Vaccine Vector Comparison Study

摘要 由新出现的传染病生物体引起的大流行疾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)会引起没有有效暴露后治疗方法的疾病。因此，发展疫苗载体平台是当务之急。该项目的目标是比较多个载体，以确定哪一个最适合开发针对新出现感染的疫苗。这项研究比较了以下表达牛痘B5R的疫苗载体免疫小鼠后产生的体液免疫反应：DNA、重组腺病毒、重组水泡性口炎病毒、耻垢分枝杆菌、改良的安卡拉牛痘病毒和委内瑞拉马脑炎病毒复制子颗粒。在异源PRIME/BOOST组合中检测载体，用ELISA定量免疫小鼠血清中的抗B5R抗体。在加强免疫后三个月，用牛痘WR挑战动物，以评估保护效果。我们在此报道，在所测试的七个启动载体中，rAd5-B5R产生了最高的B5R初始滴度。在初次免疫后6周，用rAd5-B5R或rVSV-B5R加强免疫小鼠。加强免疫后，大多数动物(无论启动载体)血清B5R抗体效价均显着升高，并持续到攻击时。在加强免疫后四周内产生最高抗B5R效价的主要加强组合是：rAd5Prime/rVSV Boost、Protein Prime/rAd5 Boost和Protein Prime/rVSV Boost。这三个优质/强化组之间的滴度没有显著差异，但都产生了显著高于其他十个测试组合的滴度。总体而言，rVSV加强免疫的动物的滴度显著高于使用启动载体或单独使用rVSV免疫的水平，这表明主/加强免疫的协同效应。相反，rAd5增强的动物的滴度很少会高于单独接受rAd5的动物的滴度，这表明rAd5可能是最佳的启动剂，而不是增强载体。在第二个试验中，我们通过鼻腔而不是肌肉注射疫苗载体。该试验仅包括rAd5、rVSV和VEE-VRP载体。鼻腔给药提高了所有测试载体的免疫原性，其中VSV PRIME-VRP增强的动物具有最高的总滴度。 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各种新出现的疾病的安全有效的疫苗。该项目的目标是确定制造人类疫苗的最佳疫苗平台或载体。从这个项目中获得的信息应该可以让研究人员为某种疾病选择最好的疫苗平台，也应该减少将新疫苗投入公众使用所需的时间。

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.