Structural insight into SARS-CoV-2 neutralizing antibodies and modulation of syncytia

Asarnow, Daniel; Wang, Bei; Lee, Wen-Hsin; Hu, Yuanyu; Huang, Ching-Wen; Faust, Bryan; Lon Ng, Patricia Miang; Xian Ngoh, Eve Zi; Bohn, Markus; Bulkley, David; Pizzorno, Andrés; Ary, Beatrice; Tan, Hwee Ching; Lee, Chia Yin; Minhat, Rabiatul Adawiyah; Terrier, Olivier; Soh, Mun Kuen; Teo, Frannie Jiuyi; Chin Yeap, Yvonne Yee; Kheng Seah, Shirley Gek; Zuo Chan, Conrad En; Connelly, Emily; Young, Nicholas J.; Maurer-Stroh, Sebastian; Renia, Laurent; Hanson, Brendon John; Rosa-Calatrava, Manuel; Manglik, Aashish; Cheng, Yifan; Craik, Charles S.; Wang, Cheng-I

Infection by SARS-CoV-2 is initiated by binding of viral Spike protein to host receptor angiotensin-converting enzyme 2 (ACE2), followed by fusion of viral and host membranes. While antibodies that block this interaction are in emergency use as early COVID-19 therapies, precise determinants of neutralization potency remain unknown. We discovered a series of antibodies that all potently block ACE2 binding, yet exhibit divergent neutralization efficacy against live virus. Strikingly, these neutralizing antibodies can either inhibit or enhance Spike-mediated membrane fusion and formation of syncytia, which are associated with chronic tissue damage in COVID-19 patients. Multiple cryogenic electron microscopy structures of Spike-antibody complexes reveal distinct binding modes that not only block ACE2 binding, but also alter the Spike protein conformational cycle triggered by ACE2 binding. We show that stabilization of different Spike conformations leads to modulation of Spike-mediated membrane fusion, with profound implications in COVID-19 pathology and immunity.