Intra-host evolution of SARS-CoV-2 from REGN-COV

Monoclonal antibodies (mAb) directed against the spike of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are potent therapeutic options to combat infections in patients with high risk for severe COVID-19. Here, we report the intra-host adaptation of SARS-CoV-2 to the mAb cocktail REGN-COV in a kidney transplant patient with acquired hypogammaglobulinemia. Following mAb treatment, the patient did not clear the infection. During the viral persistence, SARS-CoV-2 acquired three novel spike mutations. These mutations caused a complete escape from REGN-COV while reducing binding to the ACE2 receptor. Viral clearance occurred upon decrease of the immunosuppressive regimen and total IgG substitution. In depth serology suggests that the development of highly neutralizing IgM rather than IgG substitution aided clearance. Collectively, we show that selection pressure by mAbs on SARS-CoV-2 can lead to rapid development of escape variants in immunocompromised patients. If possible, modification of immunosuppressive therapy can support viral clearance.