Development of a broadly neutralizing influenza virus vaccine

开发广泛中和流感病毒疫苗

• 批准号: 8028160
• 负责人: Anette Schneemann
• 金额: $ 23.69万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8028160
• 关键词: Accounting; Antibodies; Antibody Formation; Binding; Biological Assay; Clinical; Cloning; Cryoelectron Microscopy; Development; Disease; Effectiveness; Enzyme-Linked Immunosorbent Assay; Epitopes; Goals; Hemagglutinin; Housing; Human; Immune response; Infection; Influenza A Virus, H1N1 Subtype; Influenza Hemagglutinin; Influenza vaccination; Insect Viruses; Lead; Life; Membrane Proteins; Monoclonal Antibodies; Morbidity - disease rate; Mus; Mutate; Mutation; Population; Proteins; Research; Resistance; Seasons; Serum; Solutions; Structure; Surface; Testing; Vaccinated; Vaccination; Vaccine Design; Vaccines; Viral; Virion; Virus; Virus Diseases; Virus-like particle; base; design; design and construction; expectation; falls; human subject; image reconstruction; in vivo; influenza outbreak; influenza virus strain; influenza virus vaccine; influenzavirus; mortality; neutralizing antibody; neutralizing monoclonal antibodies; novel strategies; pandemic disease; particle; research and development; swine flu; vaccine development

DESCRIPTION (provided by applicant): Influenza viruses cause significant morbidity and mortality every year. Vaccines that protect from influenza virus infection are available but they have to be re-formulated annually because their effectiveness is limited to seasonal strains. The high mutation rate of influenza virus, specifically the highly variable antigenic structure of the viral surface protein hemagglutinin (HA) is at the core of this problem. The influenza virus vaccine is reliant on an antibody response to HA and vaccines are manufactured based on predictions of which strains are the most likely to circulate in a given season. These predictions can be inaccurate, leading to ineffective vaccines. Moreover, they do not account for the emergence of pandemic strains as exemplified by the H1N1 "swine flu" outbreak in 2009. Annual vaccination campaigns are also costly and there is increasing resistance to vaccination in a significant segment of the population. A universal influenza virus vaccine that affords lifetime protection against seasonal and pandemic strains would be a solution to these problems. We propose a novel strategy to develop such a universal influenza virus vaccine. The strategy is based on the recent discovery of a broadly neutralizing epitope in the influenza HA. We plan to graft this epitope onto the surface of a virus-like particle (VLP) platform that is based on the insect virus Flock House virus (FHV). FHV VLPs allow presentation of foreign epitopes in a polyvalent manner and induce a potent antibody response. Chimeric FHV particles displaying the HA epitope will be structurally characterized by cryoEM and image reconstruction as well as binding assays using the broadly neutralizing monoclonal antibodies. The particles will then be used to vaccinate mice and their antibody response will be characterized by ELISA and microneutralization assays. It is expected that immunized mice generate neutralizing antibodies and this will be confirmed by challenge studies with live virus. If successful, the proposed research could lead to a transformation in flu vaccination by eliminating the challenges currently associated with this endeavor. PUBLIC HEALTH RELEVANCE: In this application we propose to develop a new influenza virus vaccine that needs to be administered only once and then protects for a lifetime against all seasonal and pandemic strains. The strategy that we will use is based on a recent discovery that there is a region in the influenza hemagglutinin protein that does not mutate and can give rise to antibodies that neutralize many different influenza viruses. We will isolate this region of the hemagglutinin protein and graft it on a carrier particle that is known to induce a very potent immune response.

描述（由申请人提供）：流感病毒每年都会导致显着的发病率和死亡率。预防流感病毒感染的疫苗是可用的，但必须每年重新配制，因为它们的有效性仅限于季节性毒株。流感病毒的高突变率，特别是病毒表面蛋白血凝素（HA）高度可变的抗原结构是这个问题的核心。流感病毒疫苗依赖于对 HA 的抗体反应，并且疫苗是根据对特定季节最有可能传播的毒株的预测来生产的。这些预测可能不准确，导致疫苗无效。此外，它们没有考虑到大流行毒株的出现，例如 2009 年 H1N1“猪流感”爆发。每年的疫苗接种活动成本也很高，而且很大一部分人口对疫苗接种的抵抗力日益增强。一种能够提供针对季节性和大流行毒株的终生保护的通用流感病毒疫苗将是解决这些问题的方法。我们提出了一种开发这种通用流感病毒疫苗的新策略。该策略基于最近在流感 HA 中发现的广泛中和表位。我们计划将该表位移植到基于昆虫病毒 Flock House 病毒 (FHV) 的病毒样颗粒 (VLP) 平台的表面。 FHV VLP 允许以多价方式呈现外源表位并诱导有效的抗体反应。显示 HA 表位的嵌合 FHV 颗粒将通过冷冻电镜和图像重建以及使用广泛中和单克隆抗体的结合测定来进行结构表征。然后，这些颗粒将用于给小鼠接种疫苗，并通过 ELISA 和微中和测定来表征其抗体反应。预计免疫小鼠会产生中和抗体，这将通过活病毒的攻击研究得到证实。如果成功，拟议的研究可能会消除目前与这一努力相关的挑战，从而导致流感疫苗接种的转变。 公共卫生相关性：在此应用中，我们建议开发一种新的流感病毒疫苗，只需注射一次，即可终生预防所有季节性和大流行病毒株。我们将使用的策略基于最近的一项发现，即流感血凝素蛋白中有一个区域不会突变，并且可以产生中和许多不同流感病毒的抗体。我们将分离血凝素蛋白的这个区域，并将其移植到已知能诱导非常有效的免疫反应的载体颗粒上。