Human CoV spikes evolve to escape neutralizing antibodies

Eguia, ..., Bloom (2021)

Human sera from 1985-1990 neutralizes contemporaneous CoV-229E spikes quite well, but as virus evolves into the "future", neutralization is eroded. There is substantial heterogeneity in the rate of erosion across sera from different human individuals.

Antibody selection concentrated in RBD

Sites of evolutionary change in spike of CoV-229E over last four decades

Sites of mutations in SARS-CoV-2 Omicron BQ.1.1 spike relative to Wuhan-Hu-1

Greaney*, Starr*, Gilchuk*, Zost*, ..., Crowe, Bloom

RBD

fluorescently labeled antibody

yeast

fluorescent tag on RBD

Experiments combine flow cytometry and deep sequencing of a library of yeast expressing all RBD mutants

These measurements can be made on ~10,000 to ~100,000 mutants all at once 

Escape map from one antibody (LY-CoV555, ie bamlanivimab)

484

452

490

This turned out be an unfortunate choice of an antibody for Eli Lilly to develop as drug, as mutations at sites 484 and 452 were prevalent by early to mid 2021

Infection / vaccination elicit polyclonal antibodies 

How do mutations affect polyclonal antibodies? First, consider an equal mix of three monoclonal antibodies.

Interactive version of this mini example is at https://jbloomlab.github.io/SARS2_RBD_Ab_escape_maps/mini-example-escape-calc/

LY-CoV555 is escaped at both sites 484 and 490, so mutating either site has same overall effect

Average escape across all antibodies

Mutating site 484 or 490 eliminates neutralization by antibody LY-CoV555, as reflected in thick black line showing average

Interactive version of this mini example is at https://jbloomlab.github.io/SARS2_RBD_Ab_escape_maps/mini-example-escape-calc/

From Yunlong Cao, we have deep mutational scanning data on ~1000s antibodies that neutralize XBB

See here for summary of how successful escape calculator has been so far in pinpointing sites of evolution.

Escape calculator has been used 120,000 times by 18,000 users 

Bloom lab

Tyler Starr (now at University of Utah)

Allie Greaney

Bernadeta Dadonaite

Peking University

Yunlong Cao

Fanchong Jian

These slides: https://slides.com/jbloom/sars2-rbd-escape-calc

Thanks

Use the escape calculator at https://jbloomlab.github.io/SARS2-RBD-escape-calc/