Virus-Encoded B7-2 Costimulation Molecules Enhance the Protective Capacity of a Replication-Defective Herpes Simplex Virus Type 2 Vaccine in Immunocompetent Mice

Abstract

Herpes simplex virus 2 (HSV-2) and, to a lesser extent, HSV-1 cause the majority of sexually transmitted genital ulcerative disease. No effective prophylactic vaccine is currently available. Replication-defective HSV stimulates immune responses in animals but produces no progeny virus, making it potentially useful as a safe form of live vaccine against HSV. Because it does not replicate and spread in the host, however, replicationdefective virus may have relatively limited capacity to solicit professional antigen presentation. We previously demonstrated that in mice devoid of B7-1 and B7-2 costimulation molecules, replication-defective HSV-2 encoding B7-1 or B7-2 induces stronger immune responses and protection against HSV-2 challenge than immunization with replication-defective virus alone. Here, we vaccinated wild-type mice fully competent to express endogenous B7 costimulation molecules with replication-defective HSV-2 or replication-defective virus encoding B7-2 and compared their capacities to protect against vaginal HSV-2 infection and disease. Replication-defective virus encoding B7-2 induced more IFN-␥-producing CD4 T cells than did replication-defective virus alone. Immunization with B7-2-expressing virus decreased challenge virus replication in the vaginal mucosa, genital and neurological disease, and mortality more effectively than did immunization with the parental replication-defective virus. Prior immunization with B7-expressing, replication-defective virus also effectively suppressed infection of the nervous system compared to immunization with the parental virus. Thus, B7 costimulation molecules expressed at the site of HSV infection can enhance vaccine efficacy even in a fully immunocompetent host.

Of mice and not humans: How reliable are animal models for evaluation of herpes CD8+-T cell-epitopes-based immunotherapeutic vaccine candidates?

“…Current concepts of sub-unit based prophylactic vaccines for ocular and genital herpes are promising but not successful in therapeutic settings [6, 7]. To achieve a successful therapeutic vaccine against recurrent virus shedding and recurrent disease, we are currently working on a novel prime-boost homologous and heterologous vaccine strategy that uses “asymptomatic” lipopeptide epitopes priming followed by replication incompetent recombinant adenovirus vector 5, 26 or 35 (rAd5, rAd26 and/or rAd35) boosting, with the lipopeptides and the rAds delivering the same “asymptomatic” CD8 + T cells epitopes.…”

“…Most importantly, HSV-2 infected individuals are at higher risk (4 fold) of HIV-1 acquisition than HSV-2 non-infected individuals [5]. HSV-1 & HSV-2 establish latency in sensory ganglia followed by sporadic and spontaneous reactivations and recurrent shedding in mucocutaneous surfaces [3, 6-10]. The natural history of HSV-1 and HSV-2 infections is illustrated in Fig.…”

The Immunologic Basis for Severe Neonatal Herpes Disease and Potential Strategies for Therapeutic Intervention

“…However, it is not clear whether some of these alterations of the virus may remove important targets of human immunity. Other modifications to the viral genome, such as inserting a dominant-negative mutant gene [229] or inserting costimulatory genes [230, 231], may carry the risk of gene transfer to a wild-type virus through heterologous recombination [232]. Novel delivery systems or adjuvants need to be produced in a cost-effective manner, require careful evaluation for safety in humans, and may promote unacceptable inflammatory responses [233].…”

The challenge of developing a herpes simplex virus 2 vaccine

“…Immunization of mice with this vaccine increased the number of IFN-γ-producing T cells and reduced challenge virus replication in the vaginal mucosa, and neurologic and genital disease, and mortality compared with vaccination with replication-defective virus not expressing B7 [74]. …”