Herpes simplex virus type 2 (HSV-2) is the leading cause of genital ulcers and infects a half-billion people worldwide. Genital herpes is emotionally distressing, is life threatening to newborns infected during delivery, and is a major risk factor fr acquiring and transmitting HIV infection. Daily suppressive antiviral therapy is currently the only treatment available for recurrent genital herpes infections;however, this approach is only partially successful in preventing outbreaks and is ineffective in reducing HIV acquisition. We will evaluate the efficacy of two immunotherapeutic vaccines at controlling HSV-2 recurrent infection. The vaccines were pioneered in our lab;one involves a HSV-2 replication competent, attenuated live virus (gE2-del) and the other a trivalent subunit antigen vaccine (gC2/gD2/gE2). A replication competent varicella zoster live virus vaccine is currently used to prevent shingles, which is a recurrent infection caused by a closely related herpes virus. We will evaluate the live virus and subunit antigen vaccines individually and in combination with the expectation that the live virus vaccine will stimulate CD4+ and CD8+ T-cell responses, while the gC2/gD2/gE2 subunit antigen vaccine will improve humoral immunity. HSV-2 gD is included to enhance neutralizing antibodies, gD2 and gE2 to stimulate antibodies that block cell-to-cell spread, and gC2 and gE2 to produce antibodies that prevent immune evasion from antibody and complement. The impressive efficacy of the trivalent subunit antigens as a prophylactic vaccine for primary genital herpes in mice supports the concept of blocking immune evasion as immunotherapy for recurrent infections. In the R21 phase, we will evaluate the live virus and trivalent subunit antigen vaccines for their ability to reduce the frequency and severity of recurrent genital infection in guinea pigs. We will determine whether immunotherapy reduces the infiltration into genital tissues of CD4+ T-cells that are permissive for HIV replication (R33 phase). We will evaluate the immune correlates of protection against recurrent genital infection by measuring innate, antibody and T cell immune responses in HSV-2 infected guinea pigs that are either mock-vaccinated or immunized with the best-performing therapeutic vaccine (R33 phase). Defining the immune correlates of protection will facilitate future studies that address whether comparable immune responses can be generated in HSV-2 infected humans. We will determine whether therapeutic immunization with gC2/gD2/gE2 subunit antigens selects for mutants that emerge under immune pressure in vivo by using single genome amplification (SGA) technology to compare mutant variants detected in the virus inoculum, virus isolated during acute infection and virus isolated after therapeutic immunization (R21 and R33 phases). SGA provides an accurate detection assay for minor mutant variants within a virus pool that is more sensitive for detecting mutations in conformational epitopes that other sequencing methods and is an innovative approach to identify potentially unwanted consequences of an otherwise successful immunotherapeutic vaccine.

Public Health Relevance

Herpes simplex virus type 2 (HSV-2) is the leading cause of genital ulcer disease and infects a half billion people worldwide. Recurrent HSV-2 infections are common, account for most cases of HSV-2 transmission to sexual partners, and render the infected individual more likely to acquire or transmit HIV infection. A vaccine that prevents recurrent HSV-2 infections is a high public health priority. We propose a therapeutic vaccine that will stimulate CD4+ and CD8+ T-cells and a potent antibody response and that will prevent the virus from evading innate and acquired immunity. Studies are proposed in guinea pigs to determine the efficacy of the vaccine and to assess whether immune escape mutants develop in response to therapeutic vaccination.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI105959-02
Application #
8720691
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
David, Hagit S
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104