Kisalu, N. K., King, C. R., Rawlings, D. J., Pepper, M.. 2025-12-24. Anti-malaria RTS,S/AS01 vaccine generates a limited pool of memory B cells expressing specificities associated with protection. https://doi.org/10.64898/2025.12.22.696031

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