Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch (HPFB), Health Canada and WHO Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, Canada.
Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
Front Immunol. 2019 Mar 29;10:597. doi: 10.3389/fimmu.2019.00597. eCollection 2019.
Respiratory syncytial virus (RSV) infection is a severe threat to young children and the elderly. Despite decades of research, no vaccine has been approved. Notably, instead of affording protection, a formalin-inactivated RSV vaccine induced severe respiratory disease including deaths in vaccinated children in a 1960s clinical trial; however, recent studies indicate that other forms of experimental vaccines can also induce pulmonary pathology in pre-clinical studies. These findings suggest that multiple factors/pathways could be involved in the development of enhanced respiratory diseases. Clearly, a better understanding of the mechanisms underlying such adverse reactions is critically important for the development of safe and efficacious vaccines against RSV infection, given the exponential growth of RSV vaccine clinical trials in recent years. By employing an integrated systems biology approach in a pre-clinical cotton rat model, we unraveled a complex network of pulmonary canonical pathways leading to disease development in vaccinated animals upon subsequent RSV infections. Cytokines including IL-1, IL-6 GRO/IL-8, and IL-17 in conjunction with mobilized pulmonary inflammatory cells could play important roles in disease development, which involved a wide range of host responses including exacerbated pulmonary inflammation, oxidative stress, hyperreactivity, and homeostatic imbalance between coagulation and fibrinolysis. Moreover, the observed elevated levels of MyD88 implicate the involvement of this critical signal transduction module as the central node of the inflammatory pathways leading to exacerbated pulmonary pathology. Finally, the immunopathological consequences of inactivated vaccine immunization and subsequent RSV exposure were further substantiated by histological analyses of these key proteins along with inflammatory cytokines, while hypercoagulation was supported by increased pulmonary fibrinogen/fibrin accompanied by reduced levels of plasma D-dimers. Enhanced respiratory disease associated with inactivated RSV vaccine involves a complex network of host responses, resulting in significant pulmonary lesions and clinical manifestations such as tachypnea and airway obstruction. The mechanistic insight into the convergence of different signal pathways and identification of biomarkers could help facilitate the development of safe and effective RSV vaccine and formulation of new targeted interventions.
呼吸道合胞病毒（RSV）感染对婴幼儿和老年人是一个严重的威胁。尽管经过几十年的研究，仍没有疫苗被批准。值得注意的是，在 20 世纪 60 年代的临床试验中，一种福尔马林灭活的 RSV 疫苗不仅没有提供保护，反而导致接种儿童出现严重的呼吸道疾病，包括死亡；然而，最近的研究表明，其他形式的实验性疫苗也可以在临床前研究中诱导肺部病理学。这些发现表明，多种因素/途径可能参与了增强型呼吸道疾病的发展。显然，更好地了解这些不良反应的机制对于开发针对 RSV 感染的安全有效的疫苗至关重要，因为近年来 RSV 疫苗临床试验呈指数级增长。通过在临床前棉鼠模型中采用综合系统生物学方法，我们揭示了一个复杂的肺经典途径网络，该网络导致接种动物在随后的 RSV 感染后发展为疾病。细胞因子，包括白细胞介素-1（IL-1）、白细胞介素-6（GRO/IL-8）和白细胞介素-17（IL-17），以及募集的肺部炎性细胞，可能在疾病发展中发挥重要作用，涉及宿主的广泛反应，包括肺部炎症加剧、氧化应激、高反应性以及凝血和纤维蛋白溶解之间的平衡失调。此外，观察到的 MyD88 水平升高表明，该关键信号转导模块作为导致肺部病理学加剧的炎症途径的中心节点参与其中。最后，通过对这些关键蛋白和炎症细胞因子进行组织学分析，进一步证实了灭活疫苗免疫接种和随后 RSV 暴露的免疫病理学后果，同时通过增加的肺纤维蛋白原/纤维蛋白和降低的血浆 D-二聚体水平支持了高凝状态。与灭活 RSV 疫苗相关的增强型呼吸道疾病涉及宿主反应的复杂网络，导致明显的肺部病变和临床症状，如呼吸急促和气道阻塞。对不同信号通路汇聚的机制见解以及生物标志物的鉴定，可能有助于促进 RSV 疫苗的安全有效开发和新靶向干预措施的制定。
