Human vaccination against Plasmodium vivax Duffy-binding protein induces strain-transcending antibodies

Abstract

BACKGROUND. Plasmodium vivax is the most widespread human malaria geographically; however, no effective vaccine exists. Red blood cell invasion by the P. vivax merozoite depends on an interaction between the Duffy antigen receptor for chemokines (DARC) and region II of the parasite’s Duffy-binding protein (PvDBP_RII). Naturally acquired binding-inhibitory antibodies against this interaction associate with clinical immunity, but it is unknown whether these responses can be induced by human vaccination.METHODS. Safety and immunogenicity of replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and modified vaccinia virus Ankara (MVA) viral vectored vaccines targeting PvDBP_RII (Salvador I strain) were assessed in an open-label dose-escalation phase Ia study in 24 healthy UK adults. Vaccines were delivered by the intramuscular route in a ChAd63-MVA heterologous prime-boost regimen using an 8-week interval.RESULTS. Both vaccines were well tolerated and demonstrated a favorable safety profile in malaria-naive adults. PvDBP_RII–specific ex-vivo IFN-γ T cell, antibody-secreting cell, memory B cell, and serum IgG responses were observed after the MVA boost immunization. Vaccine-induced antibodies inhibited the binding of vaccine homologous and heterologous variants of recombinant PvDBP_RII to the DARC receptor, with median 50% binding-inhibition titers greater than 1:100.CONCLUSION. We have demonstrated for the first time to our knowledge that strain-transcending antibodies can be induced against the PvDBP_RII antigen by vaccination in humans. These vaccine candidates warrant further clinical evaluation of efficacy against the blood-stage P. vivax parasite.TRIAL REGISTRATION. Clinicaltrials.gov NCT01816113.FUNDING. Support was provided by the UK Medical Research Council, UK National Institute of Health Research Oxford Biomedical Research Centre, and the Wellcome Trust.

Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

“…There were no serious adverse events (SAEs) or unexpected reactions and no safety concerns during the course of the trial. The reactogenicity of the vaccines was similar to that seen in previous malaria vaccine trials using the same viral vectors at similar doses in healthy adults (37,43,48), with the higher doses of both vaccines associated with an increased number and higher severity of reported AEs (Figure 2). The majority of AEs following ChAd63 RH5 were mild, but moderate AEs were reported by some volunteers in both groups, and 2 volunteers who received the full dose reported severe AEs on the day of vaccination that resolved within 24 hours.…”

“…No data on cellular responses to this antigen have been reported following natural P. falciparum infection; however, given that vaccination elicited peptide-restimulated responses spanning the entire RH5 sequence, the RH5_FL molecule does not appear to lack T cell epitopes. The kinetics and magnitude of the response were also similar to those previously reported following human vaccination with the same vectors encoding P. falciparum or P. vivax antigens (36)(37)(38)(39)43). Similarly, studies using chimpanzee adenovirus vectors followed by MVA boost (44,46,58) have routinely shown that a mixed antigen-specific CD4 + /CD8 + T cell response is induced in humans.…”

“…Likewise, the clinical safety of MVA as a recombinant vaccine vector for many infectious diseases and cancer is now well documented (57). MVA RH5 appeared to be more reactogenic than the ChAd63 vector at the higher dose, consistent with previous vaccine trials using this orthopoxvirus vector (38,39,43,44,46,58).…”

“…We show in healthy malaria-naive UK adult volunteers that a recombinant ChAd63-MVA heterologous prime-boost immu-nization regimen has a favorable safety profile and can induce functional RH5-specific-serum antibody responses, in addition to B and T cell responses. Reactogenicity of the ChAd63 RH5 vector was similar to that seen with the same doses of ChAd63 vectored vaccines encoding the P. falciparum antigen multiepitope string-thrombospondin-related adhesion protein (ME-TRAP), circumsporozoite protein (CSP), MSP1, or AMA1 (36-39, 52, 54) or the P. vivax antigen Duffy-binding protein region II (PvDBP_RII) (43). The same vectors encoding ME-TRAP have similarly been safe following immunization of adults, children, and infants residing in malaria-endemic areas (41,42).…”

“…These vectors, delivering antigens from P. falciparum, have now been shown to be safe and immunogenic for T cell and antibodies in healthy European and American adult volunteers (36)(37)(38)(39)(40), as well as African adults, children, and infants (41,42). More recently, similar adenovirus-poxvirus vectored vaccine technologies have been used to immunize humans against numerous other pathogens including P. vivax malaria (43), Ebola virus (44), hepatitis C virus (HCV) (45), respiratory syncytial virus (RSV) (46) and HIV-1 (47).…”