A tri-modular feline infectious peritonitis virus nanoparticle vaccine confers complete protection in female cats without detectable antibody-dependent enhancement

Antibody-dependent enhancement (ADE) complicates coronavirus vaccine development. Feline infectious peritonitis virus (FIPV) is a classic model of coronavirus vaccine-mediated ADE. Here, we develop ferritin-based FIPV nanoparticle vaccines displaying nucleocapsid (N) antigen, antigen-presenting cell (APC)-targeting ligands, and immunostimulatory factors, and evaluate their protective efficacy, serum-mediated ADE risk, and associated immune features. Compared with soluble N protein, the single-module FIPV N nanoparticle vaccine (sfNnps) enhances FIPV N-specific T-cell responses yet confers only 25.0% (2/8) protection. Dual-module vaccines incorporating either the APC-targeting ligand HCV E2 (dfN/Hnps) or the immunostimulatory factor IFNγ (dfN/Inps) further boost N-specific T-cell responses and confer 50.0% (4/8) and 62.5% (5/8) protection, respectively. The tri-modular vaccine co-displaying N, HCV E2, and IFNγ (tfN/HInps) elicits the most robust N-specific T-cell responses and affords 100% (8/8) protection in female cats, while showing no detectable serum-mediated ADE under the tested conditions and reducing peripheral-blood viral RNA levels by 73.0%. Immune profiling associates tfN/HInps with increased cDC1 representation and antigen-presentation gene expression, as well as a shift toward CD8⁺ effector-memory T cells and a FOXO1-centered program linked to transcriptional features of increased proliferation, memory formation, and cytotoxicity. Overall, this engineered FIPV nano‑display vaccine could provide a framework for cellular‑immunity‑oriented vaccine development against ADE‑prone coronaviruses. This study shows that a tri-modular ferritin nanoparticle vaccine against feline infectious peritonitis virus elicits strong cellular immunity and provides protection in female cats without detectable serum-mediated antibody-dependent enhancement.