Strategies for next-generation flavivirus vaccine development

下一代黄病毒疫苗开发策略

• 批准号: 10751480
• 负责人: Helen S Jung
• 金额: $ 5.27万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-02-02 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751480
• 关键词: Adaptive Immune System; Address; Adult; Affinity; Amino Acid Substitution; Antibodies; Antibody Repertoire; Antibody Response; Antibody Therapy; Antibody-Dependent Enhancement; Antigens; Antiviral Therapy; Arthralgia; Autoantibodies; B-Cell Antigen Receptor; B-Lymphocytes; Bacteriophage M13; Bacteriophages; Binding; Biological Assay; Case Study; Cell-Matrix Junction; Cells; Clinical; Communities; Complication; Culicidae; Data; Dengue Virus; Disease; Disease Progression; Distal; E protein; Endothelium; Engineering; Enzyme-Linked Immunosorbent Assay; Epitopes; Exanthema; Flavivirus; Flavivirus Infections; Global Change; Glycoproteins; Goals; Guillain Barré Syndrome; Hemorrhagic Shock; Homologous Gene; Hydrophobic Surfaces; Immune; Immune system; Immunization; Immunologic Memory; Immunotherapy; In Vitro; Infection; Inflammatory; Knowledge; Lateral; Libraries; Membrane; Memory B-Lymphocyte; Methods; Microcephaly; Molecular Conformation; Mosquito-borne infectious disease; Mus; Mutagenesis; Mutate; Neonatal; Nonstructural Protein; Pathogenesis; Pathologic; Pathology; Patients; Persons; Phage Display; Phylogenetic Analysis; Plasma Cells; Play; Populations at Risk; Primary Infection; Publishing; Recording of previous events; Risk; Sequence Homology; Serotyping; Serum; Severity of illness; Structure; Subunit Vaccines; Symptoms; Syndrome; Techniques; Testing; Therapeutic; Vaccinated; Vaccines; Variant; Viral; Viral Hemorrhagic Fevers; Viremia; Virus; Virus Diseases; Virus Replication; Wing; X ray diffraction analysis; Zika Virus; adaptive immune response; climate change; crosslink; cytokine; design; dimer; effectiveness study; endothelial dysfunction; extracellular; flu; immunogenicity; in vivo; infection risk; mosaic; mosquito-borne; mutant; nanoparticle; neutralizing antibody; next generation; novel; novel vaccines; receptor; response; risk minimization; secondary infection; severe dengue; therapy development; transmission process; uptake; vaccination strategy; vaccine development

Dengue virus (DENV; DV) is the most common mosquito-borne virus in the world, with 4 billion people living in regions that put them at risk for infection by any of its four serotypes (DV1-4). Infection by DV and its related flavivirus Zika virus (ZIKV; ZV) may clinically manifest as mild flu-like symptoms, rash, and arthralgia. Severe DV cases can progress into hemorrhagic fever and shock syndrome, while severe complications of ZV infection include Guillain-Barre syndrome in adults and neonatal microcephaly. Severe dengue is associated with antibody-dependent enhancement (ADE) of infection, a phenomenon seen as potentially fatal. In response to a primary DV infection, the immune system produces antibodies that can bind and neutralize that serotype to resolve infection. However, during a subsequent infection by a heterotypic DV serotype or ZV, some antibodies from the primary infection are re-elicited but may poorly neutralize the heterotypic infection; thus, instead of eliminating infection, these antibodies promote uptake of active virus into Fcγ receptor-expressing immune cells and increase viremia and levels of pro-inflammatory cytokines. Currently, there is a need for vaccines and anti- viral therapies for DV and ZV that do not carry the risk of inducing ADE. To avoid ADE, a significant goal for DV and ZV vaccine development is to elicit broadly protective antibodies, as opposed to broadly reactive, non- neutralizing ones. We determined two glycoproteins expressed by DV and ZV as favorable candidates for immunogen design. Neutralizing, protective antibodies against DV and ZV have shown to target domain III (DIII) of E glycoprotein, which is critical for viral entry and cell attachment. However, non-neutralizing, ADE-inducing antibodies were also identified to bind to other motifs on WT DIII. Targeting WT NS1 glycoprotein, which plays a key role in viral replication and endothelial dysfunction, may reduce disease severity without ADE, but it may elicit non-neutralizing, even autoreactive antibodies. To address these challenges, structure-based approaches may be used for immunogen mutagenesis and multivalent display of these immunogens. This proposal will investigate methods to increase the immunodominance of heterologous epitopes found on the lateral ridge (LR) of DIII and the β-ladder of NS1, while masking certain epitopes on these immunogens, to induce broad humoral protection and mitigate severity of disease. We previously demonstrated the strong immunoprotecting potential of a homotypic ZV immunization strategy, which involved the multivalent display of a LR-focused DIII mutant onto nanoparticles. We will study the effectiveness of various heterotypic nanoparticles as cross-immunization strategies against ZV and DV and characterize underlying humoral responses to the immunizations in mice (Aim 1). We will then explore the design of miniβ, a novel NS1 mutant which may be employed to curb disease progression without eliciting ADE or autoreactive antibodies (Aim 2). These studies will further our understanding of the adaptive immune response to flavivirus infections and may provide a framework for developing novel vaccines and antibody-based therapeutics.

