Translational feline models for immunopathogenesis and vaccine efficacy against SARS-CoV-2 variants

The COVID-19 pandemic underscored the urgent need to understand viral evolution, host immune responses, and preventive strategies across human and animal systems. Using the domestic cat as a translational model, here we explore how immunodeficiency, variant specific adaptation, and novel vaccines shape SARS-CoV-2 outcomes with direct relevance to human health. Coinfection studies demonstrated that immunodeficiency alters disease course, as untreated FIV-positive cats showed impaired CD4⁺ T-cell responses, distinct pulmonary pathology, and persistent viral RNA with evidence of positive selection. These findings emphasize the importance of antiretroviral therapy in limiting viral persistence and the emergence of adaptive mutations. Comparative investigations of Delta (B.1.617.2) and Omicron (XBB.1.5) revealed divergent strategies of replication and host interaction. Delta exhibited aggressive replication, transmissibility, and lower respiratory tract damage, whereas Omicron favored upper respiratory tract restriction with pronounced immune-mediated responses. Transcriptional profiling highlighted Delta’s broader adaptability and host-specific remodeling, underscoring mechanistic differences between variants. Building on these insights, a SARS-CoV-2 mutant vaccine was shown to elicit rapid recovery, reduced viral loads, minimal pathology, and strong early neutralizing antibody responses against both Delta and Omicron. Collectively, our research positions the cat as a powerful model for studying SARS-CoV-2 pathogenesis, coinfections, and vaccine strategies, while advancing one-health approaches to anticipate zoonotic risks and enhance pandemic preparedness.