Development of a Universal Influenza Seasonal Vaccine

描述（由申请人提供）：非常需要开发新的流感疫苗接种方法。目前的策略是等待识别每个季节的新菌株，然后主要基于鸡蛋产量来构建匹配的疫苗，这并不理想。由于这种匹配菌株的要求和对基于蛋的生产的限制，由于供应的限制和每年给整个美国人口接种疫苗的不可能任务，美国被迫给我们的人口接种疫苗。该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HA集合，其编码一组集中的共有H1、H3和HB免疫原作为鸡尾酒，其一起产生针对季节性和大流行性H1、H3和HB病毒的广泛HI和u中和。我们使用一种改进的DNA技术，完全消除了病毒培养。我们组建了一支优秀的调查团队，他们共同帮助开发了支持这一重要应用的技术和进步。有四个具体的目标，使这一申请。目标1：为了验证我们可以创建合成H1 HA免疫原的假设，该合成H1 HA免疫原在小鼠和雪貂模型中产生针对所有四种H1大流行毒株以及针对过去20年季节性H1病毒的广泛HI抗体应答。目标二：为了检验我们可以创建合成H3 HA以及HBHA的假设，其将各自在小鼠和雪貂模型中产生针对H3和HB病毒的季节性变体的广泛HI应答。目标3：为了检验我们可以开发H1、H3和HB免疫原的联合免疫策略的假设，该策略导致在保护水平下的广泛HI活性（在指示动物物种-雪貂中大于1/40 HI滴度）。雪貂研究将包括大流行和季节性毒株的攻毒。我们将在恒河猴模型中确认该组合疫苗的免疫效力，这将为优化的增强递送DNA平台的免疫效力提供进一步的证据。目标4：在一项初步安全性和免疫原性研究中，使用H1、H3、HB通用DNA疫苗联合给药至健康志愿者时，检验我们可以使用耐受性良好的平台安全诱导人体保护性HI水平的假设。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。 公共卫生相关性：一种新的、合成的、基于DNA的季节性流感疫苗，包括免疫相关的、高度保守的病毒组分，将比从鸡蛋中的病毒培养物中纯化疫苗更具成本效益，并且可能比传统方法更广泛有效。

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