An antibody escape calculator for the SARS-CoV-2 receptor binding domain (RBD)

 

Jesse Bloom

Fred Hutch Cancer Center / HHMI

 

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

 

@jbloom_lab

Human CoV spikes evolve to escape neutralizing antibodies

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

Deep mutational scanning to map RBD mutations that escape antibody binding

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.

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

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.

Sites of escape in XBB

Clear differences between one and two Omicron infections: eg, site 498 only major site of escape after two Omicron infections

We will probably see viral evolution at many of these sites of escape

 

See here for summary of how deep mutational scanning has predicted many of sites of antigenic evolution in the SARS-CoV-2 RBD over last few years

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

 

Thanks

SARS2-RBD-escape-calc

By Jesse Bloom

SARS2-RBD-escape-calc

An antibody escape calculator for the SARS-CoV-2 receptor binding domain

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