{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T23:30:17Z","timestamp":1778887817707,"version":"3.51.4"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T00:00:00Z","timestamp":1751846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The recently licenced R21\/Matrix-M vaccine induces a protective antibody response. In this study, we examined vaccine-induced responses in semi-immune adults in a controlled human malaria infection (CHMI) Phase IIb clinical trial.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Plasma and peripheral blood mononuclear cells from healthy adult volunteers living in coastal Kenya were analysed following vaccination with R21\/Matrix-M (<jats:italic>n<\/jats:italic> = 19) and CHMI challenge with <jats:italic>Plasmodium falciparum<\/jats:italic> (<jats:italic>Pf<\/jats:italic>SPZ NF54) sporozoites (<jats:italic>n<\/jats:italic> = 17). Humoral immunity was evaluated by quantifying antigen specific antibody subtypes and subclasses via ELISA, alongside functional antibody properties including avidity and complement fixation elicited by vaccination and challenge. Antigen-specific memory B cells were characterised using FluoroSpot assays to detect concurrent secretion of multiple antibody isotypes and the frequency and phenotypes of circulating Tfh (cTfh) cells were assessed using multiparametric flow cytometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Vaccination increased antibody titres across IgA, IgM, and IgG isotypes and IgG1 and IgG3 subclasses but not IgG2 or IgG4 subclasses, targeting different vaccine antigens (full-length R21, NANP, and C-terminus), indicating a broad and heterogeneous response. The responses were maintained over time and, importantly, they demonstrated complement-fixing capabilities. IgG+ and IgA+ antigen-specific memory B cells were boosted but were short-lived for IgA. We observed an increase in total CXCR5+\/PD1+ cTfh cells following vaccination and challenge with the predominant Th2\/Th17 population.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>We provide insights into the diverse immune responses induced by R21\/Matrix-M vaccination and their potential contribution to protection against malaria. These findings highlight the potential of the R21\/Matrix-M vaccination and protection in adults with varying levels of prior malaria exposure.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1620365","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T05:27:57Z","timestamp":1751866077000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["R21\/Matrix-M malaria vaccine drives diverse immune responses in pre-exposed adults: insights from a phase IIb controlled human malaria infection trial"],"prefix":"10.3389","volume":"16","author":[{"given":"Elizabeth","family":"Kibwana","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline","family":"Bundi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Domtila","family":"Kimani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lydia","family":"Nyamako","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelvias","family":"Keter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agnes","family":"Mutiso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodney","family":"Ogwang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Duncan","family":"Bellamy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katerina","family":"Rapi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amelia","family":"Bajer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel","family":"Provstgaard-Morys","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Stockdale","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivia","family":"Munoz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mehreen S.","family":"Datoo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison","family":"Lawrie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando","family":"Ramos-Lopez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mainga","family":"Hamaluba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrian V. 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