Herpes simplex viruses (HSV) 1 and 2 are causes of disease worldwide. These are mainly mucocutaneous pathologies, with perioral localization (HSV-1), or to the genitals (HSV-2), but they can also affect the conjunctiva and cornea (neonatal herpetic keratitis), and the central nervous system (encephalitis, meningitis). Herpetic infection persists throughout life, so it can relapse, become chronic and spread, especially in people with immature (newborn) or immunosuppressed (elderly) immune systems, or compromised by other infections (HIV) or conditions (malnutrition, stress, radiological and chemotherapy treatments, etc.). WHO has identified the development of HSV vaccines as an important global goal, especially for low- and middle-income countries, with the aim of reducing the burden of HSV-associated diseases, including: i) mortality and morbidity due to neonatal herpes; ii) the impact on sexual and reproductive health and iii) the acquisition and transmission of HIV associated with HSV-2 infection in high prevalence populations. Despite scientific advances and numerous attempts, there is currently no preventive or therapeutic vaccine against the HSV-1 and HSV-2 viruses. CNAIDS is conducting preclinical studies with the aim of developing a vaccine against HSV, exploiting the ability of HIV Tat to induce cell-type immune responses, essential for the control of HSV infection.
The chronicity of herpetic infections and the periodic reactivations are considered important factors in the aging process. Recent data indicate that the control of HSV infections requires the presence of CD8+ T cells that recognize regions (epitopes) of HSV associated with protection in natural infections. In order to develop an anti-herpetic vaccine capable of inducing CD8+ T lymphocytes with these properties, CNAIDS, in collaboration with the University of Ferrara, has chosen to exploit the immunomodulatory properties of the HIV-1 Tat protein that promotes development of Th-1 responses required for induction of CD8+ T cells. Therefore, the HIV-1 tat gene was introduced into attenuated or replicating HSV-1 vectors (herpes vectors). In mice, vaccination with these Tat-expressing herpes vectors induces extensive and prolonged HSV-specific CD8+ T cell responses and anti-HSV antibodies that are associated with viral load reduction and protection from death after experimental infection with lethal doses of the virus. These studies, conducted in collaboration with the University of Ferrara, show that Tat has extrinsic "immunomodulatory" activity capable of enhancing immunity against intracellular pathogens capable of escaping the immune response.
The goal of the project is the preclinical development for the approval for human testing of preventive and therapeutic anti-herpes vaccines based on attenuated and/or replication-defective HSV-1 vectors expressing the HIV-1 tat gene. If successful, the project will continue with the evaluation in humans (clinical trial). In perspective, this innovative strategy could be used for the development of vaccines against other "persistent" infections, such as those from Epstein-Barr virus (EBV), Cytomegalovirus (CMV), Varicella-Zoster virus (VZV), as well as tuberculosis.
The project has been founded by the Ministry of Health (Ricerca Finalizzata RF-2019-12368996).