Development of an H2O2-Inactivated Dengue Virus Vaccine

描述（由申请方提供）：登革病毒（DENV）是一种新出现/再出现的传染病，可导致显著的人类发病率和死亡率。据估计，每年有2500万至1亿例DENV感染病例，25亿人处于危险之中。流行国家的儿童和婴儿占每年发生的25，000例DENV相关死亡的大多数。目前还没有商业疫苗。我们已经开发了一种创新的疫苗平台，在两种独立的模型（西尼罗河病毒和黄热病病毒）中显示出对致死性黄病毒感染的体内有效性，在此应用中，我们将在此基础上扩展开发和生产针对DENV的新四价疫苗。目前开发减毒活DENV疫苗的方法所面临的关键障碍是病毒干扰，这是一种宿主优先对四种DENV血清型中的一种或两种（但不是全部）产生免疫应答的现象，如果暴露于错误的DENV血清型，则使接种疫苗的受试者未受保护或处于严重疾病的潜在增加的风险中。为了解决这个问题，我们的方法利用先前减毒的DENV疫苗株（显示在人类受试者中是安全的），然后用我们专有的基于过氧化氢（H2 O2）的疫苗技术灭活，以制备具有引起对所有四种DENV血清型的平衡免疫应答的潜力的高度免疫原性制剂。该疫苗项目涵盖RFA-AI-11-014中列出的许多关键产品开发目标，包括：候选先导疫苗优化;安全性、毒性和免疫原性评价;适当攻毒模型中的有效性评价;最佳和升高储存温度下的稳定性评价;以及适合完成所有适用IND临床前研究的疫苗材料的cGMP生产。这些目标的成功完成将产生适合未来启动I期临床试验的cGMP级疫苗材料， 这是针对这一重要的NIAID A类优先病原体的人类疫苗发展的一个重要里程碑。

DESCRIPTION (provided by applicant): Dengue virus (DENV) represents an emerging/re-emerging infectious disease that causes significant human morbidity and mortality. It is estimated that there are 25 to 100 million cases of DENV infection each year and 2.5 billion people are at risk. Children and infants in endemic countries account for the majority of the 25,000 DENV-associated deaths that occur annually. There is currently no commercial vaccine available. We have developed an innovative vaccine platform that has shown in vivo efficacy against lethal flavivirus infection in two independent models (West Nile virus and Yellow Fever virus) and in this application we will expand on this foundation to develop and produce a new tetravalent vaccine against DENV. The critical obstacle faced by current approaches to live attenuated DENV vaccine development is viral interference, a phenomenon in which the host preferentially mounts an immune response to one or two (but not all) of the four DENV serotypes, leaving the vaccinated subject either unprotected or at potentially increased risk for severe disease if exposed to the wrong DENV serotype. To resolve this problem, our approach utilizes previously attenuated DENV vaccine strains (shown to be safe in human subjects) followed by inactivation with our proprietary hydrogen peroxide (H2O2)-based vaccine technology to prepare highly immunogenic formulations with the potential to elicit a balanced immune response to all four DENV serotypes. This vaccine project encompasses many of the key product development goals listed in RFA-AI-11-014 including, lead vaccine candidate optimization; evaluation of safety, toxicity, and immunogenicity; evaluation of efficacy in appropriate challenge models; evaluation of stability at optimal and elevated storage temperatures; and cGMP manufacturing of vaccine material suitable for completing all applicable IND-enabling preclinical studies. The successful completion of these objectives will result in cGMP-grade vaccine material suitable for future initiation of a Phase I clinical trial, a crucial milestone in the advancement of a human vaccine for this important NIAID Category A Priority Pathogen.