Adenoviral Vector-based Pandemic Influenza Vaccine

基于腺病毒载体的大流行性流感疫苗

• 批准号: 10618965
• 负责人: SURESH K MITTAL
• 金额: $ 46.71万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618965
• 关键词: Adenovirus Vector; Adenoviruses; Africa; Amino Acids; Animals; Antigens; Asia; Autophagocytosis; Avian Influenza; Avian Influenza A Virus; Birds; Canis familiaris; Cattle; Cessation of life; China; Country; DNA cassette; Disease; Disease Outbreaks; Domestic Fowls; Dose; Event; Extracellular Domain; Far East; Felis catus; Ferrets; Generations; Genes; Genetic; Genotype; H5 influenza virus; Hemagglutinin; Human; Immune response; Immunity; Immunization; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H5N2 Subtype; Influenza A Virus, H7N7 Subtype; Influenza A Virus, H7N9 Subtype; Influenza A Virus, H9N2 Subtype; Influenza A virus; Influenza B Virus; Leucine Zippers; Link; Lung; Memory B-Lymphocyte; Modeling; Monitor; Morbidity - disease rate; Mus; Mutation; Mycobacterium tuberculosis; Natural Immunity; Nature; Outcome; Pathogenicity; Peptide Signal Sequences; Peptides; Porcine Influenza A Virus; Probability; Public Health; Reporting; Respiratory Disease; Seasons; System; T cell response; T-Lymphocyte; Technology; Testing; Upper respiratory tract; Vaccinated; Vaccines; Variant; Viral; Virus; Virus Diseases; Virus Replication; Zoonoses; adaptive immunity; cell mediated immune response; cross reactivity; design; enzootic; future pandemic; immunogenic; immunogenicity; improved; influenza virus strain; influenza virus vaccine; influenzavirus; mortality; mouse model; multiple myeloma M Protein; new pandemic; novel; pandemic disease; pandemic influenza; pandemic potential; pandemic preparedness; pandemic virus; prevent; protective efficacy; protein aminoacid sequence; seasonal influenza; stem; transmission process; universal influenza vaccine; unvaccinated; vaccine candidate; vaccine delivery; vaccine formulation; vaccine platform; vector; viral transmission

PROJECT SUMMARY The ability of both low and highly pathogenic avian influenza (HPAI) viruses of H5, H7, and H9 subtypes to repeatedly infect humans reveals their zoonotic nature and pandemic potential. Besides, the seasonal influenza viruses (H1N1, H3N2 & influenza B) continue to evolve and pose significant public health threats worldwide. While candidate vaccine viruses can be made for individual influenza strains, it is impractical to prepare significant vaccine stocks for each of the potentially pandemic viruses. The significance of developing a universal influenza vaccine is of utmost importance for developing a better strategy for combatting seasonal as well as potential pandemic influenza viruses. We have developed a novel replication-defective bovine adenovirus (Ad) type 3 (BAd3)-based vaccine platform, which is better than the currently available Ad vector systems for providing heterologous influenza protection with dose sparing and is not impacted by the pre-existing human Ad vector immunity. Recently, we have revealed that the BAd vaccine platform induces significantly higher expression levels of the immunogen and innate and adaptive immunity-related factors compared to that of human Ad vectors in mice. We have also identified a 22 amino acid residues Autophagy-Inducing Peptide (AIP) C5 (AIP-C5) from the CFP10 protein of M. tuberculosis that enhances robust T cell immune responses in mice to NP of H7N9 influenza virus when delivered through an Ad vector. It conferred complete protection (from disease, death, or lung viral titers) against H1N1, H3N2, H5N2, H7N9, and H9N2 influenza viruses. Immunization of mice with an Ad vector expressing H5N1 M2e-HA2 [the extracellular domain of matrix 2 linked to the stem portion (HA2) of hemagglutinin (HA) with the HA signal peptide and the GCN4 leucine zipper trimerization domain] led to a significant reduction in lung viral titers following challenge with an H5N1 virus. This proposal is based on the hypothesis that a combination of heterosubtypic cell-mediated immune (CMI) responses against NP and the cross-reactive (not necessarily cross-neutralizing) humoral immune responses against NP or other conserved domains (M2e-HA2), when expressed with AIP-C5 and delivered through the BAd vaccine platform, will provide broad protection against potential pandemic H5, H7, or H9 avian influenza viruses as well as seasonal H1, H3, and influenza B viruses. The aims of this proposal are: i) To investigate immunogenicity and protective efficacy of novel antigen design and vaccine delivery platform in a mouse model for developing universal influenza vaccines (Aim 1); ii) To ascertain immunogenicity and protective efficacy of two selected universal influenza vaccine formulations in ferrets (Aim 2); and iii) To monitor virus transmission from the vaccinated to non-vaccinated animals, the quality of memory B and T cell responses, the durability of protective and vector immunity, and potential vaccine-associated enhancement of respiratory disease (Aim 3), utilizing the state-of-the-art technologies.

