Development of a Universal Influenza Seasonal Vaccine

描述(申请人提供)：非常需要开发新的流感疫苗接种方法。目前的策略是等待每个季节确定新的毒株，然后主要根据鸡蛋产量构建匹配的疫苗，这是不理想的。由于这种匹配菌株的要求和对鸡蛋生产的限制，美国被迫为我们的人口接种不足的疫苗，因为供应有限，而且每年为整个美国人口接种疫苗是不可能的任务。这项申请提出了一种新的疫苗方法，如果成功，可能会导致季节性流感疫苗开发的变革性转变。我们建议开发一种合成的HAS集合，编码一组一致的H1、H3和HB免疫原作为鸡尾酒，共同产生广泛的HI和u中和作用，以对抗季节性和大流行的H1、H3和HB病毒。我们使用了一种改进的DNA技术，完全消除了病毒培养。我们已经组建了一支出色的研究团队，他们共同帮助生产了支撑这一重要应用的技术和进步。这个应用程序有四个具体目标。目的1：在小鼠和雪貂模型中，验证我们可以创造一种合成的H1HA免疫原，它能产生针对所有四种H1大流行毒株的广泛的HI抗体反应，以及对过去20年的季节性H1病毒的抗体反应。目的2：在小鼠和雪貂模型中验证我们可以创造合成的H3HA和HBHA的假设，这些H3HA和HBHA都能产生针对H3和HB病毒季节性变异的广泛的HI反应。目的3：验证一种假设，即我们可以为H1、H3和HB免疫原制定一种组合免疫策略，从而在保护水平上产生广泛的HI活性(在指示动物物种雪貂中，HI滴度大于1/40HI滴度)。对雪貂的研究将包括应对大流行和季节性菌株的挑战。我们将在恒河猴模型中确认这种组合疫苗的免疫效力，这将为优化的增强型递送DNA平台的免疫效力提供进一步的证据。目的：在使用H1、H3、Hb通用DNA疫苗接种给健康志愿者的先导性安全性和免疫原性研究中，验证我们可以使用耐受性良好的平台安全地诱导人类保护性HI水平的假设。总而言之，这些目标代表了流感疫苗开发以及整个DNA疫苗领域的变革性转变。 公共卫生相关性：一种新型的、合成的、基于DNA的季节性流感疫苗，含有免疫上相关的、高度保守的病毒成分，将比从鸡蛋中的病毒培养物中提纯疫苗更具成本效益，并可能比传统方法更广泛地有效

DESCRIPTION (provided by applicant): There is a great need to develop new vaccination approaches for influenza. The current strategy based on waiting to identify each seasons new strains and then building a matching vaccine based mostly on egg production is not ideal. Because of this requirement to match strains and the limits on egg based production, the US is forced to under vaccinate our population due to limitations in supply and the impossible task of vaccinating the entire US population each year. This application proposes a new vaccine approach that if successful can result in a transformative shift in the development of seasonal influenza vaccines. We propose to develop a synthetic collection of HAs encoding a focused set of consensus H1, H3 & HB immunogens as a cocktail that together produce broad HI and uNeutralization against seasonal and pandemic H1, H3 and HB viruses. We use an improved DNA technology which eliminates virus culture entirely. We have assembled an outstanding team of investigators who together have helped to produce the technology and the advances that underpin this important application. There are four specific aims that make up this application. Aim 1: To test the hypothesis that we can create a synthetic H1HA immunogen which generates broad HI antibody responses against all four H1 pandemic strains as well against the last 20 years seasonal H1 viruses in mice and ferret models. Aim 2: To test the hypothesis that we can create a synthetic H3HA as well as HBHA which will each generate broad HI responses against seasonal variants of H3 and HB viruses in mice and ferret models. Aim 3: To test the hypothesis that we can develop a combination immunization strategy for H1, H3 and HB immunogens resulting in broad HI activity at protective levels (greater than 1/40 HI titers in an indicator animal species - Ferrets). Studies in ferrets will include challenge with pandemic as well as seasonal strains. We will confirm the immune potency of this combination vaccine in the Rhesus Macaque model which will provide further evidence of the immune potency of the optimized enhanced delivery DNA platform. Aim 4: To test the hypothesis that we can safely induce, using a well tolerated platform, protective HI levels in humans in a pilot safety and immunogenicity study using the combination H1, H3, HB universal DNA vaccine when delivered to healthy volunteers. Together these aims represent transformational shifts for the development of vaccines to influenza as well as for the DNA vaccine field as a whole. PUBLIC HEALTH RELEVANCE: A novel, synthetic, DNA-based vaccine against seasonal influenza comprising immunologically relevant, highly conserved viral components would be more cost-effective than purifying vaccine from viral culture in chicken eggs and potentially more broadly effective than the traditional methodology