Rational development of a protective P. vivax vaccine evaluated with transgenic rodent parasite challenge models

Ahmed M Salman,Cesar Lopez-Camacho,Fernando Reis,Chris J Janse,Florian Brod,Amar Lall,Shahid M Khan,Lilia González-Cerón,Heather West,Adrian V S Hill,Karolis Bauza,Erwan Atcheson,Leontios Pappas,Eduardo Montoya-Díaz,Jai Ramesar,Katharine A Collins,Arturo Reyes-Sandoval

doi:10.1038/srep46482

Abstract

Development of a protective and broadly-acting vaccine against the most widely distributed human malaria parasite, Plasmodium vivax, will be a major step towards malaria elimination. However, a P. vivax vaccine has remained elusive by the scarcity of pre-clinical models to test protective efficacy and support further clinical trials. In this study, we report the development of a highly protective CSP-based P. vivax vaccine, a virus-like particle (VLP) known as Rv21, able to provide 100% sterile protection against a stringent sporozoite challenge in rodent models to malaria, where IgG2a antibodies were associated with protection in absence of detectable PvCSP-specific T cell responses. Additionally, we generated two novel transgenic rodent P. berghei parasite lines, where the P. berghei csp gene coding sequence has been replaced with either full-length P. vivax VK210 or the allelic VK247 csp that additionally express GFP-Luciferase. Efficacy of Rv21 surpassed viral-vectored vaccination using ChAd63 and MVA. We show for the first time that a chimeric VK210/247 antigen can elicit high level cross-protection against parasites expressing either CSP allele, which provide accessible and affordable models suitable to support the development of P. vivax vaccines candidates. Rv21 is progressing to GMP production and has entered a path towards clinical evaluation.

Highlights

The evaluation of the protective efficacy of P. falciparum vaccine candidates and vaccine formulations has greatly benefited from immunization-challenges studies performed in clinical trials using wild-type parasites in controlled human malaria infection (CHMI) studies[6,9,11,12,13,14]
The resulting recombinant viruses contained a series of P. vivax circumsporozoite protein (PvCSP) expression cassettes encoding the PvCSP N- and C-terminal sequences of the Salvador I strain of Plasmodium vivax, including or excluding the most common central repeat sequences present in the two major PvCSP alleles VK210 and VK247 (Fig. 1A)[8]
None of these other mouse strains (C3H/He, BALB/c or outbred CD1) showed detectable antigen-specific T cell responses (Fig. 1B,C) and we concluded that the PvCSP molecules that we used in our vv do not have immunodominant T cell epitopes in the animal models tested under our experimental conditions

Summary

Introduction

The evaluation of the protective efficacy of P. falciparum vaccine candidates and vaccine formulations has greatly benefited from immunization-challenges studies performed in clinical trials using wild-type parasites in controlled human malaria infection (CHMI) studies[6,9,11,12,13,14]. VLPs are known to stimulate B cells to induce high antibody titers; RTS,S/AS01 uses a similar VLP approach[5], which presents a hybrid polypeptide consisting of a portion of the P. falciparum CSP repeat and C-terminal regions fused to the amino terminal end of the hepatitis B virus surface (HepB-S) protein[26]. This VLP has a four-fold excess of HBsAg monomers in the VLP, required to allow expression of the particle in Saccharomyces yeast. This work identifies a highly promising new candidate sporozoite vaccine for P. vivax that provides protection against the two major allelic types and highlights the potential and utility of the rodent challenge model to support the development of an efficacious P. vivax malaria vaccine

Methods

Results

Conclusion