Strategies for next-generation flavivirus vaccine development

下一代黄病毒疫苗开发策略

基本信息

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
项目类别：
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

项目摘要

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媒病毒，有 40 亿人生活在使他们面临感染 DV 四种血清型（DV1-4）及其相关病毒的风险的区域。黄病毒寨卡病毒（ZIKV；ZV）临床上可能表现为轻度流感样症状、皮疹和严重关节痛。 DV病例可进展为出血热和休克综合征，而ZV感染则出现严重并发症包括成人格林-巴利综合征和新生儿小头畸形与严重登革热有关。抗体依赖性感染增强（ADE），这种现象被认为可能是致命的。原发性 DV 感染后，免疫系统会产生抗体，可以结合并中和该血清型然而，在随后的异型 DV 血清型或 ZV 感染过程中，一些抗体会出现。来自原发感染的病毒被重新引发，但可能很难中和异型感染；这些抗体可促进表达 Fcγ 受体的免疫细胞吸收活性病毒，从而消除感染目前，需要疫苗和抗病毒药物。不存在诱发 ADE 风险的 DV 和 ZV 病毒疗法避免 ADE，这是 DV 的一个重要目标。 ZV 疫苗的开发是为了引发广泛的保护性抗体，而不是广泛的反应性、非我们确定了 DV 和 ZV 表达的两种糖蛋白作为有利的候选者。针对 DV 和 ZV 的中和保护性抗体已显示出以结构域 III (DIII) 为目标。 E 糖蛋白，这对于病毒进入和细胞附着至关重要，然而，它是非中和性的，ADE 诱导的。抗体还被鉴定为与 WT DIII 上的其他基序结合，从而发挥作用。在病毒复制和内皮功能障碍中发挥关键作用，无需 ADE 即可降低疾病严重程度，但也可能引发非中和性甚至自身反应性抗体为了应对这些挑战，基于结构的方法。可用于免疫原诱变和这些免疫原的多价展示。研究增加侧脊（LR）上发现的异源表位免疫优势的方法 DIII 和 NS1 的 β-阶梯，同时掩盖这些免疫原上的某些表位，以诱导广泛的体液免疫我们之前证明了强大的免疫保护潜力。同型 ZV 免疫策略的研究，其中涉及以 LR 为中心的 DIII 突变体的多价展示我们将研究各种异型纳米粒子作为交叉免疫的有效性。针对 ZV 和 DV 的策略并表征小鼠对免疫接种的潜在体液反应（Aim 1) 然后我们将探索 miniβ 的设计，这是一种可用于抑制疾病的新型 NS1 突变体。不会引起 ADE 或自身反应性抗体的进展（目标 2）。对黄病毒感染的适应性免疫反应的研究，可能为开发新的疫苗和基于抗体的疗法。