Mouse Adapted Omicron BA.5 Induces A Fibrotic Lung Disease Phenotype in BALB/c Mice

Following SARS-CoV-2 Omicron BA.1, subsequent Omicron sub-lineages have continued to emerge, challenging the development of intervention and prevention strategies, including monoclonal antibodies and vaccines. To better understand the pathogenic effects caused by Omicron BA.5 infection, we developed a mouse-adapted virus with overt disease burden in BALB/c mice. Acute disease was characterized by significant weight loss and lung dysfunction following high-dose challenges. In survivor animals that were followed through 107 days post-infection, subpleural fibrosis with associated tertiary lymphoid structures was noted. Serum from these mice demonstrated potent neutralization against BA.5, with substantially reduced neutralization titers against early epidemic, zoonotic, and more recent contemporary XBB.1.5 variants. Intervention with pre-clinical monoclonal antibodies revealed that robust protection from BA.5-induced lung disease was possible after prophylactic administration. Together, this model enables the investigation of therapeutic approaches for both acute and post-acute sequelae of COVID-19.