Following SARS-CoV-2 Omicron BA.1, subsequent Omicron sub-lineages have 32 continued to emerge, challenging the development of intervention and prevention 33 strategies, including monoclonal antibodies and vaccines. To better understand the 34 pathogenic effects caused by Omicron BA.5 infection, we developed a mouse-adapted 35 virus with overt disease burden in BALB/c mice. Acute disease was characterized by 36 significant weight loss and lung dysfunction following high-dose challenges. In survivor 37 animals that were followed through 107 days post-infection, subpleural fibrosis with 38 associated tertiary lymphoid structures was noted. Serum from these mice 39 demonstrated potent neutralization against BA.5, with substantially reduced 40 neutralization titers against early epidemic, zoonotic, and more recent contemporary 41 XBB.1.5 variants. Intervention with pre-clinical monoclonal antibodies revealed that 42 robust protection from BA.5-induced lung disease was possible after prophylactic 43 administration. Together, this model enables the investigation of therapeutic 44 approaches for both acute and post-acute sequelae of COVID-19.