Broadly neutralizing anti-S2 antibodies protect against all three human betacoronaviruses that cause deadly disease

• Published in: Immunity (Cambridge, Mass.) Mass.), 2023-03, Vol.56 (3), p.669-686.e7
• Main Authors: Zhou, Panpan, Song, Ge, Liu, Hejun, Yuan, Meng, He, Wan-ting, Beutler, Nathan, Zhu, Xueyong, Tse, Longping V., Martinez, David R., Schäfer, Alexandra, Anzanello, Fabio, Yong, Peter, Peng, Linghang, Dueker, Katharina, Musharrafieh, Rami, Callaghan, Sean, Capozzola, Tazio, Limbo, Oliver, Parren, Mara, Garcia, Elijah, Rawlings, Stephen A., Smith, Davey M., Nemazee, David, Jardine, Joseph G., Safonova, Yana, Briney, Bryan, Rogers, Thomas F., Wilson, Ian A., Baric, Ralph S., Gralinski, Lisa E., Burton, Dennis R., Andrabi, Raiees
• Format: Article
• Language: English
• Subjects: Antibodies, Neutralizing; Antibodies, Viral; broad coronavirus protection; Broadly Neutralizing Antibodies; coronavirus spike; coronaviruses; COVID-19; Humans; Immunology; pan-betacoronavirus vaccines; S2 stem-helix site; SARS-CoV-2; SARS-CoV-2 variants of concern
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2023.02.005

Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against novel pandemic coronaviruses and to more effectively respond to SARS-CoV-2 variants. The emergence of Omicron and subvariants of SARS-CoV-2 illustrates the limitations of solely targeting the receptor-binding domain (RBD) of the spike (S) protein. Here, we isolated a large panel of broadly neutralizing antibodies (bnAbs) from SARS-CoV-2 recovered-vaccinated donors, which targets a conserved S2 region in the betacoronavirus spike fusion machinery. Select bnAbs showed broad in vivo protection against all three deadly betacoronaviruses, SARS-CoV-1, SARS-CoV-2, and MERS-CoV, which have spilled over into humans in the past two decades. Structural studies of these bnAbs delineated the molecular basis for their broad reactivity and revealed common antibody features targetable by broad vaccination strategies. These bnAbs provide new insights and opportunities for antibody-based interventions and for developing pan-betacoronavirus vaccines. [Display omitted] •Isolated a large panel of stem-helix bnAbs from SARS-CoV-2 recovered-vaccinated humans•Stem-helix bnAbs possess recurrent germline features desired for targeted vaccines•IGHV1-46-encoded stem-helix bnAbs are public clonotypes with two binding modes•Stem-helix bnAbs prophylactically protect against SARS-CoV-1, SARS-CoV-2, and MERS-CoV challenge Pan-betacoronavirus broadly neutralizing antibodies (bnAbs) may hold the key to developing broadly protective vaccines against pandemic coronaviruses and SARS-CoV-2 variants. Zhou et al. isolate a large panel of S2 stem-helix bnAbs to betacoronaviruses and reveal their public features. Select stem-helix bnAbs protect against all three human betacoronaviruses that cause deadly disease.