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Nucleoside-modified mRNA vaccine for prevention and treatment of genital herpes

用于预防和治疗生殖器疱疹的核苷修饰mRNA疫苗

基本信息

批准号：
10734345
负责人：
Harvey Michael Friedman
金额：
$ 81.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734345
关键词：
Acyclovir Address Affect Animal Model Antibodies Antibody Response Antigens Antiviral Agents Antiviral Therapy Binding Biological Assay Biosensor Blocking Antibodies CD8-Positive T-Lymphocytes Capsid Cavia Cells Clinical Complement Complement 3b Complement Activation Complex DNA Disease Outbreaks Encapsulated Epitope Mapping Epitopes Failure Fc domain Female Frequencies Funding Future GD2 Binding Genital Genitalia Glycoproteins Goals Grant HSV glycoprotein C Herpesvirus 1 Herpesvirus Type 3 Human Human Herpesvirus 2 Immune Immune Evasion Immune response Immunization Immunize Immunocompromised Host Immunoglobulin G Immunotherapy Individual Infection Infection prevention Lesion Measures Mediating Messenger RNA Monoclonal Antibodies Mus Nucleosides Outcome Persons Phase Prevention Preventive vaccine RNA vaccine Receptor Cell Recurrence Risk Risk Marker Sampling Schedule Serum Site T cell response Technology Therapeutic Studies Vaccine Production Vaccines Viral Physiology Virus Virus Receptors antibody test antibody-dependent cell cytotoxicity detection assay efficacy study experimental study genital herpes high standard inhibiting antibody interest latent infection lipid nanoparticle male mouse model phase I trial pre-clinical prevent primary endpoint prophylactic resistance mutation response success therapeutic vaccine therapeutically effective transmission process vaccine candidate vaccine development vaccine efficacy vaccine formulation vaccine-induced immunity valacyclovir

项目摘要

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.

摘要