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Principal Investigator: Betsy C. Herold
Organization: ALBERT EINSTEIN COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $603,661
Funding agency: National Institute of Allergy and Infectious Diseases
There are no effective vaccines or monoclonal antibodies available for the prevention or treatment of
herpes simplex viral infections. This application addresses this global public health priority. We developed
a novel single-cycle vaccine strain deleted in glycoprotein D (gD), designated DgD-2. DgD-2 completely
protects mice from lethal challenges with clinical isolates of both HSV-1 and HSV-2. Protection is
mediated by IgG2 antibodies that have little neutralizing activity but activate Fc gamma receptors to
promote antibody-dependent cellular cytotoxicity (ADCC). The central role for ADCC in mediating
protection is supported by the observations that immune serum from DgD-2 vaccinated mice completely
protects naïve wild-type, but not Fcg receptor IV knockout (FcgRIV-/-) mice. FcgRIV is the primary receptor
responsible for mediating ADCC in mice. We isolated a highly protective monoclonal antibody (mAb),
BMPC-23, from DgD-2 vaccinated mice that exhibits potent FcgRIV activating activity and mapped its
epitope to domain IV of viral glycoprotein B. Notably, in contrast to the response to DgD-2, the humoral
response to acute HSV infection or to vaccination with gD subunit protein vaccines in both mice and
humans is neutralizing with little or no ADCC. These observations suggest that gD may interfere with the
elicitation of ADCC antibodies. We hypothesized that this novel immune evasion mechanism may be
mediated by interactions between gD and the co-signaling molecule switch molecule herpes virus entry
mediator (HVEM), which is expressed by most immune cells. When gD binds HVEM, the interactions
between HVEM and its natural ligands (LIGHT, lymphotoxin-a, CD160 and BTLA) may be inhibited.
Supporting our hypothesis, IgG2 ADCC responses were reduced and protection against HSV was lost
when Hvem−/− (knockout) mice were vaccinated with DgD-2. This need for HVEM to elicit IgG2 ADCC
responses may be generalizable since similar results were obtained with other vaccines. Based on these
data, we propose that the enhanced ADCC response to DgD-2 compared to natural HSV infection or to
gD protein vaccines reflects differences in viral targets recognized, IgG subclasses generated and ability
to overcome gD-HVEM mediated immune evasion. We will isolate and characterize mAbs generated in
response to DgD-2, primary and recurrent HSV infection in wild-type compared to Hvem−/− mice to
determine how HVEM signaling contributes to the antigenic repertoire, subclass and antibody function.
We will test the mAbs that are generated in response to DgD-2 vaccination or infection individually and
in combination (with BMPC-23 and other combinations) for their ability to protect and treat acute or
recurrent HSV-1 and HSV-2 disease following vaginal and skin (male and female) infection as well as in
models of neonatal disease. Together, these studies will yield important new fundamental and
translational knowledge applicable to the development of vaccines and mAbs that mediate ADCC.
Terms: <2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><7S Gamma Globulin><Ab-dependent cellular cytotoxicity><Acceleration><Acute><Address><Adopted><Antibodies><Antibody-Dependent Enhancement><Antigenic Determinants><Antisera><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><Biological Markers><Bp50><CD40><CDW40><COVID-19 S protein><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><Cell Body><Cell Communication and Signaling><Cell Junctions><Cell Signaling><Cells><Clinical><Clinical Treatment Moab><Clinical Trials><Closure by Ligation><Complement><Complement Proteins><Cryo-electron Microscopy><Cryoelectron Microscopy><Cytolysis><Data><Development><Disease><Disorder><Dose><EBOV><Ebola virus><Ebola-like Viruses><Electron Cryomicroscopy><Engineering><Epitopes><Exhibits><Female><Generations><Genital Organs><Genitalia><Germinal Center><Glycoproteins><Goals><HHV-2><HHV2><HSV><HSV-1><HSV-2><HSV-2 glycoprotein D><HSV-2 gpD><HSV1><HSV2><HVEM protein><Herpes Simplex><Herpes Simplex Infections><Herpes Simplex Type 1><Herpes Simplex Virus><Herpes Simplex Virus 1><Herpes Simplex Virus 2><Herpes Simplex Virus Type 1><Herpes Simplex Virus Type 2><Herpes labialis Virus><Herpes simplex disease><Herpesvirus 1><Herpesvirus 2 (alpha), Human><Herpesvirus hominis disease><Herpesvirus progenitalis><Human><Human (alpha) herpes virus 2><Human Herpesvirus 2><Human herpes simplex virus type 2><HveA protein><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IgG><IgG Receptors><IgG1><IgG2><Immune><Immune Evasion><Immune Interferon><Immune Sera><Immune response><Immunes><Immunoglobulin G><Immunoglobulin G Receptor><Immunological response><Individual><Infection><Intercellular Junctions><Interferon Gamma><Interferon Type II><Intracellular Communication and Signaling><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Ligands><Ligation><Light><Lymphotoxin><Lymphotoxin A><Lymphotoxin-alpha><Lymphotoxin-α><Lysis><MGC9013><Maps><Mediating><Member 1 TNF Superfamily><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><Neonatal><Null Mouse><Pathway interactions><Phagocytosis><Photoradiation><Play><Prevention><Production><Protein Subunits><Proteins><Receptor Protein><Recombinants><Recurrence><Recurrent><Role><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Simplexvirus><Skin><Structure of germinal center of lymph node><Subunit Vaccines><T-Cells><T-Lymphocyte><TNF-b><TNF-beta><TNF-β><TNFRSF14><TNFRSF5><TNFRSF5 gene><TNFSF1><TNFβ><TR2 protein><Testing><Tumor Necrosis Factor Receptor Superfamily Member 5 Gene><Tumor Necrosis Factor-Beta><Tumor Necrosis Factor-β><Up-Regulation><Upregulation><Vaccinated><Vaccination><Vaccines><Vagina><Viral><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Virus Diseases><antibody dependent cell mediated cytotoxicity><antibody dependent cytotoxicity><antibody mediated cellular cytotoxicity><antibody-dependent cell cytotoxicity><antibody-dependent cellular cytotoxicity><antibody-mediated cytotoxicity><bio-markers><biologic marker><biological signal transduction><biomarker><cell type><complementation><congenic><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><cryo-EM><cryoEM><cryogenic electron microscopy><develop a vaccine><develop vaccines><development of a vaccine><developmental><gamma Fc Receptors><glycoprotein D-herpes simplex virus type 2><herpes simplex i><herpes simplex ii><herpes simplex virus 1 infection><herpes simplex virus infection><herpes simplex-1><herpesvirus entry mediator><host response><human alphaherpesvirus 2><immune evasive><immune serum><immune system response><immunoresponse><knowledge translation><lFN-Gamma><mAbs><male><monoclonal Abs><mouse model><murine model><neonatal mice><neonate><neutralizing antibody><novel><p50><pathogen><pathway><pre-clinical study><preclinical study><prevent><preventing><public health priorities><receptor><response><social role><spike proteins on SARS-CoV-2><thymus derived lymphocyte><tumor necrosis factor receptor subfamily, member 14><vaccine antibodies><vaccine candidate><vaccine development><vaccine induced antibodies><vaccine-induced antibodies><viral infection><virus infection><virus protein><virus-induced disease>