Development of vaccination strategies to elicit broadly protective immunity against influenza

制定疫苗接种策略以引发针对流感的广泛保护性免疫力

• 批准号: 9796595
• 负责人: Peter Palese
• 金额: $ 86.48万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-18 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9796595
• 关键词: Affinity; Antibodies; Antibody Response; Antigen-Antibody Complex; Antigens; Avian Influenza A Virus; B-Lymphocytes; Cell Maturation; Cell physiology; Cells; Cellular Immunity; Containment; Dendritic Cells; Development; Disease Outbreaks; Domestic Fowls; Engineering; Epidemic; Epitopes; Exposure to; Fc domain; Formulation; Glycoproteins; Head; Hemagglutinin; Human; Humoral Immunities; IgG(T); Immune response; Immunity; Immunization; Immunodominant Epitopes; Immunoglobulin G; Immunologics; In Vitro; Infection; Influenza; Influenza A virus; Influenza Hemagglutinin; Influenza vaccination; Knowledge; Leukocytes; Life; Mediating; Modification; Mosaicism; Mutation; Pathway interactions; Phylogenetic Analysis; Prevention Measures; Process; Production; Proteins; Regimen; Regulatory Pathway; Research; Seasons; Seeds; Series; Signal Transduction; Site; Specificity; Surface; T cell response; T-Lymphocyte; Vaccination; Vaccine Production; Vaccines; Viral; Virus; Virus Diseases; adaptive immune response; adaptive immunity; anti-influenza; antiviral immunity; base; cost; cost effective; design; egg; immunogenic; immunogenicity; immunoregulation; improved; in vivo; influenza virus strain; influenza virus vaccine; influenzavirus; innovation; mouse model; next generation; novel; pandemic disease; preclinical evaluation; receptor; response; universal influenza vaccine; universal vaccine; vaccination strategy

ABSTRACT The most effective measure for the prevention of influenza virus infection is vaccination. However, due to ongoing antigenic drift, current influenza vaccines need annual reformulation to provide sufficient protection. Furthermore, immune responses elicited upon influenza vaccination are strain-specific and fail to provide protection against novel seasonal and pandemic viruses, necessitating the development of a universal influenza vaccine with the capacity to elicit lifelong protection against diverse influenza virus strains. A major target for the development of protective immunity against influenza is the hemagglutinin glycoprotein (HA), which comprises two distinct functional domains: the globular head, which participates in viral entry and is subject to antigenic drift, and the stalk domain, which is highly conserved and mediates viral fusion. Immunodominant antigenic sites on the HA head elicit high-affinity, strain-specific anti-HA Ab responses, whereas in contrast, Abs against conserved epitopes can mediate broadly protective activity, but are immunosubdominant. To overcome the inherent immunodominance of the HA head and refocus immunity towards conserved, cross-protective epitopes, we will engineer innovative mosaic HA protein immunogens in which HA head antigenic sites will be silenced. Our prior research demonstrated that vaccination with HA:anti-HA IgG immune complexes (ICs) can modulate adaptive immunity through specific interactions of the Fc domain of the IgG with Fcγ receptors (FcγR) on the surface of effector leukocytes. Our in-depth studies revealed that engagement of specific FcγRs: CD23 on B-cells and FcγRIIa on dendritic cells (DCs), is critical for the induction of high-affinity IgG responses and T-cell immunity, respectively. Based on this knowledge, we will exploit these pathways to broaden specificity, increase affinity and select for long-lived humoral and cellular immunity to conserved influenza epitopes. We will design and evaluate the immunogenicity of IC-based immunogens comprising mosaic HAs and Fc-engineered anti-HA IgGs with selective affinity for specific human FcγR types. These studies will lead to the development and pre-clinical evaluation of vaccination strategies to elicit robust and long-lasting antiviral immunity, which could improve the breadth of current seasonal vaccines, but could also be employed in the development of novel, next-generation universal influenza virus vaccines.

抽象的 预防流感病毒感染最有效的措施是接种疫苗。然而，由于持续 由于抗原漂移，目前的流感疫苗需要每年重新配制才能提供足够的保护。此外， 流感疫苗接种后引发的免疫反应是毒株特异性的，无法提供针对流感的保护 新型季节性和大流行性病毒，需要开发一种通用流感疫苗 获得针对多种流感病毒株的终身保护的能力。发展的主要目标 针对流感的保护性免疫是血凝素糖蛋白（HA），它包含两种不同的 功能域：球状头，参与病毒进入并受到抗原漂移的影响，以及 茎结构域，高度保守并介导病毒融合。 HA 上的免疫显性抗原位点 头引发高亲和力、菌株特异性抗 HA 抗体反应，而相反，针对保守的抗体 表位可以介导广泛的保护活性，但具有免疫抑制性。为了克服固有的 HA 头的免疫优势并将免疫重新集中于保守的、交叉保护性表位，我们将 设计创新的镶嵌 HA 蛋白免疫原，其中 HA 头抗原位点将被沉默。我们之前的 研究表明，接种 HA：抗 HA IgG 免疫复合物 (IC) 可以调节适应性 通过 IgG 的 Fc 结构域与表面的 Fcγ 受体 (FcγR) 的特异性相互作用来产生免疫 效应白细胞。我们的深入研究表明，特定 FcγR：CD23 对 B 细胞和 树突状细胞 (DC) 上的 FcγRIIa 对于诱导高亲和力 IgG 反应和 T 细胞免疫至关重要， 分别。基于这些知识，我们将利用这些途径来扩大特异性、增加亲和力 并选择针对保守流感表位的长效体液和细胞免疫。我们将设计和 评估包含嵌合 HA 和 Fc 工程抗 HA IgG 的基于 IC 的免疫原的免疫原性 对特定人类 FcγR 类型具有选择性亲和力。这些研究将导致开发和临床前 评估疫苗接种策略，以产生强大而持久的抗病毒免疫力，这可以改善 当前季节性疫苗的广度，但也可用于开发新型下一代疫苗 通用流感病毒疫苗。