Recombinant RSV G protein vaccine induces enhanced respiratory disease via IL-13 and mucin overproduction

The G protein expressed on the surface of respiratory syncytial virus (RSV) is important for adhesion to host cells and as a vaccine target antigen. The corresponding vaccines can effectively eliminate RSV, but exacerbate pulmonary immunopathology, such as eosinophil infiltration into the lungs, after the RSV challenge in animal models, raising concerns about enhanced respiratory disease (ERD), creating a need for approaches that mitigate these effects. Herein, we aimed to examine the mechanisms of G protein vaccine-induced ERD in mice, using recombinant G protein as a vaccine antigen. After the RSV challenge, G protein-vaccinated mice exhibited lung weight gain, lung tissue damage, and increased infiltration of eosinophils, neutrophils, and CD4+ T cells into the lungs. We set lung weight gain as the endpoint for ERD and examined the impact of each infiltrating cell on lung weight gain. We observed that CD4+ T cells, but not eosinophils or neutrophils, that infiltrate the lungs are responsible for lung weight gain. In addition, T helper 2 cell-mediated IL-13 induced mucin hypersecretion and lung weight gain. Mucin hypersecretion may contribute to weight gain in the lungs. In conclusion, our results indicate a novel mechanism of G protein vaccine-induced ERD via IL-13 and mucin hypersecretion, which could lead to the development of safe G protein vaccines and the elucidation of the causes of ERD associated with other vaccines. Overall design: To thoroughly evaluate the ERD inflammatory response induced by the G protein vaccine, we analyzed the gene expression profile from an RNA-seq data obtained from the lungs of mice subjected to control and experimental treatments (four treatments in total). Comparative gene expression profiles from lungs of mice vaccinated with PBS or G protein, then treated with an IgG isotype control or anti-CD4 antibody, and subsequently challenged with RSV. Samples from mice treated with anti-CD4 antibodies served as reference samples.