Pre-clinical development of a simian adenovirus vectored respiratory syncytial virus (RSV) vaccine

呼吸道合胞病毒（RSV）引起每年冬季呼吸道疾病暴发，在6个月以下的婴儿中严重RSV疾病的发病率最高。虽然几乎所有儿童在2岁时都感染了呼吸道合胞病毒，但自然感染后的免疫是不完全的，并且在整个生命中再次感染是很常见的。在健康成年人中，呼吸道合胞病毒通常会引起与普通感冒相似的症状。然而，在老年人和免疫功能低下的患者中，疾病可能会很严重。目前没有有效的疫苗，以前使用灭活病毒疫苗接种婴儿的尝试导致呼吸道合胞病毒感染后呼吸道疾病增加。RSV感染诱导的相对无效的免疫反应和疫苗增强疾病的阴影使开发安全有效的RSV疫苗的尝试变得混乱。目前还没有针对呼吸道合胞病毒的抗病毒治疗方法，尽管在冬季可以定期给患有严重疾病的高风险个体注射抗体制剂。因此，显然需要一种安全有效的RSV疫苗。该项目的目的是临床前表征的病毒载体RSV疫苗，刺激保护性抗体和细胞免疫反应。猿猴腺病毒载体不会在人体内复制或引起疾病，也不会被人腺病毒感染引起的预先存在的免疫所中和，因此可以单独使用，也可以与痘病毒MVA载体一起采用异源启动-增强策略。MVA是一种减毒病毒，已被用于安全、成功地为超过12万人接种天花疫苗。为此，将制备不同的黑猩猩腺病毒（AdCh）载体和表达RSV抗原的减毒痘病毒MVA载体，并在小鼠中检测抗原表达、生产力、遗传稳定性和免疫原性。一旦确定了最佳候选AdCh-RSV载体，将评估其在RSV感染小鼠和棉花大鼠模型以及小牛（RSV自然感染模型）中诱导RSV保护性免疫的能力。拟议的研究将提供概念证明，即接种AdCh-RSV载体可以保护动物免受RSV感染，并将直接导致将研究结果转化为人体临床试验。

Respiratory syncytial virus (RSV) causes annual winter outbreaks of respiratory disease, with a peak incidence of severe RSV disease in infants less than 6 months of age. Although nearly all children are infected with RSV by 2 years of age, immunity following natural infection is incomplete and re-infections are common throughout life. In healthy adults, RSV usually causes symptoms similar to those of the common cold. However, diseases can be severe in the elderly and immunocompromised patients. There is currently no effective vaccine and previous attempts at vaccination of infants, using an inactivated virus vaccine, resulted in enhanced respiratory disease following RSV infection. The relatively ineffective immune response induced by RSV infection and the spectre of vaccine-enhanced disease have confounded attempts to develop a safe and effective RSV vaccine. There is currently no anti-viral treatment for RSV, although individuals at high risk of severe disease can be given regular injections of an antibody preparation during the winter months. There is, therefore, a clear need for a safe and effective RSV vaccine. The aim of this project is the preclinical characterization of a viral vectored RSV vaccine that stimulates protective antibody and cellular immune responses. Simian adenovirus vectors, which do not replicate or cause disease in man and which are not neutralized by pre-existing immunity induced by human adenovirus infection will be used either alone, or in a heterologous prime-boost strategy with poxvirus MVA vectors. MVA is an attenuated virus which has been used to safely and successfully vaccinate over 120,000 humans against smallpox. To this end, different chimpanzee adenovirus (AdCh) vectors and an attenuated poxvirus MVA vector expressing RSV antigens will be generated and tested for antigen expression, productivity, genetic stability and immunogenicity in mice. Once the best candidate AdCh-RSV vector has been identified, it will be evaluated for its ability to induce protective immunity against RSV in a mouse and cotton rat model of RSV infection, and also in calves, a natural infection model of RSV. The proposed study will provide Proof of Concept that vaccination with an AdCh-RSV vector protects animals against RSV infection and will lead directly to translation of the findings into clinical trials in man.