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: 9313764
• 负责人: SURESH K MITTAL
• 金额: $ 38.54万
• 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 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313764
• 关键词: Adenovirus Vector; Adenoviruses; Advanced Development; Africa; Asia; Avian Influenza; Avian Influenza A Virus; Birds; Case Fatality Rates; Cattle; Cellular Immunity; Cessation of life; China; Country; Development; Disease Outbreaks; Domestic Fowls; Epitopes; Evaluation; Event; Far East; Ferrets; Generations; Genes; Genetic; Goals; H7N7; Hemagglutinin; Human; Immune response; Immunity; Immunization; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N9 Subtype; Influenza A Virus, H9N2 Subtype; Influenza vaccination; Knowledge; Lead; Link; Longevity; Morbidity - disease rate; Mus; Mutation; Nature; Neuraminidase; Nucleoproteins; Outcome; Outcomes Research; Pathogenicity; Population; Porcine Influenza A Virus; Proteins; Public Health; Publications; Reporting; Series; Serotyping; Sialic Acids; System; T-Lymphocyte Epitopes; Testing; Time; Upper respiratory tract; Vaccines; Virus; Virus Replication; World Health Organization; alpha helix; base; cell mediated immune response; cross reactivity; efficacy study; immunogenic; immunogenicity; improved; influenza virus strain; influenza virus vaccine; influenzavirus; mortality; mouse model; neutralizing antibody; novel; pandemic disease; pandemic influenza; pandemic preparedness; prevent; protective efficacy; public health relevance; receptor internalization; response; seasonal influenza; stem; transmission process; vaccine development; vector; vector-based vaccine

 DESCRIPTION (provided by applicant): Since 1996, there have been numerous reports of human infections with avian influenza A viruses of subtypes H5N1, H7N7 and H9N2. In 2013, a new avian influenza virus strain of H7N9 subtype emerged in China causing more than 450 infections in humans resulting in 175 deaths so far. Although human-to-human transmission has been infrequent and limited, genetic reassortment between avian and human/porcine influenza viruses or mutations in some of the genes leading to virus replication in the upper respiratory tract in humans could result in the generation of a novel pandemic influenza virus strain that not only would infect but also effectively transmit among the human population which would have little or no immunity to the new virus. Our immunogenicity and protective efficacy studies showed that adenovirus (Ad) vector-based H5N1, H7N7 and H9N2 vaccines provide excellent humoral and cell-mediated immune responses leading to complete protection against challenges with H5N1, H7N7 and H9N2 influenza viruses. To further improve the breadth of protective efficacy, inclusion of neuraminidase (NA), in addition to hemagglutinin (HA) and nucleoprotein (NP), in the Ad vector-based vaccine formulations will be explored (first generation vaccines). The other strategy to enhance the breadth of protective efficacy against avian influenza viruses will be to include relatively conserved domains of influenza proteins for multi-epitope-based vaccines (second generation vaccines). This proposal is based on the hypothesis that a combination of heterosubtypic cell-mediated immunity against NP and the cross-reactive (not necessarily cross-neutralizing) humoral immune responses against other immunogenic proteins or domains will provide broad protection against potential pandemic H5N1, H7N9 or H9N2 avian influenza viruses as well as other H5, H7 or H9 divergent viruses. The vaccine approach will be based on the bovine adenovirus vector which induces improved levels of protective immune responses even in the presence of high levels of neutralizing antibodies against human Ad. The goals of this revised competitive renewal proposal are: Aim 1) Development and evaluation of the immunogenicity and protective efficacy of broadly protective Ad-based influenza vaccines (HA, NP & NA-based or immunogenic multi-epitope-based) against H5N1, H7N9, and H9N2 avian influenza viruses in mice; Aim 2) Evaluation of the immunogenicity and protective efficacy of selected broadly protective Ad-based vaccines against H5N1, H7N9, and H9N2 viruses in ferrets; and Aim 3) Determination of the longevity of protective influenza immunity and the decline of Ad vector immunity with time and its effect on repeat immunization with the same Ad vector. Our efforts will be directed towards the generation of broadly protective vaccines against H5, H7 and H9 influenza subtypes which would significantly lower morbidity, hinder transmission and prevent mortality in a pandemic situation before a strain-matched vaccine can be produced. The outcome of this research will significantly impact the development efforts for better vaccines against seasonal influenza viruses.

 描述（由申请人提供）：自1996年以来，已有大量人感染H5 N1、H7 N7和H9 N2亚型禽流感病毒的报告。2013年，中国出现了一种新的H7N9亚型禽流感病毒株，迄今已造成450多人感染，175人死亡。虽然人传人的情况并不常见，而且有限，但禽流感病毒和人/猪流感病毒之间的基因重组或导致病毒在人类上呼吸道复制的某些基因突变，可能导致产生一种新型大流行性流感病毒株，这种病毒株不仅会感染，而且会在对新病毒几乎没有免疫力或没有免疫力的人群中有效传播。 我们的免疫原性和保护效力研究表明，基于腺病毒（Ad）载体的H5 N1、H7 N7和H9 N2疫苗提供优异的体液和细胞介导的免疫应答，从而导致针对H5 N1、H7 N7和H9 N2流感病毒的攻击的完全保护。为了进一步提高保护效力的广度，将探索在基于Ad载体的疫苗制剂中除了血凝素（HA）和核蛋白（NP）之外还包括神经氨酸酶（NA）（第一代疫苗）。另一种增强抗禽流感病毒保护效力的策略是将流感蛋白的相对保守的结构域包括在基于多表位的疫苗（第二代疫苗）中。该提议基于以下假设：针对NP的异亚型细胞介导的免疫和针对其他免疫原性蛋白或结构域的交叉反应性（不一定是交叉中和性）体液免疫应答的组合将提供针对潜在的大流行性H5 N1、H7N9或H9 N2禽流感病毒以及其他H5、H7或H9趋异病毒的广泛保护。该疫苗方法将基于牛腺病毒载体，其即使在存在高水平的针对人Ad的中和抗体的情况下也诱导提高水平的保护性免疫应答。这项修订后的竞争性更新提案的目标是：目的1）开发和评价广泛保护性的基于Ad的流感疫苗的免疫原性和保护效力（基于HA、NP和NA的或基于免疫原性多表位的）抗小鼠中的H5 N1、H7N9和H9 N2禽流感病毒;目的2）评价H5 N1、H7N9和H9 N2三种亚型广泛保护性腺病毒疫苗在雪貂中的免疫原性和保护效果;目的3）测定流感病毒保护性免疫的寿命和Ad载体免疫随时间的下降及其对同一Ad载体重复免疫的影响。 我们的工作将针对H5、H7和H9流感亚型，在能够生产毒株匹配的疫苗之前，生产具有广泛保护性的疫苗，以显著降低发病率，阻止传播，并防止大流行情况下的死亡。这项研究的结果将对开发更好的季节性流感病毒疫苗产生重大影响。