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Derek J Royer, Hem Raj Gurung, Jeremy K. Jinkins, William Halford, Daniel J Carr; Humoral immunity is requisite for vaccine-mediated protection against ocular HSV-1 infection. Invest. Ophthalmol. Vis. Sci. 2016;57(12):No Pagination Specified.
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© ARVO (1962-2015); The Authors (2016-present)
The correlate(s) of immunologic protection (CIP) requisite for an efficacious herpes simplex virus type 1 (HSV-1) vaccine remains unclear with respect to viral pathogenesis and clinical disease. This study investigated the hypothesis that neutralizing antibody is the primary CIP against HSV-1.
Eight-week old female CD-1 mice were vaccinated using a prime-boost regimen with a glycoprotein D subunit vaccine (gD-2) or a recombinant, live-attenuated virus (0ΔNLS). Vaccinated and naive mice were ocularly challenged with HSV-1 McKrae (LD50 inoculum) and surveyed for survival, corneal pathology, tissue viral burden, and neuronal latency as determinants of vaccine efficacy. CIP were assessed by serum virus neutralization assay, flow cytometry, and passive immunization. One-way ANOVAs were used for statistical analysis; data reflect 2-5 independent experiments.
Directly vaccinated mice survived HSV-1 challenge with higher frequency than naive (p<0.01). Viral replication in the cornea and trigeminal ganglion (TG) were not detectable in 0ΔNLS-vaccinated mice during acute infection, yet viral replication was unabated in gD-2-vaccinated mice relative to naive controls. Latent virus was nearly undetectable by PCR in TG from 0ΔNLS-vaccinated mice, yet 10 and 104-fold higher in gD-2-vaccinated (p<0.01) and naive (p<0.001) mice, respectively. Directly vaccinated mice exhibited minimal T cell activation in draining lymph nodes and did not develop corneal neovascularization. Corneal sensation was reduced in naive and gD-2-vaccinated mice, yet preserved in 0ΔNLS-vaccinated mice (p<0.001). Protection correlated with serum neutralization antibody titers. Passive immunization with 0ΔNLS antisera inhibited acute viral shedding, protected recipients from lethal encephalitis (90%), reduced viral latency in the TG (p<0.001 relative to naive), and largely prevented corneal neovascularization. However, 40% of mice immunized with gD-2 antisera succumbed to HSV-1 challenge, while survivors exhibited severe corneal neovascularization and had no reduction in acute viral shedding or latent virus relative to naive mice (p<0.001 relative to 0ΔNLS antisera). Mice receiving immunoglobulin-depleted antiserum showed no signs of protection.
Overall, the 0ΔNLS vaccine affords remarkable humoral immune protection against HSV-1 by impeding viral replication, dissemination, latency, and ocular pathology.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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