Influenza vaccines inducing broadly cross protective immunity

描述(申请人提供)：目前的流感疫苗的目标是诱导对可变抗原血凝素和神经氨酸酶的免疫反应，这两种抗原对毒株特异性保护有效。然而，这种疫苗接种不能防止出现抗原性不同的毒株，2009年H1N1大流行在暴发初期未能控制就表明了这一点。我们提议的项目的目标是开发新型流感疫苗，在没有佐剂的情况下，诱导对抗原漂移毒株的广泛交叉保护免疫。为了实现这一目标，将提出新的方法，以免疫原性的形式开发高度保守的抗原靶，并将其纳入流感疫苗接种。膜蛋白M2含有高度保守的胞外区，是一个很有希望作为保守抗原靶点的候选蛋白。膜锚定形式的病毒样颗粒(VLP)上的M2将处于一种构象，使M2即使在没有佐剂的情况下也能具有免疫原性并提供广泛的交叉保护M2免疫。我们假设，含有高度保守的抗原靶点的流感疫苗，如流感M2 VLP，将诱导广泛的交叉保护和异亚型免疫。为了验证这一假设，在特定目标1中，将产生包含膜锚定嵌合形式的四聚体M2胞外区的新结构的重组VLP疫苗，并将与野生型M2蛋白进行比较，评估其交叉保护效果。我们还将提出一种新的方法，以克服现有疫苗对毒株特异性保护的局限性和对M2弱的交叉保护免疫。具体目标2将研究基于M2的保守免疫增强交叉保护广度的作用机制。此外，有助于交叉保护的免疫相关性将使用包括耗尽特定免疫成分在内的传统和新方法来确定。在具体目标3中，将进一步评估有希望的候选疫苗的交叉保护效力和交叉保护的持续时间，这是测试人类临床前疫苗的更相关的动物模型。提高疫苗接种后对流感病毒的交叉保护免疫广度，而不使用佐剂，是一种适用于人类的可取和实用的方法，对于推进疫苗领域至关重要。 公共卫生相关性：目前的流感疫苗接种不能提供保护，防止出现抗原性不同的流行毒株或具有大流行潜力的新流感病毒。开发一种安全有效的流感疫苗，对更广泛的变异病毒产生广泛的交叉保护性免疫，将对改善公共卫生产生重大影响。

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.