title: Recombinant viral-vectored vaccines expressing Plasmodium chabaudi AS apical membrane antigen 1: mechanisms of vaccine-induced blood-stage protection.
abstract: 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.
authors.affiliation: Jenner Institute, University of Oxford, Oxford OX3 7DQ, United Kingdom. sumi.biswas@ndm.ox.ac.uk
authors.forename: Sumi
authors.initials: S
authors.lastname: Biswas
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Spencer
authors.forename: Emily K
authors.initials: EK
authors.lastname: Forbes
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Gilbert
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Holder
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Draper
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis / Q000097:blood; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000097:blood; D000953:Antigens, Protozoan / Q000097:blood / Q000235:genetics* / Q000276:immunology; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D016778:Malaria, Falciparum / Q000097:blood / Q000276:immunology* / Q000517:prevention & control; D008565:Membrane Proteins / Q000097:blood / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D008969:Molecular Sequence Data; D016788:Plasmodium chabaudi / Q000235:genetics / Q000276:immunology; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology*; D015800:Protozoan Proteins / Q000097:blood / Q000235:genetics* / Q000276:immunology; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology
chemical_list: D000913:Antibodies, Protozoan; D000914:Antibodies, Viral; D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D008565:Membrane Proteins; D015800:Protozoan Proteins; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; C090077:apical membrane antigen I, Plasmodium