![]() ![]() Indeed, chimeric RSV FG glycoprotein ( 12), recombinant vaccinia virus RSV-G ( 9), low RSV F doses of post-fusion F ( 13), ultra violet inactivated RSV, and purified fusion protein ( 14), along with ring-nanostructures formed by the recombinant nucleoprotein N of hRSV ( 15), have all resulted in VERD following RSV infection. As mentioned earlier, it is important to note that VERD is not exclusive to formalin inactivated vaccines. Moreover, it is recommended that vaccine candidates eliciting high levels of IL-4 and/or IL-13 and/or inducing non-neutralizing antibodies in pre-clinical studies be excluded for progression into clinical trials for seronegative individuals ( 11). Clearly, along with the uncovering of additional immunological correlates ( 4– 7), increasing research activities toward better understanding of VERD is of critical importance to develop safe and effective RSV vaccine ( 8, 9).Īs of today, there are at least 25 ongoing RSV vaccine trials in the Unites States and 15 registered trials at the WHO, with provision of data on VERD investigation of candidate vaccines being one of the regulatory requirements prior to progression into clinical trials ( 10). While formalin, the inactivation agent for the RSV vaccine preparation, might play a role in VERD development, recent studies suggest that other forms of RSV vaccines also induce VERD, suggesting multiple pathways could be involved in this phenomenon. The slow progress in RSV vaccine development is partially due to the unusual disease associated with a formalin-inactivated RSV vaccine (FI-RSV) which caused vaccine-associated enhanced respiratory disease (VERD), with two fatalities and hospitalization of 80% of vaccine recipients in a clinical trial in the 1960s ( 2, 3). Despite decades of research, no vaccine has been licensed. Respiratory syncytial virus (RSV) is the most frequent cause of serious respiratory illness in infants, the elderly and immunocompromised adults ( 1). 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. 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. 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. 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. 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. 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. 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. These findings suggest that multiple factors/pathways could be involved in the development of enhanced respiratory diseases. 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. Despite decades of research, no vaccine has been approved. Respiratory syncytial virus (RSV) infection is a severe threat to young children and the elderly.
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