Prime-boost immunization with adenoviral and modified vaccinia virus Ankara vectors enhances the durability and polyfunctionality of protective malaria CD8+ T-cell responses.
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, IFN-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.
Reyes-Sandoval
Arturo
A
The Jenner Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom. arturo.reyes@ndm.ox.ac.uk
Berthoud
Tamara
T
Alder
Nicola
N
Siani
Loredana
L
Gilbert
Sarah C
SC
Nicosia
Alfredo
A
Colloca
Stefano
S
Cortese
Riccardo
R
Hill
Adrian V S
AV
D000256:Adenoviridae; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D005260:Female; D007115:Immunization Schedule; D007117:Immunization, Secondary; D017780:Malaria Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D016778:Malaria, Falciparum / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D015800:Protozoan Proteins / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology; D014616:Vaccinia virus / Q000145:classification
D017780:Malaria Vaccines; D015800:Protozoan Proteins; D014614:Vaccines, Synthetic