IAI Accepts, published online ahead of print on 26 October 2009

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Infect. Immun. doi:10.1128/IAI.00740-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Prime-boost immunization with adenoviral and MVA vectors enhances the durability and polyfunctionality of protective malaria CD8⁺ T cell responses

Arturo Reyes-Sandoval^*, Tamara Berthoud, Nicola Alder, Loredana Siani, Sarah C. Gilbert, Alfredo Nicosia, Stefano Colloca, Riccardo Cortese, and Adrian V.S. Hill

The Jenner Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK; Centre for Statistics in Medicine, Wolfson College Annexe, Linton Road, Oxford, OX2 6UD, UK; Okairòs, Via dei Castelli Romani 22, 00040 Pomezia, Rome, Italy

^* To whom correspondence should be addressed. Email: arturo.reyes{at}ndm.ox.ac.uk.

Protection against liver stage malaria relies on the induction of high frequencies of antigen-specific CD8⁺ T cells. We have previously reported high protective levels against mouse malaria, albeit short-lived, by a single vaccination with adenoviral vectors coding for a liver-stage antigen (ME.TRAP). Here, we report that prime-boost regimes using Modified Vaccinia Ankara (MVA) and adenoviral vectors encoding ME.TRAP can enhance both short- and long-term sterile protection against malaria. Protection persisted for at least six months when simian adenoviruses AdCh63 and AdC9 were used as priming vectors. Kinetic analysis showed that the MVA boost made the adenoviral-primed T cells markedly more polyfunctional, with the number of INF-/TNF-/IL-2 triple- and INF-/TNF- double-positive cells increasing over time, while INF- single-positive cells declined with time. However, IFN- production prevailed as the main immune correlate of protection, while neither an increase of polyfunctionality, nor a high integrated Mean Fluorescence Intensity (iMFI) correlated with protection. These data highlight the ability of optimized viral vector prime-boost regimes to generate more protective and sustained CD8⁺ T cell responses and our results encourage a more nuanced assessment of the importance of inducing polyfunctional CD8⁺ T cells by vaccination.