Improved influenza A virus vaccines using alpha-Gal epitope modification

描述（由申请人提供）：人类会产生针对一种叫做Gal的糖分子的天然抗体，这种糖分子存在于大多数其他物种的蛋白质和脂质中。这些抗体是抵御细菌、寄生虫和病毒感染的最强天然屏障之一。NewLink Genetics已将该技术授权为HyperAcute(c)疫苗，该疫苗作为一种癌症免疫疗法正在进行I期和II期临床试验。在这个应用中，我们将使用这种抗体反应作为一种天然生物疗法来增强流感候选疫苗。流感是一个主要的人类健康威胁，研究新的疫苗策略是一个优先研究领域。这项建议有三个具体目标。(1)我们将检测三种不同的流感疫苗（血凝素蛋白、病毒样颗粒和热灭活全病毒）添加或不添加Gal表位，以确定该分子的疫苗接种效果。(2)我们将测试三种不同的将Gal分子添加到单一疫苗中的策略，以确定哪种修饰策略能产生最佳的疫苗反应。(3)我们将在免疫衰老的临床前模型中验证使用含Gal的病毒疫苗会增强免疫反应的假设。这些临床前研究将是将这些实验转移到II期应用的第一步，届时我们将提炼最佳候选疫苗，为进入临床试验做准备。公共卫生相关性：就人类健康和经济损失而言，流感对美国和世界都是一个巨大的负担。本提案中的研究侧重于一种新的佐剂，它将有助于开发更有效的流感疫苗配方。我们进一步提出，用我们的佐剂开发的疫苗也可能增加老年人对流感的免疫反应。

DESCRIPTION (provided by applicant): Humans develop natural antibodies against a sugar molecule called Gal, which is present on proteins and lipids in most other species. These antibodies represent one of the strongest natural barriers to infection with bacteria, parasites and viruses. NewLink Genetics has licensed this technology as the HyperAcute(c) vaccine and it is in Phase I and II clinical trials as a cancer immunotherapy. In this application, we will use this antibody response as a natural biologic therapy to enhance influenza vaccine candidates. Influenza is a major human health threat and investigation of new vaccine strategies is a priority area of research. There are three specific aims in this proposal. (1) We will examine three different influenza vaccines (hemagglutinin protein, virus-like particles and heat-killed whole virus) with or without addition of the Gal epitopes to determine the vaccination efficacy of this molecule. (2) We will test three different strategies for adding the Gal molecule to a single vaccine in order to determine which modification strategy gives the best vaccine response. (3) We will test the hypothesis that use of Gal containing viral vaccines will enhance the immune response in a preclinical model of immunosenescence. These preclinical studies will be the first step in moving these experiments into a Phase II application where we will refine the best candidate vaccine in preparation for movement into clinical trials. PUBLIC HEALTH RELEVANCE: Influenza is a huge burden for the United States and the world, both in terms of human health and economic losses. The studies in this proposal focus on a novel adjuvant that will facilitate the development of more effective influenza vaccine formulations. We further propose that vaccines devloped with our adjuvant may also increase the immune response to influenza in the elderly.