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 (∼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 (TEM) phenotype. By contrast, vaccination with poxviral vectors did not confer protection to P. berghei and induced a predominantly CD8+ central memory T cell (TCM) response. Multifunctional CD8+ T cell responses (co-expressing IFN-γ, TNF-α and IL-2) were also induced by the Ad in higher percentages than the poxviral vectors. Our data suggest that TEM 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. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.