Development Of Vaccines For Genital Herpes Simplex Infection

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Herpes simplex virus 2 (HSV-2) causes genital herpes and increases the risk of transmission and infection with HIV. Thus, a vaccine for HSV-2 would not only reduce the rate of genital herpes, but also might reduce spread of HIV. Several HSV-2 vaccines have been tested in humans for prevention or reduction of genital herpes disease, but none has been licensed for use in humans. We performed a randomized, double blind, placebo-controlled clinical trial of a replication-defective vaccine for HSV2 termed HSV529. This vaccine can infect cells, but not replicate in the cells. We vaccinated three groups of 20 subjects with three doses (at 0, 1, and 6 months) of HSV529 (15 subjects per group) or saline placebo injection (5 subjects per group). The groups were a) subjects who were infected with HSV2 in the past but may or may not have been infected with HSV-1 (HSV1+/-/HSV2+), (b) subjects who were infected only with HSV1 (HSV1+/HSV2-), and (c) subjects who were not infected with HSV1 or HSV2 (HSV1-/HSV2-). Each subject was followed after vaccination, and safety, the primary endpoint, and immune responses to the vaccine were studied. Seventy-eight percent of HSV1-/HSV2- vaccine recipients had > 4-fold rises in neutralizing antibody titer after three doses of vaccine, whereas none of the participants in the other serogroups had such responses. Unlike subunit vaccines for HSV2 that only induce antibodies to one or a few HSV-2 proteins, the HSV529 vaccine is expected to produce antibodies to most of the HSV2 proteins in vaccine recipients. Both sex and prior exposure to pathogens are known to influence responses to immune challenges, but their combined effects are not well established in humans, particularly in early innate responses critical for shaping subsequent outcomes. In 2023 we used systems immunology approaches to study responses to a replication-defective, herpes simplex virus (HSV) 2 vaccine in men and women either naive or previously exposed to HSV. Analysis of cellular gene expression in blood (transcriptomics) and cell population profiling showed substantial changes on day 1 after vaccination, but the responses depended on sex and whether the vaccinee was naive or previously exposed to HSV. The magnitude of early transcriptional responses was greatest in HSV naive women where type I interferon (IFN) signatures were prominent and associated negatively with vaccine-induced neutralizing antibody titers, suggesting that a strong early antiviral response reduced the antibody response to this replication-defective virus vaccine. While HSV seronegative vaccine recipients had upregulation of gene sets in type I IFN (e.g. IFN-alpha) responses, HSV2 seropositive vaccine recipients tended to have responses focused more on type II IFN (IFN-gamma) genes. These results together show that prior exposure and sex interact to shape early innate responses that then impact subsequent adaptive immune phenotypes.