Influenza vaccines inducing broadly cross protective immunity

流感疫苗诱导广泛的交叉保护性免疫

• 批准号: 8416164
• 负责人: SANG-MOO KANG
• 金额: $ 43.84万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416164
• 关键词: Influenza; vaccines; inducing; broadly; cross

DESCRIPTION (provided by applicant): Current influenza vaccines are targeted to induce immune responses to the variable antigens hemagglutinin and neuraminidase, which are effective for strain-specific protection. However, such vaccination does not provide protection against the emergence of antigenically distinct strains as shown by the failure to control the 2009 H1N1 pandemic at the early stage of its outbreak. The goal of our proposed project is to develop novel influenza vaccines that will induce broadly cross protective immunity against antigenically drifted strains in the absence of adjuvants. To achieve this goal, novel approaches will be proposed to develop a highly conserved antigenic target in an immunogenic form and to incorporate this into the influenza vaccination. A promising candidate as a conserved antigenic target is the membrane protein M2 containing a highly conserved extracellular domain. M2 on virus-like particles (VLPs) in a membrane-anchored form (M2 VLPs) will be in a conformation enabling M2 to be immunogenic and confer broadly cross-protective M2 immunity even without an adjuvant. We hypothesize that influenza vaccines containing highly conserved antigenic targets such as influenza M2 VLPs will induce broadly cross-protective and heterosubtypic immunity. To test this hypothesis, in specific aim 1, recombinant VLP vaccines containing novel constructs of the tetrameric M2 extracellular domain in a membrane-anchored chimeric form will be generated and their cross protective efficacy will be evaluated in comparison with the wild type M2 protein. We will also propose a novel approach to overcome the limitation of strain-specific protection by current vaccines and weak cross-protective immunity to M2. Specific aim 2 will investigate action mechanisms by which conserved M2 based immunity enhances the breadth of cross protection. Also, immune correlates contributing to cross protection will be determined using traditional and novel approaches including depletion of specific immune components. In specific aim 3, the cross-protective efficacy of promising vaccine candidates and the duration of cross protection will be further evaluated in ferrets, which is a more relevant animal model for testing pre-clinical vaccines for humans. Improving the breadth of cross protective immunity against influenza viruses after vaccination without using adjuvant is a desirable and practical approach applicable to humans and critically important for advancing the vaccine field.

描述（由申请人提供）：目前的流感疫苗旨在诱导针对可变抗原血凝素和神经氨酸酶的免疫反应，这对于毒株特异性保护是有效的。然而，此类疫苗接种并不能针对抗原性不同毒株的出现提供保护，2009 年 H1N1 流感大流行未能在其爆发的早期阶段得到控制就表明了这一点。我们提出的项目的目标是开发新型流感疫苗，在没有佐剂的情况下，该疫苗将诱导针对抗原漂移毒株的广泛交叉保护性免疫。为了实现这一目标，将提出新方法来开发免疫原性形式的高度保守的抗原靶标，并将其纳入流感疫苗接种中。作为保守抗原靶标的一个有希望的候选者是含有高度保守的胞外结构域的膜蛋白 M2。膜锚定形式的病毒样颗粒 (VLP) 上的 M2 (M2 VLP) 将处于使 M2 具有免疫原性的构象，即使没有佐剂也能赋予广泛的交叉保护性 M2 免疫力。我们假设含有高度保守抗原靶点（例如流感 M2 VLP）的流感疫苗将诱导广泛的交叉保护性和异亚型免疫。为了检验这一假设，在具体目标 1 中，将产生含有膜锚定嵌合形式的四聚体 M2 胞外结构域的新型构建体的重组 VLP 疫苗，并将与野生型 M2 蛋白进行比较，评估其交叉保护功效。我们还将提出一种新方法来克服现有疫苗对毒株特异性保护的限制以及对 M2 的交叉保护免疫力较弱的限制。具体目标 2 将研究基于保守 M2 的免疫增强交叉保护广度的作用机制。此外，将使用传统和新颖的方法（包括消除特定免疫成分）来确定有助于交叉保护的免疫相关因素。在具体目标3中，将在雪貂中进一步评估有希望的候选疫苗的交叉保护功效和交叉保护的持续时间，雪貂是测试人类临床前疫苗的更相关的动物模型。在不使用佐剂的情况下接种疫苗后提高针对流感病毒的交叉保护免疫的广度是适用于人类的理想且实用的方法，对于推进疫苗领域至关重要。