Surrogate endpoints for correlating protective immunity in response to influenza

流感反应中保护性免疫相关的替代终点

• 批准号: 7608534
• 负责人: Gary Fujii
• 金额: $ 30万
• 依托单位: MOLECULAR EXPRESS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7608534
• 关键词: Active immunity; Amino Acids; Animals; Antigens; Biological; Bird Flu vaccine; Chimeric Proteins; Complex; DNA Sequence Rearrangement; Epidemic; Epitopes; Evaluation; Ferrets; Goals; Haemophilus influenzae; Hemagglutinin; Human; Immune response; Immunity; Immunization; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza vaccination; Lipid Bilayers; Liposomes; M2 protein; Membrane Proteins; Modeling; Monitor; Mus; Mutation; N-terminal; Neuraminidase; Phase; Population; Primates; Procedures; Property; Proteins; Recombinant Fusion Proteins; Recombinant Proteins; Small Business Innovation Research Grant; Structural Protein; Surrogate Endpoint; Technology; Tertiary Protein Structure; Testing; Vaccines; Variant; Viral; Viral Genome; Viral Proteins; Virus; Virus Diseases; Water; base; comparative; design; efficacy evaluation; influenza virus vaccine; nonhuman primate; novel strategies; novel vaccines; pandemic disease; programs; research clinical testing; response; vaccine candidate; vaccine development; water solubility; weapons

DESCRIPTION (provided by applicant): Influenza represents one of the most serious and common pandemic/epidemic viral diseases of human populations. Rapid mutations and rearrangements of the viral genome allow the virus to evade host immune responses, making the frequent development of vaccines to new viral variants necessary. We have developed a new approach to immunization for influenza that combines a unilamellar liposome carrier with a recombinant protein expressing specific antigenic epitopes. The recombinant protein immunogen incorporates a conserved N-terminal sequence of the structural M2 protein prospectively constructed to represent a variety of influenza H and N subtypes. The antigenic component of the protein is fused to a water-soluble hydrophobic protein domain that facilitates efficient integration of the antigen to lipid bilayer membranes. The water solubility properties of the hydrophobic fusion protein allows for its isolation and purification using commercially viable preparative procedures. We have previously shown that a M2e-based influenza vaccine (L-IAVM2e1-HD) stimulates active protective responses in mice and the objective of our present proposal is to confirm that the L-IAVM2e1-HD vaccine will provide similar protective immunity in ferrets and non-human primates. Comparative evaluation of the L-IAVM2e1-HD vaccine in ferrets and non-human primates are important studies because: 1) the ferret is a widely accepted model for testing of influenza vaccine candidates prior to clinical testing and; 2) the correlates of protective immunity are unknown for M2-based vaccines in higher animals and thus, the establishment of surrogate endpoints for monitoring protective immune responses will be essential for setting the criteria for clinical testing of other M2 vaccine candidates where evaluation of efficacy, i.e., as in the case of an avian influenza vaccine, will not be possible. We believe that testing of the LIAVM2e1- HD vaccine will demonstrate that it is a highly effective means of stimulating protective responses against a structural, conserved viral protein, thereby facilitating the development of a vaccine against influenza that would not be rendered ineffective by antigenic shifts and/or drifts associated with mutations of the influenza H and N surface proteins. Vaccines based upon recombinant protein technologies also offer the opportunity to rapidly and efficiently adjust to changes in the virus, either natural or man-made, to generate new vaccines as needed. Taken together, the attractive features of this vaccine technology are designed to provide a major improvement in our ability to respond to influenza infections and the potential use of influenza as a biological weapon. PUBLICE HEALTH RELEVANCE: The long range goal of this vaccine program is to develop a unique new approach to immunization against pandemic/epidemic strains of IAV that will provide protection from infection by a variety of different viral subtypes. This approach is based on the use of the N-terminal ectodomain segment of the Matrix 2 (M2e) protein as an alternative to the haemagglutinin (H or HA) or neuraminidase (N) antigens for vaccine development. Our central hypothesis is that the M2e recombinant fusion protein, when presented in a multimeric configuration as a liposomal complex, can be used as a human vaccine that will provide broader protection against infection by different H and N influenza subtypes. The underlying rationale guiding our hypothesis is that the M2e structural protein is highly conserved and thus, the development of a vaccine that is capable of stimulating active immunity to the N-terminal amino acid ectodomain segment would provide protection against infection by multiple strains of IAV. The studies proposed in this SBIR AT Phase I application are focused on demonstrating the ability of an M2e-based vaccine to stimulate protective immune responses against an H1N1 strain of IAV in ferrets and a non-human influenza primate model.

