Adenoviral Vector-based Pandemic Influenza Vaccine

基于腺病毒载体的大流行性流感疫苗

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：自1996年以来，已经有许多人类感染的禽类影响了亚型H5N1，H7N7和H9N2的病毒。 2013年，中国出现了一种新的鸟类影响H7N9亚型的病毒菌株，导致人类450多种感染，导致175例死亡。尽管人类到人类的传播很少且有限，但在某些基因中，鸟类与人类/猪的影响或突变在人类的上呼吸道复制的某些基因中产生了或突变，这会导致新的大流行病毒菌株产生，这不仅会感染，而且在人群中也不会有效地传播，而这些病毒也几乎没有免疫学传播到新的免疫学上。我们的免疫原性和受保护的有效性研究表明，基于腺病毒（AD）载体的H5N1，H7N7和H9N2疫苗提供了出色的体液和细胞介导的免疫调查，从而完全保护了H5N1，H7N7和H9N2影响的挑战。为了进一步提高保护性效率的广度，还将探索基于AD载体的疫苗配方（第一代疫苗），除了血凝素（HA）（HA）和核蛋白（NP）外，还包括神经毒素酶（NA）（NA）。提高针对鸟类流感病毒的保护效率广度的另一种策略是包括基于多蛋白质的疫苗（第二代疫苗）的流感蛋白的相对组成的域。 This proposal is based on the hypothesis that a combination of heterosubtypic cell-mediated immunohistochastic NP and the cross-reactive (not necessarily cross-neutralizing) humoral immunoresponses against other immunogenic proteins or domains will provide broad protection against potential pandemic H5N1, H7N9 or H9N2 avian influences viruses as well as other H5, H7 or H9 divergent病毒。该疫苗方法将基于牛腺病毒载体，该脂肪病毒载体即使在对人AD的高水平中和抗体的情况下，也会诱导受保护的免疫复杂水平。这项修订的竞争性更新提案的目标是：目标1）针对H5N1，H7N9和H9N2 AVIAN在小鼠中的H5N1，H7N9和H9N2 Avian的影响，对广泛保护的AD基于AD的影响疫苗的免疫原性和保护效果的开发和评估；目标2）评估雪貂中选定的广泛保护基于AD的疫苗的免疫原性和受保护的有效性；目标3）确定受保护影响的寿命和随时间的降低和AD载体免疫史的下降及其对使用相同AD载体重复免疫排放的影响。我们的努力将针对对H5，H7和H9影响亚型的广泛保护的疫苗产生，这些疫苗将显着降低发病率，阻碍传播并防止在大流行状况下死亡，然后才能产生菌株匹配的疫苗。这项研究的结果将极大地影响更好的疫苗与季节性影响病毒的开发工作。