LAIV Inducing Cross Protection

 描述(由申请人提供)：减毒活疫苗(LAIV)是一个安全有效的人类使用平台，并被证明在儿童中具有比灭活疫苗更高的效力。尽管如此，目前的流感疫苗，包括LAIV，并没有针对抗原性不同的流行毒株或意外出现的新大流行毒株提供交叉保护。提高基于血凝素(HA)免疫的毒株特异性疫苗的交叉保护效果的广度是当务之急。我们的初步研究表明，对高度保守的流感M2蛋白(M2e)的免疫反应提供了更广泛的交叉保护(H1、H3和H5亚型)。此外，我们最近产生了新的流感突变体，表达嵌合保守的M2e-HA，它表现出减弱的表型，并提供显著广泛和增强的交叉保护。这些发现有力地表明，产生高度交叉保护和安全的LAIV是可能的。因此，将保守的保护性M2e引入HA中将克服HA的毒株特异性保护以及M2的免疫原性差，因此人们对此寄予厚望。中心假设是含有M2e-HA的重组LAIV将更安全和更有效地诱导更广泛的交叉保护。第一个目标(目标1)是制备含有M2e-HA的重组LAIV，并确定重组LAIV的安全性和交叉保护效果。Aim 2将在雪貂身上测试重组LAIV-M2e疫苗，这是测试流感疫苗的更相关的动物模型。

 DESCRIPTION (provided by applicant): Live attenuated influenza vaccine (LAIV) is a safe and effective platform for human use, and shown to have higher efficacy in children than inactivated vaccine. Nonetheless, current influenza vaccines including LAIV do not provide cross-protection against antigenically distinct epidemic strains or the unanticipated emergence of new pandemic strains. It is of a high priority to improve the breadth of cross protective efficacy of strain-specific vaccines based on hemagglutinin (HA) immunity. Our preliminary studies demonstrated that immune responses to highly conserved influenza M2 protein (M2e) provided a broader range of cross-protection (H1, H3, and H5 subtypes). In addition, we recently generated novel influenza mutants that express a chimeric conserved M2e-HA, which showed attenuated phenotypes as well as provided significantly broad and enhanced cross-protection. These findings strongly suggest that it should be possible to produce highly cross protective and safe LAIV. Thus, it is highly expected that incorporating conserved-protective M2e into HA will overcome the strain-specific protection of HA as well as poor immunogenicity of M2. The central hypothesis is that recombinant LAIV containing M2e-HA will be safer and more effective in inducing a broader range of cross-protection. The first goal (aim 1) is to generate recombinant LAIV containing M2e-HA and to determine the safety and cross-protective efficacy of recombinant LAIV. The aim 2 will test recombinant LAIV-M2e vaccines in ferrets, which is a more relevant animal model for testing influenza vaccines.