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

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Abstract

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.

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Figure 1: Effector T cells are recruited to the vagina by topical chemokine treatment.
Figure 2: Chemokine pull is specific for highly activated effector T cells.
Figure 3: Virus-specific T cells recruited by chemokine pull are retained in the vagina long term.
Figure 4: Prime and pull protects mice from lethal genital HSV-2 challenge.

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Acknowledgements

We thank E. Foxman and R. Medzhitov for critical reading of the manuscript, and N. Iijima, H. Dong and B. Yordy for technical support. H.S. is supported by NIAID grant F32AI091024. This work is supported by NIH grants AI054359 and AI062428 to A.I.

Author information

Experiments were conceived and designed by H.S. and A.I. Experiments were performed by H.S. Data were analysed by H.S. and A.I. The paper was written by H.S. and A.I.

Correspondence to Akiko Iwasaki.

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The authors declare no competing financial interests.

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Shin, H., Iwasaki, A. A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature 491, 463–467 (2012) doi:10.1038/nature11522

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