RSV Vaccine-Enhanced Disease Is Orchestrated by the Combined Actions of Distinct CD4 T Cell Subsets

Abstract

There is no currently licensed vaccine for respiratory syncytial virus (RSV) despite being the leading cause of lower respiratory tract infections in children. Children previously immunized with a formalin-inactivated RSV (FI-RSV) vaccine exhibited enhanced respiratory disease following natural RSV infection. Subsequent studies in animal models have implicated roles for CD4 T cells, eosinophils and non-neutralizing antibodies in mediating enhanced respiratory disease. However, the underlying immunological mechanisms responsible for the enhanced respiratory disease and other disease manifestations associated with FI-RSV vaccine-enhanced disease remain unclear. We demonstrate for the first time that while CD4 T cells mediate all aspects of vaccine-enhanced disease, distinct CD4 T cell subsets orchestrate discrete and specific disease parameters. A Th2-biased immune response, but not eosinophils specifically, was required for airway hyperreactivity and mucus hypersecretion. In contrast, the Th1-associated cytokine TNF-α was necessary to mediate airway obstruction and weight loss. Our data demonstrate that individual disease manifestations associated with FI-RSV vaccine-enhanced disease are mediated by distinct subsets of CD4 T cells.

Animal models of respiratory syncytial virus infection

“…However, a study in which vaccine virus was produced in serum-free medium in different cells from that used for challenge virus, showed that FI-hRSV primed both Th1 and Th2 responses. Th2 responses mediated enhanced pulmonary pathology, pulmonary eosinophilia, mucus hypersecretion and AHR, whereas TNF-α contributed to airway obstruction and weight loss; eosinophils did not contribute to any disease parameters associated with FI-hRSV vaccine-enhanced disease in mice [89].…”

“…FI-hRSV vaccine-enhanced disease in mice is associated with priming of a Th2 response and is characterised by pulmonary eosinophilia, increased pulmonary pathology, mucus hypersecretion, weight loss, increased airway obstruction and AHR, and a reduction in lung viral load [88], [89]. Depletion of CD4 + cells or IL-4 and IL-10 abrogates vaccine-enhanced pathology [90], [91].…”

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

“…Of course, enhanced RSV disease can be observed in the absence of eosinophil infiltration. A recent study demonstrated the same level of RSV disease in eosinophil-deficient mice although there were high levels of IL-5 expression (154). The level of RSV disease was more dependent upon the activation of Th2 subsets than on infiltration by eosinophils.…”

Monoclonal Antibody against G Glycoprotein Increases Respiratory Syncytial Virus Clearance In Vivo and Prevents Vaccine-Enhanced Diseases

“…In the 1960s, a formalin-inactivated RSV (FI-RSV) as a vaccine candidate was tested in clinical trials. However, FI-RSV trial resulted in the death of two toddlers, and most of the volunteers were hospitalized due to vaccine-enhanced disease after subsequent natural RSV infection [7–10]. Despite prolonged efforts to develop vaccines, there is no licensed vaccine to prevent RSV infection yet.…”