TY - JOUR
T1 - Epistasis lowers the genetic barrier to SARS-CoV-2 neutralizing antibody escape
AU - Witte, Leander
AU - Baharani, Viren A.
AU - Schmidt, Fabian
AU - Wang, Zijun
AU - Cho, Alice
AU - Raspe, Raphael
AU - Guzman-Cardozo, Camila
AU - Muecksch, Frauke
AU - Canis, Marie
AU - Park, Debby J.
AU - Gaebler, Christian
AU - Caskey, Marina
AU - Nussenzweig, Michel C.
AU - Hatziioannou, Theodora
AU - Bieniasz, Paul D.
N1 - Generated from Scopus record by KAUST IRTS on 2023-02-15
PY - 2023/12/1
Y1 - 2023/12/1
N2 - Waves of SARS-CoV-2 infection have resulted from the emergence of viral variants with neutralizing antibody resistance mutations. Simultaneously, repeated antigen exposure has generated affinity matured B cells, producing broadly neutralizing receptor binding domain (RBD)-specific antibodies with activity against emergent variants. To determine how SARS-CoV-2 might escape these antibodies, we subjected chimeric viruses encoding spike proteins from ancestral, BA.1 or BA.2 variants to selection by 40 broadly neutralizing antibodies. We identify numerous examples of epistasis, whereby in vitro selected and naturally occurring substitutions in RBD epitopes that do not confer antibody resistance in the Wuhan-Hu-1 spike, do so in BA.1 or BA.2 spikes. As few as 2 or 3 of these substitutions in the BA.5 spike, confer resistance to nearly all of the 40 broadly neutralizing antibodies, and substantial resistance to plasma from most individuals. Thus, epistasis facilitates the acquisition of resistance to antibodies that remained effective against early omicron variants.
AB - Waves of SARS-CoV-2 infection have resulted from the emergence of viral variants with neutralizing antibody resistance mutations. Simultaneously, repeated antigen exposure has generated affinity matured B cells, producing broadly neutralizing receptor binding domain (RBD)-specific antibodies with activity against emergent variants. To determine how SARS-CoV-2 might escape these antibodies, we subjected chimeric viruses encoding spike proteins from ancestral, BA.1 or BA.2 variants to selection by 40 broadly neutralizing antibodies. We identify numerous examples of epistasis, whereby in vitro selected and naturally occurring substitutions in RBD epitopes that do not confer antibody resistance in the Wuhan-Hu-1 spike, do so in BA.1 or BA.2 spikes. As few as 2 or 3 of these substitutions in the BA.5 spike, confer resistance to nearly all of the 40 broadly neutralizing antibodies, and substantial resistance to plasma from most individuals. Thus, epistasis facilitates the acquisition of resistance to antibodies that remained effective against early omicron variants.
UR - https://www.nature.com/articles/s41467-023-35927-0
UR - http://www.scopus.com/inward/record.url?scp=85146485512&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-35927-0
DO - 10.1038/s41467-023-35927-0
M3 - Article
C2 - 36653360
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
ER -