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）：流感代表了人类人群中最严重，最常见的大流行/流行病病毒疾病之一。病毒基因组的快速突变和重排使病毒逃避宿主的免疫反应，从而使疫苗频繁开发到必要的新病毒变异体中。我们已经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结合在一起。重组蛋白免疫原结合了前瞻性构建的结构M2蛋白的保守N末端序列，该蛋白代表了多种流感H和N亚型。该蛋白质的抗原成分融合到水溶性疏水蛋白结构域，促进抗原与脂质双层膜的有效整合。疏水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。我们先前已经表明，基于M2E的流感疫苗（L-IAVM2E1-HD）刺激小鼠中的主动保护反应，而我们目前的建议的目的是确认L-IAVM2E1-HD疫苗将在雪貂和非人类灵长类动物中提供类似的保护性免疫。雪貂和非人类灵长类动物中L-IAVM2E1-HD疫苗的比较评估是重要的研究，因为：1）雪貂是在临床测试之前候选流感疫苗候选物的广泛接受的模型。 2）在高等动物中，基于M2的疫苗的保护性免疫相关性是未知的，因此，建立用于监测保护性免疫反应的替代端点对于设定其他M2疫苗候选临床测试的标准至关重要。我们认为，对LIAVM2E1-HD疫苗的测试将表明，这是一种刺激针对结构性，保守的病毒蛋白的保护性反应的一种高效手段，从而促进了针对流感的疫苗的发展，而抗幻想的转移和/或漂移蛋白与Intece Intece Inte and and trance Inte and and and trance Inte and Intece and and Intece and and trance toce and and and Inte trout and and and and tose则不得不效率无效。基于重组蛋白技术的疫苗还提供了机会，可以快速有效地适应天然或人造病毒的变化，以根据需要生成新的疫苗。综上所述，这种疫苗技术的吸引人特征旨在为我们对流感感染的反应和潜在使用流感作为生物武器的能力提供了重大改进。公众健康相关性：该疫苗计划的远距离目标是开发一种针对IAV的大流行/流行病菌株的独特的免疫方法，该方法将通过各种不同的病毒亚型提供保护免受感染的保护。这种方法基于使用基质2（M2E）蛋白的N末端外部域段用作血凝素（H或HA）或神经氨酸酶（N）抗原来替代疫苗的发育。我们的中心假设是，当在多聚体构型中作为脂质体络合物呈现M2E重组融合蛋白，可以用作人类疫苗，该疫苗将提供更广泛的保护，以通过不同的H和N流感亚型提供更广泛的保护，以防止感染。指导我们假设的基本原理是M2E结构蛋白是高度保守的，因此，能够刺激对N末端氨基酸型群节段的活跃免疫的疫苗的发育将通过多种IAV菌株提供防御感染的保护。在I阶段应用下，该SBIR提出的研究重点是证明基于M2E的疫苗刺激雪貂和非人类流感灵长类动物模型中IAV H1N1菌株的保护性免疫反应的能力。