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

Abstract

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-naïve 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.

Characterization of two in vivo challenge models to measure functional activity of monoclonal antibodies to Plasmodium falciparum circumsporozoite protein

“…Antibodies against the NANP repeat regions of CSP induced by RTS,S have been linked to its protective efficacy and these wane after vaccination with kinetics that mimic the decline in efficacy [5]. A second vaccine that targets CSP, R21, has also shown efficacy in nonclinical studies [6] and recently in clinical testing [7]. Radiation attenuated sporozoites, PfSPZ, administered by intravenous (i.v.)…”

Structural and biophysical correlation of anti-NANP antibodies within vivoprotection againstP. falciparum

“…A similar vaccine candidate, R21, composed only of the same HBsAg-CSP fusion (i.e. without extra HBsAg), and formulated with Matrix-M adjuvant, has recently entered phase 2 clinical testing and is showing comparable efficacy levels in early clinical studies (19). Another candidate is the attenuated, whole-sporozoite-based PfSPZ vaccine (20), delivered by direct venous inoculation.…”

Structural and biophysical correlation of anti-NANP antibodies with in vivo protection against P. falciparum

“…RTS,S displayed~40 % efficacy against clinical malaria disease over 4 years of follow-up in phase 3 clinical testing; vaccine efficacy is highest in the period immediately following immunization and declines coincident with decay of induced Ab titers to CSP [15][16][17][18] . A similar vaccine candidate, R21, composed only of the same HBsAg-CSP fusion (i.e., without extra HBsAg), and formulated with Matrix-M adjuvant, has recently entered phase 2 clinical testing and is showing comparable efficacy levels in early clinical studies 19 . Another candidate is the attenuated, whole-sporozoite-based PfSPZ vaccine 20 , delivered by direct venous inoculation.…”