Development Of Vaccines For Genital Herpes Simplex Infection

National Institute Of Allergy And Infectious Diseases

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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. In FYI 2021 we report that HSV1-/HSV2- recipients of the HSV529 vaccine developed antibodies to epitopes of multiple HSV proteins; however, fewer antibody epitopes were detected in vaccine recipients compared with naturally infected persons. In addition, we measured levels of serum antibody that mediate HSV2-specific NK cell activation, a surrogate for antibody-dependent cellular cytotoxicity which is important for the immune system to kill virus-infected cells. The HSV529 vaccine induced antibodies that mediated HSV2-specific NK cell activation in HSV1-/HSV2- recipients of the HSV529 vaccine. While most studies of HSV2 vaccines measure the level of antibodies in the blood, the infection occurs in the genital tract. Therefore, we measured HSV2 antibody levels in cervicovaginal fluid in HSV1-/HSV2- recipients of the HSV529 vaccine. HSV2 gD antibody was detected in cervicovaginal fluid at about one-third the level of that in serum. Thus, a vaccine that induces potent serum antibodies transported to the genital tract might reduce HSV genital infection.