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Apical membrane Ag 1 (AMA1) is one of the leading candidate Ags for inclusion in a subunit vaccine against blood-stage malaria. However, the efficacy of Ab-inducing recombinant AMA1 protein vaccines in phase IIa/b clinical trials remains disappointing. In this article, we describe the development of recombinant human adenovirus serotype 5 and modified vaccinia virus Ankara vectors encoding AMA1 from the Plasmodium chabaudi chabaudi strain AS. These vectors, when used in a heterologous prime-boost regimen in BALB/c mice, are capable of inducing strong transgene-specific humoral and cellular immune responses. We show that this vaccination regimen is protective against a nonlethal P. chabaudi chabaudi strain AS blood-stage challenge, resulting in reduced peak parasitemias. The role of vaccine-induced, AMA1-specific Abs and T cells in mediating the antiparasite effect was investigated by in vivo depletion of CD4(+) T cells and adoptive-transfer studies into naive and immunodeficient mice. Depletion of CD4(+) T cells led to a loss of vaccine-induced protection. Adoptive-transfer studies confirmed that efficacy is mediated by both CD4(+) T cells and Abs functioning in the context of an intact immune system. Unlike previous studies, these results confirm that Ag-specific CD4(+) T cells, induced by a clinically relevant vaccine-delivery platform, can make a significant contribution to vaccine blood-stage efficacy in the P. chabaudi model. Given that cell-mediated immunity may also contribute to parasite control in human malaria, these data support the clinical development of viral-vectored vaccines that induce both T cell and Abs against Plasmodium falciparum blood-stage malaria Ags like AMA1.

Original publication

DOI

10.4049/jimmunol.1101106

Type

Journal article

Journal

J Immunol

Publication Date

15/05/2012

Volume

188

Pages

5041 - 5053

Keywords

Adenoviruses, Human, Animals, Antibodies, Protozoan, Antibodies, Viral, Antigens, Protozoan, Female, Genetic Vectors, Humans, Malaria Vaccines, Malaria, Falciparum, Membrane Proteins, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Nude, Molecular Sequence Data, Plasmodium chabaudi, Plasmodium falciparum, Protozoan Proteins, Vaccines, Subunit, Vaccines, Synthetic, Vaccinia virus