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）代表一种新兴/重新出现的传染病，会引起人类的大量发病率和死亡率。据估计，每年有25至1亿例DENV感染病例，有25亿人处于危险之中。中等国家的儿童和婴儿占每年发生的25,000例DENV相关死亡中的大多数。目前尚无商业疫苗。我们已经开发了一种创新的疫苗平台，该平台在两个独立模型（西尼罗河病毒和黄热病病毒）中显示了针对致命的黄病毒感染的体内功效，在此应用中，我们将扩展基础，以开发并生产新的四甲壳虫疫苗对DENV。当前的死亡DENV疫苗发育方法所面临的关键障碍是病毒干扰，这种现象在这种现象中优先对四种DENV血清型中的一两个（但并非全部）产生免疫反应，从而使接种疫苗的受试者受到未受保护的受试者的疫苗接种，或者如果暴露于错误的DENV血清型，则可能增加了严重疾病的风险。为了解决这个问题，我们的方法利用先前减弱的DENV疫苗菌株（在人类受试者中显示出安全），然后与我们的专有的过氧化氢（H2O2）基于基于的疫苗技术灭活，以准备高度免疫原性的配方，以使对所有四个DENVSEROTYPES的免疫反应可能产生平衡的免疫反应。该疫苗项目涵盖了RFA-AI-11-014中列出的许多关键产品开发目标，包括铅疫苗候选候选者优化；评估安全性，毒性和免疫原性；在适当的挑战模型中评估功效；评估最佳储存温度和升高的稳定性；和CGMP制造疫苗材料，适合完成所有适用的临床前研究。这些目标的成功完成将导致CGMP级疫苗材料适合将来开始I期临床试验，A 对于这种重要的NIAID类别的人类疫苗的发展，至关重要的里程碑是优先病原体。