Development of a Universal Influenza Vaccine Against Influenza A and B Viruses

开发针对甲型和乙型流感病毒的通用流感疫苗

• 批准号: 10291415
• 负责人: Harvinder Singh Gill
• 金额: $ 68.74万
• 依托单位: TEXAS TECH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-12 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291415
• 关键词: Allergen Immunotherapy; Amino Acid Sequence; Amino Acids; Antibodies; Antibody titer measurement; Antigens; Antiviral Therapy; Avian Influenza; B-Lymphocytes; Binding; Biochemistry; Biodistribution; Birds; Blood; Cells; Cellular Assay; Cellular Immunity; Child; Complement; Complex; Consensus; Consensus Sequence; Development; Disease Outbreaks; Dose; Elderly; Enzyme-Linked Immunosorbent Assay; Epidemic; Epitopes; Extracellular Domain; Family suidae; Ferrets; Formulation; Freeze Drying; Future; Gills; Gold; Growth; Head; Hemagglutinin; High temperature of physical object; Human; Humoral Immunities; Immune; Immunity; In Vitro; Inbred BALB C Mice; Inbred Mouse; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Influenza B Virus; Influenza vaccination; Ion Channel; Longevity; Membrane Proteins; Modeling; Molecular Conformation; Morbidity - disease rate; Mus; Neuraminidase; Organ; Pathogenicity; Peptides; Phenotype; Population; Proteins; Public Health; Research; Role; Safety; Serum; Solid; Standardization; Structure; Surface; System; T-Lymphocyte; Testing; Time; Tissues; Transgenic Mice; Vaccinated; Vaccine Antigen; Vaccine Design; Vaccines; Virus; Zoonoses; base; design; genetic makeup; immunogenic; immunogenicity; in vitro Assay; in vivo; influenza virus strain; influenza virus vaccine; influenzavirus; mortality; nanoGold; pandemic disease; pandemic influenza; pathogen; protein aminoacid sequence; response; seasonal influenza; swine influenza; transmission process; universal influenza vaccine; vaccine delivery; vaccine development; vaccine efficacy; vaccine evaluation; vaccine formulation; vaccine immunotherapy; vaccine response; vaccine-induced immunity; vaccinology

Development of a Universal Influenza Vaccine Against Influenza A and B Viruses Influenza virus causes widespread mortality and morbidity every year. In addition, the threat of an influenza pandemic continues to persist. For current seasonal licensed vaccines to be effective the influenza strain in the formulation should match that which is circulating in the human population. Unfortunately, making a prediction of the influenza strains that are likely to circulate in the human population in the future is not very reliable. As a result, an error in this prediction can make the vaccine ineffective. This unreliability of the vaccine exists because the vaccine is based on one of the most abundant membrane proteins called hemagglutinin found on the influenza virus surface. Because hemagglutinin changes from one strain to the next, a proper match between circulating influenza strains and that in the vaccine is important. Furthermore, because the identity of a future pandemic strain cannot be predicted, it is hard to develop a vaccine for pandemic influenza based on hemagglutinin's head region as an antigen. To overcome the limitation of the current vaccine design we propose to use highly conserved antigens to formulate an influenza vaccine. One of these conserved antigens is from the ion channel membrane protein called matrix 2 (M2). The domain of M2 exposed on the surface of the virus is called M2e, and it has remained highly conserved in human influenza A strains. By attaching consensus human M2e on the gold nanoparticle surface we have shown breadth of protection against H1N1 and H3N2 influenza A strains, and even the highly pathogenic avian influenza strain H5N1. The vaccine was however only partially protective against the highly pathogenic avian influenza A H7N9 strain. The reason is that M2e on avian and swine influenza strains shows some dissimilarity from M2e of human influenza strains. Therefore, we propose that inclusion of M2e of human, avian and swine influenza strains as the vaccine antigen will increase the breadth of protection. The second conserved antigen is an epitope from the neuraminidase membrane protein of the influenza virus. This epitope is conserved across influenza A and B strains. We hypothesize that inclusion of both M2e and the conserved neuraminidase epitope will help to design a universal influenza vaccine protective against a broad range of strains. Our specific aims are: AIM 1: Develop the multi-antigen vaccine formulation, and establish its breadth and longevity of protection in Balb/c mice. AIM 2: Characterize the role of humoral and cellular immunity in the mechanism of protection, and assess biodistribution and safety profile of the vaccine. AIM 3: Establish vaccine efficacy in ferrets, and evaluate vaccine thermal stability. The influenza vaccine designed through this research is expected to have a broad and significant impact on public health. If successful, the vaccine will offer broad protection against both influenza A and B strains, eliminating the need for seasonal vaccines, and significantly reducing the threat of pandemic outbreaks due to influenza virus.

开发针对流感和B病毒的普遍流感疫苗 流感病毒每年会导致广泛的死亡率和发病率。此外，流感的威胁 大流行继续持续存在。为了使当前的季节性许可疫苗有效 配方应与人口中循环的配方匹配。不幸的是，做出预测 未来可能在人口中流通的流感菌株中，这不是很可靠。作为 结果，该预测中的错误可能会使疫苗无效。疫苗的这种不可靠性存在 因为该疫苗是基于最丰富的膜蛋白之一，称为血凝素 流感病毒表面。因为血凝集素从一个菌株变为下一个，所以适当的匹配 在循环流感菌株和疫苗中的循环菌株之间很重要。此外，因为 无法预测未来的大流行菌株，很难基于 血凝素的头部作为抗原。 为了克服当前疫苗设计的限制，我们建议使用高度保守的抗原 制定流感疫苗。这些保守的抗原之一是来自离子通道膜蛋白 称为矩阵2（M2）。暴露在病毒表面上的M2的域称为M2E，并且保留 在人类流感A菌株中高度保守。通过将共识的人类M2E连接到金纳米颗粒上 表面我们显示了针对H1N1和H3N2流感菌株的保护广度，甚至高度 致病性禽流感H5N1。然而，疫苗仅部分保护 致病性禽流感A H7N9菌株。原因是M2E在鸟类和猪流感菌株上显示 与人类流感菌株的M2E有些不同。因此，我们建议包含M2E 人，禽和猪流感菌株作为疫苗抗原将增加保护的广度。这 第二保守的抗原是流感病毒神经氨酸酶膜蛋白的表位。这 在流感和B菌株中保存了表位。 我们假设包括M2E和保守的神经氨酸酶表位将有助于 设计一种通用的流感疫苗保护剂，以针对各种菌株进行保护。我们的具体目的是：目标1： 开发多抗原疫苗配方，并在BALB/C中建立保护的广度和寿命 老鼠。目标2：表征体液和细胞免疫在保护机理中的作用，以及 评估疫苗的生物分布和安全性。目标3：在雪貂中建立疫苗功效，并 评估疫苗的热稳定性。通过这项研究设计的流感疫苗预计将具有 对公共卫生的广泛影响。如果成功，该疫苗将为两者提供广泛的保护 流感和B菌株，消除了对季节性疫苗的需求，并大大减少了威胁 流感病毒引起的大流行爆发。