Landscape of infection enhancing antibodies in COVID-19 and healthy donors

To assess the frequency of SARS-CoV-2 infection in the general population, we searched over 64 million heavy chain antibody sequences from healthy unvaccinated, healthy BNT162b2 vaccinated and COVID-19 patient repertoires for sequences similar to 11 previously reported enhancing antibodies. Although the distribution of sequence identities was similar in all three groups of repertoires, the COVID-19 and healthy vaccinated hits were significantly more clonally expanded than healthy unvaccinated hits. Furthermore, among the tested hits, 17 out of 94 from COVID-19 and 9 out of 59 from healthy vaccinated, compared with only 2 out of 96 from healthy unvaccinated, bound to the enhancing epitope. A total of 9 of the 28 epitope-binding antibodies enhanced ACE2 receptor binding to the spike protein. Together, this study revealed that infection enhancing-like antibodies are far more frequent in COVID-19 patients or healthy vaccinated donors than in healthy unvaccinated donors, but a reservoir of potential enhancing antibodies exists in healthy donors that could potentially mature to actual enhancing antibodies upon infection.