Journal Article

A full-length recombinant Plasmodium falciparum PfRH5 protein induces inhibitory antibodies that are effective across common PfRH5 genetic variants

Bartholdson, S. Josefin, Rayner, Julian C., Campos, Marta G., Kwiatkowski, Dominic P., Nguon, Chea, Wanaguru, Madushi, Wright, Gavin J., Crosnier, Cecile, Bustamante, Leyla Y.

2013

Overview

► PfRH5 is essential for Plasmodium falciparum erythrocyte invasion. ► Antibodies raised against full-length functional PfRH5 potently blocked invasion. ► Five common PfRH5 polymorphisms were identified across 290 clinical isolates. ► Antibodies raised against one variant inhibited all other common PfRH5 variants. ► Correctly folded recombinant PfRH5 is a strong P. falciparum vaccine candidate. 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.

• Publisher: Elsevier Ltd,Elsevier,Elsevier Science
• Subject: Allergy and Immunology / antibodies / Antibodies, Protozoan - immunology / antigens / Antigens, Protozoan - genetics / Antigens, Protozoan - immunology / Applied microbiology / binding proteins / Biological and medical sciences / Blood stage / Carrier Proteins - genetics / Carrier Proteins - immunology / data collection / Erythrocyte invasion / erythrocytes / Erythrocytes - immunology / Erythrocytes - parasitology / evolution / Fundamental and applied biological sciences. Psychology / genetic variation / Human protozoal diseases / Humans / immune response / Infectious diseases / Life cycle. Host-agent relationship. Pathogenesis / Malaria / Malaria Vaccines - genetics / Malaria Vaccines - immunology / Malaria, Falciparum - blood / Malaria, Falciparum - immunology / Malaria, Falciparum - parasitology / Malaria, Falciparum - prevention & control / Medical sciences / Microbiology / parasites / Parasitic diseases / pathogenesis / Plasmodium falciparum / Plasmodium falciparum - genetics / Plasmodium falciparum - immunology / Polymorphism, Single Nucleotide / Protozoa / Protozoal diseases / Recombinant Proteins - genetics / Recombinant Proteins - immunology / sequence analysis / single nucleotide polymorphism / Vaccine / vaccine development / vaccines / Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects)