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.

项目摘要 据估计，全世界有7100万人感染HCV，并处于严重肝病的高风险之中。 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 治疗是可用的，只有HCV疫苗将有助于预防感染，相关的病理，并有效地 减少全球疾病负担。累积的证据表明，B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E1 E2糖蛋白，保护性抗体的天然靶标。基于E1 E2的免疫原需要 以引发针对多个表位的广泛中和抗体（bnAb），以克服 HCV分离株，并具有足够的滴度，以实现保护性免疫。我们的做法得到了我们最近的支持， E1 E2的分泌形式（sE 1 E2）保持其天然样特性，并可引起更广泛的中和作用 抗体反应比膜结合形式的E1 E2和分泌的E2。此外，我们已经表明， 将sE 1 E2呈递为包含HCV核心的多价病毒模拟聚合物组装体（VMPA） 蛋白质可以引发针对sE 1 E2和核心抗原的细胞免疫应答，具有潜在的免疫增强作用， 对B和T细胞应答的活性。因此，我们的中心假设是，理性的结构导向设计， E1 E2和与保守HCV T细胞抗原共制剂作为VMPA疫苗将导致最佳呈递 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 以下特定目的：目的1，合理的E1 E2抗原设计。我们将推进我们的结构引导E1 E2 设计以增加bnAb表位的免疫原性，并稳定天然样sE 1 E2复合物， 合成支架目的2、HCV包膜复合物的结构表征。我们将在结构上 表征与关键bnAb复合的E1 E2异二聚体，新结构将用于进一步的E1 E2 优化.目的3，拟病毒聚合物组装体的制备与表征。我们计划进一步 开发用于E1 E2和T细胞抗原的多聚体呈递的E1 E2的超分子组装体。目标4， 动物模型中B和T细胞应答的免疫学评价。我们疫苗的免疫学评估 候选人将在小鼠、豚鼠和猕猴中进行。这些研究将包括审查 中和抗体反应的特异性以及全身和组织驻留记忆T细胞。目标5， 攻毒模型系统中的疫苗效力。保护性研究将利用仅有的两个可用挑战 模型第一，免疫活性的人源化小鼠模型，以测试我们的铅的保护功效 候选疫苗第二，人-小鼠肝脏嵌合体模型，可以感染抗原性 不同的临床HCV分离株，以证明来自被动转移的免疫猕猴的血清抗体 对嵌合体小鼠有保护作用整个计划将导致一个合理设计的候选疫苗 诱导广泛中和抗体和长期记忆T细胞应答，以预防HCV感染。