First let's look at another human coronavirus: CoV-229E causes common colds and has been circulating in humans since at least 1960s.
We experimentally generated CoV-229E spikes at ~8 year intervals so we could study them in the lab:
Note "ladder-like" shape of tree
Serum collected in 1985 neutralizes virus with spike from 1984, but less effective against more recent viruses.
We are studying basis of these differences, as ideally vaccines would elicit more evolution-resistant sera as on the right.
Plot of sequence variability across CoV-229E spike taken from Eguia, ..., Bloom, PLoS Pathogens (2021) . See also Wong, ..., Rini, Nature Communications (2017) and Li, ..., Rini, eLife (2019) for detailed structural studies of evolution in receptor-binding loops.
Similar to SARS-CoV-2 variants like Omicron except they also have cluster of mutations at S1-S2 furin cleavage site boundary.
Human respiratory viruses that undergo rapid antigenic evolution tend to have a "ladder-like" tree because they evolve under "winner-take-all" paradigm where most successful variant displaces others. Viruses that evolve without antigenic selection (or have high diversity over geographic space) have more balanced trees.
CoV-229E tree looks like this
Human H3N2 influenza also tends to have ladder-like trees, and in years where it hasn't that's made vaccine strain selection difficult (vaccine strains marked with x).
Human CoV-OC43 has split into two lineages, although each lineage has a ladder-like tree. Something similar has happened with influenza B.
After early fixation of D614G, the SARS-CoV-2 tree has not been ladder-like
Other coronaviruses evolve antigenically with mutations in same regions as SARS-CoV-2 variants (exception is SARS-CoV-2 variants also have mutations is S1-S2 furin-cleavage site, probably because initial virus was poorly adapted to its furin-cleavage site).
Other antigenically evolving viruses have ladder-like phylogenetic trees, which is key to enabling vaccine updates as it provides some level of predictability (the next variant usually is descended from the last one).
So far SARS-CoV-2 has mostly defied ladder-like paradigm: Omicron not descended from Delta; Delta not descended from Alpha. However, it's still early and right now we are seeing combined effect of selection for antibody escape and increased transmissibility--presumably transmissibility will eventually plateau.
We have used deep mutational scanning to measure how all individual mutations in "original" (Wuhan-Hu-1) RBD affect ACE2 affinity: two-thirds of mutations in Omicron's RBD are individually deleterious for ACE2 affinity
It is also possible that there is epistasis among other combinations of mutations in Omicron, although this has not yet been experimentally elucidated.
Omicron represents first major example where the effects of combined RBD mutations could not be predicted fairly well from single mutants.
fluorescently labeled antibody
fluorescent tag on RBD
See Seth Zost's thread for best summary of therapeutic antibodies and Omicron
Monoclonal antibodies bind one epitope, so can usually be escaped by single mutation
Polyclonal antibodies can bind many epitopes, so often more resistant to escape
We use the antibody classification scheme from Barnes et al Nature (2020). The extension of these antibody classes to escape mapping is in Greaney et al (2021), and escape maps are available here. Class 1, 2, and 3 antibodies are often potently neutralizing, while class 4 antibodies are less neutralizing (see: Piccoli et al (2020), Dejnirattisai et al (2021), Liu et al (2020), Zost, et al (2020)).
Toy example of calculating escape from polyclonal mix:
Escape-calculator with deep mutational scanning data from many antibodies:
Predictions correlate well with neutralization assays:
See here for details on how to use interactive version of this plot at https://jbloomlab.github.io/SARS2_RBD_Ab_escape_maps/escape-calc/
Crowe lab (Vanderbilt)
Chu lab (Univ Wash)
Veesler lab (Univ Wash)
King lab (Univ Wash)
Li lab (Brigham & Women's)
Boeckh lab (Fred Hutch)
Alex Greninger (Univ Wash)
Nussenzweig lab (Rockefeller)
Bjorkman lab (Caltech)
Bloom lab (Fred Hutch)