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.