Monoclonal Antibodies, Derived from Humans Vaccinated with the RV144 HIV Vaccine Containing the HVEM Binding Domain of Herpes Simplex Virus (HSV) Glycoprotein D, Neutralize HSV Infection, Mediate Antibody-Dependent Cellular Cytotoxicity, and Protect Mice from Ocular Challenge with HSV-1

Abstract

The RV144 HIV vaccine trial included a recombinant HIV glycoprotein 120 (gp120) construct fused to a small portion of herpes simplex virus 1 (HSV-1) glycoprotein D (gD) so that the first 40 amino acids of gp120 were replaced by the signal sequence and the first 27 amino acids of the mature form of gD. This region of gD contains most of the binding site for HVEM, an HSV receptor important for virus infection of epithelial cells and lymphocytes. RV144 induced antibodies to HIV that were partially protective against infection, as well as antibodies to HSV. We derived monoclonal antibodies (MAbs) from peripheral blood B cells of recipients of the RV144 HIV vaccine and showed that these antibodies neutralized HSV-1 infection in cells expressing HVEM, but not the other major virus receptor, nectin-1. The MAbs mediated antibody-dependent cellular cytotoxicity (ADCC), and mice that received the MAbs and were then challenged by corneal inoculation with HSV-1 had reduced eye disease, shedding, and latent infection. To our knowledge, this is the first description of MAbs derived from human recipients of a vaccine that specifically target the HVEM binding site of gD. In summary, we found that monoclonal antibodies derived from humans vaccinated with the HVEM binding domain of HSV-1 gD (i) neutralized HSV-1 infection in a cell receptor-specific manner, (ii) mediated ADCC, and (iii) reduced ocular disease in virus-infected mice. IMPORTANCE Herpes simplex virus 1 (HSV-1) causes cold sores and neonatal herpes and is a leading cause of blindness. Despite many trials, no HSV vaccine has been approved. Nectin-1 and HVEM are the two major cellular receptors for HSV. These receptors are expressed at different levels in various tissues, and the role of each re-

Intramuscular vaccination of mice with the human herpes simplex virus type-1(HSV-1) VC2 vaccine, but not its parental strain HSV-1(F) confers full protection against lethal ocular HSV-1 (McKrae) pathogenesis

“…Recently, two HSV-1 vaccine studies [18,19] reported the involvement of antibody in conferring protection against ocular challenge. Moreover, human anti-HSV-1 gD specific monoclonal antibody prevented the acquisition of infection in mice [49]. Although pre-challenge HSV-1 specific serum antibody titer was not different among groups, serum antibody response went significantly higher in VC2-vaccinated group followed by the challenge.…”

“…In addition to CD8 T cell, anti-HSV antibody had been reported to have beneficial role against HSV-1 infection [18,19,[49][50][51][52][53]. Recently, two HSV-1 vaccine studies [18,19] reported the involvement of antibody in conferring protection against ocular challenge.…”

Herpes Simplex Virus Type 1 Interactions with the Interferon System

“…Initial binding occurs through envelope glycoprotein C (gC) and/or gB binding to heparin sulfate proteoglycans, allowing gD to then bind to one of three receptors to initiate viral entry; herpesvirus entry mediator (HVEM), nectin-1, and 3-O sulfated heparin sulfate [ 22 , 23 , 24 ]. The receptor involved is cell type dependent, e.g., nectin-1 is the main receptor for epithelial cells, neuronal cells, and fibroblasts [ 25 , 26 , 27 , 28 , 29 ], whereas HVEM is the main receptor for T-cells and corneal epithelial cells [ 24 , 30 ]. However, there is evidence that the loss of one receptor can be compensated for by another [ 26 ].…”

Generation of a cost-effective cell line for support of high-throughput isolation of primary human B cells and monoclonal neutralizing antibodies

“…The isolation of pathogen-specific monoclonal antibodies (mAbs) generated during natural human infections with human immunodeficiency virus (HIV), influenza virus, respiratory syncytial virus, human cytomegalovirus (CMV), Epstein-Barr virus (EBV), Zika virus and dengue virus has helped define critical epitopes on these pathogens and advanced vaccine design ( Rappuoli et al, 2016 ; Burton, 2017 ; Snijder et al, 2018 ; Robbiani et al, 2017 ). Moreover pathogen-specific mAbs can provide critical proof of concept to establish the protective efficacy of antibodies against pathogenic challenge ( Mascola et al, 2000 ; Hessell et al, 2009 ; Hessell et al, 2007 ; Parren et al, 2001 ; Wang et al, 2018 ; Shingai et al, 2014 ; Magnani et al, 2017 ; Wang et al, 2017 ; Renegar and Small Jr., 1991 ; Pinto et al, 2020 ), with demonstrated prophylactic or therapeutic potential if delivered passively ( Caskey et al, 2019 ). Importantly, the rapid isolation of mAbs is a powerful method that can be used to understand the human immune response to infection in the context of rapidly emerging infections, such as the current COVID-19 pandemic ( Pinto et al, 2020 ; Traggiai et al, 2004 ; Seydoux et al, 2020 ; Ju et al, 2020 ; Shi et al, 2020 ).…”