Impact of type 1 interferon on the safety and immunogenicity of an experimental live-attenuated herpes simplex virus type 1 vaccine in mice.

Viral fitness dictates virulence and capacity to evade host immune defenses. Understanding the biological underpinnings of such features is essential for rational vaccine development. We have previously shown that the live-attenuated herpes simplex virus 1 (HSV-1) mutant lacking the nuclear localization signal (NLS) on the ICP0 gene (0 Delta NLS) is sensitive to inhibition by interferon beta (IFN-beta) in vitro and functions as a highly efficacious experimental vaccine. Here, we characterize the host immune response and in vivo pathogenesis of HSV-1 0 Delta NLS relative to its fully virulent parental strain in C57BL/6 mice. Additionally, we explore the role of type 1 interferon (IFN-alpha/beta) signaling on virulence and immunogenicity of HSV-1 0 Delta NLS and uncover a probable sex bias in the induction of IFN-alpha/beta in the cornea during HSV-1 infection. Our data show that HSV-1 0 Delta NLS lacks neurovirulence even in highly immunocompromised mice lacking the IFN-alpha/beta receptor. These studies support the translational viability of the HSV-1 0 Delta NLS vaccine strain by demonstrating that, while it is comparable to a virulent parental strain in terms of immunogenicity, HSV-1 0.NLS does not induce significant tissue pathology. IMPORTANCE HSV-1 is a common human pathogen associated with a variety of clinical presentations ranging in severity from periodic "cold sores" to lethal encephalitis. Despite the consistent failures of HSV subunit vaccines in clinical trials spanning the past 28 years, opposition to live-attenuated HSV vaccines predicated on unfounded safety concerns currently limits their widespread acceptance. Here, we demonstrate that a live-attenuated HSV-1 vaccine has great translational potential.