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：
7618413
负责人：
LAURA J WHITE
金额：
$ 87.09万
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 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7618413
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 Relative (related person)Replicon Risk Safety Secondary Immunization Series Serotyping Serum Solid Source System Testing Time Transcript Treatment Protocols 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）：本应用程序中提出的临床前实验的目的是选择一种疫苗模态，希望能解决当前正在开发的候选den疫苗的明显缺陷。活的减毒疫苗可能无法诱导对单型免疫母亲出生的婴儿的所有四种DEN血清型的内源性反应，并在母体抗体衰减之前免疫。如果通过延迟疫苗接种来避免此问题，直到母体抗体衰减充足以允许使用活衰减的疫苗，那么在此期间，这些婴儿将不受严重DEN疾病的保护。 DEN的DNA疫苗可能会规避母体抗体问题，但是DNA疫苗通常在人类试验中令人失望，尤其是在诱导体液反应方面，这是保护DEN的最重要反应。我们提出了一系列实验，该序列将首先确定E蛋白在诱导小鼠和猕猴中最有效的E蛋白的构型，以可溶性形式测试E的新型E新构型，该构型显示出明显改善的中和响应。其次，我们将在小鼠和婴儿猕猴中确定VRP疫苗鸡尾酒是否会诱导对所有四种血清型的平衡反应，并且可以安全地进行，并且在存在被动转移的中和中和中和抗体的情况下，这将是我们先前与小鼠中DEN2-VRP的实验所预测的那样。第三，我们将测试新开发的DNA启动的VEE向量形式，用于其效用a）在小鼠和猕猴中，b）面对抗抑制抗体中和抗体，c）在与VEE的中和抗体存在下。最后，我们将测试可能代表基于VEE的疫苗媒介的最佳疫苗接种策略的混合模态促进方案。我们认为，在这些研究的结论中，我们将建立一个可靠的理由，以进步基于VEE的疫苗候选DEN进入I期人类试验。