A vaccine for genital herpes that achieves sterilizing immunity

实现绝育免疫力的生殖器疱疹疫苗

• 批准号: 9915856
• 负责人: Harvey Michael Friedman
• 金额: $ 79.62万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915856
• 关键词: Affect; Animal Model; Animals; Antibodies; Antibody Response; Antibody titer measurement; Antigens; Biosensor; Blocking Antibodies; Cavia; Cells; Cessation of life; Clinical; Complement; DNA; DNA Vaccines; Data Analyses; Development; Disease; Emotional; Enzyme-Linked Immunosorbent Assay; Epitopes; Female; Future; Genetic Translation; Genital system; Glycoproteins; Goals; Gold; HIV; HSV glycoprotein C; Helper-Inducer T-Lymphocyte; Herpesviridae Infections; Herpesvirus 1; Human; Human Herpesvirus 2; Humoral Immunities; Immune; Immune Evasion; Immune response; Immunity; Immunization; Immunize; Impairment; Individual; Infection; Influenza; Lesion; Life; Measures; Mediating; Messenger RNA; Methods; Modification; Mucous Membrane; Mumps; Mus; Newborn Infant; Nucleosides; Pain; Poliomyelitis; Prevention; Prevention trial; Preventive vaccine; Protein Subunits; Proteins; Public Health; Rabies; Recurrence; Reporting; Research; Risk; Rodent; Rotavirus; Rubella; Serum; Sexually Transmitted Diseases; Simplexvirus; Spinal Ganglia; Structure; Talents; Translations; Uridine; Vaccine Antigen; Vaccines; Vagina; Viral Physiology; Virus; Woman; Yellow Fever; antibody-dependent cell cytotoxicity; design; emotional distress; genital herpes; genital infection; glycoprotein D-herpes simplex virus type 2; immunogenicity; improved; inhibiting antibody; innovation; lipid nanoparticle; male; neonatal infection; neutralizing antibody; novel; novel strategies; prevent; prophylactic; public health priorities; response; sensor; sex; success; tool; transmission process; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vaccine trial; vaccine-induced immunity

Abstract A vaccine for prevention of genital herpes is a high public health priority. Herpes vaccines that performed well in rodents have not protected humans; therefore, novel approaches are needed. We propose the following: 1) Set a much higher bar for vaccine efficacy in animal models than used previously. The “gold standard” for a herpes vaccine is sterilizing immunity, defined as no genital lesions and no evidence of subclinical infection as measured by negative day 2 vaginal titers post-infection, no recurrent episodes of vaginal shedding of HSV-2 DNA and no HSV-2 DNA in dorsal root ganglia. Prior herpes candidate vaccines have prevented death and reduced genital lesions, but none has come close to achieving sterilizing immunity by preventing subclinical infection. We have set sterilizing immunity in >95% of animals as our goal. 2) Devise strategies to prevent the virus from evading vaccine-induced immunity. Antibodies correlate with protection for the vast majority of our effective human vaccines. HSV encodes glycoproteins C (gC) and E (gE) that are immune evasion molecules that inhibit antibody and complement. Our vaccine strategy builds upon the immunity provided by gD and blocks the ability of the virus to evade antibody and complement attack. 3) Modify antigen delivery methods. We use nucleoside-modified mRNA, rather than subunit proteins as immunogens. We report preliminary results in mice using a trivalent vaccine that contains modified mRNA encoding glycoproteins C, D and E (gC2/gD2/gE2) administered in lipid nanoparticles. The modified mRNA replaces uridine nucleosides with 1-methylpseudouridine residues. We achieve sterilizing immunity in 63/64 (98%) mice compared with 14/20 (70%) immunized with subunit antigens. We will extend this exciting result to include studies in naïve and HSV-1 positive guinea pigs as a more stringent test of vaccine efficacy, evaluate male and female animals, and determine cross-protection against genital HSV-1. 4) Define the immune correlates required to achieve sterilizing immunity. We will assess serum ELISA titers, neutralizing titers, antibodies that block cell-to-cell spread, antibodies that block gC and gE immune evasion, antibody-dependent cellular cytotoxicity titers, and mucosal ELISA and neutralizing antibodies as immune correlates of protection. These studies will help establish immunogenicity targets for future human trials. 5) Determine whether mRNA immunization produces antibodies to crucial epitopes. The crucial epitopes include those on gC and gD that neutralize virus, gC and gE that inhibit complement and antibody, and gD and gE involved in cell-to-cell spread. We will use a novel high throughput biosensor platform to determine whether immunization produces antibodies to these crucial epitopes. Measuring epitope specific antibody responses will identify gaps in immunogenicity and guide us on those epitopes to modify to enhance vaccine protection. The four labs have the combined expertise to develop a genital herpes vaccine that achieves sterilizing immunity in animals and subsequently in humans.

