Evaluation Studies of a Dengue-2 DNA Vaccine in Monkeys

猴子登革热 2 DNA 疫苗的评价研究

• 批准号: 6779943
• 负责人: IDALI MARTINEZ-MARTINEZ
• 金额: $ 26.08万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6779943
• 关键词: Macaca mulatta; active immunization; cell mediated lymphocytolysis test; dengue virus; enzyme linked immunosorbent assay; glycolates; immunity; lactates; vaccine development; vaccine evaluation; vector vaccine; viral vaccines; virus envelope

DESCRIPTION (provided by applicant): Dengue fever and dengue hemorrhagic fever result from the infection with any of the four serotypes of dengue (DEN) viruses. These diseases have become a global public health problem, affecting 100 million people anually. Moreover, DEN viruses are potential bioterrorism agents since neither an effective treatment nor vaccine is available. Thus, research is needed to develop an effective and safe vaccine that will prevent infection and disease caused by any of these viruses. The objective of this study is to develop a DNA vaccine capable of inducing protective immune responses in rhesus macaques against DEN-2 virus infection. Our long-term objective is to develop a tetravalent DEN DNA vaccine. Our vaccine strategy is focused on the dengue envelope because this protein mediates the early binding and entry steps of infection. Neutralizing antibodies (Nab) against this protein were shown to be protective against pathogenic virus infection and disease. In this study we plan to evaluate immune responses generated in monkeys by our DNA vaccine candidate, Vec-D2 which encodes prM and env proteins of DEN-2, using four different vaccination regimens. Monkeys will be immunized with Vec-D2 either alone or absorbed onto polylactide-co-glycolide (PLG) microparticles, followed by the administration of an inactivated DEN-2 virus boost adjuvanted in MF59 or MF59 alone. Our hypothesis is that immune responses induced by Vec-D2 will be enhanced by coupling the plasmid DNA to PLG and that these responses could be further boosted by administration of inactivated virus in MF59. Immune responses will be monitored by ELISA, virus neutralization, CTL and proliferation assays. The level of protection induced by the different vaccine strategies against DEN-2 virus infection will be also ascertained: Complete protection will be determined by the absence of detectable viremia and of anamnestic immune responses. Results obtained from these studies will provide important information for the design and development of DNA vaccines expressing the envelope protein of DEN-l, DEN -3 and DEN-4.

描述（由申请人提供）：登革热和登革出血热由感染登革热（DEN）病毒的四种血清型中的任何一种引起。这些疾病已成为全球公共卫生问题，每年影响1亿人。此外，DEN病毒是潜在的生物恐怖主义制剂，因为既没有有效的治疗方法，也没有疫苗。因此，需要进行研究以开发一种有效和安全的疫苗，以预防由这些病毒引起的感染和疾病。本研究的目的是开发一种DNA疫苗，能够诱导恒河猴对DEN-2病毒感染产生保护性免疫反应。我们的长期目标是开发一种四价DEN DNA疫苗。我们的疫苗战略侧重于登革热包膜，因为这种蛋白介导感染的早期结合和进入步骤。针对该蛋白的中和抗体（Nab）被证明对致病性病毒感染和疾病具有保护作用。在这项研究中，我们计划使用四种不同的疫苗接种方案，评估我们的DNA候选疫苗Vec-D2在猴子身上产生的免疫反应，Vec-D2编码DEN-2的prM和env蛋白。猴子将被单独接种Vec-D2或被吸收到聚乳酸-羟基乙酸酯（PLG）微粒上进行免疫，然后被注射灭活的DEN-2病毒增强剂（MF59佐剂或单独MF59佐剂）。我们的假设是，Vec-D2诱导的免疫反应将通过将质粒DNA与PLG偶联而增强，并且这些反应可以通过在MF59中给予灭活病毒进一步增强。免疫反应将通过ELISA、病毒中和、CTL和增殖试验来监测。还将确定不同疫苗策略对DEN-2病毒感染的保护水平：完全保护将由没有可检测到的病毒血症和遗忘性免疫反应确定。这些研究结果将为设计和开发表达DEN- 1、DEN -3和DEN-4包膜蛋白的DNA疫苗提供重要信息。