510. Secretory IgA in the Vaginal Mucosa Inhibits Herpes Simplex Virus Infection

Abstract Background HSV2 increases HIV risk and is twice as common among women. We previously showed that cervicovaginal secretions exhibit innate anti-HSV2 activity that was lower in adolescents and women with HIV-- conditions associated with vaginal dysbiosis and increased HSV shedding. Our current study aims to test the hypothesis that vaginal dysbiosis is associated with low anti-HSV activity and to explore the molecules and mechanisms that contribute. Methods Cervicovaginal lavage (CVL) (10 ml normal saline wash) was collected from 20 women who presented with clinical bacterial vaginosis (BV) (Day 0) and then 1 and 4 weeks after completing a 7-day oral metronidazole course; parent study results were reported (PMID 34003290). Anti-HSV2 activity of CVL (diluted 1:4) was determined by plaque reduction assay. CVL IgG, IgA, cytokines and antimicrobial peptides were quantified by ELISA or multiplex Luminex and select microbiota by quantitative real-time PCR. CVL was enriched for IgA and IgG using protein L (binds all Ig) and Protein G (binds only IgG). HSV-specific antibodies in CVL were assessed by ELISA. Statistical analyses including Spearman correlation coefficients (SCC) were performed with GraphPad Prism version 9.1.2 software. Results Anti-HSV2 activity of CVL was highly variable at Day 0 (mean 18.6% SD 36.7) and trended to increase after treatment (mean 22.56% SD 33.8). The anti-HSV2 activity correlated positively with Nugent scores (SCC= -0.28, p= 0.03) and qPCR levels of BV-associated microbes (SCC = -0.2 to -0.3, p< -0.1) but positively with IgA (r= 0.49, p< 0.01) and IgG (r= 0.33, p= 0.01). IgA and IgG were isolated from pools of CVL with high inhibitory activity greater than 40% (n= 8). The anti-HSV2 activity mapped to the IgA fraction (56.5% inhibition) compared to the IgG or non-Ig fraction (0% inhibition) even though, as expected, the CVL concentration of IgG was higher than IgA (8.3μg/mL vs 4.9 μg/mL). The anti-HSV2 activity did not correlate with HSV-specific Ig in CVL. Conclusion Our findings suggest that secretory vaginal IgA contributes to innate anti-HSV2 activity and may trap viral particles to prevent viral entry. We speculate that sialidases, which cleave IgA and are elaborated by BV-associated microbiota, contribute to the low anti-HSV2 activity observed in high-risk cohorts. Disclosures Betsy Herold, MD, Viracor (Eurofins): Advisor/Consultant|X-Vax, Technologies: Advisor/Consultant|X-Vax, Technologies: Grant/Research Support|X-Vax, Technologies: Serve on Scientific Advisory Board for X-Vax, Technologies and receiving reserach funding for related worl. Betsy Herold, MD, Viracor (Eurofins): Advisor/Consultant|X-Vax, Technologies: Advisor/Consultant|X-Vax, Technologies: Grant/Research Support|X-Vax, Technologies: Serve on Scientific Advisory Board for X-Vax, Technologies and receiving reserach funding for related worl.