A Tetravalent Dengue Vaccine Based on Alphavirus Replicons

基于甲病毒复制子的四价登革热疫苗

基本信息

批准号：
7796862
负责人：
LAURA J WHITE
金额：
$ 93.37万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7796862
关键词：
Address Alphavirus Animal Model Antibodies Antibody Formation Antigens Area Attenuated Attenuated Live Virus Vaccine Bypass Cell Culture Techniques Cellular Immunity Chimera organism Clinical Complex DNA DNA Vaccines Dengue Dengue Hemorrhagic Fever Dengue Shock Syndrome Development Disease E protein Effectiveness Equilibrium Evaluation Face Failure Funding Generations Genes Goals Human Immune Immune response Immunity Immunization Individual Infant Infection Left Life Macaca Maternal antibody Membrane Membrane Proteins Modality Modeling Mothers Mus Newborn Animals Outcome Phase Pilot Projects Plasmids Population Primates Principal Investigator Protocols documentation RNA replication Recording of previous events Regimen Relative (related person)Replicon Risk Safety Secondary Immunization Series Serotyping Serum Solid Source System Testing Time Transcript United States National Institutes of Health Vaccination Vaccine Design Vaccines Venezuelan Equine Encephalitis Virus Vertebral column Virus Virus Diseases Yellow Fever base design env Gene Products extracellular immunogenicity improved neutralizing antibody novel vaccines particle pre-clinical programs protein E replicon vaccine research study response vaccination strategy vaccine candidate vector vector vaccine vector-based vaccine virus envelope

项目摘要

DESCRIPTION (provided by applicant): The objective of the pre-clinical experiments proposed in this application is to select a vaccine modality that hopefully will address significant deficiencies in the slate of candidate DEN vaccines currently in development. Live attenuated vaccines likely will fail to induce endogenous responses to all four DEN serotypes in infants born to monotypically immune mothers and immunized prior to the decay of maternal antibody. If this problem is avoided by delaying vaccination until maternal antibody decays sufficiently to allow use of live attenuated vaccines, then these infants will be left unprotected from severe DEN disease during this period. DNA vaccines for DEN are likely to circumvent the maternal antibody problem, but DNA vaccines generally have been disappointing in human trials, especially in terms of inducing humoral responses which are the most important responses for protection against DEN. We have proposed a sequence of experiments that will first determine the configuration of the E protein most effective in inducing responses in mice and macaques, testing a promising new configuration of E in soluble form that showed a significantly improved neutralizing response. Second, we will determine in mice and infant macaques whether a VRP vaccine cocktail induces a balanced response to all four serotypes and does so safely and in the presence of passively transferred neutralizing antibodies, as would be predicted from our previous experiments with DEN2-VRP in mice. Third, we will test a newly developed DNA launched form of the VEE vectors for their utility a) in mice and macaques, b) in the face of anti-DEN neutralizing antibodies, and c) in the presence of neutralizing antibodies to VEE. Finally, we will test mixed modality prime-boost regimens that may well represent the optimal vaccination strategy for VEE based vaccine vectors. We feel that at the conclusion of these studies, we will have established a solid justification for advancement of a VEE based vaccine candidate for DEN into phase I human trials.

描述（由申请人提供）：本申请中提出的临床前实验的目的是选择一种疫苗方式，有望解决目前正在开发的候选 DEN 疫苗中的重大缺陷。减毒活疫苗可能无法在单型免疫母亲所生并在母源抗体衰减之前进行免疫的婴儿中诱导对所有四种 DEN 血清型的内源性反应。如果通过推迟疫苗接种直到母体抗体充分衰减以允许使用减毒活疫苗来避免这个问题，那么这些婴儿在此期间将无法受到严重 DEN 疾病的保护。用于 DEN 的 DNA 疫苗可能会规避母体抗体问题，但 DNA 疫苗在人体试验中通常令人失望，特别是在诱导体液反应方面，而体液反应是预防 DEN 的最重要反应。我们提出了一系列实验，首先确定在小鼠和猕猴中最有效诱导反应的 E 蛋白的构型，测试可溶形式的 E 的有前途的新构型，该构型显示出显着改善的中和反应。其次，我们将在小鼠和幼年猕猴中确定 VRP 疫苗混合物是否能诱导对所有四种血清型的平衡反应，并且在被动转移中和抗体存在的情况下安全地实现这一点，正如我们之前在 DEN2-VRP 中进行的实验所预测的那样。老鼠。第三，我们将测试新开发的 DNA 启动形式的 VEE 载体的用途：a) 在小鼠和猕猴中，b) 面对抗 DEN 中和抗体，以及 c) 在存在 VEE 中和抗体的情况下。最后，我们将测试混合模式初免-加强方案，该方案很可能代表基于 VEE 的疫苗载体的最佳疫苗接种策略。我们认为，在这些研究结束时，我们将为基于 VEE 的 DEN 候选疫苗进入 I 期人体试验奠定坚实的基础。