Reduced blood-stage malaria growth and immune correlates in humans following RH5 vaccination.
Minassian AM., Silk SE., Barrett JR., Nielsen CM., Miura K., Diouf A., Loos C., Fallon JK., Michell AR., White MT., Edwards NJ., Poulton ID., Mitton CH., Payne RO., Marks M., Maxwell-Scott H., Querol-Rubiera A., Bisnauthsing K., Batra R., Ogrina T., Brendish NJ., Themistocleous Y., Rawlinson TA., Ellis KJ., Quinkert D., Baker M., Lopez Ramon R., Ramos Lopez F., Barfod L., Folegatti PM., Silman D., Datoo M., Taylor IJ., Jin J., Pulido D., Douglas AD., de Jongh WA., Smith R., Berrie E., Noe AR., Diggs CL., Soisson LA., Ashfield R., Faust SN., Goodman AL., Lawrie AM., Nugent FL., Alter G., Long CA., Draper SJ.
BACKGROUND: 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 Plasmodium falciparum. METHODS: We undertook a phase I/IIa clinical trial in healthy adults in the United Kingdom of the RH5.1 recombinant protein vaccine, targeting the P. falciparum reticulocyte-binding protein homolog 5 (RH5), formulated in AS01B adjuvant. We assessed safety, immunogenicity, and efficacy against blood-stage CHMI. Trial registered at ClinicalTrials.gov, NCT02927145. FINDINGS: The RH5.1/AS01B 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 P. falciparum, 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 in vitro using purified immunoglobulin G (IgG) antibody strongly correlates with in vivo 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. CONCLUSIONS: Our data provide a new framework to guide rational design and delivery of next-generation vaccines to protect against malaria disease. FUNDING: This study was supported by USAID, UK MRC, Wellcome Trust, NIAID, and the NIHR Oxford-BRC.