An infectivity-enhancing site on the SARS-CoV-2 spike protein is targeted by COVID-19 patient antibodies

Liu, Yafei; Soh, Wai Tuck; Tada, Asa; Arakawa, Akemi; Matsuoka, Sumiko; Nakayama, Emi E.; Li, Songling; Ono, Chikako; Torii, Shiho; Kishida, Kazuki; Jin, Hui; Nakai, Wataru; Arase, Noriko; Nakagawa, Atsushi; Shindo, Yasuhiro; Kohyama, Masako; Nakagami, Hironori; Tomii, Keisuke; Ohmura, Koichiro; Ohshima, Shiro; Okada, Masato; Matsuura, Yoshiharu; Standley, Daron M.; Shioda, Tatsuo; Arase, Hisashi

SARS-CoV-2 infection causes severe symptoms in a subset of patients, suggesting the presence of certain unknown risk factors. Although antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike have been shown prevent SARS-CoV-2 infection, the effects of antibodies against other spike protein domains are largely unknown. Here, we screened a series of anti-spike monoclonal antibodies from COVID-19 patients, and found that some of antibodies against the N-terminal domain (NTD) dramatically enhanced the binding capacity of the spike protein to ACE2, and thus increased SARS-CoV2 infectivity. Surprisingly, mutational analysis revealed that all the infectivity-enhancing antibodies recognized a specific site on the surface of the NTD. The antibodies against this infectivity-enhancing site were detected in all samples of hospitalized COVID-19 patients in the study. However, the ratio of infectivity-enhancing antibodies to neutralizing antibodies differed among patients. Furthermore, the antibodies against the infectivity-enhancing site were detected in 3 out of 48 uninfected donors, albeit at low levels. These findings suggest that the production of antibodies against SARS-CoV-2 infectivity-enhancing site could be considered as a possible exacerbating factors for COVID-19 and that a spike protein lacking such antibody epitopes may be required for safe vaccine development, especially for individuals with pre-existing enhancing antibodies.