Vaccine Vector Comparison Study

疫苗载体比较研究

• 批准号: 7652093
• 负责人: Elizabeth Anne Ramsburg
• 金额: $ 26.94万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652093
• 关键词: Adenoviruses; Animals; Antibodies; Avian Influenza; Cowpox; Disease; Ebola virus; Goals; Human; Immune response; Immunization; Infection; Infectious Agent; Modified Vaccinia Virus Ankara; Mus; Proteins; Public Health; Recombinant DNA; Recombinants; Replicon; Reporting; Research Personnel; Serum; Testing; Time; Vaccines; Vaccinia; Venezuelan Equine Encephalitis Virus; Vesicular stomatitis Indiana virus; Week; West Nile virus; abstracting; immunogenicity; novel vaccines; pandemic disease; particle; pathogen; vaccine development; vector; vector vaccine

Abstract The threat of pandemic disease caused by emerging infectious organisms is an immediate and ongoing concern. Many emerging pathogens (Ebola virus, avian influenza) cause disease for which no effective post-exposure treatment exists. Thus, development of vaccine vector platforms is a priority. The goal of this project is to compare multiple vectors to determine which is best suited for developing vaccines against emerging infections. This study compares humoral immune responses generated after immunization of mice with the following vaccine vectors expressing cowpox B5R: DNA, recombinant adenovirus, recombinant vesicular stomatitis virus, M. smegmatis, modified vaccinia Ankara, and Venezuelan equine encephalitis virus replicon particles. Vectors were tested in heterologous prime/boost combinations, using ELISAs to quantify anti-B5R antibody in the serum of immunized mice. At three months post boost animals were challenged with vaccinia WR to evaluate protection. We report here that of the seven priming vectors tested, rAd5-B5R generated the highest initial titers to B5R. At six weeks post primary immunization mice were boosted with either rAd5-B5R or rVSV-B5R. After boosting most animals (regardless of priming vector) had significantly increased serum antibody titers to B5R which persisted until the time of challenge. The prime boost combinations generating the highest anti-B5R titers by four weeks post boost were: rAd5 prime/rVSV boost, protein prime/rAd5 boost, and protein prime/rVSV boost. Titers were not significantly different between these three prime/boost groups, but all generated significantly higher titers than the other ten combinations tested. In general, titers of rVSV boosted animals increased to levels significantly higher than those achieved via immunization either with the priming vector, or with rVSV alone, indicating a synergistic effect of the prime/boost. In contrast, titers of rAd5 boosted animals rarely increased above titers of animals receiving rAd5 alone, indicating that rAd5 may be used optimally as a priming, rather than a boosting vector. In a second trial we delivered vaccine vectors intranasally rather than intramuscularly. This trial included only rAd5, rVSV, and VEE-VRP vectors. Intranasal delivery increased immunogenicity of all vectors tested, with VSV prime- VRP boosted animals having the highest overall titers. Relevance to Public Health: Safe and effective vaccines for a variety of emerging diseases such as avian influenza, Ebola virus, and West Nile virus are urgently needed. The goal of this project is to identify the best vaccine ¿platforms¿ or ¿vectors¿ for making human vaccines. Information gained in this project should allow researchers to pick the best vaccine platform for a certain disease, and should also decrease the time it takes to bring a new vaccine into public use.

摘要 由新出现的传染性生物体引起的大流行病的威胁是一个直接和持续的关切。许多新出现的病原体（埃博拉病毒、禽流感）引起的疾病，没有有效的接触后治疗。因此，疫苗载体平台的开发是一个优先事项。该项目的目标是比较多种载体，以确定哪种载体最适合开发针对新出现的感染的疫苗。本研究比较了表达牛痘B5 R的DNA、重组腺病毒、重组水泡性口炎病毒、M. smeglavirus、修饰的安卡拉牛痘和委内瑞拉马脑炎病毒复制子颗粒。在异源初免/加强组合中测试载体，使用ELISA定量免疫小鼠血清中的抗B5 R抗体。在加强后三个月，用牛痘WR攻击动物以评估保护。我们在此报告，在所测试的七种引发载体中，rAd 5-B5 R对B5 R产生最高的初始滴度。在初次免疫后六周，用rAd 5-B5 R或rVSV-B5 R加强小鼠。在加强免疫后，大多数动物（不考虑初免载体）对B5 R的血清抗体滴度显著增加，并持续至攻毒时。在加强后四周产生最高抗B5 R滴度的初免加强组合为：rAd 5初免/rVSV加强、蛋白质初免/rAd 5加强和蛋白质初免/rVSV加强。这三个初免/加强组之间的滴度无显著差异，但均产生显著高于其他10个检测组合的滴度。通常，rVSV加强的动物的滴度增加至显著高于通过用初免载体或单独用rVSV免疫所实现的水平，表明初免/加强的协同效应。相比之下，rAd 5加强的动物的滴度很少增加到高于单独接受rAd 5的动物的滴度，表明rAd 5可以最佳地用作引发载体，而不是加强载体。在第二次试验中，我们通过鼻内而不是肌肉内递送疫苗载体。该试验仅包括rAd 5、rVSV和VEE-VRP载体。鼻内递送增加了所有测试载体的免疫原性，其中VSV初免- VRP加强的动物具有最高的总体滴度。 与公共卫生的相关性：迫切需要针对禽流感、埃博拉病毒和西尼罗河病毒等多种新兴疾病的安全有效的疫苗。该项目的目标是确定用于制造人类疫苗的最佳疫苗平台或载体。该项目获得的信息将使研究人员能够为某种疾病选择最佳的疫苗平台，并缩短将新疫苗投入公众使用的时间。