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）：流感病毒A（IFV）在全球范围内仍然是一个重大的公共卫生问题。在美国，每年的IFV归因于20,000至40,000人。引入新的抗原亚型，要么是由于天然发生的抗原转移或生物恐怖主义引起的，可能导致大流行，并带来毁灭性的后果。当前可用的杀死和亚基IFV疫苗对流感大流行菌株的成功只有有限的成功。下一个流感大流行可能随时发生，几乎没有警告。人类中最近出现的鸟类流感H5N1，H7N7和H9N2病毒突显了至少某些禽类亚型将物种屏障跨越人类的能力。这些事件可能会因禽类人群重新成熟病毒的出现而引起流行性流行病，并能够在天真的人群中迅速传播。 已知腺病毒载体会激活先天免疫，并且可以通过粘膜或肠胃外途径进行给药。通常，腺病毒载体是体液（包括粘膜）和细胞介导的免疫（CMI）的强诱导剂。在特定的目标1下，将开发并评估表达出H7N7或H9N2的H7N7或H9N2的HA的腺病毒载体，表达血凝蛋白（HA），核蛋白（NP）或基质蛋白2（M2），以诱导对IFV对IFV挑战的保护和CMI响应和CMI响应和CMI响应和程度。 NP和M2蛋白在IFV亚型中相对保守，并诱导良好的细胞免疫，从而扩大了针对流感的免疫反应的范围。防御素，是由Toll样受体激活诱导的小分子量蛋白，可以募集炎症细胞并扩大先天和适应性免疫反应。使用H5N 1病毒纯化的HA的免疫研究表明，该HA的免疫原性很差，因此，可以通过使用表达防御能力的腺病毒载体来进一步增强腺病毒载体HA的免疫原性（H5N 1，H7N7和H9N2）。在特定的目标2下，将评估具有表达新型HA类型的腺病毒载体的持久和宽阔的IFV免疫的策略，通过对非人类和人类腺病毒载体的顺序给药，以有或没有防御能力的形式表达新型HA类型或HA，NP和M2。幼稚和灌注的近交小鼠和杂种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光谱。该项目的成功完成将提高我们对持久和广泛免疫力所需的免疫力和免疫原样类型的理解，以有效保护大流行IFV。