Development of an H2O2-Inactivated Dengue Virus Vaccine

H2O2 灭活登革热病毒疫苗的研制

基本信息

批准号：
8463114
负责人：
MARK K SLIFKA
金额：
$ 158.91万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8463114
关键词：
Accounting Antibody Formation Arenavirus Attenuated Categories Cessation of life Child ChimeriVax Clinical Communities Consultations Country Cyclic GMP Data Dengue Dengue Virus Development Diamond Disease Drug Formulations Emerging Communicable Diseases Equilibrium Evaluation Flavivirus Flavivirus Infections Formaldehyde Foundations Funding Future Goals Growth Hospitalization Human Hydrogen Peroxide Immune response Immunity Immunization Immunology In Vitro Inactivated Vaccines Inbred BALB C Mice Industry Infant Infection Knowledge Lead Left Letters Life Macaca mulatta Modeling Mus National Institute of Allergy and Infectious Disease New Zealand Orthopoxvirus Oryctolagus cuniculus Outcome Phase I Clinical Trials Population Heterogeneity Preclinical Testing Proteins Recommendation Regulatory Affairs Research Infrastructure Resources Risk Safety Schedule Serotyping Technology Temperature Testing Toxic effect Toxicity Tests Toxicology United States National Institutes of Health Universities Vaccinated Vaccine Production Vaccines Vero Cells Viral Viral Interference Viremia Virion Virus Diseases Washington West Nile virus Work Yellow Fever Yellow fever virus base design dosage efficacy evaluation human morbidity human mortality human subject immunogenic immunogenicity improved in vivo innovation manufacturing process development meetings neutralizing antibody nonhuman primate novel novel strategies novel vaccines pathogen potency testing preclinical study prevent product development protective efficacy prototype safety testing vaccine candidate vaccine development virology

项目摘要

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.

描述（由申请人提供）：登革热病毒（DENV）代表一种新出现/重新出现的传染病，可导致严重的人类发病率和死亡率。据估计，每年有 25 至 1 亿例 DENV 感染病例，25 亿人面临风险。每年发生的 25,000 例 DENV 相关死亡中，大多数是流行国家的儿童和婴儿。目前还没有商业疫苗可用。我们开发了一种创新的疫苗平台，该平台已在两种独立模型（西尼罗河病毒和黄热病病毒）中显示出针对致命黄病毒感染的体内功效，在此应用中，我们将在此基础上进行扩展，开发和生产针对登革热病毒（DENV）的新型四价疫苗。目前开发减毒登革热病毒活疫苗的方法面临的关键障碍是病毒干扰，在这种现象中，宿主优先对四种登革病毒血清型中的一种或两种（但不是全部）产生免疫反应，使接种疫苗的受试者要么不受保护，要么如果接触错误的 DENV 血清型，患严重疾病的风险可能会增加。为了解决这个问题，我们的方法利用先前减毒的 DENV 疫苗株（已证明对人类受试者是安全的），然后使用我们专有的基于过氧化氢 (H2O2) 的疫苗技术灭活，以制备高免疫原性制剂，有可能引发平衡的免疫对所有四种 DENV 血清型都有反应。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，包括先导候选疫苗优化；安全性、毒性和免疫原性评估；评估适当挑战模型的功效；评估最佳储存温度和升高储存温度下的稳定性；适合完成所有适用的 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，针对这种重要的 NIAID A 类优先病原体的人类疫苗的进展至关重要。