SA55 broadly neutralizes SARS-CoV-2 and robustly prevents viral escape by JN.1 sublineages

SARS-CoV-2 monoclonal antibodies remain the only option for the prevention or treatment of COVID-19 for those with immunodeficiencies or drug interactions with antiviral agents. Here, we assess the neutralizing activity of the authorized antibody pemivibart and the candidate antibody SA55 against major historical and currently dominant viral variants, including the JN.1 subvariants KP.3.1.1 and XEC. Our findings show that SA55 demonstrates broad neutralizing potency while pemivibart exhibits reduced neutralizing activity against currently dominant variants. Then we employ replication-competent vesicular stomatitis virus with the JN.1 spike (rVSVΔG-JN.1) to select escape variants of SA55. Following this, we conduct a systematic comparison of escape profiles for these two antibodies, revealing that SA55 is remarkably resilient to escape mutations under antibody selection, which is consistent with our SPR data indicating that SA55 possesses a substantially stronger binding affinity. Moreover, an immunobridging analysis suggests that SA55 may have superior clinical efficacy to pemivibart in preventing SARS-CoV-2 infection under the current variant landscape. Together, this work highlights the promise of SA55 as a potential therapeutic option in the prevention and treatment of COVID-19, especially in immunocompromised populations.