Abstract
Heterologous prime-boost strategies hold promise for vaccination against tuberculosis. However, the T-cell characteristics required for protection are not known. We proposed that boost vaccines should induce long-lived functional and phenotypic changes to T cells primed by Bacille Calmette Guerin (BCG) and/or natural exposure to mycobacteria. We characterized changes among specific CD4+ T cells after vaccination with the MVA85A vaccine in adults, adolescents, and children. CD4+ T cells identified with Ag85A peptide-bearing HLA class II tetramers were characterized by flow cytometry. We also measured proliferative potential and cytokine expression of Ag85A-specific CD4+ T cells. During the effector phase, MVA85A-induced specific CD4+ T cells coexpressed IFN-γ and IL-2, skin homing integrins, and the activation marker CD38. This was followed by contraction and a transition to predominantly IL-2-expressing, CD45RA−CCR7+CD27+ or CD45RA+CCR7+CD27+ specific CD4+ T cells. These surface phenotypes were similar to Ag85A-specific T cells prior to MVA85A. However, functional differences were observed postvaccination: specific proliferative capacity was markedly higher after 6–12 months than before vaccination. Our data suggest that MVA85A vaccination may modulate Ag85A-specific CD4+ T-cell function, resulting in greater recall potential. Importantly, surface phenotypes commonly used as proxies for memory T-cell function did not associate with functional effects of vaccination.
Highlights
ResultsAfter clean water, vaccination is the most effective global public health intervention [1]
While protection by most currently licensed vaccines correlates with levels of induced antibodies, protection against pathogens such as HIV-1 and Mycobacterium tuberculosis (M. tb) is thought to rely, at least in part, on specific T-cell responses [2, 3]
It is thought that the capacity to expand after T cells reencounter antigen is an important function that may be measured in vaccine trials [11]
Summary
Vaccination is the most effective global public health intervention [1]. The response peaked 7 days postvaccination and had returned to prevaccination levels after 2 months (Fig. 1D) This kinetic profile was remarkably similar to that of specific CD4+ T-cell frequencies measured by IFN-γ ELISpot assay, following incubation of PBMCs with peptides spanning the entire Ag85A protein (Fig. 1E). To determine the tissue homing potential of Ag85A-specific CD4+ T cells induced by intradermal MVA85A vaccination, we measured expression of homing markers associated with trafficking to skin (cutaneous lymphocyte antigen, CLA [20]), gut (α4β7 [21]), and lung (α4β1 [22]) on DR3-Ag85A tetramer+ CD4+ T cells (Fig. 2A). To further characterize the function of MVA85A-induced memory cells, we measured the relative proportions of Ag85A-specific CD4+ T cells expressing IFN-γ and/or IL-2 at 7, 28, and 168 days after MVA85A vaccination (Fig. 4D). These data suggest that most of the CD45RA+CCR7+CD27+ naive-like memory CD4+ T cells are not TSCM cells
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