Abstract
SummaryBackgroundDevelopment 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.MethodsWe 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.FindingsThe 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.ConclusionsOur data provide a new framework to guide rational design and delivery of next-generation vaccines to protect against malaria disease.FundingThis study was supported by USAID, UK MRC, Wellcome Trust, NIAID, and the NIHR Oxford-BRC.
Highlights
Despite major advances in malaria control, estimates in 2018 suggest that there were still 228 million clinical cases leading to 405,000 deaths.[1]
Three immunizations at monthly intervals with 2, 10, or 50 mg reticulocyte-binding protein homolog 5 (RH5).1 in 0.5 mL AS01B were compared with a delayed fractional dosing (DFx) regimen, where two monthly immunizations of 50 mg RH5.1 were followed by a third immunization at one-fifth dose (10 mg RH5.1) in 0.5 mL AS01B and delayed to 6 months after the first immunization
In healthy adults in the United Kingdom,[18,22] with the booster vaccinations generally associated with a higher grading of systemic adverse events (AEs) and local redness (STAR Methods, safety analysis)
Summary
Despite major advances in malaria control, estimates in 2018 suggest that there were still 228 million clinical cases leading to 405,000 deaths.[1] there remains a pressing need for a highly effective and durable vaccine.[2] Encouragingly, whole-parasite and subunit strategies targeting the invasive sporozoite and/or liver stage of Plasmodium falciparum have shown moderate levels of efficacy in field trials.[3] these approaches continue to face various challenges related to durability or breadth of protection and immunopotency in target populations They necessitate sterilizing immunity to prevent the subsequent pathogenic blood stage of infection. Historical efforts to develop anti-merozoite vaccines have been thwarted by substantial levels of target antigen polymorphism,[4] redundancy of erythrocyte invasion pathways,[5] and a poor understanding of immune mechanisms that can provide in vivo protection in humans
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
