Development of a Universal Influenza Seasonal Vaccine

描述（由申请人提供）：我们非常需要开发新的流感疫苗接种方法。目前的策略是等待确定每个季节的新菌株，然后主要基于鸡蛋生产制造匹配的疫苗，这种策略并不理想。由于这种匹配菌株的要求和基于鸡蛋生产的限制，由于供应限制和每年为整个美国人口接种疫苗的不可能任务，美国被迫对我们的人口接种疫苗。这一申请提出了一种新的疫苗方法，如果成功，可能导致季节性流感疫苗开发的革命性转变。我们建议开发一种合成的HAs集合，编码一组重点的共识H1， H3和HB免疫原，作为一种鸡尾酒，共同产生广泛的HI和非中和，以对抗季节性和大流行性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。我们组建了一支杰出的研究团队，他们共同帮助开发了支撑这一重要应用的技术和进步。这个应用程序有四个特定的目标。目的1：为了验证我们可以创造一种合成的H1HA免疫原的假设，该免疫原可以对所有四种H1大流行毒株以及过去20年在小鼠和雪貂模型中的季节性H1病毒产生广泛的HI抗体反应。目的2：为了验证我们可以在小鼠和雪貂模型中创造一种合成的H3HA和HBHA，它们将分别对H3和HB病毒的季节性变异产生广泛的HI反应。目的3：验证假设，我们可以开发H1， H3和HB免疫原的联合免疫策略，从而产生具有保护水平的广泛的HI活性（在指示动物物种-雪貂中大于1/40的HI滴度）。对雪貂的研究将包括流行病和季节性毒株的挑战。我们将在恒河猴模型中确认该联合疫苗的免疫效力，这将进一步证明优化的增强递送DNA平台的免疫效力。目的4：在一项试验性安全性和免疫原性研究中，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，该研究使用H1、H3、HB通用DNA联合疫苗，并将其交付给健康志愿者。这些目标共同代表了流感疫苗开发以及整个DNA疫苗领域的转型转变。

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