A PfRH5-Based Vaccine Is Efficacious against Heterologous Strain Blood-Stage Plasmodium falciparum Infection in Aotus Monkeys

Abstract

SummaryAntigenic diversity has posed a critical barrier to vaccine development against the pathogenic blood-stage infection of the human malaria parasite Plasmodium falciparum. To date, only strain-specific protection has been reported by trials of such vaccines in nonhuman primates. We recently showed that P. falciparum reticulocyte binding protein homolog 5 (PfRH5), a merozoite adhesin required for erythrocyte invasion, is highly susceptible to vaccine-inducible strain-transcending parasite-neutralizing antibody. In vivo efficacy of PfRH5-based vaccines has not previously been evaluated. Here, we demonstrate that PfRH5-based vaccines can protect Aotus monkeys against a virulent vaccine-heterologous P. falciparum challenge and show that such protection can be achieved by a human-compatible vaccine formulation. Protection was associated with anti-PfRH5 antibody concentration and in vitro parasite-neutralizing activity, supporting the use of this in vitro assay to predict the in vivo efficacy of future vaccine candidates. These data suggest that PfRH5-based vaccines have potential to achieve strain-transcending efficacy in humans.

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

“…In the case of this approach, a recombinant replication-deficient adenovirus (of human or simian serotype) is used to prime the immune response, followed by a booster vaccination (typically 8 weeks later) with an attenuated poxvirus recombinant for the same antigen (33). This heterologous prime-boost approach has shown antibody induction against difficult-to-express malaria antigens in numerous animal models, including nonhuman primates (32,34,35). 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).…”

Towards an anti-disease malaria vaccine

“…One option, which leads to sterile protection in immunized volunteers, but has challenges associated with deployment in malaria endemic regions, is whole parasite-based vaccines, such as attenuated sporozoites [6]. In addition, promising molecular targets for intervention have been identified for each stage, including components of the circumsporozoite protein (CSP) for the liver stage (already the active component of the RTS,S vaccine) [2], RH5 for the blood stage [7,8] and HAP2, Pfs48/45 and Pfs230 for gamete fusion [9]. All are under active consideration as vaccine candidates.…”

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“…Rh5 has recently become a leading malaria vaccine candidate [26], due to evidence from previous studies, which have shown it has a limited number of single nucleotide polymorphisms (SNPs), only five nonsynonymous SNPs [27]. There has been no demonstration of Rh5 allele-specific immunity [28], additionally Rh5 antibodies were shown to inhibit RBC invasion [29][30][31] and have been associated with protection against malaria [32].…”

“…The crystal structure of EBA175-RII showing (A) the overlap between the predicted CD8+ epitope (aa 553-561) and the glycan binding sites at residues Lys-553 and Met-554, (B) the overlap between the predicted CD4+ epitope (aa 440-456) and the glycan binding sites at residue Asp-442, (C) the overlap between the predicted BCE (aa [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] and the glycan binding sites at residues Lys-28, Asn-29, Arg-31, Ser-32 and Asn-33, (D) the overlap between the predicted BCE (aa 420-440) and the glycan binding sites at residue Lys-439 and (E) the overlap between the predicted BCE (aa 528-547) and the glycan binding sites at residues Gln-542 and Tyr-546.…”