How SARS-CoV-2 evolution affects antibodies and vaccines

 

Jesse Bloom lab

Fred Hutch Cancer Research Center / HHMI

 

Slides at https://slides.com/jbloom/gs-retreat-2021

 

@jbloom_lab

Only sometimes does virus evolution erode immunity

  • Measles virus: Does not evolve to escape immunity. People infected at most once in their lives. Vaccine developed in 1960s still works today.

 

  • Influenza virus: Evolves to escape immunity. People infected every ~5 years. Vaccine needs to be updated annually.

How will viral evolution impact immunity to SARS-CoV-2?

We can address this question by studying historical evolution of other human coronaviruses.

 

We chose CoV-229E, which causes common colds and has circulated in humans since at least 1960s.

Quantifying how viral evolution impacts neutralizing antibody immunity

 old virus (e.g., 1984)

Quantifying how viral evolution impacts neutralizing antibody immunity

 old virus (e.g., 1984)

extent of virus neutralization

Measure how old serum neutralizes old virus

Quantifying how viral evolution impacts neutralizing antibody immunity

 old virus (e.g., 1984)

extent of virus neutralization

Measure how old serum neutralizes newer virus

 newer viruses

measles-like

influenza-like

Evolution of coronavirus 229E erodes human serum antibody neutralization

Eguia, ..., Bloom. PLoS Pathogens (2021)

Reconstructing evolution of CoV-229E spike

We experimentally generated CoV-229E spikes at ~8 year intervals so we could study them in the lab:

- 1984

- 1992

- 2001

- 2008

- 2016

Eguia, ..., Bloom. PLoS Pathogens (2021)

Coronavirus evolution erodes antibody immunity of people at different rates

We are studying basis of these differences, as ideally vaccines would elicit more evolution-resistant sera as on the right.

Eguia, ..., Bloom. PLoS Pathogens (2021)

Most mutations in RBD & NTD

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.

What specific SARS-CoV-2 mutations will affect antibody immunity?

To measure how mutations affect antibody binding, we yeast display SARS-CoV-2 RBD

RBD

fluorescently labeled antibody

yeast

fluorescent tag on RBD

Starr*, Greaney*, ..., Bloom. Cell (2020)

Library of yeast, each expressing different RBD mutant with identifying 16 nt barcode

Starr*, Greaney*, ..., Bloom. Cell (2020)

Click here for details on how library is made.

We map escape mutations by sorting for RBD variants that don't bind antibody

In maps, tall letters indicate strong escape mutations

Greaney*, Starr*, Gilchuk*, Zost*, ..., Crowe, Bloom. Cell Host & Microbe (2021)

https://jbloomlab.github.io/SARS-CoV-2-RBD_MAP_LY-CoV555/

Escape map from a single antibody

Escape maps from lots of antibodies

https://jbloomlab.github.io/SARS2_RBD_Ab_escape_maps/

Crowe lab (Vanderbilt): James Crowe, Seth Zost, Pavlo Gilchuk

Chu lab (Univ Wash): Helen Chu, Caitlin Wolf

Veesler lab (Univ Wash): David Veesler, Alexandra Walls, Ale Tortorici

King lab (Univ Wash): Neil King, Dan Ellis

Li lab (Brigham & Women's): Jonathan Li, Manish Choudhary

Whelan lab (Wash U)

Boeckh lab (Fred Hutch): Terry Stevens-Ayers

Alex Greninger (Univ Wash)

Janet Englund (Seattle Children's)

These slides: https://slides.com/jbloom/gs-retreat-2021

  • Adam Dingens

  • Will Hannon

  • Amin Addetia

  • Keara Malone

Tyler Starr

Allie Greaney

Rachel Eguia

Bloom lab (Fred Hutch)

Sarah Hilton

Kate Crawford

Andrea Loes