Impact of a blood-stage vaccine on Plasmodium vivax malaria

Abstract

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.

Analyses of vaccine-specific circulating and bone marrow-resident B cell populations reveal benefit of delayed vaccine booster dosing with blood-stage malaria antigens

“…The data presented here contribute to growing efforts seeking to understand the impact of (GIA) with a transgenic P. knowlesi strain expressing P. vivax DBPRII [11]). In contrast, while differences in CD4+ and CD8+ T cell responses are observed between platforms by intracellular cytokine staining (ICS), there are no discernible differences between protein/adjuvant dosing regimens and no correlation is observed between IVGI and T cell immunogenicity [11].…”

“…Nunc MaxiSorp™ flat-bottom ELISA plates (44-2404-21, Invitrogen) were coated overnight with 2µg/mL (for total IgG titres) or 5µg/mL (for IgG1, IgG3, IgG4, IgA, IgA1 and IgM titres) of DBPRII SalI protein or 2µg/mL of sd3 protein in PBS. DBPRII protein was produced as previously described [11], while sd3 protein was produced by transient transfection of Expi395F cells with a plasmid encoding a monoFc, DBP Subdomain 3 (sequence as per UniProt P22290 PVDR residues P387-S508) and a C-terminal c-tag. The monoFc was cleaved using TEV protease and sd3 was purified by affinity chromatography (c-tag) and size exclusion chromatography.…”

“…In vivo growth inhibition (IVGI) has been reported elsewhere for the DBPRII trial [11]. In brief, IVGI was calculated for each vaccinee as the percentage reduction in parasite multiplication rate (PMR) relative to the mean PMR of the unvaccinated controls.…”

“…Taken together, our data support delayed booster vaccination in the next phase of P. vivax DBPRII and P. falciparum RH5 vaccine development and, more broadly, support consideration of alternative dosing regimens for vaccines against a range of pathogens where protection is antibody-mediated. $ Reflects sample size of groups completing full vaccination regimen in clinical trials [11]. All trial participants were healthy adults.…”

The challenges of Plasmodium vivax human malaria infection models for vaccine development

“…In addition, the inoculum has been used to test the only two available clinical-stage blood-stage P. vivax vaccine candidates; viral-vectors ChAd63 and MVA expressing P. vivax Duffy-binding protein region II (PvDBPII) and protein-in-adjuvant PvDBPII in Matrix-M™ adjuvant ( 58 , 59 ). As a direct result of this work, the first ever efficacy result has been obtained for a P. vivax blood-stage vaccine ( 60 ). The next steps include efficacy testing of this leading vaccine candidate in both naïve and exposed populations in endemic Thailand.…”