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

Abstract

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 Fcγ-receptor 3 or interferon-α/β 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 subunit-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.

Distinguishing Features of High- and Low-Dose Vaccine against Ocular HSV-1 Infection Correlates with Recognition of Specific HSV-1–Encoded Proteins

“…However, a previous study found PBS-vaccinated tdTomato fluorescent reporter mice that did survive the acute infection to 30 DPI displayed a similar phenotype as that shown with 1 3 10 3 PFU 0ΔNLS-vaccinated animals (36). In summary, all doses of the HSV-1 0ΔNLS vaccine tested showed protection against ocular HSV-1 challenge in terms of cumulative survival and viral spread and replication in the TG, although the lowest dose evaluated displayed no efficacy against HSV-1 replication in the cornea, which correlated with a low neutralizing Ab titer and higher virus copy number found in the TG of latent-infected mice.…”

“…Notably, the efficacy of the vaccine in the control of virus replication in the cornea was linked to early expression of complement and the neonatal Fc receptor, which supported the correlate of protection to be Ab (35). Finally, HSV-1 0ΔNLS-vaccinated mice retained corneal function with preservation of the visual axis in the first study to report such findings (36). In the current investigation, a dose-response study was conducted using the HSV-1 0ΔNLS vaccine to determine the lowest dose required to maximize the protective efficacy.…”

“…Mice were subsequently exsanguinated, and the corneas were assessed for opacity as previously described (41) and subsequently processed for neovascularization (39). dose of 1 3 10 5 PFU for the primary immunization and boost (33)(34)(35)(36). To formalize the minimal efficacious dose of vaccine to maximize the protective effect against subsequent challenge, mice were immunized with doses ranging from 1 3 10 3 to 1 3 10 5 PFU prior to challenge.…”

“…Absolute number of monocytes (CD45 + CD11b + Ly-6G Corneal neovascularization is greatly diminished in highdose HSV-1 0ΔNLS-vaccinated mice Corneal neovascularization is a hallmark of herpetic stromal keratitis in rodents and humans alike (8). Previously, we reported a loss of vision in mice as a result of HSV-1 infection could be linked to severe corneal opacity and gross neovascularization (36). Therefore, we investigated the impact of vaccine doses on the severity of corneal blood and lymphatic vessel genesis at 30 DPI, a time when maximum angiogenesis is evident (54).…”

Characteristics of herpes simplex virus infection and pathogenesis suggest a strategy for vaccine development

“…It could be proposed that immune pressure from the host has pushed HSV to fully exploit its genomic evolution by encoding a series of functional molecules and gradually creating different pathways for blocking or weakening innate and adaptive immunity during the continuous interplay between viruses and humans . Of note, a recently published paper indicates that the HSV1 0ΔNLS vaccine elicits antibody responses against heterogeneous viral proteins, including nonstructural proteins . However, to some extent, the characterized pathological processes of HSV in infected individuals, including primary acute infection, immune evasion, latent infection, and reactivated infection in neurons, can be viewed as clinical phenotypes that reflect the mechanisms by which viral molecules compete with, interfere with, activate, and hijack host defense.…”