| Summary: | <p><strong>Background:</strong> Development of an effective vaccine against the pathogenic blood-stage infection of human malaria has proved challenging, and no candidate vaccine has affected blood-stage parasitemia following controlled human malaria infection (CHMI) with blood-stage <i>Plasmodium falciparum</i>.</p>
<p><strong>Methods:</strong> We undertook a phase I/IIa clinical trial in healthy adults in the United Kingdom of the RH5.1 recombinant protein vaccine, targeting the <i>P. falciparum</i> reticulocyte-binding protein homolog 5 (RH5), formulated in AS01<sub>B</sub> adjuvant. We assessed safety, immunogenicity, and efficacy against blood-stage CHMI. Trial registered at ClinicalTrials.gov, NCT02927145.</p>
<p><strong>Findings:</strong> The RH5.1/AS01<sub>B</sub> formulation was administered using a range of RH5.1 protein vaccine doses (2, 10, and 50 μg) and was found to be safe and well tolerated. A regimen using a delayed and fractional third dose, in contrast to three doses given at monthly intervals, led to significantly improved antibody response longevity over ∼2 years of follow-up. Following primary and secondary CHMI of vaccinees with blood-stage <i>P. falciparum</i>, a significant reduction in parasite growth rate was observed, defining a milestone for the blood-stage malaria vaccine field. We show that growth inhibition activity measured <i>in vitro</i> using purified immunoglobulin G (IgG) antibody strongly correlates with <i>in vivo</i> reduction of the parasite growth rate and also identify other antibody feature sets by systems serology, including the plasma anti-RH5 IgA1 response, that are associated with challenge outcome.</p>
<p><strong>Conclusions:</strong> Our data provide a new framework to guide rational design and delivery of next-generation vaccines to protect against malaria disease.</p>
<p><strong>Funding:</strong> This study was supported by USAID, UK MRC, Wellcome Trust, NIAID, and the NIHR Oxford-BRC.</p>
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