Development of an H2O2-Inactivated Dengue Virus Vaccine

描述(申请人提供)：登革病毒(DENV)是一种新出现/再次出现的传染病，会导致严重的人类发病率和死亡率。据估计，每年有2500万至1亿人感染登革热病毒，25亿人处于危险之中。在每年发生的25000例与DENV相关的死亡中，流行国家的儿童和婴儿占大多数。目前还没有商业疫苗可用。我们开发了一个创新的疫苗平台，在两个独立的模型(西尼罗河病毒和黄热病病毒)上显示了对致命黄病毒感染的体内效果，在这一应用中，我们将在此基础上扩展，开发和生产一种新的针对DENV的四价疫苗。目前开发减毒活疫苗所面临的关键障碍是病毒干扰，这种现象是宿主优先对四种DENV血清型中的一种或两种(但不是所有)产生免疫反应，使接种对象要么没有保护，要么如果接触错误的DENV血清型，可能会增加严重疾病的风险。为了解决这个问题，我们的方法利用先前减毒的DENV疫苗毒株(被证明在人类受试者中是安全的)，然后用我们基于过氧化氢(H2O2)的专有疫苗技术灭活，以制备高度免疫原性的制剂，有可能引起对所有四种DENV血清型的平衡免疫反应。该疫苗项目包括RFA-AI-11-014中列出的许多关键产品开发目标，包括优化主要候选疫苗；评估安全性、毒性和免疫原性；评估在适当挑战模型中的效力；评估在最佳和较高储存温度下的稳定性；以及cGMP生产适合完成所有适用的IND使能临床前研究的疫苗材料。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 这是针对这种重要的NIAID A类优先病原体的人类疫苗进展的关键里程碑。

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.