登革热病毒（DENV; DV）是世界上最常见的蚊子传播病毒，有40亿人居住 使它们有四种血清型中的任何一个（DV1-4）中的任何地区都有感染的风险。 DV及其相关感染 黄病毒寨卡病毒（ZIKV; ZV）在临床上可能表现为轻度流感样症状，皮疹和关节痛。严重 DV病例可以发展为出血热和休克综合征，而ZV感染的严重并发症 包括成年人和新生儿小头畸形的Guillain-Barre综合征。严重的粉丝与 感染的抗体依赖性增强（ADE），这种现象被视为潜在致命。响应一个 原发性DV感染，免疫系统产生可以结合并中和该血清型与的抗体 解决感染。但是，在随后被异型DV血清型或ZV感染期间，某些抗体 从原发性感染中得到重新引起的，但可能无法中和异型感染。因此，而不是 消除感染，这些抗体促进了活性病毒对表达Fcγ受体的免疫细胞的摄取 并增加促炎细胞因子的病毒血症和水平。目前，需要疫苗和抗 DV和ZV的病毒疗法不承担诱发ADE的风险。为了避免ADE，DV的重要目标 ZV疫苗的开发是引起广泛保护的抗体，而不是广泛反应性，非反应性的抗体 中和。我们确定了DV和ZV表达的两种糖蛋白是有利的候选者 免疫原设计。针对DV和ZV中和，受保护的抗体已证明靶向域III（DIII） E糖蛋白的含量，这对于病毒进入和细胞附着至关重要。但是，非中和，诱导 还鉴定出抗体与WT DIII上的其他基序结合。靶向WT NS1糖蛋白 在病毒复制和内皮功能障碍中的关键作用可能在没有ADE的情况下降低疾病的严重程度，但可以 引起非中和，甚至自动反应性抗体。为了应对这些挑战，基于结构的方法 该提议将 研究增加在侧脊（LR）上发现异源表位的免疫力的方法 diii和NS1的β-磁通剂，同时掩盖了这些免疫原子上的某些表位，以诱导广泛的体液 保护和缓解疾病的严重程度。我们以前证明了强大的免疫保护潜力 同型ZV免疫策略，该策略涉及以LR为中心的DIII突变体的多价显示 到纳米颗粒上。我们将研究各种异型纳米颗粒作为交叉免疫的有效性 针对ZV和DV的策略，表征了对小鼠免疫接种的基本体液反应（AIM 1）。然后，我们将探索Miniβ的设计，Miniβ是一种新型的NS1突变体，可用于遏制疾病 进展而不引起ADE或自动反应性抗体（AIM 2）。这些研究将进一步我们的理解 对黄病毒感染的自适应免疫反应，并可能为开发新颖的框架提供一个框架 疫苗和基于抗体的治疗。