title: Combining liver- and blood-stage malaria viral-vectored vaccines: investigating mechanisms of CD8+ T cell interference.
abstract: Replication-deficient adenovirus and modified vaccinia virus Ankara (MVA) vectors expressing single pre-erythrocytic or blood-stage Plasmodium falciparum Ags have entered clinical testing using a heterologous prime-boost immunization approach. In this study, we investigated the utility of the same immunization regimen when combining viral vectored vaccines expressing the 42-kDa C terminus of the blood-stage Ag merozoite surface protein 1 and the pre-erythrocytic Ag circumsporozoite protein in the Plasmodium yoelii mouse model. We find that vaccine coadministration leads to maintained Ab responses and efficacy against blood-stage infection, but reduced secondary CD8(+) T cell responses against both Ags and efficacy against liver-stage infection. CD8(+) T cell interference can be minimized by coadministering the MVA vaccines at separate sites, resulting in enhanced liver-stage efficacy in mice immunized against both Ags compared with just one. CD8(+) T cell interference (following MVA coadministration as a mixture) may be caused partly by a lack of physiologic space for high-magnitude responses against multiple Ags, but is not caused by competition for presentation of Ag on MHC class I molecules, nor is it due to restricted T cell access to APCs presenting both Ags. Instead, enhanced killing of peptide-pulsed cells is observed in mice possessing pre-existing T cells against two Ags compared with just one, suggesting that priming against multiple Ags may in part reduce the potency of multiantigen MVA vectors to stimulate secondary CD8(+) T cell responses. These data have important implications for the development of a multistage or multicomponent viral vectored malaria vaccine for use in humans.
authors.affiliation: The Jenner Institute, University of Oxford, Oxford, United Kingdom. ekforbes@hotmail.com
authors.forename: Emily K
authors.initials: EK
authors.lastname: Forbes
authors.forename: Sumi
authors.initials: S
authors.lastname: Biswas
authors.forename: Katharine A
authors.initials: KA
authors.lastname: Collins
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Gilbert
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Draper
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000469:parasitology; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors; D017780:Malaria Vaccines / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology* / Q000517:prevention & control; D020066:Merozoite Surface Protein 1 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010963:Plasmodium falciparum / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics
chemical_list: D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D020066:Merozoite Surface Protein 1