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A universal influenza vaccine by dual-domain fusion with a novel carrier protein

一种与新型载体蛋白双结构域融合的通用流感疫苗

基本信息

批准号：
8305459
负责人：
Yawei Ni
金额：
$ 27.79万
依托单位：
KJ BIOSCIENCES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-22 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8305459
关键词：
Adjuvant Amino Acids Animal Model Animals Antibodies Antigens Archaea Bacteria Carrier Proteins Cells Chimeric Proteins Clinical Research DNA-Binding Proteins Development Epidemic Escherichia coli Evaluation Ferrets Future Generations Goals Heating High temperature of physical object Hour Immune response Industry Influenza Influenza A virus Influenza B virus Life Measures Membrane Proteins Modeling Mus Mutation Peptides Phase Positioning Attribute Primates Process Property Reaction Recombinant DNA Refrigeration Resistance Stress Sulfolobus solfataricus Surface Surface Antigens System Techniques Tertiary Protein Structure Testing Toxicology Vaccines Virus aluminum sulfate base hyperthermophile immunogenicity influenza epidemic influenza virus strain influenza virus vaccine influenzavirus meetings nanoparticle novel pandemic disease pre-clinical protective effect research study vaccine candidate vaccine development vaccine effectiveness

项目摘要

DESCRIPTION (provided by applicant): The rapid genetic changes of influenza viruses continue to cause great difficulties with current strain- specific influenza vaccines in providing adequate control for influenza epidemics and effective countermeasures against pandemics. Thus, a universal vaccine that targets conserved antigen domains and provides protection against all influenza virus strains is urgently needed. The M2e and fusion peptide (FP) are the two most highly conserved antigen domains found in influenza virus surface proteins. The M2e (24 amino acids) is conserved among all influenza A viruses and the FP (14 amino acids) is conserved among both influenza A and B viruses. Current development efforts for a universal vaccine have primarily focused on single-domain constructs based on M2e. As the conserved antigen domains consist of just short peptides, an effective multivalent protein carrier system is critical in enhancing vaccine effectiveness and product feasibility with respect to manufacturing, storage, distribution, and use. KJ Biosciences aims to meet this urgent need by developing a novel dual-domain universal influenza vaccine incorporating both M2e and FP antigen domains that will provide protection against all influenza A and B viruses and can therefore be used to control influenza epidemics as well as pandemics. It will be produced by dual-domain fusion with a unique nanoparticle protein carrier that has both N- and C-termini exposed on the surface for antigen attachment. The vaccine product can also be stabilized at room or higher temperatures based on the unique properties of the carrier protein. A thermostable vaccine will significantly reduce the logistical requirements for storage, distribution, and use of the vaccine product, which is especially important when facing a pandemic. The goal of this proposal is to continue to develop this dual-domain universal influenza vaccine based on the promising results from preliminary studies. The proposed studies have two specific aims. Specific aim 1: Generation and characterization of the fusion proteins. Dual-domain fusion proteins with M2e and FP antigen domains arranged in different positions will be generated with the nanoparticle carrier protein by recombinant DNA techniques. They will be tested to demonstrate nanoparticle formation, reaction with antibodies specific to the antigen domains, and stability at room or higher temperatures. Specific aim 2: Immunogenicity and protection. Selected dual-domain fusion protein vaccine candidate (s) will be tested in animal models to demonstrate that the vaccine candidate can induce specific antibodies and protect animals against challenge with live influenza viruses. Completion of these two specific aims will form the basis for further preclinical immunogenicity evaluation and process development to produce the candidate vaccine for toxicology and phase I clinical studies. Successful development of this vaccine will afford an effective measure for controlling influenza epidemics and also greatly enhance our ability to respond to future pandemics.

描述（由申请方提供）：流感病毒的快速遗传变化继续给当前株特异性流感疫苗提供充分控制流感流行和有效对抗大流行带来巨大困难。因此，迫切需要靶向保守抗原结构域并提供针对所有流感病毒株的保护的通用疫苗。M2 e和融合肽（FP）是在流感病毒表面蛋白中发现的两个最高度保守的抗原结构域。M2 e（24个氨基酸）在所有甲型流感病毒中是保守的，FP（14个氨基酸）在甲型流感病毒和B流感病毒中都是保守的。目前通用疫苗的开发工作主要集中在基于M2 e的单结构域构建体上。由于保守的抗原结构域仅由短肽组成，因此有效的多价蛋白载体系统对于增强疫苗有效性和关于制造、储存、分配和使用的产品可行性至关重要。 KJ Biosciences旨在通过开发一种新型双结构域通用流感疫苗来满足这一迫切需求，该疫苗包含M2 e和FP抗原结构域，将提供针对所有甲型和B型流感病毒的保护，因此可用于控制流感流行和大流行。它将通过与独特的纳米颗粒蛋白载体的双结构域融合产生，该载体具有暴露在表面上用于抗原附着的N-和C-末端。基于载体蛋白的独特性质，疫苗产品也可以在室温或更高温度下稳定。热稳定性疫苗将显著降低疫苗产品的储存、分配和使用的物流要求，这在面临大流行时尤其重要。该提案的目标是在初步研究的有希望结果的基础上继续开发这种双结构域通用流感疫苗。拟议的研究有两个具体目标。具体目标1：融合蛋白的产生和表征。将通过重组DNA技术用纳米颗粒载体蛋白产生具有排列在不同位置的M2 e和FP抗原结构域的双结构域融合蛋白。将对它们进行测试以证明纳米颗粒形成、与抗原结构域特异性抗体的反应以及在室温或更高温度下的稳定性。具体目标2：免疫原性和保护。选定的双结构域融合蛋白候选疫苗将在动物模型中进行测试，以证明候选疫苗可以诱导特异性抗体并保护动物免受活流感病毒的攻击。这两个具体目标的完成将为进一步的临床前免疫原性评价和工艺开发奠定基础，以生产用于毒理学和I期临床研究的候选疫苗。该疫苗的研制成功将为控制流感流行提供一种有效的手段，也将大大提高我们应对未来流感大流行的能力。