Sublingual Immunization With an RSV G Glycoprotein Fragment Primes IL-17-Mediated Immunopathology Upon Respiratory Syncytial Virus Infection

Abstract

Respiratory syncytial virus (RSV) is the leading cause of serious respiratory tract disease but there is no licensed RSV vaccine. Immunopathological mechanisms have long been suspected as operating in the development of severe RSV disease and have hampered the development of safe and effective vaccines. Here, we show that unlike intranasal immunization, sublingual immunization with RSV glycoprotein fragment containing the central conserved region (Gcf) primes the host for severe disease upon RSV challenge. This increased pathology does not require replication by the challenge virus and is associated with massive infiltration of inflammatory cells, extensive cell death, and excessive mucus production in the airway and lungs. This exacerbated RSV disease primed by sublingual Gcf immunization is distinct from the immunopathology by G-expressing vaccinia virus or formalin-inactivated RSV, and preceded by prominent IL-17 production. IL-17 deficiency abolished the enhanced disease. Our results suggest a novel mechanism of RSV vaccine-induced immunopathology by IL-17, and highlights the importance of vaccination site.

Interleukin‐17—A multifaceted cytokine in viral infections

“…Wang et al, 2016). IL-17A is also there is no vaccine available against RSV and its precise mechanism of pathogenesis is not fully explored (Cheon et al, 2019). Upregulation of Th17 cells and IL-17A responses in RSV infection are associated with increased neutrophil recruitment and pulmonary pathogenesis in infants as well as in BALB/c mouse model of RSV (Mukherjee et al, 2011).…”

Immunopathology of RSV: An Updated Review

“…Other studies have shown that RSV G protein priming modulates eosinophil trafficking and function [130][131][132], and sublingual administration with the RSV G protein CCD primes mice for pulmonary eosinophilia and results in greater eosinophils compared to FI-RSV priming [133]. Sublingual priming was also shown to prime both pulmonary eosinophilia and neutrophilia in the lung tissue [134].…”

Current Insights in the Development of Efficacious Vaccines Against RSV

“…Many vaccine prototypes are focused on viral surface proteins ( 36 , 37 ). One of the most common viral targets for antibodies is the RSV fusion (F) protein ( 38 , 39 ).…”

“…The choice of administration route is an important decision in vaccine development, with most vaccines being delivered via the sublingual, intramuscular, or intranasal route. Sublingual administration of an RSV G protein vaccine induced enhanced cellular infiltration and pro-inflammatory cytokine production compared to intranasal delivery ( 37 ). Similar results were observed when a recombinant RSV attachment (G) protein containing the central regions for both RSV A and B serotypes was administrated either intranasally or sublingually ( 44 ).…”

“…Respiratory Syncytial Virus (RSV) is the leading cause of acute lower respiratory tract infections (ALRTI) in children under the age of 2 (3) and adults over 65 (4). RSV-induced disease can range from symptoms similar to the common cold to complex respiratory diseases, such as pneumonia or bronchiolitis, leading to extrapulmonary sequelae in the brain and other tissues (5). During the 1960s, a formalin-inactivated RSV (FI-RSV) vaccine was evaluated in children.…”