A non-neutralizing glycoprotein B monoclonal antibody protects against herpes simplex virus disease in mice

• Published in: The Journal of clinical investigation Vol. 133; no. 3; pp. 1 - 15
• Main Authors: Kuraoka, Masayuki, Aschner, Clare Burn, Windsor, Ian W, Mahant, Aakash Mahant, Garforth, Scott J, Kong, Susan Luozheng, Achkar, Jacqueline M, Almo, Steven C, Kelsoe, Garnett, Herold, Betsy C
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-02-2023
• Subjects: Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; Antibodies, Viral; Antigenic determinants; Antigens; B cells; Biomarkers; Biomedical research; Biotechnology industry; Bone marrow; Clinical trials; Cloning; Cytotoxicity; Disease; Drug therapy; Epitopes; Glycoprotein B; Glycoproteins; Health aspects; Herpes simplex; Herpes Simplex - prevention & control; Herpes simplex virus; Herpes viruses; Herpesvirus 1, Human; Herpesvirus vaccines; Humans; Immunization; Immunoglobulin G; Immunological memory; Infectious disease; Lymphocytes B; Medical research; Medicine, Experimental; Memory cells; Mice; Monoclonal antibodies; Mutation; Palivizumab; Pharmaceutical research; Prevention; Scientific equipment and supplies industry; Severe acute respiratory syndrome coronavirus 2; Vaccination; Vaccines; Viral Envelope Proteins - genetics; Virus diseases; United States; New York; Antigen; Infectious disease; Immunoglobulins; Vaccines
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI161968

There is an unmet need for monoclonal antibodies (mAbs) for prevention or as adjunctive treatment of herpes simplex virus (HSV) disease. Most vaccine and mAb efforts focus on neutralizing antibodies, but for HSV this strategy has proven ineffective. Preclinical studies with a candidate HSV vaccine strain, ΔgD-2, demonstrated that non-neutralizing antibodies that activate Fcγ receptors (FcγRs) to mediate antibody-dependent cellular cytotoxicity (ADCC) provide active and passive protection against HSV-1 and HSV-2. We hypothesized that this vaccine provides a tool to identify and characterize protective mAbs. We isolated HSV-specific mAbs from germinal center and memory B cells and bone marrow plasmacytes of ΔgD-2-vaccinated mice and evaluated these mAbs for binding, neutralizing, and FcγR-activating activity and for protective efficacy in mice. The most potent protective mAb, BMPC-23, was not neutralizing but activated murine FcγRIV, a biomarker of ADCC. The cryo-electron microscopic structure of the Fab-glycoprotein B (gB) assembly identified domain IV of gB as the epitope. A single dose of BMPC-23 administered 24 hours before or after viral challenge provided significant protection when configured as mouse IgG2c and protected mice expressing human FcγRIII when engineered as a human IgG1. These results highlight the importance of FcR-activating antibodies in protecting against HSV.