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

• Published in: The Journal of infectious diseases Vol. 221; no. 5; pp. 729 - 738
• Main Authors: Kao, Carol M, Goymer, Jessica, Loh, Lip Nam, Mahant, Aakash, Aschner, Clare Burn, Herold, Betsy C
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 18-02-2020
• Subjects: Animal models; Animals; Animals, Newborn; Antibodies; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Antibody-Dependent Cell Cytotoxicity; Antibody-dependent cell-mediated cytotoxicity; Cytotoxicity; Disease Models, Animal; Fc receptors; Female; Herpes simplex; Herpes Simplex - prevention & control; Herpes Simplex - virology; Herpes viruses; Herpesvirus 1, Human - genetics; Herpesvirus 1, Human - immunology; Herpesvirus 2, Human - genetics; Herpesvirus 2, Human - immunology; Immune response (humoral); Immunization; Juveniles; Latency; Major and Brief Reports; Mice; Mice, Inbred C57BL; Morbidity; Neonates; Newborn babies; Pregnancy; Pregnancy Complications, Infectious - prevention & control; Pregnancy Complications, Infectious - virology; Receptors, IgG - metabolism; Vaccination; Viral Vaccines - therapeutic use; neonatal herpes; HSV vaccines; antibody-dependent cellular cytotoxicity
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiz521

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.
Transfer of placental and breastmilk antibodies mediating antibody-dependent cytolysis, which are elicited in response to vaccination of female mice with a single-cycle HSV-2 glycoprotein D-null candidate vaccine, provides significant protection to pups challenged with clinical isolates of HSV-1 or HSV-2.