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Principal Investigator: Harvey Michael Friedman
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $812,498
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
Genital herpes affects 650 million people globally. Vaccines are urgently needed to prevent infection and treat
individuals already infected. During the current funding cycle, we developed a candidate vaccine for preventing
genital herpes that uses nucleoside-modified mRNA encapsulated within lipid nanoparticles (LNP) to express
herpes simplex virus type 2 (HSV-2) glycoproteins C, D, and E (gC2, gD2, gE2). The vaccine targets an entry
molecule, gD2, and two immune evasion molecules, gC2 and gE2. Our vaccine candidate will enter phase 1
human trials in December 2022. Our new goals are to define the immune correlates of protection for the
trivalent vaccine using sera we collected from immunized mice and guinea pigs during this grant cycle, and to
develop an mRNA-based vaccine as immunotherapy.
In Aim 1, we will define the immune correlates of protection. Our hypothesis is that by defining immune
correlates, we will better understand the mechanisms of vaccine protection and the immune responses required
for success in human trials. We will use high throughput biosensor technology and our extensive panel of gC2,
gD2, and gE2 monoclonal antibodies to determine whether the trivalent vaccine produces antibodies to crucial
epitopes on gC2, gD2 and gE2. The epitopes of interest include those on gC2 that bind complement component
C3b to inhibit complement activation, gE2 that bind the IgG Fc domain to block Fc-mediated activities including
complement activation and antibody-dependent cellular cytotoxicity, and gD2 that bind to cell receptors for virus
entry and mediate cell-to-cell spread. We will correlate antibody binding to these important epitopes with
protection against clinical outcomes including genital lesions and latent infection. The epitope mapping studies
will enable us to assess the contribution of each of the glycoprotein immunogens to protection.
Aim 2 uses mRNA immunogens to develop a genital herpes therapeutic vaccine. We hypothesize that T cell
responses will be particularly important for a successful therapeutic vaccine. In Preliminary studies, we infected
guinea pigs intravaginally with HSV-2 and once recovered, we immunized with glycoproteins E and I (gE2/gI2)
mRNA-LNP. gE2/gI2 mRNA-LNP reduced the number of days with recurrent genital lesions by 47%, an excellent
start towards our primary endpoint of >70% reduction in recurrent genital lesions. To achieve our goal of >70%,
we will incorporate other antigens, including additional glycoproteins, immediate early, capsid and tegument
immunogens and assess CD4 and CD8 T cell responses in male and female mice. We will advance the best
candidates for efficacy studies in guinea pigs. We will focus initially on glycoprotein immunogens because of the
remarkable success of a therapeutic vaccine for a closely related virus, varicella zoster virus, that uses
glycoprotein E as the antigen. We will include the trivalent gC2/gD2/gE2 vaccine in the therapeutic studies to
determine whether one vaccine formulation will be effective for prevention and treatment. If successful, the
studies in Aims 1 and 2 will have a positive impact on billions of people by preventing and treating genital herpes.
Terms: <7S Gamma Globulin><Ab-dependent cellular cytotoxicity><Acicloftal><Aclovir><Acycloguanosine><Acyclovir><Address><Affect><Animal Model><Animal Models and Related Studies><Anti-viral Agents><Anti-viral Therapy><Antibodies><Antibody Response><Antigenic Determinants><Antigens><Assay><Binding><Binding Determinants><Bioassay><Biological Assay><Biosensor><Blocking Antibodies><Blood Serum><C3b><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Capsid><Cargosil><Cavia><Cell Body><Cells><Chickenpox Virus><Clinical><Clinical Treatment Moab><Complement><Complement 3b><Complement Activation><Complement C3b><Complement Proteins><Complex><DNA><Deoxyribonucleic Acid><Disease Outbreaks><Encapsulated><Epitope Mapping><Epitopes><Failure><Fc domain><Female><Frequencies><Funding><Future><GD2 Binding><Genital Herpes Simplex><Genital Organs><Genitalia><Glycoproteins><Goals><Grant><Guinea Pigs><Guinea Pigs Mammals><HHV-2><HHV-3><HHV2><HHV3><HSV glycoprotein C><HSV type 1 glycoprotein gC><HSV-1><HSV-1 gC-1><HSV-2><HSV-I glycoprotein C><HSV1><HSV2><Herpes Genitalis><Herpes Simplex Type 1><Herpes Simplex Virus 1><Herpes Simplex Virus 2><Herpes Simplex Virus Type 1><Herpes Simplex Virus Type 2><Herpes zoster Virus><Herpesvirus 1><Herpesvirus 2 (alpha), Human><Herpesvirus Type 3><Herpesvirus progenitalis><Herpesvirus varicellae><Human><Human (alpha) herpes virus 2><Human Herpesvirus 2><Human herpes simplex virus type 2><IgG><Immune><Immune Evasion><Immune mediated therapy><Immune response><Immunes><Immunization><Immunize><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunoglobulin G><Immunological response><Immunologically Directed Therapy><Immunosuppressed Host><Immunotherapy><Individual><Infection><Infection prevention><Lesion><Measures><Mediating><Messenger RNA><Mice><Mice Mammals><Modern Man><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><Nucleosides><Ocular Herpes zoster Virus><Outbreaks><Outcome><Persons><Phase><Poviral><Prevent infection><Preventative vaccine><Prevention><Preventive vaccine><Prophylactic vaccine><RNA vaccine><RNA-based vaccine><Receptor Cell><Recurrence><Recurrent><Risk><Risk Marker><Sampling><Schedule><Serum><Site><T cell response><T8 Cells><T8 Lymphocytes><Technology><Therapeutic Studies><Therapy Research><Transmission><VZ Virus><Vaccination acquired immunity><Vaccination induced immunity><Vaccine Production><Vaccines><Varicella-Zoster Virus><Viral Activity><Viral Function><Viral Physiology><Viral Receptor><Virorax><Virus><Virus Receptors><Virus-Genital Herpes><Zovirax><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antibody assay><antibody based test><antibody dependent cell mediated cytotoxicity><antibody dependent cytotoxicity><antibody mediated cellular cytotoxicity><antibody test><antibody-dependent cell cytotoxicity><antibody-dependent cellular cytotoxicity><antibody-mediated cytotoxicity><biological sensor><complement pathway regulation><complementation><detection assay><develop a vaccine><develop vaccines><development of a vaccine><efficacy study><experiment><experimental research><experimental study><experiments><genital herpes><glycoprotein C><herpes genitalia><herpes simplex i><herpes simplex ii><herpes simplex virus-1 glycoprotein C><herpes simplex-1><high standard><host response><human alphaherpesvirus 2><immune evasive><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunoresponse><immunosuppressed patient><inhibiting antibody><interest><latent infection><lipid based nanoparticle><lipid nanoparticle><mAbs><mRNA><mRNA lipid nano particle vaccine><mRNA vaccine><mRNA-LNP based vaccine><mRNA-LNP combination vaccines><mRNA-LNP vaccines><mRNA-based vaccine><male><model of animal><monoclonal Abs><mouse model><murine model><phase 1 trial><phase I trial><pre-clinical><preclinical><prevent><preventing><primary end point><primary endpoint><produce vaccines><prophylactic><resistance mutation><resistant mutation><response><risk predictor><risk predictors><success><therapeutic vaccine><therapeutically effective><transmission process><treatment vaccines><vaccine acquired immunity><vaccine associated immunity><vaccine candidate><vaccine development><vaccine efficacy><vaccine for the treatment><vaccine for treatment><vaccine formulation><vaccine-induced immunity><vaccine-induced protection><valacyclovir><venereal herpes><viral infectious disease treatment>