Incorporation of membrane-bound, mammalian-derived immunomodulatory proteins into influenza whole virus vaccines boosts immunogenicity and protection against lethal challenge.
Incorporation of membrane-bound, mammalian-derived immunomodulatory proteins into influenza whole virus vaccines boosts immunogenicity and protection against lethal challenge.
复制标题
DOI：
10.1186/1743-422x-6-42
复制
发表时间：
2009-04-24
期刊：
影响因子：
4.8
通讯作者：
Roberts PC
中科院分区：
文献类型：
--
作者：
Herbert AS;Heffron L;Sundick R;Roberts PC
尽管进行了广泛的疫苗接种工作，流感流行仍继续在人群中造成发病率和死亡率。这沿着禽流感（H5 N1）大流行的不祥威胁，表明需要一种改进得多、更复杂的流感疫苗。我们已经开发了一种用于生产膜结合的携带细胞因子的流感疫苗（CYT-IVAC）的体外模型系统。许多细胞因子参与指导先天性和适应性免疫，我们的目标是利用单个细胞因子和其他免疫调节蛋白的特性来创建更具免疫原性的疫苗。我们已经使用致死性流感病毒攻击的小鼠模型评价了灭活的携带精氨酸的流感疫苗的免疫原性。CYT-IVAC通过用融合至病毒血凝素的膜锚定结构域的小鼠来源的细胞因子（GM-CSF、IL-2和IL-4）稳定转染MDCK细胞系来产生。流感病毒在这些细胞系中的复制导致在病毒出芽和释放期间吸收生物活性膜结合的细胞因子。体内疗效研究显示，单次低剂量的携带IL-2或IL-4的CYT-IVAC在小鼠模型中提供针对致死性流感攻击的保护方面具有上级优势，并提供更平衡的Th 1/Th 2体液免疫应答，类似于活病毒感染。我们已经在流感病毒感染的哺乳动物模型中验证了CYT-IVAC的保护功效。这项技术在目前的流感病毒疫苗开发中具有广泛的应用，并且可能被证明在增强老年人的免疫反应方面特别有用，因为目前的疫苗效果最低。
Influenza epidemics continue to cause morbidity and mortality within the human population despite widespread vaccination efforts. This, along with the ominous threat of an avian influenza pandemic (H5N1), demonstrates the need for a much improved, more sophisticated influenza vaccine. We have developed an in vitro model system for producing a membrane-bound Cytokine-bearing Influenza Vaccine (CYT-IVAC). Numerous cytokines are involved in directing both innate and adaptive immunity and it is our goal to utilize the properties of individual cytokines and other immunomodulatory proteins to create a more immunogenic vaccine. We have evaluated the immunogenicity of inactivated cytokine-bearing influenza vaccines using a mouse model of lethal influenza virus challenge. CYT-IVACs were produced by stably transfecting MDCK cell lines with mouse-derived cytokines (GM-CSF, IL-2 and IL-4) fused to the membrane-anchoring domain of the viral hemagglutinin. Influenza virus replication in these cell lines resulted in the uptake of the bioactive membrane-bound cytokines during virus budding and release. In vivo efficacy studies revealed that a single low dose of IL-2 or IL-4-bearing CYT-IVAC is superior at providing protection against lethal influenza challenge in a mouse model and provides a more balanced Th1/Th2 humoral immune response, similar to live virus infections. We have validated the protective efficacy of CYT-IVACs in a mammalian model of influenza virus infection. This technology has broad applications in current influenza virus vaccine development and may prove particularly useful in boosting immune responses in the elderly, where current vaccines are minimally effective.