Abstract
Vivax malaria is a major cause of morbidity and mortality worldwide, with several million clinical cases per year and 2.5 billion at risk of infection. A vaccine is urgently needed but the most advanced malaria vaccine, VMP001, confers only very low levels of protection against vivax malaria challenge in humans. VMP001 is based on the circumsporozoite protein (CSP) of Plasmodium vivax. Here a virus-like particle, Qβ, is used as a platform to generate very high levels of antibody against peptides from PvCSP in mice, in order to answer questions important to further development of P. vivax CSP (PvCSP) vaccines. Minimal peptides from the VK210 and VK247 allelic variants of PvCSP are found to be highly protective as Qβ-peptide vaccines, using transgenic P. berghei parasites expressing the homologous PvCSP allelic variant. A target of neutralising antibodies within the nonamer unit repeat of VK210, AGDR, is found, as a Qβ-peptide vaccine, to provide partial protection against malaria challenge, and enhances protective efficacy when combined with full-length PvCSP vaccination. A truncated form of PvCSP, missing the N-terminal domain, is found to confer much higher levels of protective efficacy than full-length PvCSP. Peptides derived from highly conserved areas of PvCSP, RI and RII, are found not to confer protective efficacy as Qβ-peptide vaccines.
Highlights
Malaria caused by Plasmodium vivax causes several million clinical cases per year [1], with 2.5 billion at risk of infection [2], mainly in South East Asia and Latin America [3]
Following challenge with transgenic P. berghei sporozoites with native Plasmodium berghei circumsporozoite protein (PbCSP) replaced by the corresponding allelic variant of P. vivax circumsporozoite protein (PvCSP), the VK210 Qbpeptide vaccines conferred high levels of protection (100% (6/6 protected/challenged) and 83% (5/6) sterile protection for 210agdr and 210qpag respectively), and moderate protection conferred by 247gang (33% (2/6) sterile protection) (Fig. 1E, F)
A tetramer, AGDR, within the nonamer unit repeat of the central repeat region, did confer protection and was used in combination to enhance the protective efficacy of full-length PvCSP
Summary
Malaria caused by Plasmodium vivax causes several million clinical cases per year [1], with 2.5 billion at risk of infection [2], mainly in South East Asia and Latin America [3] It is a highly neglected tropical disease; a vaccine would have enormous impact in control and elimination programs and is urgently needed [2,3]. The present study uses a virus-like particle, Qb, as a platform for eliciting strong antibody responses against PvCSP peptides, followed by challenge of vaccinated mice with transgenic P. berghei parasites expressing the homologous PvCSP protein. By this means basic questions about the protective efficacy of B-cell epitopes
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