Effector and central memory poly-functional CD4+ and CD8+ T cells are boosted upon ZOSTAVAX® vaccination

ZOSTAVAX (R) is a live attenuated varicella-zoster virus (VZV) vaccine that is licensed for the protection of individuals >= 50 years against shingles and its most common complication, postherpetic neuralgia. While IFN gamma responses increase upon vaccination, the quality of the T cell response has not been elucidated. By using polychromatic flow cytometry, we characterized the breadth, magnitude, and quality of ex vivo CD4(+) and CD8(+) T cell responses induced 3-4 weeks after ZOSTAVAX vaccination of healthy adults. We show, for the first time that the highest frequencies of VZV-specific CD4(+) T cells were poly functional CD154(+)IFN gamma+IL-2(+)TNF alpha(+) cells, which were boosted upon vaccination. The CD4(+) T cells were broadly reactive to several VZV proteins, with immediate early (IE) 63 ranking the highest among them in the fold rise of poly-functional cells, followed by IE62, gB, open reading frame (ORF) 9, and gE. We identified a novel poly-functional ORF9-specific CD8(+) T cell population in 62% of the subjects, and these were boosted upon vaccination. Poly-functional CD4(+) and CD8(+) T cells produced significantly higher levels of IFN gamma, IL-2, and TNF alpha compared to mono-functional cells. After vaccination, a boost in the expression of IFN gamma by poly-functional IE63- and ORF9-specific CD4(+) T cells and IFN gamma, IL-2, and TNF alpha by ORF9-specific poly-functional CD8(+) T cells was observed. Responding poly-functional T cells exhibited both effector (CCR7(-)CD45RA(-)CD45RO(+)), and central (CCR7(+)CD45RA(-)CD45RO(+)) memory phenotypes, which expressed comparable levels of cytokines. Altogether, our studies demonstrate that a boost in memory poly-functional CD4(+) T cells and ORF9-specific CD8(+) T cells may contribute toward ZOSTAVAX efficacy.