抽象的 预防生殖器疱疹的疫苗是公共卫生的重中之重。表现良好的疱疹疫苗 在啮齿类动物中没有保护人类；因此，需要新的方法。我们提出以下建议： 1）为动物模型中的疫苗功效设定比以前更高的标准。的“黄金标准” 疱疹疫苗是灭菌免疫，定义为没有生殖器病变，也没有亚临床证据 感染后第 2 天阴道滴度呈阴性，无阴道反复发作 背根神经节中 HSV-2 DNA 脱落和无 HSV-2 DNA。先前的疱疹候选疫苗有 预防了死亡并减少了生殖器损伤，但还没有一个能够接近通过以下方式实现绝育免疫力： 预防亚临床感染。我们的目标是让 >95% 的动物具有绝育免疫力。 2）制定策略以防止病毒逃避疫苗诱导的免疫力。抗体相关 保护我们绝大多数有效的人类疫苗。 HSV 编码糖蛋白 C (gC) 和 E (gE) 它们是抑制抗体和补体的免疫逃避分子。我们的疫苗战略建立在 gD 提供的免疫力并阻止病毒逃避抗体和补体攻击的能力。 3) 修改抗原递送方法。我们使用核苷修饰的 mRNA，而不是亚基蛋白作为 免疫原。我们报告了使用含有修饰 mRNA 的三价疫苗的小鼠的初步结果 编码糖蛋白 C、D 和 E (gC2/gD2/gE2)，以脂质纳米颗粒形式给药。修饰后的mRNA 用 1-甲基假尿苷残基取代尿苷核苷。在63/64实现杀菌免疫力 (98%) 小鼠与用亚单位抗原免疫的 14/20 (70%) 小鼠相比。我们将延续这一令人兴奋的 结果包括对幼稚豚鼠和 HSV-1 阳性豚鼠进行的研究，作为对疫苗功效的更严格测试， 评估雄性和雌性动物，并确定针对生殖器 HSV-1 的交叉保护。 4) 定义实现灭菌免疫所需的免疫相关因素。我们将评估血清 ELISA 滴度， 中和滴度、阻止细胞间传播的抗体、阻止 gC 和 gE 免疫逃避的抗体， 抗体依赖性细胞毒性滴度，粘膜 ELISA 和中和抗体作为免疫 保护的相关性。这些研究将有助于为未来的人体试验建立免疫原性目标。 5) 确定 mRNA 免疫是否产生针对关键表位的抗体。关键表位 包括中和病毒的 gC 和 gD，抑制补体和抗体的 gC 和 gE，以及抑制补体和抗体的 gD 和 gE 参与细胞间传播。我们将使用新型高通量生物传感器平台来确定是否 免疫产生针对这些关键表位的抗体。测量表位特异性抗体反应 将确定免疫原性的差距，并指导我们修改这些表位以增强疫苗保护。 这四个实验室拥有综合专业知识，可开发出可实现绝育的生殖器疱疹疫苗 动物的免疫力，随后是人类的免疫力。