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Abstract
Plasmodium vivax is the world's most widely distributed malaria parasite and a potential cause of morbidity and mortality for approximately 2.85 billion people living mainly in Southeast Asia and Latin America. Despite this dramatic burden, very few vaccines have been assessed in humans. The clinically relevant vectors modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAd63 are promising delivery systems for malaria vaccines due to their safety profiles and proven ability to induce protective immune responses against Plasmodium falciparum thrombospondin-related anonymous protein (TRAP) in clinical trials. Here, we describe the development of new recombinant ChAd63 and MVA vectors expressing P. vivax TRAP (PvTRAP) and show their ability to induce high antibody titers and T cell responses in mice. In addition, we report a novel way of assessing the efficacy of new candidate vaccines against P. vivax using a fully infectious transgenic Plasmodium berghei parasite expressing P. vivax TRAP to allow studies of vaccine efficacy and protective mechanisms in rodents. Using this model, we found that both CD8+ T cells and antibodies mediated protection against malaria using virus-vectored vaccines. Our data indicate that ChAd63 and MVA expressing PvTRAP are good preerythrocytic-stage vaccine candidates with potential for future clinical application.
Highlights
Plasmodium vivax is the world’s most widely distributed malaria parasite and a potential cause of morbidity and mortality for approximately 2.85 billion people living mainly in Southeast Asia and Latin America
The rodent malaria model Plasmodium berghei has been used to generate transgenic parasites expressing the ookinete surface protein P25 to assess a P. vivax transmission-blocking vaccine [6], an approach that has been extended to P. vivax antigens from preerythrocytic stages, such as the circumsporozoite protein (CSP) [7], and in this paper, we report the use of the thrombospondin-related anonymous protein (TRAP) expressed in transgenic P. berghei parasites
We chose to evaluate different experimental vaccines against P. vivax TRAP in mice infected with a transgenic P. berghei parasite, in which the endogenous P. berghei TRAP (PbTRAP) gene was irreversibly replaced with its ortholog from P. vivax (PvTRAP)
Summary
Plasmodium vivax is the world’s most widely distributed malaria parasite and a potential cause of morbidity and mortality for approximately 2.85 billion people living mainly in Southeast Asia and Latin America Despite this dramatic burden, very few vaccines have been assessed in humans. We report a novel way of assessing the efficacy of new candidate vaccines against P. vivax using a fully infectious transgenic Plasmodium berghei parasite expressing P. vivax TRAP to allow studies of vaccine efficacy and protective mechanisms in rodents Using this model, we found that both CD8؉ T cells and antibodies mediated protection against malaria using virus-vectored vaccines. Heterologous prime-boost vaccinations using the clinically relevant recombinant chimpanzee adenovirus ChAd63 (Ad) and MVA viral vectors expressing the P. vivax TRAP (PvTRAP) transgene were assessed for immunogenicity and protection efficacy in various mouse strains, using a fully infectious transgenic P. berghei parasite carrying a perfect allelic replacement of the P. berghei TRAP (PbTRAP) gene with P. vivax TRAP. Our results indicate that protection was mediated by CD8ϩ T cells, and by antibodies, which contrasts with previous findings for P. falciparum, where only T cells play a role in protection [11]
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