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。

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.