title: Single-dose immunogenicity and protective efficacy of simian adenoviral vectors against Plasmodium berghei.
abstract: Simian adenoviral vectors (SAd) offer an attractive alternative to standard human adenovirus serotype 5 (AdH5) subunit vaccination, due to pre-existing immunity affecting vaccine performance. We have used a mouse model of liver-stage malaria to test the efficiency of three chimpanzee-origin adenoviral vectors, AdC6, AdC7 and AdC9 containing ME.TRAP as an insert. AdC7 and AdC9 elicited strong immunogenicity ( approximately 20% of CD8(+) T cells in spleen), equivalent to or outperforming AdH5 and inducing sterile protection in 92% (C9), 83% (H5 and C7) and 67% (C6) of the mice, providing the first evidence of single-dose protection to Plasmodium berghei. Protection was afforded by the SAd despite high levels of pre-existing immunity to AdH5. Phenotypic analysis showed that all adenoviral vectors (Ad) elicited CD8(+) T cell responses with an effector memory T cell (T(EM)) phenotype. By contrast, vaccination with poxviral vectors did not confer protection to P. berghei and induced a predominantly CD8(+) central memory T cell (T(CM)) response. Multifunctional CD8(+) T cell responses (co-expressing IFN-gamma, TNF-alpha and IL-2) were also induced by the Ad in higher percentages than the poxviral vectors. Our data suggest that T(EM) cells are important as a first line of defense against fast-replicating pathogens such as murine Plasmodium and demonstrate the potential of replication-defective SAd as future malaria vaccines for humans.
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. arturo@well.ox.ac.uk
authors.forename: Arturo
authors.initials: A
authors.lastname: Reyes-Sandoval
authors.forename: Saranya
authors.initials: S
authors.lastname: Sridhar
authors.forename: Tamara
authors.initials: T
authors.lastname: Berthoud
authors.forename: Anne C
authors.initials: AC
authors.lastname: Moore
authors.forename: John T
authors.initials: JT
authors.lastname: Harty
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Gilbert
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.forename: Hildegund C J
authors.initials: HC
authors.lastname: Ertl
authors.forename: James C
authors.initials: JC
authors.lastname: Wilson
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
mesh_terms: D000261:Adenoviruses, Simian / Q000235:genetics*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D053804:Granzymes / Q000378:metabolism; D007271:Injections, Intradermal; D007371:Interferon-gamma / Q000378:metabolism; D008288:Malaria / Q000276:immunology / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000276:immunology*; D011212:Poxviridae / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D019444:Vaccines, DNA; C069428:thrombospondin-related adhesive protein, protozoan; D007371:Interferon-gamma; D053804:Granzymes; C509214:Gzmb protein, mouse