Long-lived tissue resident HIV-1 specific memory CD8+ T cells are generated by skin immunization with live virus vectored microneedle arrays

Abstract

The generation of tissue resident memory (TRM) cells at the body surfaces to provide a front line defence against invading pathogens represents an important goal in vaccine development for a wide variety of pathogens. It has been widely assumed that local vaccine delivery to the mucosae is necessary to achieve that aim. Here we characterise a novel micro-needle array (MA) delivery system fabricated to deliver a live recombinant human adenovirus type 5 vaccine vector (AdHu5) encoding HIV-1 gag. We demonstrate rapid dissolution kinetics of the microneedles in skin. Moreover, a consequence of MA vaccine cargo release was the generation of long-lived antigen-specific CD8+ T cells that accumulate in mucosal tissues, including the female genital and respiratory tract. The memory CD8+ T cell population maintained in the peripheral mucosal tissues was attributable to a MA delivered AdHu5 vaccine instructing CD8+ T cell expression of CXCR3+, CD103+, CD49a+, CD69+, CD127+ homing, retention and survival markers. Furthermore, memory CD8+ T cells generated by MA immunization significantly expanded upon locally administered antigenic challenge and showed a predominant poly-functional profile producing high levels of IFNγ and Granzyme B. These data demonstrate that skin vaccine delivery using microneedle technology induces mobilization of long lived, poly-functional CD8+ T cells to peripheral tissues, phenotypically displaying hallmarks of residency and yields new insights into how to design and deliver effective vaccine candidates with properties to exert local immunosurveillance at the mucosal surfaces.

Skin immunisation activates an innate lymphoid cell-monocyte axis regulating CD8+ effector recruitment to mucosal tissues

“…Immunisation was performed by intradermal injection (ID) and by a promising microneedle array (MA) platform progressing through the clinic 27 , whose immunising properties we reported are dependent on dermal DCs 27 . At 1 × 10 9 viral particles (vp) Ad-CN54 gag, both skin immunisation routes elicited as expected high frequency CD8 + T cells tracked by tetramer (Tet) to the immunodominant D b -restricted HIV-1 CN54 gag 308–318 epitope (D b /CN54 gag) 17 in blood, spleen and inguinal LN (Fig. 1a–d).…”

“…with replication defective viral vectors, including adenovirus (Ad) and pox viruses can effectively elicit and recruit polyfunctional antigen-specific CD8 + T cells to mucosal barrier tissues 15–18 . These responses can be long-lived and confer protection 17 . For example, scarification of the skin with vaccinia virus (VV) or modified VV Ankara protects from respiratory pathogen challenge in animal models 19,20 .…”

A Systematic Review: The Role of Resident Memory T Cells in Infectious Diseases and Their Relevance for Vaccine Development

“…A micro-needle array delivery system that utilizes a recombinant adenovirus vector containing the HIV-1 protein Gag, has also produced promising results in generating T RM . These HIV-specific T RM were found in the female reproductive tract and respiratory tract of immunized mice and responded to local antigenic stimulation through expansion and production of IFN-γ and granzyme B ( 69 ). Using this micro-needle array delivery system as a priming strategy followed by intravaginal delivery of a booster concoction serving as a pull strategy may be an interesting protocol worth exploring.…”

Tumor Resident Memory T Cells: New Players in Immune Surveillance and Therapy

“…In a glioblastoma preclinical model, the injection of tumor cells by distinct routes (intraperitoneal, intracranial and subcutaneous) was shown to promote different patterns of integrins on specific T lymphocytes isolated from the respective tumor-draining lymph nodes ( 15 ). These results suggest a mechanistic explanation of the impact of the immunization route in the generation of Trm cells ( 16 – 23 ).…”