title: CD8+ T effector memory cells protect against liver-stage malaria.
abstract: Identification of correlates of protection for infectious diseases including malaria is a major challenge and has become one of the main obstacles in developing effective vaccines. We investigated protection against liver-stage malaria conferred by vaccination with adenoviral (Ad) and modified vaccinia Ankara (MVA) vectors expressing pre-erythrocytic malaria Ags. By classifying CD8(+) T cells into effector, effector memory (T(EM)), and central memory subsets using CD62L and CD127 markers, we found striking differences in T cell memory generation. Although MVA induced accelerated central memory T cell generation, which could be efficiently boosted by subsequent Ad administration, it failed to protect against malaria. In contrast, Ad vectors, which permit persistent Ag delivery, elicit a prolonged effector T cell and T(EM) response that requires long intervals for an efficient boost. A preferential T(EM) phenotype was maintained in liver, blood, and spleen after Ad/MVA prime-boost regimens, and animals were protected against malaria sporozoite challenge. Blood CD8(+) T(EM) cells correlated with protection against malaria liver-stage infection, assessed by estimation of number of parasites emerging from the liver into the blood. The protective ability of Ag-specific T(EM) cells was confirmed by transfer experiments into naive recipient mice. Thus, we identify persistent CD8 T(EM) populations as essential for vaccine-induced pre-erythrocytic protection against malaria, a finding that has important implications for vaccine design.
authors.affiliation: The Jenner Institute, University of Oxford, Oxford OX3 7DQ, United Kingdom. arturo.reyes@ndm.ox.ac.uk
authors.forename: Arturo
authors.initials: A
authors.lastname: Reyes-Sandoval
authors.forename: David H
authors.initials: DH
authors.lastname: Wyllie
authors.forename: Karolis
authors.initials: K
authors.lastname: Bauza
authors.forename: Anita
authors.initials: A
authors.lastname: Milicic
authors.forename: Emily K
authors.initials: EK
authors.lastname: Forbes
authors.forename: Christine S
authors.initials: CS
authors.lastname: Rollier
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000469:parasitology* / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D006183:H-2 Antigens / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics; D008109:Liver Diseases, Parasitic / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D008288:Malaria / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010962:Plasmodium berghei / Q000235:genetics / Q000276:immunology; D015800:Protozoan Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D019076:Transgenes / Q000276:immunology; D014615:Vaccinia / Q000235:genetics / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan; C069428:thrombospondin-related adhesive protein, protozoan