描述（由申请人提供）：流感是人类最严重和最常见的大流行/流行性病毒性疾病之一。病毒基因组的快速突变和重排使病毒能够逃避宿主的免疫反应，因此有必要频繁开发针对新病毒变种的疫苗。我们开发了一种新的流感免疫方法，该方法将单层脂质体载体与表达特定抗原表位的重组蛋白相结合。重组蛋白免疫原包含预期构建的结构 M2 蛋白的保守 N 端序列，以代表多种流感 H 和 N 亚型。该蛋白质的抗原成分与水溶性疏水蛋白结构域融合，有利于抗原有效整合到脂质双层膜上。疏水性融合蛋白的水溶性特性允许使用商业上可行的制备程序进行分离和纯化。我们之前已经证明，基于 M2e 的流感疫苗 (L-IAVM2e1-HD) 可刺激小鼠的主动保护性反应，我们目前提案的目的是确认 L-IAVM2e1-HD 疫苗将在雪貂和雪貂中提供类似的保护性免疫。非人类灵长类动物。 L-IAVM2e1-HD 疫苗在雪貂和非人类灵长类动物中的比较评估是重要的研究，因为：1) 雪貂是临床测试前测试候选流感疫苗的广泛接受的模型； 2) 对于高等动物中基于 M2 的疫苗，保护性免疫的相关性尚不清楚，因此，建立监测保护性免疫反应的替代终点对于制定其他 M2 候选疫苗的临床测试标准至关重要，其中评估功效，即，就像禽流感疫苗一样，这是不可能的。我们相信，LIAVM2e1-HD 疫苗的测试将证明它是一种非常有效的方法，可以刺激针对结构性保守病毒蛋白的保护性反应，从而促进流感疫苗的开发，该疫苗不会因抗原转变而失效，并且/或与流感H和N表面蛋白突变相关的漂移。基于重组蛋白技术的疫苗还提供了快速有效地适应天然或人造病毒变化的机会，以根据需要生产新疫苗。总而言之，这种疫苗技术的吸引人的特点旨在大大提高我们应对流感感染的能力以及流感作为生物武器的潜在用途。公共健康相关性：该疫苗计划的长期目标是开发一种独特的新方法来免疫 IAV 的大流行/流行株，从而提供免受各种不同病毒亚型感染的保护。该方法基于使用 Matrix 2 (M2e) 蛋白的 N 端胞外域片段作为疫苗开发中血凝素（H 或 HA）或神经氨酸酶 (N) 抗原的替代品。我们的中心假设是，当 M2e 重组融合蛋白以脂质体复合物的多聚体结构存在时，可以用作人类疫苗，为不同 H 型和 N 型流感亚型的感染提供更广泛的保护。指导我们假设的基本原理是 M2e 结构蛋白高度保守，因此，开发能够刺激对 N 端氨基酸胞外域片段主动免疫的疫苗将提供针对多种 IAV 菌株感染的保护。 SBIR AT I 期申请中提出的研究重点是证明基于 M2e 的疫苗能够在雪貂和非人类流感灵长类动物模型中刺激针对 H1N1 IAV 株的保护性免疫反应。