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: 10519103
• 负责人: Harvinder Singh Gill
• 金额: $ 66.8万
• 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 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10519103
• 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; 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, H7N9 Subtype; Influenza A virus; Influenza B Virus; Influenza vaccination; Ion Channel; Licensing; Longevity; Membrane Proteins; Modeling; Molecular Conformation; Morbidity - disease rate; Mus; Neuraminidase; Organ; Pathogenicity; Peptides; Phenotype; Population; Proteins; Public Health; Research; Role; Safety; Seasons; Serum; Solid; Standardization; Structure; Surface; System; T-Lymphocyte; Testing; Time; Tissues; Transgenic Mice; Vaccinated; Vaccine Antigen; Vaccine Design; Vaccines; Virus; Zoonoses; design; future pandemic; genetic makeup; immunogenic; immunogenicity; in vitro Assay; in vivo; influenza virus strain; influenza virus vaccine; influenzavirus; inhibiting antibody; mortality; nanoGold; pandemic disease; pandemic influenza; pandemic potential; 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.

抗甲型和乙型流感病毒通用流感疫苗的研制

项目成果

Peptide Cross-Linking Using Tyrosine Residues Facilitated by an Exogenous Nickel-Histidine Complex: A Facile Approach for Enhancing Vaccine-Specific Immunogenicity.

利用外源镍-组氨酸复合物促进的酪氨酸残基进行肽交联：一种增强疫苗特异性免疫原性的简便方法。

• DOI: 10.1021/acsinfecdis.2c00265
• 发表时间: 2022
• 期刊: ACS infectious diseases
• 影响因子: 5.3
• 作者: Wilks,LoganR;Joshi,Gaurav;Kang,Sang-Moo;Wang,Bao-Zhong;Gill,HarvinderSingh
• 通讯作者: Gill,HarvinderSingh

Tyrosine-Based Cross-Linking of Peptide Antigens to Generate Nanoclusters with Enhanced Immunogenicity: Demonstration Using the Conserved M2e Peptide of Influenza A.

• DOI: 10.1021/acsinfecdis.1c00219
• 发表时间: 2021-09-10
• 期刊: ACS infectious diseases
• 影响因子: 5.3
• 作者: Wilks LR;Joshi G;Grisham MR;Gill HS
• 通讯作者: Gill HS

M2e conjugated gold nanoparticle influenza vaccine displays thermal stability at elevated temperatures and confers protection to ferrets.

• DOI: 10.1016/j.vaccine.2021.07.032
• 发表时间: 2021-08-09
• 期刊: Vaccine
• 影响因子: 5.5
• 作者: Ingrole RSJ;Tao W;Joshi G;Gill HS
• 通讯作者: Gill HS