Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice

Abstract

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 (0ΔNLS) is sensitive to inhibition by interferon beta (IFN-␤) in vitro and functions as a highly efficacious experimental vaccine. Here, we characterize the host immune response and in vivo pathogenesis of HSV-1 0ΔNLS relative to its fully virulent parental strain in C57BL/6 mice. Additionally, we explore the role of type 1 interferon (IFN-␣/␤) signaling on virulence and immunogenicity of HSV-1 0ΔNLS and uncover a probable sex bias in the induction of IFN-␣/␤ in the cornea during HSV-1 infection. Our data show that HSV-1 0ΔNLS lacks neurovirulence even in highly immunocompromised mice lacking the IFN-␣/␤ receptor. These studies support the translational viability of the HSV-1 0ΔNLS vaccine strain by demonstrating that, while it is comparable to a virulent parental strain in terms of immunogenicity, HSV-1 0ΔNLS 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.KEYWORDS HSV-1, T cells, antibody, cornea, mouse, neovascularization S trategies for vaccine development have transitioned largely from empirical to so-called "next-generation" or rational approaches during the past 2 decades, a shift largely driven by technological advances and a better understanding of how innate immunity influences the generation of adaptive protection (1, 2). Despite these breakthroughs, the average person still acquires multiple herpesvirus infections during childhood (3). A licensed vaccine, however, exists only for varicella-zoster virus (VZV) (4). The live-attenuated Oka vaccine for VZV is generally well tolerated and has significantly reduced the incidence of VZV infection, morbidity, and mortality in the United States (5, 6). Furthermore, epidemiologic studies indicate that acquisition of herpes simplex virus 1 (HSV-1) has shifted toward early to late adolescence in recent decades within the United States, potentially creating an opportunity to introduce an effective prophylactic HSV-1 vaccine into the childhood vaccine regimen (7). HSV vaccines have been tested in multiple clinical trials, but these studies have focused on protein subunit vaccines

The Neonatal Fc Receptor and Complement Fixation Facilitate Prophylactic Vaccine-Mediated Humoral Protection against Viral Infection in the Ocular Mucosa

“…Moreover, anamnestic responses against the gD-2 subunit reflect approximately 1% of the HSV-1 proteome, whereas the antigenic coverage of the hepatitis B surface antigen is 12% (53). In contrast, the HSV-1 0ΔNLS vaccine encodes nearly 99% of the native viral proteome and elicits humoral immune responses similar to that observed during natural infection (17, 18). Results herein from a delayed challenge model mirror previous data showing that the HSV-1 0ΔNLS vaccine can prevent both corneal sensation loss and neovascularization; however, data here show that the immune response elicited by HSV-1 0ΔNLS sustains its protective effect over time (Fig.…”

“…Serum titers were assessed for virus neutralizing titers in the presence of guinea pig complement (Rockland, Limerick, PA) on confluent Vero cells (American Type Culture Collection, Manassas, VA) as previously described (17). Virus-specific antibody subclass profiling was quantified by ELISA using immobilized HSV-1 virions as a target and alkaline phosphatase-conjugated anti-mouse immunoglobulin subclass-specific detection antibodies (Southern Biotechnology, Birmingham, AL) as described (18). To quantify titers of infectious virus, corneas were swabbed with cotton-tipped applicators to collect free virus shed in the tear film and tissues excised for downstream analysis by standard plaque assay on Vero cells (17).…”

“…For detection of latent virus, RNA was extracted from cornea-innervating trigeminal ganglia (TG) harvested from mice at day 30 post infection (PI), RNA converted into cDNA, and viral transcript expression evaluated by PCR relative to beta-actin expression and normalized to uninfected control samples as previously described (17). Alternatively, direct quantification of viral genome copy number was performed by PCR on DNA isolated from the TG of challenged mice using a proprietary primer-probe mix according to the manufacturer’s directions (Primerdesign Ltd. Chandler’s Ford, United Kingdom) as described (18). …”

“…However, our recent findings comprehensively established that humoral immunity is a strong correlate of protection against HSV-1 pathogenesis and resultant ocular disease in mice using a glycoprotein D (gD-2) subunit and a live-attenuated vaccine designated HSV-1 0ΔNLS (17). This live-attenuated vaccine strain is avirulent and highly immunogenic due to the deletion of the nuclear localization sequence (NLS) in the infected cell protein 0 (ICP0) gene (17, 18). Prophylactic vaccine-induced HSV-specific serum antibody concentration is also recognized as a major correlate of protection against HSV-1-associated disease in humans (19).…”

“…Here, we explore the dynamics and mechanisms of prophylactic vaccine-mediated humoral protection against HSV-1 in the eye. First, we distinguish that the longevity of humoral protection elicited by a glycoprotein D subunit vaccine is short-lived in mice compared to the recently characterized live-attenuated HSV-1 0ΔNLS vaccine (17, 18). We compare various routes of immunization and identify that the efficacy of the HSV-1 0ΔNLS vaccine is limited following classical intramuscular injection alone.…”