The development of a highly effective vaccine remains a key strategic goal to aid the control and eventual eradication of Plasmodium falciparum malaria. In recent years, the reticulocyte-binding protein homolog 5 (RH5) has emerged as the most promising blood-stage P. falciparum candidate antigen to date, capable of conferring protection against stringent challenge in Aotus monkeys. We first reported on a dose-escalation phase Ia study in healthy, malaria-naive adult volunteers using established viral vectors, the replication-deficient chimpanzee adenovirus serotype 63 (ChAd63), and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA). Vaccine-induced anti-RH5 serum antibodies exhibited cross-strain functional growth inhibition activity (GIA) in vitro, targeted linear and conformational epitopes within RH5, and inhibited key interactions within the RH5 invasion complex. Next, we undertook a phase I/IIa clinical trial of the RH5.1 recombinant protein vaccine, formulated in AS01B adjuvant. We show that GIA strongly correlates with in vivo reduction of the parasite growth rate in a controlled human blood-stage malaria infection model, establishing a crucial correlate of protection for blood-stage malaria vaccine development. We also demonstrate that the protein/AS01B platform induces a higher-magnitude antigen-specific circulating Tfh cell response and that this correlates with peak anti-PfRH5 IgG concentrations (10-fold higher in protein/AS01B versus viral vector vaccinees), frequency of PfRH5-specific memory B cells, and antibody functionality. Also notable in the protein/AS01B trial is that a booster dosing regimen using a delayed and fractional third dose (DFx), in contrast to three doses given at monthly intervals, led to significantly improved serum antibody longevity over ∼2 years of follow-up. Subsequent analyses of RH5-specific B cells revealed enriched plasma cell and Ig / protein export signals in the monthly dosing group as compared to DFx vaccinees. Taken together, our data provide a framework to guide rational design and delivery of next-generation vaccines to protect against malaria disease.
Dr Carolyn Nielsen is a Senior Immunologist working with Prof Simon Draper’s Blood-Stage Malaria Group in the Department of Biochemistry (previously based at the Jenner Â鶹ÊÓƵ), University of Oxford. The focus of her current work and recent Sir Henry Wellcome Postdoctoral Fellowship is on the impact of vaccine platform and booster dosing regimen on the cellular drivers of humoral immunity. Dr Nielsen is particularly interested in cytometry, sequencing, and systems approaches to understand heterogeneity in B cell immunogenicity. Prior to her postdoctoral work in Oxford, Dr Nielsen completed her PhD with Prof Eleanor Riley at the London School of Hygiene and Tropical Medicine.
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