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.

抽象的生殖器疱疹在全球影响6.5亿人。迫切需要疫苗以防止感染和治疗个人已经被感染了。在当前的资金周期中，我们开发了一种候选疫苗，以防止生殖器疱疹，使用核苷修饰的mRNA封装在脂质纳米颗粒（LNP）中的生殖器疱疹以表达单纯疱疹病毒2型（HSV-2）糖蛋白C，D和E（GC2，GD2，GE2）。疫苗针对入口分子，GD2和两个免疫逃避分子GC2和GE2。我们的疫苗候选者将进入第1阶段 2022年12月的人类试验。我们的新目标是定义保护的免疫相关性三价疫苗使用血清我们在此赠款周期中从免疫的小鼠和豚鼠收集，然后开发基于mRNA的疫苗作为免疫疗法。在AIM 1中，我们将定义保护的免疫相关性。我们的假设是通过定义免疫相关，我们将更好地了解疫苗保护的机制和所需的免疫反应在人类试验中的成功。我们将使用高吞吐量生物传感器技术和我们的GC2广泛面板， GD2和GE2单克隆抗体，以确定三价疫苗是否产生至关重要的抗体 GC2，GD2和GE2上的表位。感兴趣的表位包括绑定补体组件的GC2上的表位 C3b抑制补体激活，将IgG FC结构域结合以阻止FC介导的活性的GE2 补体激活和抗体依赖性细胞毒性，以及与病毒结合的细胞受体结合的GD2 进入并介导细胞间扩散。我们将将抗体结合与这些重要表位的结合与保护包括生殖器病变和潜在感染在内的临床结局。表位图研究将使我们能够评估每种糖蛋白免疫原子对保护的贡献。 AIM 2使用mRNA免疫原来开发生殖器疱疹治疗疫苗。我们假设T细胞反应对于成功的治疗疫苗尤其重要。在初步研究中，我们感染了豚鼠用HSV-2插入式静脉内并恢复后，我们用糖蛋白E和I（GE2/GI2）进行了免疫 mRNA-LNP。 GE2/GI2 mRNA-LNP将复发性生殖器病变的天数减少了47％从复发性生殖器病变降低> 70％的主要终点。为了实现> 70％的目标，我们将掺入其他抗原，包括其他糖蛋白，立即提早，Capsid和Tegument 免疫原并评估雄性和雌性小鼠的CD4和CD8 T细胞反应。我们会晋升最好的豚鼠疗效研究的候选人。由于使用治疗疫苗在使用的紧密相关病毒的水痘带状疱疹病毒中取得了显着成功糖蛋白E作为抗原。我们将在治疗研究中包括三价GC2/GD2/GE2疫苗确定一种疫苗配方是否有效预防和治疗。如果成功，目标1和2中的研究将通过预防和治疗生殖器疱疹对数十亿人产生积极影响。