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

Abstract

Recent insight into the mechanisms of induction of tissue-resident memory (T RM) CD8 + T cells (CD8 + T RM) 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 RM. 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 RM. Secondary genital CD8 + T RM 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 highrisk 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 RM provides a rationale to develop novel vaccines against sexually transmitted infections and to treat human papillomavirus neoplasia.

A Systemic Prime–Intrarectal Pull Strategy Raises Rectum-Resident CD8+ T Cells for Effective Protection in a Murine Model of LM-OVA Infection

“…Although we cannot exclude the possibility that the level of circulating antigen-specific T cells contributes to such interval effect, this observation is in agreement with previous finding that the trafficking capacity of activated circulating T cells positively correlates with their freshness, probably due to the transient upregulation of α4β7, the homing receptor for MAdCAM-1 expressed on the endothelial cell surface (32). Interestingly, several most recent studies applying prime-and-pull strategy to induce vaginal TRM used a prime-pull interval up to 3 or 4 weeks (44,46), indicating the generation of TRM from prime-established memory pools. Although newly activated effector T cells have a clear advantage over memory T cells in terms of size of the population, the effect of length of the interval between prime and pull on TRM generation is worth future investigations.…”

Vaccination against the digestive enzyme Cathepsin B using a YS1646Salmonella entericaTyphimurium vector provides almost complete protection againstSchistosoma mansonichallenge in a mouse model

“…Chen and colleagues have also used YS1646 as a vector to test single- and multi-modality approaches for a bivalent vaccine candidate (Sj23LHD-GST) targeting S. japonicum in a similar murine model [29]. Although some authors have promoted so-called ‘prime-pull’ strategies to optimize mucosal responses (ie: ‘prime’ in the periphery then ‘pull’ to the target mucosa) [50], it is interesting that both the Chen group and our own findings suggest that PO→IM dosing may be the optimal strategy. In the S. japonicum model targeting the long hydrophobic domain of the surface exposed membrane protein Sj23LHD and a host-parasite interface enzyme (glutathione S-transferase or GST), the PO→IM vaccination schedule led to important reductions in both worm numbers (51.4%) and liver egg burden (62.6%) [29].…”

Inducing Immunity Where It Matters: Orthotopic HPV Tumor Models and Therapeutic Vaccinations

“…Similarly, follow-up studies to the HPV pseudovirus vaccinations mentioned above, with adenovirus vectors encoding HPV16 E6 and E7, showed that an i.m. prime vaccination with a subsequent vaginal boost was more effective in inducing HPV-specific CD8 + T cells and their trafficking to the cervicovaginal tract than only vaginal vaccination (54,55).…”