Abstract
Malaria continues to be a pressing global health issue, causing nearly half a million deaths per year. An effective malaria vaccine could radically improve our ability to control and eliminate this pathogen. The most advanced malaria vaccine, RTS,S, confers only 30% protective efficacy under field conditions, and hence the search continues for improved vaccines. New antigens and formulations are always first developed at a pre-clinical level. This paper describes the development of a platform to supplement existing tools of pre-clinical malaria vaccine development, by displaying linear peptides on a virus-like particle (VLP). Peptides from PfCSP, particularly from outside the normal target of neutralizing antibodies, the central NANP repeat region, are screened for evidence of protective efficacy. One peptide, recently identified as a target of potent neutralizing antibodies and lying at the junction between the N-terminal domain and the central repeat region of PfCSP, is found to confer protective efficacy against malaria sporozoite challenge in mice when presented on the Qβ VLP. The platform is also used to explore the effects of increasing numbers of NANP unit repeats, and including a universal CD4+ T-cell epitope from tetanus toxin, on immunogenicity and protective efficacy. The VLP-peptide platform is shown to be of use in screening malaria peptides for protective efficacy and answering basic vaccinology questions in a pre-clinical setting.
Highlights
The need for an effective malaria vaccine is pressing, with almost half a million deaths and 148–304 million clinical cases every year caused by this parasite[1]
The immunogenicity of short peptides is enhanced by coupling them to virus-like particles (VLPs)[9], the aim of this paper is not necessarily to advocate VLP-peptide vaccines for clinical use, nor is the aim to obtain high levels of protective efficacy against challenge; one of the main metrics of vaccine efficacy used here is a delay in time to reach 1% blood-stage parasitaemia, previously validated[10,11] and a more sensitive metric to use when testing the hypothesis that combining vaccines enhances efficacy since sterile protection represents saturation[12]
The focus of this paper is to explore the potential of VLP-peptide vaccines in pre-clinical screening of epitopes for potential protective efficacy and to answer other basic questions useful to malaria vaccine development
Summary
The need for an effective malaria vaccine is pressing, with almost half a million deaths and 148–304 million clinical cases every year caused by this parasite[1]. The leading malaria vaccine, RTS,S represents a major milestone in malaria vaccine development It is only about 30% efficacious under field conditions[2], which (at $5–10 per dose) will make it less cost-effective at preventing severe malaria than long-lasting insecticide-treated bednets[3]. A peptide-based vaccine was amongst the first malaria vaccines to reach clinical study[4] It consisted of three copies of the NANP tetramer motif from the central repeat region of the major malaria sporozoite antigen, circumsporozoite protein (CSP). This region, and the NANP motif, in particular, had been shown to be a target of neutralising antibodies[5,6].
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