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

呼吸道合胞病毒(RSV)导致每年冬季呼吸道疾病的暴发，6个月以下婴儿的严重RSV疾病的发病率最高。尽管几乎所有儿童在2岁时都感染了RSV，但自然感染后的免疫不完全，再感染在一生中很常见。在健康的成年人中，RSV通常会引起类似于普通感冒的症状。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为婴儿接种疫苗的尝试导致了RSV感染后呼吸道疾病的加重。RSV感染引起的相对无效的免疫反应和疫苗增强型疾病的幽灵使开发安全有效的RSV疫苗的努力变得混乱。目前还没有针对RSV的抗病毒治疗，尽管在冬季的几个月里，严重疾病的高危人群可以定期注射抗体制剂。因此，显然需要一种安全有效的RSV疫苗。该项目的目的是研究一种能够刺激保护性抗体和细胞免疫反应的病毒载体RSV疫苗的临床前特征。猿腺病毒载体不会在人身上复制或致病，也不会被人腺病毒感染诱导的原有免疫中和，它将单独使用，或与痘病毒MVA载体一起使用。MVA是一种减毒病毒，已被用于安全和成功地为超过12万人接种天花疫苗。为此，将构建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，并在小鼠身上检测抗原表达、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，将在RSV感染的小鼠和棉鼠模型中以及在RSV的自然感染模型小牛中评估其诱导针对RSV的保护性免疫的能力。这项拟议的研究将提供概念证据，证明用AdCH-RSV载体接种疫苗可以保护动物免受RSV感染，并将直接导致将研究结果转化为人类临床试验。

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.