A vectored measles virus induces hepatitis B surface antigen antibodies while protecting Macaques against measles virus challenge
A vectored measles virus induces hepatitis B surface antigen antibodies while protecting Macaques against measles virus challenge
复制标题
DOI：
10.1128/jvi.00923-07
复制
发表时间：
2007-10-01
影响因子：
5.4
通讯作者：
Cattaneo, Roberto
中科院分区：
文献类型：
--
作者：
del Valle, Jorge Reyes;Devaux, Patricia;Cattaneo, Roberto
乙肝病毒(乙肝病毒)急性和慢性感染仍然是一个主要的世界性健康问题。为了开发一种具有单剂方案潜力的抗乙肝疫苗，我们设计了具有疫苗毒株背景和表达载体特性的传染性麻疹病毒(MV)基因组cDNA。将乙肝表面抗原(HBs-Ag)表达盒插入到该c DNA中，产生了3个不同水平表达HBs-Ag的MV。所有携带病毒的W以亚病毒颗粒的形式分泌乙肝表面抗原，在对MV敏感的转基因小鼠中都能引起体液反应。然而，乙肝表面抗原表达的微小差异导致了巨大不同的乙肝表面抗原抗体水平。将诱导产生最高水平的乙肝表面抗原抗体的两个载体接种恒河猴(Macaca Mulatta)。在用致病性MV毒株(Davis(87))攻击后，对照幼猴表现出典型的麻疹皮疹和高病毒载量。相比之下，用疫苗或对照非载体重组疫苗或表达乙肝表面抗原的载体W免疫的所有猴子都保持健康，病毒载量很低或检测不到。在单剂疫苗接种后，只有表达最高水平的乙肝表面抗原的载体在四只动物中的两只身上产生了保护水平的乙肝表面抗原抗体。这些观察揭示了有效诱导乙肝表面抗原体液免疫反应的表达阈值。老鼠的这一阈值比猕猴的低。讨论了基于减毒活病毒的二价疫苗开发的意义。
Hepatitis B virus (HBV) acute and chronic infections remain a major worldwide health problem. Towards developing an anti-HBV vaccine with single-dose scheme potential, we engineered infectious measles virus (MV) genomic cDNAs with a vaccine strain background and expression vector properties. Hepatitis B surface antigen (HBsAg) expression cassettes were inserted into this cDNA and three MVs expressing HBsAg at different levels generated. All vectored Ws, which secrete HBsAg as subviral particles, elicited humoral responses in MV-susceptible genetically modified mice. However, small differences in HBsAg expression elicited vastly different HBsAg antibody levels. The two vectors inducing the highest HBsAg antibody levels were inoculated into rhesus monkeys (Macaca mulatta). After challenge with a pathogenic MV strain (Davis(87)), control naive monkeys showed a classic measles rash and high viral loads. In contrast, all monkeys immunized with vaccine or a control nonvectored recombinant vaccine or HBsAg-expressing vectored W remained healthy, with low or undetectable viral loads. After a single vaccine dose, only the vector expressing HBsAg at the highest levels elicited protective levels of HBsAg antibodies in two of four animals. These observations reveal an expression threshold for efficient induction of HBsAg humoral immune responses. This threshold is lower in mice than in macaques. Implications for the development of divalent vaccines based on live attenuated viruses are discussed.