Re-infection with SARS-CoV-2 is associated with increased antibody breadth and potency against diverse sarbecovirus strains.

The ease with which emerging SARS-CoV-2 variants escape neutralizing antibodies limits the protection afforded by a prior exposure, be it infection or vaccination. While rare, broadly neutralizing antibodies with activity toward diverse sarbecoviruses have been detected in convalescent serum. Motivated by findings that plasma responses show increased neutralization breadth and potency with continued antigen exposure, we isolated monoclonal antibodies (mAbs) after a SARS-CoV-2 re-infection and compared them to those isolated 1 year prior, after the first breakthrough infection. Among clonal lineage members identified at both time points, mAbs from the later time point showed improved neutralization potency and breadth. One mAb isolated after re-infection, C68.490, targets a conserved region in the receptor binding domain and shows remarkable activity not only against SARS-CoV-2 variants, but also diverse sarbecoviruses from more distant clades present in animal reservoirs. These findings suggest that a focus on individuals with diverse and repeated antigen exposure could lead to the identification of antibodies with therapeutic utility not just toward current and future SARS-CoV-2 variants, but also distant sarbecoviruses in the event of a future spillover.IMPORTANCESpillover of SARS-related viruses (sarbecoviruses) from animal reservoirs into humans has occurred multiple times in the past few decades. The most recent spillover due to SARS-CoV-2 continues to cause significant disease burden, and treatment options are few, in part because of selection for new variants due to immune escape. Thus, discovering antibodies that can block infection with sarbecoviruses, including SARS-CoV-2 variants, remains critical for both the current pandemic as well as those to come. Our study shows that an individual who was vaccinated and then had repeated breakthrough infections with distinct SARS-CoV-2 variants generated more potent antibodies after the second infection compared to the first infection. Notably, we discovered an antibody in this individual that not only neutralized the dominant SARS-CoV-2 variants but also a range of diverse sarbecoviruses present in animal reservoirs. This antibody thus holds promise as a therapeutic for both the current pandemic and future spillover events.