Rational design and efficacy testing of vaccines against HCV

HCV疫苗的合理设计和功效测试

• 批准号: 10420604
• 负责人: Alexander Andrianov
• 金额: $ 141.05万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-05 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10420604
• 关键词: Active Immunization; Acute Hepatitis C; Address; Adjuvant; Affinity; Alanine; Amino Acids; Animal Model; Antibodies; Antibody Response; Antigenic Diversity; Antigens; B-Lymphocytes; Biochemical; Biological Models; Budgets; CD81 gene; Cavia; Cellular Immunity; Chemicals; Cirrhosis; Clinical; Clinical Trials; Complex; Cryoelectron Microscopy; Data; Development; Enzyme-Linked Immunosorbent Assay; Epitopes; Evaluation; Face; Fibrosis; Formulation; Generations; Genome; Genotype; Glycoproteins; Goals; Hepatitis C; Hepatitis C Vaccine; Hepatitis C virus; Human; Hydrogels; Immune response; Immunity; Immunization; Immunize; Immunocompetent; Immunologics; Individual; Infection prevention; Lead; Liver; Liver Cirrhosis; Liver diseases; Macaca; Maps; Medical; Membrane; Modeling; Modification; Molecular Conformation; Monoclonal Antibodies; Mus; Pathology; Persons; Polymers; Primary carcinoma of the liver cells; Property; Proteins; Protocols documentation; Public Health; Research; Resolution; Risk; Scanning; Serology; Serum; Side; Specificity; Structure; System; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Tissues; United States National Institutes of Health; Vaccinated; Vaccines; Variant; Viral Hepatitis Vaccines; Virus; Work; alpha helix; aqueous; base; burden of illness; design; efficacy testing; hepatitis C virus nucleocapsid protein; humanized mouse; immunogenicity; insight; interdisciplinary approach; long term memory; macromolecule; mouse model; nanoparticle; neutralizing antibody; polyphosphazene; preservation; prevent; programs; protective efficacy; rational design; receptor binding; response; scaffold; self assembly; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; virus envelope; waiver

Project Summary An estimated 71 million people worldwide are infected with HCV and are at heightened risk for severe liver disease, including fibrosis, cirrhosis, and hepatocellular carcinoma. Although effective directly-acting antiviral treatment is available, only an HCV vaccine will help prevent infection, associated pathologies, and effectively reduce global disease burden. Cumulative evidence has shown that both B and T cell immunity contribute to the control of acute HCV infection. A major challenge is the high variability across the genome especially in the envelope E1E2 glycoproteins, the natural target of protective antibodies. An E1E2-based immunogen will need to elicit broadly neutralizing antibodies (bnAbs) to multiple epitopes to overcome the high antigenic diversity of HCV isolates and be of sufficient titers to achieve protective immunity. Our approach is supported by our recent data that a secreted form of E1E2 (sE1E2) maintains its native-like properties and can elicit broader neutralizing antibody responses than the membrane-bound form of E1E2 and secreted E2. Also, we have shown that presentation of sE1E2 as multivalent virus-mimicking polymer assemblies (VMPAs) that include HCV core protein can elicit cellular immune responses to sE1E2 and core antigens with potential immunopotentiating activity for B and T cell responses. Accordingly, our central hypothesis is that rational structure-guided design of E1E2 and co-formulation with conserved HCV T cell antigens as a VMPA vaccine will lead to optimal presentation of conserved bnAb epitopes and elicit long-lasting B and T cell mediated immunity. Towards this end, we propose the following Specific Aims: Aim 1, Rational E1E2 antigen design. We will advance our structure-guided E1E2 design to increase the immunogenicity of bnAb epitopes, and stabilize the native-like sE1E2 complex using synthetic scaffolds. Aim 2, Structural characterization of HCV envelope complexes. We will structurally characterize the E1E2 heterodimer complexed with key bnAbs, and new structures will be used for further E1E2 optimization. Aim 3, Formulation and characterization of virus-mimicking polymer assemblies. We plan to further develop supramolecular assemblies of E1E2 for multimeric presentation of E1E2 and T cell antigens. Aim 4, Immunological evaluation of B and T cell responses in animal models. Immunological assessment of our vaccine candidates will be performed in mice, guinea pigs, and macaques. These studies will include an examination of the specificity of neutralizing antibody responses as well as systemic and tissue resident memory T cells. Aim 5, Vaccine efficacy in challenge model systems. Protection studies will utilize the only two available challenge models. The first, an immunocompetent humanized mouse model to test the protective efficacy of our lead vaccine candidates. The second, a human-mouse liver chimeric model that can be infected with antigenically diverse clinical HCV isolates to demonstrate serum antibodies from vaccinated macaques passively transferred to the chimeric mice will be protective. The overall program will lead to a rationally designed vaccine candidate to induce broadly neutralizing antibodies and long-term memory T cell responses to prevent HCV infection.

