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: 7087753
• 负责人: SURESH K MITTAL
• 金额: $ 32.93万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7087753
• 关键词: Adenoviridae; cellular immunity; defensins; ferrets; hemagglutinin; immune response; influenza vaccines; influenzavirus A; laboratory mouse; toll like receptor; transfection /expression vector; virus protein

DESCRIPTION (provided by applicant): Influenza virus A (IFV) continues to be a significant public health problem worldwide. Between 20,000 and 40,000 deaths are attributed to IFV every year in the United States. Introduction of a new antigenic subtype either due to naturally occurring antigenic shift or by bioterrorism could lead to a pandemic with devastating consequences. The currently available killed and subunit IFV vaccines will have only limited success against pandemic strains of influenza. The next influenza pandemic could occur at any time and with little warning. The recent emergence of avian influenza H5N1, H7N7 and H9N2 viruses in humans has highlighted the ability of at least some avian subtypes to cross the species barrier into humans. Such events can cause pandemic outbreaks of influenza by the emergence of an avian-human reassortant virus with the ability to spread rapidly in a naive human population. Adenoviral vectors are known to activate innate immunity and can be administered via the mucosal or parenteral route. In general, adenoviral vectors are strong inducers of both humoral (including mucosal) and cell-mediated immunity (CMI). Under Specific Aim 1, adenoviral vectors expressing hemagglutinin (HA), nucleoprotein (NP), or matrix protein 2 (M2) from H5N1 or HA from H7N7 or H9N2 will be developed and evaluated for their ability to induce humoral and CMI responses and degree of protection to IFV challenge in a mouse model. NP and M2 proteins are relatively conserved among IFV subtypes and induce good cellular immunity, thus broadening the scope of immune responses against influenza. Defensins, small molecular weight proteins induced by toll-like receptor activation, can recruit inflammatory cells and amplify innate and adaptive immune responses. Immunization studies with purified HA of H5N 1 virus indicate that this HA is poorly immunogenic, therefore, the immunogenicity of HA of avian IFVs (H5N 1, H7N7 and H9N2) expressed by adenoviral vectors could be further enhanced by the use of adenoviral vectors expressing defensin. Under Specific Aim 2, the strategies for developing long-lasting and broad IFV immunity with a combination of adenoviral vectors expressing novel HA types or HA, NP, and M2 with or without defensin by sequential administration of nonhuman and human adenoviral vectors will be evaluated. Naive and primed inbred mice and outbred ferrets will be used for immunization and challenge trials to address the complex spectrum of immunity that would exist in humans. The successful completion of this project will advance our understanding towards the type of immunity and immunogen/s required for long-lasting and broad immunity for effective protection against pandemic IFV.

描述（由申请人提供）：甲型流感病毒（IFV）仍然是世界范围内的一个重大公共卫生问题。在美国，每年有 20,000 至 40,000 人死于 IFV。由于自然发生的抗原转变或生物恐怖主义而引入新的抗原亚型可能会导致大流行，带来毁灭性的后果。目前可用的灭活疫苗和亚单位 IFV 疫苗对抗大流行性流感毒株的效果有限。下一次流感大流行可能随时发生，而且几乎没有任何预警。最近在人类中出现的禽流感 H5N1、H7N7 和 H9N2 病毒凸显了至少某些禽类亚型能够跨越物种屏障进入人类。此类事件可能会因禽-人重配病毒的出现而导致流感大流行，这种病毒能够在原始人群中迅速传播。 已知腺病毒载体可以激活先天免疫，并且可以通过粘膜或肠胃外途径施用。一般来说，腺病毒载体是体液免疫（包括粘膜免疫）和细胞介导免疫（CMI）的强诱导剂。在具体目标 1 下，将开发表达 H5N1 血凝素 (HA)、核蛋白 (NP) 或基质蛋白 2 (M2) 或 H7N7 或 H9N2 HA 的腺病毒载体，并评估其诱导体液和 CMI 反应的能力以及诱导体液和 CMI 反应的能力。小鼠模型中对 IFV 攻击的保护。 NP和M2蛋白在IFV亚型中相对保守，可诱导良好的细胞免疫，从而扩大针对流感的免疫反应范围。防御素是由 Toll 样受体激活诱导的小分子量蛋白质，可以招募炎症细胞并放大先天性和适应性免疫反应。用纯化的 H5N 1 病毒 HA 进行的免疫研究表明，这种 HA 的免疫原性很差，因此，通过使用表达防御素的腺病毒载体，可以进一步增强腺病毒载体表达的禽类 IFV（H5N 1、H7N7 和 H9N2）HA 的免疫原性。 。在具体目标 2 下，将评估通过连续施用非人类和人类腺病毒载体，结合表达新型 HA 类型或 HA、NP 和 M2（有或没有防御素）的腺病毒载体来产生持久和广泛的 IFV 免疫的策略。幼稚和初免的近交小鼠和远交雪貂将用于免疫和挑战试验，以解决人类中存在的复杂免疫谱。该项目的成功完成将加深我们对持久和广泛免疫所需的免疫类型和免疫原的了解，以有效预防大流行性IFV。