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

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.

Protective Malaria Vaccine in Mice Based on the Plasmodium vivax Circumsporozoite Protein Fused with the Mumps Nucleocapsid Protein

“…For these reasons, we consider that the partial sterile protection observed in this study is at least equivalent to the previous results. Regarding other formulations that were able to confer a higher level of protection in murine models, such as Rv21 [17], the comparison is even harder: not only is the immunization route different (i.m. vs. s.c.), but transgenic parasites were also constructed using different approaches [17,36] and the challenge systems vary from i.v.…”

“…Antibodies directed against the PvCSP central repeats domain can neutralize the sporozoite infectivity, allowing for the acquisition of sterile protection [16]. A VLP formulation containing PvCSP-based antigens (VK210 and VK247) combined with HBsAg showed promising results both alone and in combination with other antigens [17,18]. However, other studies have demonstrated the importance of the three alleles in conferring worldwide protection against P. vivax malaria based on the newly developed CSP-based vaccine [19].…”

In silico design of a T-cell epitope vaccine candidate for parasitic helminth infection

“…An alternative strategy embraces the use of informatics to predict and assess MHC-II T-cell epitopes using criteria to maximize their in vivo protective potential. The fastgrowing application of VLP-based vaccines against several parasites, including Plasmodium spp [34,35], Leishmania infantum [36], Toxoplasma gondii [37], Trichinella spiralis [38], and Clonorchis sinensis [39] prompted our interest in developing a VLP-based vaccine against trichuriasis.…”

The use of transgenic parasites in malaria vaccine research

“…This synergistic effect was only evident when the two vaccines were mixed and administered into two legs. Another study, testing different vaccine delivery platforms targeting P. vivax CSP using chimeric RMP that expressed P. vivax CSP, demonstrated that superior immunogenicity was generated by virus-like particles (VLP) expressing P. vivax CSP compared to other formulations, including viral-vectored vaccines or protein plus adjuvant [40].…”