Abstract
BACKGROUND: Perinatal HSV is associated with ~60% mortality if untreated and with substantial morbidity even with appropriate therapy. We recently engineered a single-cycle virus deleted in glycoprotein-D (ΔgD-2) that induces high-titer antibodies (Abs) that are non-neutralizing but activate the Fc receptor (FcR) to elicit antibody-dependent cellular cytotoxicity (ADCC). Immunization with ΔgD-2 completely protects adult mice from HSV-1 and HSV-2 disease following vaginal, skin, intraocular, or intranasal challenge and prevents the establishment of latency (ELife, 2014, JCI Insight, 2016). Thus we hypothesize that maternal immunization with ΔgD-2 and/or passive transfer of immune serum will protect neonates from HSV. METHODS: Four- to 6-week-old C57Bl/6 female mice were primed and boosted at 3-week intervals with ΔgD-2 or an equal volume of uninfected cell lysates (VD60 cells). Two weeks post-boost, mice were mated and pups were challenged with a lethal dose of HSV-1 (Bx31.1) at day 7 of birth. To differentiate the contribution of transplacental vs. colostrum Abs, mothers were switched at birth. Alternatively, 7-day-old mice born to nonimmunized mothers received a single dose of immune serum (400 μg total Ab) intraperitoneally at time of intranasal challenge. RESULTS: Thirty-eight of 47 (81%) of the pups born to and nursed by ΔgD-2-immunized mothers survived, exhibited little or no signs of disease and were protected from latency as measured by quantifying HSV DNA by PCR in neuronal tissue. In contrast, 12/14 (86%) of pups born to control vaccinated and nursed mice developed neurological signs of disease and died (P < 0.0001, Fisher’s exact test). Survival was associated with increased ADCC Abs in the serum of neonatal mice. In contrast, passive transfer of immune serum, which consistently protects adult mice from infection, did not protect neonates. If newborns born to immunized mice suckled with control mice, protection was partially abrogated (11/19, 58% survival), suggesting that both systemic and mucosal Abs are required for complete protection. CONCLUSION: Maternal vaccination with ΔgD-2 provides significant protection against intranasal neonatal challenge but may require exposure to systemic and mucosal Abs. DISCLOSURES: W. R. Jacobs Jr., xvax: Scientific Advisor, Research support; B. C. Herold, X-vax: Grant Investigator, Research grant and Research support