Abstract
The lack of an effective licensed vaccine remains one of the most significant gaps in the portfolio of tools being developed to eliminate Plasmodium falciparum malaria. Vaccines targeting erythrocyte invasion – an essential step for both parasite development and malaria pathogenesis – have faced the particular challenge of genetic diversity. Immunity-driven balancing selection pressure on parasite invasion proteins often results in the presence of multiple, antigenically distinct, variants within a population, leading to variant-specific immune responses. Such variation makes it difficult to design a vaccine that covers the full range of diversity, and could potentially facilitate the evolution of vaccine-resistant parasite strains. In this study, we investigate the effect of genetic diversity on invasion inhibition by antibodies to a high priority P. falciparum invasion candidate antigen, P. falciparum Reticulocyte Binding Protein Homologue 5 (PfRH5). Previous work has shown that virally delivered PfRH5 can induce antibodies that protect against a wide range of genetic variants. Here, we show that a full-length recombinant PfRH5 protein expressed in mammalian cells is biochemically active, as judged by saturable binding to its receptor, basigin, and is able to induce antibodies that strongly inhibit P. falciparum growth and invasion. Whole genome sequencing of 290 clinical P. falciparum isolates from across the world identifies only five non-synonymous PfRH5 SNPs that are present at frequencies of 10% or more in at least one geographical region. Antibodies raised against the 3D7 variant of PfRH5 were able to inhibit nine different P. falciparum strains, which between them included all of the five most common PfRH5 SNPs in this dataset, with no evidence for strain-specific immunity. We conclude that protein-based PfRH5 vaccines are an urgent priority for human efficacy trials.
Highlights
The development of an effective Plasmodium falciparum vaccine is the topic of intense research
Vaccines targeting the erythrocytic stage have their origins in the observations that passive transfer of immunoglobulins from immune to non-immune individuals markedly reduced parasitemia [5], and that immune adults directly inoculated with blood stage parasites avoid clinical symptoms, emphasizing the protective effect of antibodies targeting blood-stage antigens [6]
The basigin-L ectodomain was expressed as a soluble Cd4d3+4-hexa-his tagged protein, as described [17]
Summary
The development of an effective Plasmodium falciparum vaccine is the topic of intense research. Rational arguments can be advanced to support vaccines that target pre-erythrocytic or erythrocytic stages in humans, or parasite development within the mosquito [1]. The number of stages that could be targeted is compounded by the variety of potential approaches [2], which range from genetically or physically attenuated parasites [3], to subunit-based vaccines, of which there are hundreds of theoretical. Bustamante et al / Vaccine 31 (2013) 373–379 vaccine-induced immunity must be able to protect against multiple genetic variants This is a significant challenge, the availability of genome sequences for hundreds of P. falciparum isolates [10] makes it possible to measure the true scale of the challenge by identifying for each antigen which residues are variable, and in which populations
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