DNA Vaccine for Seasonal & Pandemic Influenza

季节性 DNA 疫苗

基本信息

批准号：
7673798
负责人：
Deborah H. Fuller
金额：
$ 123.85万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-15 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7673798
关键词：
Adjuvant Aerosols Algorithms Animal Model Antibodies Antibody Formation Antigens Attenuated Live Virus Vaccine Avian Influenza Binding Blood CD4 Positive T Lymphocytes CD8B1 gene Cancer Vaccines Cells Cellular Immunity Clinical Trials Computers Cytotoxic T-Lymphocytes DNA Vaccines Detection Development Disease Distant Dose Enhancing Antibodies Epidemic Epitopes Escherichia coli Escherichia coli heat-labile toxin Event Exposure to Ferrets Genes Genetic HLA-A2 Antigen Hemagglutinin Human Immune response Immunity Immunization In Vitro Infection Infection prevention Influenza Influenza A Virus, H5N1 Subtype Lung Macaca Macaca mulatta Mamu-A 01 antigen Measures Mediating Methodology Modeling Mucous Membrane Mus Nucleoproteins Outcome Pathology Phase Phase I Clinical Trials Plasmids Population Pre-Clinical Model Production Proteolytic Processing Research Personnel Role Specificity Speed T-Lymphocyte T-Lymphocyte Epitopes Testing Time Transgenic Mice Vaccinated Vaccine Antigen Vaccine Production Vaccines Variant Vietnam Viral Viral Load result Virus aerosolized biosafety level 4 facility cell mediated immune response design enterotoxin LT immunogenicity improved in vivo influenza virus strain influenza virus vaccine influenzavirus kidney cell manufacturing process meetings mortality nonhuman primate novel novel vaccines pandemic disease pandemic influenza particle prevent programs protective efficacy protein aminoacid sequence research study response seasonal influenza success virology

项目摘要

DESCRIPTION (provided by applicant): A significant challenge for the development of new influenza vaccines is to identify strategies that can both accelerate vaccine production and protect against the emergence of epidemic and pandemic strains. This proposal will develop a DNA vaccine to meet these needs. DNA vaccines can be rapidly designed and manufactured to express multiple antigens and induce antibody and cell-mediated protection against distant drift variants. This proposal will employ particle-mediated epidermal delivery (PMED) of the DNA vaccine and builds on the recent success of a seasonal influenza PMED DNA vaccine that induced protective levels of antibody in vaccinated subjects in a phase I human clinical trial. The purpose of this proposal is to increase PMED DNA vaccine immunogenicity and further develop the vaccine as a pandemic flu product. The primary objectives of the proposal are to: 1) Broaden the specificity of the vaccine against genetically drifted strains and avian influenza by including multiple HA sequences. 2) Investigate the effects of including a nucleoprotein (NP) gene in the multivalent DNA vaccine with sequences modified and optimized to increase the breadth and potency of CD8+ T cell responses against highly conserved regions of the gene. 3) Determine if a novel genetic adjuvant that we have shown enhances antibody and cellular immune responses against other DNA vaccine antigens will similarly increase the immunogenicity and protective efficacy of the candidate pandemic influenza DNA vaccine. The vaccine will be tested for immunogenicity in the highly relevant ferret and nonhuman primate preclinical models. A model in rhesus macaques will be developed to take advantage of the information available on the Class I locus of this species required for analysis of T cell immunity. Aerosolized influenza challenges will be employed so that protective efficacy against homologous and drifted strains of avian influenza can be evaluated in a setting that mimics natural exposure in the population. These efforts will generate three candidate DNA vaccine products that induce antibody and cellular immune responses for protection against both seasonal and pandemic strains of influenza. These experiments will also test the hypothesis that vaccine induction of CD8+ T cell responses against conserved regions of the virus will increase protective efficacy against HA-drift variants and provide critical protection against mortality caused by emerging pandemic strains of influenza viruses.

描述（由申请人提供）：开发新型流感疫苗的一个重大挑战是确定既能加速疫苗生产又能防止流行性和大流行性毒株出现的策略。该提案将开发一种 DNA 疫苗来满足这些需求。 DNA 疫苗可以快速设计和制造，以表达多种抗原并诱导抗体和细胞介导的针对远处漂移变异的保护。该提案将采用 DNA 疫苗的颗粒介导表皮递送 (PMED)，并建立在季节性流感 PMED DNA 疫苗最近取得成功的基础上，该疫苗在 I 期人体临床试验中在接种疫苗的受试者中诱导了保护性抗体水平。该提案的目的是提高 PMED DNA 疫苗的免疫原性，并进一步将该疫苗开发为大流行性流感产品。该提案的主要目标是： 1) 通过包含多个 HA 序列，扩大疫苗针对基因漂移毒株和禽流感的特异性。 2) 研究在多价 DNA 疫苗中加入核蛋白 (NP) 基因的效果，该疫苗的序列经过修饰和优化，以增加 CD8+ T 细胞针对该基因高度保守区域的反应的广度和效力。 3) 确定我们已经展示的一种新型基因佐剂可以增强针对其他 DNA 疫苗抗原的抗体和细胞免疫反应，是否会同样提高候选大流行性流感 DNA 疫苗的免疫原性和保护功效。该疫苗将在高度相关的雪貂和非人灵长类动物临床前模型中测试免疫原性。将开发恒河猴模型，以利用 T 细胞免疫分析所需的该物种 I 类基因座的可用信息。将采用雾化流感挑战，以便可以在模拟人群自然暴露的环境中评估针对同源和漂移禽流感毒株的保护功效。这些努力将产生三种候选 DNA 疫苗产品，它们可诱导抗体和细胞免疫反应，以预防季节性和大流行性流感病毒。这些实验还将检验以下假设：疫苗诱导针对病毒保守区域的 CD8+ T 细胞反应将提高针对 HA 漂移变异的保护功效，并为防止新出现的大流行流感病毒株引起的死亡提供关键保护。