Influenza vaccines inducing broadly cross protective immunity

描述（由申请人提供）：目前的流感疫苗旨在诱导对可变抗原血凝素和神经氨酸酶的免疫反应，这些抗原对毒株特异性保护有效。然而，这种疫苗接种并不能提供保护，防止抗原性不同的毒株的出现，2009年H1N1大流行未能在其爆发的早期阶段加以控制就表明了这一点。我们提出的项目目标是开发新型流感疫苗，在缺乏佐剂的情况下，对抗原性漂移株诱导广泛的交叉保护免疫。为了实现这一目标，将提出新的方法，以免疫原形式开发高度保守的抗原靶点，并将其纳入流感疫苗接种。作为保守抗原靶点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。在膜锚定形式的病毒样颗粒（vlp）上的M2将处于一种构象，使M2具有免疫原性，即使在没有佐剂的情况下也能赋予广泛的交叉保护性M2免疫。我们假设含有高度保守抗原靶点（如流感M2 VLPs）的流感疫苗将诱导广泛的交叉保护和异亚型免疫。为了验证这一假设，在特定目的1中，将生成含有膜锚定嵌合形式的四聚体M2细胞外结构域的新型构建物的重组VLP疫苗，并将其与野生型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的方法来克服现有疫苗对菌株特异性保护的局限性和对M2的弱交叉保护免疫。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，将使用传统和新型方法（包括消耗特定免疫成分）确定有助于交叉保护的免疫相关因素。在具体目标3中，有希望的候选疫苗的交叉保护效果和交叉保护的持续时间将在雪貂中进一步评估，这是一种更相关的动物模型，用于测试人类临床前疫苗。在不使用佐剂的情况下提高疫苗接种后对流感病毒的交叉保护性免疫的广度是一种适用于人类的理想和实用的方法，对推进疫苗领域至关重要。

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. PUBLIC HEALTH RELEVANCE: Current influenza vaccination does not provide protection against the emergence of antigenically distinct epidemic strains or new influenza viruses with pandemic potential. Development of a safe and effective influenza vaccine inducing broadly cross protective immunity against a broader range of variant viruses will have a significant impact on improving public health.