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，全球有7100万人感染了丙型肝炎病毒，并处于严重肝病的高危状态 疾病，包括纤维化、肝硬变和肝细胞癌。虽然有效的直接作用的抗病毒 治疗是可用的，只有丙型肝炎病毒疫苗将有助于预防感染，相关的病理，并有效 减轻全球疾病负担。累积的证据表明，B细胞和T细胞免疫都有助于 控制急性丙型肝炎病毒感染。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。需要一种基于E1E2的免疫原 诱导针对多个表位的广谱中和抗体(BNAbs)，以克服猪瘟病毒高度的抗原多样性 丙型肝炎病毒分离株，并具有足够的效价，以实现保护性免疫。我们的方法得到了我们最近的 分泌形式的E1E2(SE1E2)保持其天然性质并能引起更广泛的中和作用的数据 抗体反应比膜结合形式的E1E2和分泌的E2更强。另外，我们已经证明了 将sE1E2呈现为包括丙型肝炎病毒核心的多价类病毒聚合物组件(VMPA) 蛋白质可诱导针对sE1E2和核心抗原的细胞免疫应答，具有潜在的免疫增强作用 B细胞和T细胞反应的活性。因此，我们的中心假设是，合理的结构指导设计 E1E2和与保守的丙型肝炎病毒T细胞抗原作为VMPA疫苗的联合配方将导致最佳呈现方式 保守的bNab表位，并诱导持久的B和T细胞介导的免疫。为此，我们建议 具体目标如下：目的1、合理设计E1E2抗原。我们将推进以结构为导向的E1E2 设计以提高bNab表位的免疫原性，并稳定类天然sE1E2复合体 合成脚手架。目的2、丙型肝炎病毒包膜复合体的结构特征。我们将在结构上 鉴定与关键bNAbs络合的E1E2异源二聚体，新结构将用于进一步的E1E2 优化。目的3，模拟病毒聚合物组装体的制备和表征。我们计划进一步 开发E1E2的超分子组件，用于E1E2和T细胞抗原的多聚体呈递。目标4， 动物模型中B细胞和T细胞反应的免疫学评价。我们研制的疫苗的免疫学评价 候选者将在小鼠、豚鼠和猕猴身上进行实验。这些研究将包括对 中和抗体反应以及系统和组织驻留记忆T细胞的特异性。目标5， 挑战模型系统中的疫苗效力。保护研究将利用仅有的两个可用的挑战 模特们。第一，免疫活性人源化小鼠模型，以测试我们的铅的保护效果 候选疫苗。第二，一种可以抗原性感染的人鼠肝嵌合模型 不同丙型肝炎病毒临床分离株对被动转移疫苗猕猴血清抗体的验证 对嵌合小鼠将起到保护作用。整个计划将导致一个合理设计的候选疫苗 诱导广谱中和抗体和长期记忆性T细胞反应，预防丙型肝炎病毒感染。