Efficacy of the Herpes Simplex Virus 2 (HSV-2) Glycoprotein D/AS04 Vaccine against Genital HSV-2 and HSV-1 Infection and Disease in the Cotton Rat Sigmodon hispidus Model

Abstract

Subunit vaccines based on the herpes simplex virus 2 (HSV-2) glycoprotein D (gD-2) have been the major focus of HSV-2 vaccine development for the past 2 decades. Based on the promising data generated in the guinea pig model, a formulation containing truncated gD-2, aluminum salt, and MPL (gD/AS04) advanced to clinical trials. The results of these trials, however, were unexpected, as the vaccine protected against HSV-1 infection but not against HSV-2. To address this discrepancy, we developed a Depot medroxyprogesterone acetate (DMPA)-treated cotton rat Sigmodon hispidus model of HSV-2 and HSV-1 genital infection. The severity of HSV-1 genital herpes was less than that of HSV-2 genital herpes in cotton rats, and yet the model allowed for comparative evaluation of gD/AS04 immunogenicity and efficacy. Cotton rats were intramuscularly vaccinated using a prime boost strategy with gD/AS04 (Simplirix vaccine) or control vaccine formulation (hepatitis B vaccine FENDrix) and subsequently challenged intravaginally with HSV-2 or HSV-1. The gD/AS04 vaccine was immunogenic in cotton rats and induced serum IgG directed against gD-2 and serum HSV-2 neutralizing antibodies but failed to efficiently protect against HSV-2 disease or to decrease the HSV-2 viral load. However, gD/AS04 significantly reduced vaginal titers of HSV-1 and better protected animals against HSV-1 compared to HSV-2 genital disease. The latter finding is generally consistent with the clinical outcome of the Herpevac trial of Simplirix. Passive transfer of serum from gD/AS04-immunized cotton rats conferred stronger protection against HSV-1 genital disease. These findings suggest the need for alternative vaccine strategies and the identification of new correlates of protection. IMPORTANCEIn spite of the high health burden of genital herpes, there is still no effective intervention against the disease. The significant gap in knowledge on genital herpes pathogenesis has been further highlighted by the recent failure of GSK HSV-2 vaccine Simplirix (gD/AS04) to protect humans against HSV-2 and the surprising finding that the vaccine protected against HSV-1 genital herpes instead. In this study, we report that gD/AS04 has higher efficacy against HSV-1 compared to HSV-2 genital herpes in the novel DMPA-synchronized cotton rat model of HSV-1 and HSV-2 infection. The findings help explain the results of the Simplirix trial.T he disease burden associated with herpes simplex virus 2 (HSV-2) infection, an important cause of genital herpes worldwide, is high and presents an additional threat due to its association with an increased risk of HIV acquisition and transmission (1-3). Globally, HSV-2 is a major health threat, with 16% of the U.S. population infected by age 30 and 50 to 90% of the population in sub-Saharan Africa infected (3-5). Recent reports emphasize the importance of HSV-1 as an important etiologic agent of genital herpes particularly in the United States and other developed countries (6-8). Seroprevalence of HSV-1 among 14-to 49-year-olds in the Uni...

Immune Evasion by Herpes Simplex Viruses

“…Importantly, a recent study suggests that other animal models different from the guinea pig and the mouse infection model might be better suited for testing anti-HSV vaccine formulations. For instance, the cotton rat Sigmodon hispidus parallels well the results obtained with the D/AS04 vaccine in humans, both for HSV-1 and HSV-2 [244]. On the contrary to the evidence that suggests a role for antibodies in protection against HSV infection, a recent study proposes that effective protection against ocular HSV may be achieved by eliciting a robust T cell response alone.…”

Enterovirus D-68 Infection, Prophylaxis, and Vaccination in a Novel Permissive Animal Model, the Cotton Rat (Sigmodon hispidus)

“…The species of the cotton rat (genus Sigmodon ) has been shown to be a preferred model for an impressive list of human pathogens including respiratory syncytial virus (RSV), influenza (A and B serotypes), adenoviruses (several serotypes), parainfluenza virus (type 3), measles, herpes simplex (types 1 and 2), and human metapneumovirus [35, 36, 44–48]. For many of these viruses, the cotton rat represents a reliable model that better mimics human disease [49].…”

Seminal vesicle fluid increases the efficacy of intravaginal HSV-2 vaccination

“…17,21,[32][33][34] However, effective protection against HSV-2 infection as well as the induction of a protective immune response conferred by vaccination appears also to involve an important role for antibodies. [35][36][37][38] These observations imply that the relative contribution of T and B cells in the immune response against HSV-2 might differ depending on the experimental settings. Our present results suggest that the adjuvant effect mediated by SVF is related to the improvement of a memory response mediated by T cells, but not B cells.…”