Phase I assessments of first-in-human administration of a novel malaria anti-sporozoite vaccine candidate, R21 in matrix-M adjuvant, in UK and Burkinabe volunteers

Background Improvements in malaria control have stalled recently and new tools are needed. The R21 vaccine is comprised of the malaria circumsporozoite protein fused to hepatitis B surface antigen (HBsAg). It forms particles that lack the excess HBsAg in the frequently tested malaria vaccine candidate, RTS,S/AS01B. Methods We conducted an open-label, first-in-human, Phase Ia study evaluating safety and immunogenicity of R21 administered alone and with the saponin-based adjuvant, Matrix-MTM (MM). Twenty-eight healthy adults received three doses of R21 given intramuscularly 4 weeks apart. We subsequently conducted a Phase Ib randomised, controlled trial in West African adults. Findings Vaccinations were well tolerated, and the majority of local and systemic adverse events were mild. Reactogenicity was significantly lower in Burkinabe than UK vaccinees (p<0.0001). Antibody responses increased significantly 28 days after the 2nd vaccination in UK volunteers. Antibody responses to R21 in all dose groups (2μg, 10μg and 50μg) were comparable to those of 50μg RTS,S/AS01B in malaria-naive adults at 28 days after final vaccination. The 10μg dose induced more durable responses, with 2-fold higher NANP-specific IgG titres at 6 months compared with the 2μg and 50μg dose groups. R21 also boosted baseline humoral responses in Burkinabe adults with well-maintained responses suggesting natural boosting. Interpretation R21 adjuvanted with MM is safe and has comparable immunogenicity to RTS,S/AS01B, even when administered at a five-fold lower 10μg dose in UK and African populations. This forms the basis for efficacy testing of this vaccine which could prove to be particularly cost-effective to manufacture and deploy.