Vaccination targeting ephrin-B2 ameliorates established pulmonary fibrosis

Idiopathic pulmonary fibrosis is a chronic disease with limited treatment options and a poor prognosis. Recent studies have highlighted the potential of vaccination-based immunotherapies for treating fibrosis. Ephrin-B2, a highly expressed endogenous protein in myofibroblasts, is a potent mediator of lung fibrosis and represents a promising therapeutic target. In this study, we developed a recombinant protein vaccine targeting ephrin-B2. The highly conserved ectodomain of ephrin-B2 was selected as the core antigenic epitope and fused with an immune-enhancing peptide generated from the SARS-CoV-2 spike protein at its C-terminus. The recombinant protein was expressed using the Bac-to-Bac baculovirus expression system and administered in combination with the MF59 adjuvant. In mice, therapeutic and prophylactic intramuscular vaccination strategies significantly ameliorated bleomycin-induced lung fibrosis, as evidenced by reduced α-SMA-expressing fibroblasts, normalized tissue collagen content, decreased hydroxyproline levels, and improved survival. Mechanistically, the vaccine elicited high-titer anti-ephrin-B2-specific antibodies and antigen-specific memory T cells (verified by flow cytometry and IFN-γ ELISpot). Moreover, transferring serum or T cells from immunized mice to recipients in the fibrosis model alleviated lung fibrosis, confirming that the vaccine exerts a therapeutic effect by synergistically activating both humoral immunity (through antibodies that neutralize ephrin-B2’s profibrotic activity) and cellular immunity (via T cell-mediated targeted clearance). Collectively, this study demonstrates that the vaccine targeting ephrin-B2 is promising as a novel therapeutic approach for pulmonary fibrosis.