Murine Model of Maternal Immunization Demonstrates Protective Role for Antibodies That Mediate Antibody-Dependent Cellular Cytotoxicity in Protecting Neonates From Herpes Simplex Virus Type 1 and Type 2

Abstract

Background Neonatal herpes simplex virus (HSV) disease results in unacceptable morbidity and mortality. The primary humoral immune response to natural infection is neutralizing antibodies (Abs). However, Abs that activate Fc gama receptors (FcγRs) and mediate antibody-dependent cell-mediated cytotoxicity (ADCC) may play a dominant role in protection. In adult mice, a single-cycle HSV candidate vaccine deleted in glycoprotein-D (ΔgD-2) that induces ADCC provided complete protection against HSV disease and prevented the establishment of latency. Passive transfer studies showed that Abs were sufficient for protection. The current study tested the hypothesis that maternal immunization with ΔgD-2 would protect neonates. Methods C57BL/6 female mice were vaccinated 3 weeks apart with ΔgD-2, and pups were challenged at different times postnatally with lethal doses of HSV-1 or HSV-2. Concentration and functionality of Abs and immune cells were assessed. Results Maternal ΔgD-2 immunization provided significant protection and reduced viral dissemination after lethal challenge with HSV-1 or HSV-2. Protection correlated with Abs acquired transplacentally or from breastmilk that mediated ADCC. Protection was reduced when pups were challenged on Day 1 of life, and this was associated with decreased ability of newborn cells to mediate Ab-dependent cell killing. Conclusions Antibodies mediating ADCC provide significant protection against neonatal HSV.

Vaccination Route as a Determinant of Protective Antibody Responses against Herpes Simplex Virus

“…In other studies, we found that envelope gD interferes with the generation of IgG2 subclass switched Abs through interactions with herpesvirus entry mediator (HVEM), also known as tumor necrosis factor receptor superfamily member 14 (Burn Aschner and Herold, manuscript under review). This likely contributes to the lower levels of ADCC generated by dl 5-29 as shown in the current study as well as the low levels generated in response to sublethal infection [ 17 , 18 ].…”

“…Protection is mediated by ADCC rather than neutralizing Abs, as evidenced by passive transfer studies. Immune serum from ΔgD-2, but not rgD-2-Alum/MPL vaccinated mice completely protects naïve wild-type, but not FcγR (common, FcγRIV or neonatal receptor) knockout mice from lethal challenge [ 14 , 15 , 16 , 17 , 18 ].…”

“…In preclinical murine studies, this vaccine strain, ΔgD-2, elicited high-titer non-neutralizing Abs that activate Fc gamma receptors (FcγRs) to induce antibody-dependent cell-mediated cytotoxicity (ADCC). Two doses administered subcutaneously completely protected female and/or male mice against a lethal vaginal or skin challenge with clinical isolates of HSV-1 and HSV-2 and prevented the establishment of latency [ 14 , 15 , 16 , 17 ]. This protection was mediated by antibody effector function, as passive transfer protected wild type but not FcγR or Fc neonatal receptor (FcRn) knockout mice and T cell transfer failed to provide protection [ 14 ].…”

“…This protection was mediated by antibody effector function, as passive transfer protected wild type but not FcγR or Fc neonatal receptor (FcRn) knockout mice and T cell transfer failed to provide protection [ 14 ]. Moreover, vaccination of female mice protected their pups from subsequent HSV challenge in the first week of life [ 17 ]. In contrast to adjuvanted recombinant gD, ΔgD-2 boosted the total and the ADCC Ab responses in HSV-1 seropositive mice and prevented subsequent lethal HSV-2 superinfection [ 18 ].…”

Newcastle Disease Virus as a Vaccine Vector for 20 Years: A Focus on Maternally Derived Antibody Interference

“…Many sources of evidence have shown that effector functions mediated by antibodies are critical for protection against influenza virus, human immunodeficiency virus and respiratory syncytial virus [ 117 , 118 , 119 ]. In addition, ADCC antibodies are associated with the clinical presentation of neonatal herpes simplex virus (HSV) infection [ 120 ] and are protective against HSV-1 and -2 in a mouse model of maternal immunization [ 121 ]. Based on these findings, we can assume that effector functions mediated by MDA may reduce the replication and the antigen content after immunization with vector vaccines through elimination of virus-infected cells or virus particles.…”