A vaccine strategy that protects against genital herpes by establishing local memory T cells

Abstract

A genital herpes simplex vaccine strategy of immunization using attenuated virus with peripheral local chemokine application can establish a population of protective tissue-resident memory T cells. In this study, Haina Shin and Akiko Iwasaki describe a novel vaccine approach, which they term 'prime and pull', in which effector CD8+ and CD4+ T cells generated by a conventional vaccine against herpes simplex virus 2 (HSV-2) are mobilized and maintained at potential mucosal sites of infection. They report that mice receiving subcutaneous immunization with an HSV-2 vaccine together with topical application of chemokines known to recruit T cells to epithelial surfaces had a survival rate of 100% two weeks after challenge with the virus, compared to 57% survival in mice that received vaccine only. This strategy could improve current cell-based vaccines against sexually transmitted diseases, and the authors suggest that a similar approach may boost HIV-1 vaccines. Most successful existing vaccines rely on neutralizing antibodies, which may not require specific anatomical localization of B cells. However, efficacious vaccines that rely on T cells for protection have been difficult to develop, as robust systemic memory T-cell responses do not necessarily correlate with host protection1. In peripheral sites, tissue-resident memory T cells provide superior protection compared to circulating memory T cells2,3. Here we describe a simple and non-inflammatory vaccine strategy that enables the establishment of a protective memory T-cell pool within peripheral tissue. The female genital tract, which is a portal of entry for sexually transmitted infections, is an immunologically restrictive tissue that prevents entry of activated T cells in the absence of inflammation or infection4. To overcome this obstacle, we developed a vaccine strategy that we term ‘prime and pull’ to establish local tissue-resident memory T cells at a site of potential viral exposure. This approach relies on two steps: conventional parenteral vaccination to elicit systemic T-cell responses (prime), followed by recruitment of activated T cells by means of topical chemokine application to the restrictive genital tract (pull), where such T cells establish a long-term niche and mediate protective immunity. In mice, prime and pull protocol reduces the spread of infectious herpes simplex virus 2 into the sensory neurons and prevents development of clinical disease. These results reveal a promising vaccination strategy against herpes simplex virus 2, and potentially against other sexually transmitted infections such as human immunodeficiency virus.