DNA Vaccine for Seasonal & Pandemic Influenza

描述（由申请方提供）：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和大流行毒株出现的策略。这项提案将开发一种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保护，以对抗远距离漂移变体。该提案将采用DNA疫苗的颗粒介导的表皮递送（PMED），并建立在最近成功的季节性流感PMED DNA疫苗的基础上，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保护性抗体水平。该提案的目的是增加PMED DNA疫苗的免疫原性，并进一步开发疫苗作为大流行性流感产品。该提案的主要目的是：1）通过包括多个HA序列来扩大疫苗对遗传漂移毒株和禽流感的特异性。2)研究在多价DNA疫苗中包括核蛋白（NP）基因的效果，该多价DNA疫苗具有经修饰和优化的序列，以增加针对该基因的高度保守区域的CD8+ T细胞应答的广度和效力。3)确定我们已经证明的一种新型基因佐剂是否能增强针对其他DNA疫苗抗原的抗体和细胞免疫应答，是否也能类似地增加候选大流行性流感DNA疫苗的免疫原性和保护效力。将在高度相关的雪貂和非人灵长类动物临床前模型中检测疫苗的免疫原性。将开发恒河猴模型，以利用T细胞免疫分析所需的该种属I类基因座上的可用信息。将采用雾化流感攻毒，以便在模拟人群自然暴露的环境中评估对同源和漂移的禽流感毒株的保护效力。这些努力将产生三种候选DNA疫苗产品，这些产品诱导抗体和细胞免疫应答，以保护免受季节性和大流行性流感毒株的侵害。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细胞应答将增加针对HA漂移变体的保护效力，并提供针对流感病毒新出现的大流行株引起的死亡的关键保护。

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.