Consecutive waves of
SARS-CoV-2 infection have been driven in part by the repeated emergence of variants with mutations that confer resistance to
neutralizing antibodies Nevertheless, prolonged or repeated
antigen exposure generates diverse memory B-cells that can produce affinity matured receptor binding domain (RBD)-specific
antibodies that likely contribute to ongoing protection against severe disease. To determine how SARS-CoV-2 omicron variants might escape these
broadly neutralizing antibodies, we subjected chimeric viruses encoding spike
proteins from ancestral,
BA.1 or
BA.2 variants to selection pressure by a collection of 40
broadly neutralizing antibodies from individuals with various SARS-CoV-2
antigen exposures. Notably, pre-existing substitutions in the
BA.1 and
BA.2 spikes facilitated acquisition of resistance to many
broadly neutralizing antibodies. Specifically, selection experiments identified numerous RBD substitutions that did not confer resistance to
broadly neutralizing antibodies in the context of the ancestral Wuhan-Hu-1 spike sequence, but did so in the context of
BA.1 and
BA.2. A subset of these substitutions corresponds to those that have appeared in several
BA.2 daughter lineages that have recently emerged, such as BA.5. By including as few
as 2 or 3 of these additional changes in the context of BA.5, we generated spike
proteins that were resistant to nearly all of the 40
broadly neutralizing antibodies and were poorly neutralized by plasma from most individuals. The emergence of omicron variants has therefore not only allowed SARS-CoV-2 escape from previously elicited
neutralizing antibodies but also lowered the genetic barrier to the acquisition of resistance to the subset of
antibodies that remained effective against early omicron variants.