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: 6671170
• 负责人: IDALI MARTINEZ-MARTINEZ
• 金额: $ 29.8万
• 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 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6671170
• 关键词: Macaca mulatta; active immunization; cell mediated lymphocytolysis test; dengue virus; drug screening /evaluation; 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是由四种登革热（DEN）病毒血清型中的任何一种感染引起的。这些疾病已成为全球公共卫生问题，每年影响一亿人。此外，DEN 病毒是潜在的生物恐怖主义媒介，因为既没有有效的治疗方法也没有疫苗。因此，需要研究开发一种有效且安全的疫苗来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能够在恒河猴中诱导针对 DEN-2 病毒感染的保护性免疫反应的 DNA 疫苗。我们的长期目标是开发四价 DEN DNA 疫苗。 我们的疫苗策略侧重于登革热包膜，因为这种蛋白质介导感染的早期结合和进入步骤。针对这种蛋白质的中和抗体（Nab）被证明可以预防致病病毒感染和疾病。在这项研究中，我们计划使用四种不同的疫苗接种方案，评估我们的候选 DNA 疫苗 Vec-D2 在猴子中产生的免疫反应，Vec-D2 编码 DEN-2 的 prM 和 env 蛋白。猴子将单独使用 Vec-D2 或吸收到聚丙交酯-乙交酯 (PLG) 微粒上进行免疫，然后施用以 MF59 或单独 MF59 佐剂的灭活 DEN-2 病毒加强疫苗。我们的假设是，通过将质粒 DNA 与 PLG 偶联，可以增强 Vec-D2 诱导的免疫反应，并且通过在 MF59 中施用灭活病毒可以进一步增强这些反应。将通过 ELISA、病毒中和、CTL 和增殖测定来监测免疫反应。还将确定针对 DEN-2 病毒感染的不同疫苗策略诱导的保护水平：完全保护将由不存在可检测到的病毒血症和记忆性免疫反应来确定。这些研究获得的结果将为表达DEN-1、DEN -3和DEN-4包膜蛋白的DNA疫苗的设计和开发提供重要信息。