项目概要 据估计，全球有 7100 万人感染 HCV，并且患严重肝病的风险较高 疾病，包括纤维化、肝硬化和肝细胞癌。虽然直接作用的抗病毒药物有效 治疗是可用的，只有 HCV 疫苗才能帮助预防感染和相关病理，并有效 减轻全球疾病负担。累积证据表明，B 细胞和 T 细胞免疫都有助于 控制急性HCV感染。一个主要的挑战是整个基因组的高度变异性，特别是在 包膜 E1E2 糖蛋白，保护性抗体的天然靶点。基于 E1E2 的免疫原需要 引发针对多个表位的广泛中和抗体（bnAb），以克服抗原的高度多样性 HCV 分离并具有足够的滴度以实现保护性免疫。我们的方法得到了我们最近的支持 数据表明，E1E2 (sE1E2) 的分泌形式保持其类似天然的特性，并且可以引发更广泛的中和作用 抗体反应高于膜结合形式的 E1E2 和分泌型 E2。此外，我们还证明了 sE1E2 作为包含 HCV 核心的多价病毒模拟聚合物组件 (VMPA) 的呈现 蛋白质可引发针对 sE1E2 和核心抗原的细胞免疫反应，具有潜在的免疫增强作用 B 和 T 细胞反应的活性。因此，我们的中心假设是合理的结构引导设计 E1E2 以及与保守的 HCV T 细胞抗原共同配制为 VMPA 疫苗将带来最佳表现 保守的 bnAb 表位并引发持久的 B 和 T 细胞介导的免疫。为此，我们建议 具体目标如下： 目标1，Rational E1E2抗原设计。我们将推进我们的结构导向的E1E2 设计增加 bnAb 表位的免疫原性，并使用稳定类似天然的 sE1E2 复合物 合成支架。目标 2，HCV 包膜复合物的结构表征。我们将从结构上 表征与关键bnAb复合的E1E2异二聚体，新结构将用于进一步的E1E2 优化。目标 3，模拟病毒聚合物组装体的配方和表征。我们计划进一步 开发 E1E2 的超分子组装体，用于 E1E2 和 T 细胞抗原的多聚体呈递。目标4， 动物模型中 B 和 T 细胞反应的免疫学评估。我们疫苗的免疫学评估 候选者将在小鼠、豚鼠和猕猴身上进行。这些研究将包括检查 中和抗体反应以及全身和组织驻留记忆 T 细胞的特异性。目标5， 挑战模型系统中的疫苗功效。保护研究将利用仅有的两个可用挑战 模型。第一个是免疫活性人源化小鼠模型，用于测试我们的先导药物的保护功效 候选疫苗。二是可抗原感染的人鼠肝嵌合模型 不同的临床 HCV 分离株，以证明来自已接种疫苗的猕猴的血清抗体是被动转移的 对嵌合小鼠具有保护作用。总体计划将导致合理设计候选疫苗 诱导广泛中和抗体和长期记忆 T 细胞反应，以预防 HCV 感染。