Herpes simplex virus (HSV) infections are significant global health problems. HSV-1 and HSV-2, are major causes of genital disease and perinatal transmission of either serotype often leads to severe infant morbidity. Moreover, infection with HSV-2 significantly increases the likelihood of acquiring and transmitting HIV and may increase HIV viral reservoirs. Despite major efforts, there is no effective vaccine for prevention. Recent clinical trials of HSV-2 glycoprotein D (gD2) subunit vaccines found that the vaccines induced high levels of serum neutralizing antibodies, but were not protective. Thus, novel vaccine strategies that elicit a different type of immune response are needed. We adopted a completely different strategy and, rather than focusing on gD2 as the primary immunogen, deleted the glycoprotein to test the hypothesis that deletion of gD2 would elicit a different and protective immune response. The gD2 deletion virus, HSV-2?gD, replicates to high titers when passaged on complementing cells (Vero cells that express HSV-1 gD), but forms no plaques on non- complementing cells. Intravaginal challenge of SCID mice with 107 pfu/mouse of HSV-2 ?gD revealed no evidence of disease and no virus was recovered in dorsal root ganglia, whereas doses as low as 104 pfu/mouse of wild-type virus were 100% lethal. Moreover, prime-boost subcutaneous immunization of mice with HSV-2?gD resulted in complete protection against intravaginal or skin scarification challenges with either HSV-2 or HSV-1. No virus (vaccine strain or wild-type challenge virus) was recovered from the dorsal root ganglia in either model suggesting that the vaccine prevented the establishment of latency. We measured robust humoral and cellular immunity including the induction of CD4 and CD8 T cell responses and antibodies that were rapidly transported into mucosal sites and mediated antibody dependent cell mediated cytoxicity (ADCC). Passive transfer of immune serum into nave mice completely protected them from intravaginal or skin challenge. Protection was lost, however, when the immune serum was transferred into Fc neonatal receptor or Fc? receptor knockout mice, indicating a reliance on FcR mediated mechanisms. Building on these results, we propose to determine the mechanisms and targets of immune protection and to understand why deletion of gD skews the immune response to elicit FcR-dependent rather than neutralizing antibody responses. We will also isolate germinal centers from immunized mice to characterize the antibody repertoire. We will examine efficacy against clinical isolates from both serotypes in male and female mice using the skin scarification model, in female cotton rats (intravaginal challenge) and in a new model of latent HSV-1 infection to test immunogenicity in the setting of preexisting HSV-1 immunity. The latter is important as ~60% of the world population is HSV-1 seropositive. Together these studies will provide insights into the biological basis for protection

Public Health Relevance

Over 500 million people worldwide are infected with herpes simplex virus type 2 (HSV-2) with an estimated 20 million new infections among 15-49 year olds worldwide annually. HSV-2 infection is the leading cause of genital ulcer disease, a major cofactor in the HIV epidemic, and associated with significant morbidity and mortality in newborns who are infected perinatally. Prevention efforts have focused primarily on subunit vaccines, but none have prevented disease in clinical trials; this proposal addresses this global health imperative and proposes a novel live attenuated viral vaccine strategy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Vaccines Against Microbial Diseases Study Section (VMD)
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Hiltke, Thomas J
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Albert Einstein College of Medicine, Inc
United States
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Nelson, Cody S; Herold, Betsy C; Permar, Sallie R (2018) A new era in cytomegalovirus vaccinology: considerations for rational design of next-generation vaccines to prevent congenital cytomegalovirus infection. NPJ Vaccines 3:38
Burn, Clare; Ramsey, Natalie; Garforth, Scott J et al. (2018) A Herpes Simplex Virus (HSV)-2 Single-Cycle Candidate Vaccine Deleted in Glycoprotein D Protects Male Mice From Lethal Skin Challenge With Clinical Isolates of HSV-1 and HSV-2. J Infect Dis 217:754-758
Retamal-Díaz, Angello; Weiss, Kayla A; Tognarelli, Eduardo I et al. (2017) US6 Gene Deletion in Herpes Simplex Virus Type 2 Enhances Dendritic Cell Function and T Cell Activation. Front Immunol 8:1523
Petro, Christopher D; Weinrick, Brian; Khajoueinejad, Nazanin et al. (2016) HSV-2 ?gD elicits Fc?R-effector antibodies that protect against clinical isolates. JCI Insight 1: