SJD is a named inventor on patent applications relating to PfRH5 and/or other malaria vaccines and immunisation regimens (no. GB1103293.5). AMM has an immediate family member who is listed as an inventor on patents relating to PfRH5 and/or other malaria vaccines and immunisation regimens.

BackgroundThere are no licensed vaccines against Plasmodium vivax, the most common cause of malaria outside of Africa.MethodsWe conducted two Phase I/IIa clinical trials to assess the safety, immunogenicity and efficacy of two vaccines targeting region II of P. vivax Duffy-binding protein (PvDBPII). Recombinant viral vaccines (using ChAd63 and MVA vectors) were administered at 0, 2 months or in a delayed dosing regimen (0, 17, 19 months), whilst a protein/adjuvant formulation (PvDBPII/Matrix-M™) was administered monthly (0, 1, 2 months) or in a delayed dosing regimen (0, 1, 14 months). Delayed regimens were due to trial halts during the COVID-19 pandemic. Volunteers underwent heterologous controlled human malaria infection (CHMI) with blood-stage P. vivax parasites at 2-4 weeks following their last vaccination, alongside unvaccinated controls. Efficacy was assessed by comparison of parasite multiplication rate (PMR) in blood post-CHMI, modelled from parasitemia measured by quantitative polymerase-chain-reaction (qPCR).ResultsThirty-two volunteers were enrolled and vaccinated (n=16 for each vaccine). No safety concerns were identified. PvDBPII/Matrix-M™, given in the delayed dosing regimen, elicited the highest antibody responses and reduced the mean PMR following CHMI by 51% (range 36-66%; n=6) compared to unvaccinated controls (n=13). No other vaccine or regimen impacted parasite growth. In vivo growth inhibition of blood-stage P. vivax correlated with functional antibody readouts of vaccine immunogenicity.ConclusionsVaccination of malaria-naïve adults with a delayed booster regimen of PvDBPII/ Matrix-M™ significantly reduces the growth of blood-stage P. vivax.Funded by the European Commission and Wellcome Trust; VAC069, VAC071 and VAC079 ClinicalTrials.gov numbers NCT03797989, NCT04009096 and NCT04201431.

BackgroundAntibodies are crucial for vaccine-mediated protection against many pathogens. Modifications to vaccine delivery that increase antibody magnitude, longevity, and/or quality are therefore of great interest for maximising efficacy. We have previously shown that a delayed fractional (DFx) dosing schedule (0-1-6mo) – using AS01B-adjuvanted RH5.1 malaria antigen – substantially improves serum IgG durability as compared to monthly dosing (0-1-2mo; NCT02927145). However, the underlying mechanism and whether there are wider immunological changes with DFx dosing was unclear.MethodsImmunokinetics of PfRH5-specific Ig across multiple isotypes were compared between DFx and monthly regimen vaccinees. Peak responses were characterised in-depth with a systems serology platform including biophysical and functional profiling. Computational modelling was used to define the humoral feature set associated with DFx dosing. PfRH5-specific B cells were quantified by flow cytometry and sorted for single cell RNA sequencing (scRNA-seq). Differential gene expression between DFx and monthly dosing regimens was explored with Seurat, DESeq2 and gene set enrichment analysis.ResultsDFx dosing increases the frequency of circulating PfRH5-specific B cells and longevity of PfRH5-specific IgG1, as well as other isotypes and subclasses. At the peak antibody response, DFx dosing was distinguished by a systems serology feature set comprising increased FcRn-binding, IgG avidity, and proportion of G2B and G2S2F IgG Fc glycans, alongside decreased IgG3, antibody-dependent complement deposition, and proportion of G1S1F IgG Fc glycan. At the same time point, scRNA-seq of PfRH5-specific B cells revealed enriched plasma cell and Ig / protein export signals in the monthly dosing group as compared to DFx vaccinees.ConclusionsDFx dosing of the RH5.1/AS01B vaccine had a profound impact on the humoral response. Our data suggest plausible mechanisms relating to improved FcRn-binding (known to improve Ig longevity) and a potential shift from short-lived to long-lived plasma cells. Recent reports of the positive impact of delayed boosting on SARS-CoV-2 vaccine immunogenicity highlight the broad relevance of these data.