Vaccine-induced antibodies target sequestered viral antigens to prevent ocular HSV-1 pathogenesis, preserve vision, and preempt productive neuronal infection

The cornea is essential for vision yet highly sensitive to immune-mediated damage following infection. Generating vaccines that provide sterile immunity against ocular surface pathogens without evoking vision loss is therefore clinically challenging. Here, we tested a prophylactic live-attenuated vaccine against herpes simplex virus type 1 (HSV-1), a widespread human pathogen that can cause corneal blindness. Parenteral vaccination of mice resulted in sterile immunity to subsequent HSV-1 challenge in the cornea and suppressed productive infection of the nervous system. This protection was unmatched by a relevant glycoprotein subunit vaccine. Efficacy of the live-attenuated vaccine involved a T-dependent humoral immune response and complement C3 but not Fcy-receptor 3 or interferon-a/p signaling. Proteomic analysis of viral proteins recognized by antiserum revealed an unexpected repertoire dominated by sequestered antigens rather than surface-exposed envelope glycoproteins. Ocular HSV-1 challenge in naive and su bun it-vaccinated mice triggered vision loss and severe ocular pathologies including corneal opacification, scar formation, neovascularization, and sensation loss. However, corneal pathology was absent in mice receiving the live-attenuated vaccine concomitant with complete preservation of visual acuity. Collectively, this is the first comprehensive report of a prophylactic vaccine candidate that elicits resistance to ocular HSV-1 infection while fully preserving the cornea and visual acuity.

INTRODUCTION
Vaccine immunology research classically focuses on generating sterile immunity and identifying the mechanisms responsible for protection against infection. However, this approach is inadequate when considering pathogens that affect delicate organs and tissues such as the eye and nervous system. While the eye is well known as an immune-privileged organ, it remains highly susceptible to inflammatory damage. For this reason, many regulatory mechanisms temper ocular inflammation to preserve visual clarity.1 3 Nonetheless, excessive inflammatory responses in the eye often break tolerance, contribute to permanent vision loss, and significantly impact quality of life.4 6 Clinical management of ocular infections is often challenging and requires close attention to controlling both the pathogen and host inflammation to preserve the visual axis.7`8 Accordingly, it is important to consider the potential of vaccine-induced inflammatory responses during the initial stages of vaccine development when targeting pathogens that commonly affect the eye.

Herpes simplex virus type 1 (HSV-1) is a widespread human pathogen that is of particular relevance to this topic. In addition to being a leading cause of infectious corneal blindness, HSV-1 is a clinically important cause of encephalitis and has recently emerged  as  the  leading  cause of  primary  genital  herpes  in women of childbearing age in the USA.9"11 The success of the pathogen lies in its ability to evade immune responses and establish latency in sensory neurons for the life of the host. Furthermore, the total reservoir of latent virus in the trigeminal ganglia (TG), which supply sensory innervation to orofacial mucosal sites, correlates with reactivation risk and clinical disease burden in animal models.`7`11 Chronic viral reactivation in the human eye is associated with a myriad of clinically important corneal pathologies including scarring, neovascularization, and persistent epithelial defects. Current therapies aim to suppress ocular inflammation with steroids and inhibit viral replication with nucleoside analog drugs, but such interventions do not "cure" the disease. Moreover, recurrences frequently persist even when on long-term, prophylactic treatment with these agents.8 Visual morbidity can be so severe that corneal transplantation may be necessary to restore vision, although this remedy often has diminishing returns due to increased graft rejection rates.14 Novel therapies to block HSV-1 pathogenesis are in development.15-17 Considerable effort has also been applied to developing a therapeutic HSV vaccine to alleviate viral reactivation in patients with recurrent outbreaks.18-20 However, we contend that prophylactic vaccination would be a highly effective strategy to prevent HSV-1-associated disease in the eye, skin, and nervous system.