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

Abstract

The majority of 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 (STIs), is an immunologically restrictive tissue that prevents entry of activated T cells in the absence of inflammation or infection4. To overcome this obstacle, we explored a vaccine strategy 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: 1) conventional parenteral vaccination to elicit systemic T cell responses (prime), followed by 2) recruitment of activated T cells via topical chemokine application to the restrictive genital tract (pull), where such T cells establish a long-term niche and mediate protective immunity. Prime and pull protocol reduces the spread of infectious HSV-2 into the sensory neurons and prevents development of clinical disease. These results reveal a promising vaccination strategy against HSV-2, and potentially against other STIs such as HIV-1.