项目摘要 H5，H7和H9亚型的低和高致病性禽流感（HPAI）病毒的能力 反复感染了人类的人畜共患病和大流行潜力。此外，季节性流感 病毒（H1N1，H3N2和流感b）在全球范围内继续发展并构成了重大的公共卫生威胁。 虽然可以为单个流感菌株制造候选疫苗病毒，但准备不切实际 每个潜在的大流行病毒的重要疫苗库存。发展通用的意义 流感疫苗对于制定更好的季节性策略以及 潜在的大流行性流感病毒。 我们已经开发了一种新型的复制缺陷性牛腺病毒（AD）3型（BAD3）的疫苗 平台，它比当前可用的AD矢量系统更好 保留剂量的保护，不受先前存在的人类AD载体免疫的影响。最近，我们 已经表明，不良疫苗平台可引起免疫原的表达水平明显更高 与小鼠人类AD媒介相比，与先天和适应性免疫相关的因素。我们也有 从CFP10蛋白的CFP10蛋白 结核分枝杆菌可增强小鼠对H7N9流感病毒NP的稳健T细胞免疫反应 通过广告向量传递。它授予了完全保护（疾病，死亡或肺病毒滴度） H1N1，H3N2，H5N2，H7N9和H9N2流感病毒。用AD载体表达小鼠免疫 H5N1 M2E-HA2 [基质2的细胞外结构域，与hemagglutinin（ha）的茎部分（HA2）链接 HA信号肽和GCN4亮氨酸拉链三聚化结构域]导致肺显着降低 H5N1病毒挑战后的病毒滴度。 该提议基于以下假设：异质细胞介导的免疫（CMI）的组合 针对NP的反应和交叉反应（不一定是交叉中和）体液免疫反应 用NP或其他保守域（M2E-HA2）用AIP-C5表示并通过 坏疫苗平台将为潜在的大流行H5，H7或H9禽流感提供广泛的保护 病毒以及季节性H1，H3和流感B病毒。该提议的目的是：i）调查 在小鼠模型中，新型抗原设计和疫苗输送平台的免疫原性和保护性疗效 用于开发普遍的流感疫苗（AIM 1）； ii）确定免疫原性和保护性 雪貂中的两种选定的通用流感疫苗制剂（AIM 2）； iii）监测病毒传播 从接种疫苗到未接种疫苗的动物，记忆B和T细胞反应的质量，耐用性 保护性和载体免疫，以及潜在的疫苗相关呼吸道疾病的增强（AIM 3）， 利用最先进的技术。

项目成果

Vaccine approaches conferring cross-protection against influenza viruses.

• DOI: 10.1080/14760584.2017.1379396
• 发表时间: 2017-11
• 期刊: Expert review of vaccines
• 影响因子: 6.2
• 作者: Vemula SV;Sayedahmed EE;Sambhara S;Mittal SK
• 通讯作者: Mittal SK

Beta-defensin 2 enhances immunogenicity and protection of an adenovirus-based H5N1 influenza vaccine at an early time.

• DOI: 10.1016/j.virusres.2013.09.013
• 发表时间: 2013-12-26
• 期刊: Virus research
• 影响因子: 5
• 作者: Vemula SV;Amen O;Katz JM;Donis R;Sambhara S;Mittal SK
• 通讯作者: Mittal SK

Adenoviral vector immunity: its implications and circumvention strategies.

• DOI: 10.2174/156652311796150372
• 发表时间: 2011-08
• 期刊: Current gene therapy
• 影响因子: 3.6
• 作者: Ahi YS;Bangari DS;Mittal SK
• 通讯作者: Mittal SK

Adenoviral Vector-Based Vaccine Platforms for Developing the Next Generation of Influenza Vaccines.

• DOI: 10.3390/vaccines8040574
• 发表时间: 2020-10-01
• 期刊: Vaccines
• 影响因子: 7.8
• 作者: Sayedahmed EE;Elkashif A;Alhashimi M;Sambhara S;Mittal SK
• 通讯作者: Mittal SK

Influenza Virus Infects and Depletes Activated Adaptive Immune Responders.

• DOI: 10.1002/advs.202100693
• 发表时间: 2021-08
• 期刊: Advanced science (Weinheim, Baden-Wurttemberg, Germany)
• 作者: Bohannon CD;Ende Z;Cao W;Mboko WP;Ranjan P;Kumar A;Mishina M;Amoah S;Gangappa S;Mittal SK;Lovell JF;García-Sastre A;Pfeifer BA;Davidson BA;Knight P;Sambhara S
• 通讯作者: Sambhara S