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01 2019 Journal of immunology (Baltimore, Md. : 1950)

A Prime-Pull-Amplify Vaccination Strategy To Maximize Induction of Circulating and Genital-Resident Intraepithelial CD8 Memory T Cells.

Authors

Çuburu N, Kim R, Guittard GC, Thompson CD, Day PM, Hamm DE, Pang YS, Graham BS, Lowy DR, Schiller JT

Summary

Recent insight into the mechanisms of induction of tissue-resident memory (T) CD8 T cells (CD8 T) enables the development of novel vaccine strategies against sexually transmitted infections. To maximize both systemic and genital intraepithelial CD8 T cells against vaccine Ags, we assessed combinations of i.m. and intravaginal routes in heterologous prime-boost immunization regimens with unrelated viral vectors. Only i.m. prime followed by intravaginal boost induced concomitant strong systemic and intraepithelial genital-resident CD8 T cell responses. Intravaginal boost with vectors expressing vaccine Ags was far superior to intravaginal instillation of CXCR3 chemokine receptor ligands or TLR 3, 7, and 9 agonists to recruit and increase the pool of cervicovaginal CD8 T Transient Ag presentation increased trafficking of cognate and bystander circulating activated, but not naive, CD8 T cells into the genital tract and induced in situ proliferation and differentiation of cognate CD8 T Secondary genital CD8 T were induced in the absence of CD4 T cell help and shared a similar TCR repertoire with systemic CD8 T cells. This prime-pull-amplify approach elicited systemic and genital CD8 T cell responses against high-risk human papillomavirus type 16 E7 oncoprotein and conferred CD8-mediated protection to a vaccinia virus genital challenge. These results underscore the importance of the delivery route of nonreplicating vectors in prime-boost immunization to shape the tissue distribution of CD8 T cell responses. In this context, the importance of local Ag presentation to elicit genital CD8 T provides a rationale to develop novel vaccines against sexually transmitted infections and to treat human papillomavirus neoplasia.

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