Journal
INFECTION AND IMMUNITY
Volume 78, Issue 1, Pages 145-153Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/IAI.00740-09
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Funding
- Wellcome Trust
- MRC [G0502018] Funding Source: UKRI
- Medical Research Council [G0502018] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0509-10233] Funding Source: researchfish
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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 regimens using modified vaccinia virus Ankara (MVA) and adenoviral vectors encoding ME. TRAP can enhance both short-and long-term sterile protection against malaria. Protection persisted for at least 6 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 gamma interferon (INF-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin-2 (IL-2) triple-positive and INF-gamma and TNF-alpha double-positive cells increasing over time, while INF-gamma single-positive cells declined with time. However, INF-gamma 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 regimens 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.
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