PDF(Pubmed)
Abstract：
Tuberculosis is a major global threat to human health. Since the widely used BCG vaccine is poorly effective in adults, there is a demand for the development of a new type of boost tuberculosis vaccine. We designed a novel intranasal tuberculosis vaccine candidate, TB/FLU-04L, which is based on an attenuated influenza A virus vector encoding two mycobacterium antigens, Ag85A and ESAT-6. As tuberculosis is an airborne disease, the ability to induce mucosal immunity is one of the potential advantages of influenza vectors. Sequences of ESAT-6 and Ag85A antigens were inserted into the NS1 open reading frame of the influenza A virus to replace the deleted carboxyl part of the NS1 protein. The vector expressing chimeric NS1 protein appeared to be genetically stable and replication-deficient in mice and non-human primates. Intranasal immunization of C57BL/6 mice or cynomolgus macaques with the TB/FLU-04L vaccine candidate induced Mtb-specific Th1 immune response. Single TB/FLU-04L immunization in mice showed commensurate levels of protection in comparison to BCG and significantly increased the protective effect of BCG when applied in a \"prime-boost\" scheme. Our findings show that intranasal immunization with the TB/FLU-04L vaccine, which carries two mycobacterium antigens, is safe, and induces a protective immune response against virulent M. tuberculosis.
摘要：
结核病是全球对人类健康的主要威胁。由于广泛使用的BCG疫苗在成人中效果不佳，需要开发一种新型的加强结核病疫苗。我们设计了一种新型鼻内结核候选疫苗，TB/FLU-04L,它基于编码两种分枝杆菌抗原的减毒甲型流感病毒载体，Ag85A和ESAT-6。由于结核病是一种空气传播疾病，诱导粘膜免疫的能力是流感载体的潜在优势之一。将ESAT-6和Ag85A抗原的序列插入甲型流感病毒的NS1开放阅读框以替换NS1蛋白的缺失的羧基部分。表达嵌合NS1蛋白的载体在小鼠和非人灵长类动物中似乎是遗传稳定且复制缺陷的。用TB/FLU-04L候选疫苗鼻内免疫C57BL/6小鼠或食蟹猴诱导Mtb特异性Th1免疫应答。与BCG相比，小鼠的单次TB/FLU-04L免疫显示出相当的保护水平，并且在“初免”方案中应用时，BCG的保护作用显着增加。我们的研究结果表明，用TB/FLU-04L疫苗鼻内免疫，携带两种分枝杆菌抗原，是安全的,并诱导针对毒力结核分枝杆菌的保护性免疫应答。
