How will SARS-CoV-2 evolution affect antibodies and vaccines?

 

Jesse Bloom

Fred Hutch Cancer Research Center / HHMI

 

Slides at https://slides.com/jbloom/sars-cov-2-science-advisors

 

@jbloom_lab

Disclosures

  • I consult for Moderna about SARS-CoV-2 evolution as a member of their Global Epidemiology Advisory Board.

 

  • My lab has unfunded collaborations with Vir Biotechnologies related to SARS-CoV-2 antibodies.

Why care about SARS-CoV-2 variants?

  • They might be more transmissible

 

  • They might be less recognized by immunity

Why care about SARS-CoV-2 variants?

  • They might be more transmissible

 

  • They might be less recognized by immunity

Bad, but we can't do much about it

Why care about SARS-CoV-2 variants?

  • They might be more transmissible

 

  • They might be less recognized by immunity

Bad, but we can't do much about it

Bad, and we can potentially update vaccine strategies, so I will focus on this.

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

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

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.

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?

Thanks to amazing global effort, we are good at identifying viral mutations

Phylogenetic tree of 1,142,265 full-length SARS-CoV-2 genomes provided by GISAID

Challenge is determining if/how these mutations impact immunity

Phylogenetic tree of 1,142,265 full-length SARS-CoV-2 genomes provided by GISAID

I will focus on receptor-binding domain (RBD): the part of virus that binds ACE2, and is main target of neutralizing antibodies

To measure how RBD mutations affect antibody binding, we use yeast display

RBD

fluorescently labeled antibody

yeast

fluorescent tag on RBD

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

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

We can map how all mutations to SARS-CoV-2 RBD affect antibody binding

Interactive map of escape for LY-CoV555 (antibody in Eli Lilly's bamlanivimab)

We now have escape maps for many lead clinical antibodies

Emerging variants and clinical antibodies

Studies validating these conclusions from the mapping:

lineage LY-CoV555 LY-CoV016 REGN10933 REGN10987 COV2-2196 COV2-2130
B.1.1.7
20I/501Y.V1
(UK)
none none none none none none
B.1.351
20H/501Y.V2
(S. Africa)
E484K K417N
E484K (partial)
K417N (partial) E484K (partial)
 
none E484K (slight) none
P.1
20J/501Y.V3
(Brazil)
E484K K417T
E484K (partial)
K417T (partial)
E484K (partial)
none E484K (slight) none
B.1.429
20C/CAL.20C
(USA/CA)
L452R none none none none none
B.1.526
(USA/NY)
E484K E484K (partial) E484K (partial) none E484K (slight) none

Monoclonal antibody versus polyclonal immunity from infection or vaccine

Monoclonal antibody can typically be escaped by a single viral mutation

Polyclonal antibodies bind many epitopes, so typically more resistant to evolutionary escape

We can assess which mutations affect polyclonal serum antibody binding 

frequency of mutations at site

(all sequences in GISAID)

We can assess which mutations have biggest effect on polyclonal serum antibody binding 

frequency of mutations at site

(all sequences in GISAID)

Single worst mutation for antibody immunity is E484K, which typically reduces serum neutralization by 4- to 10-fold

However, variants still recognized, albeit at reduced levels. Will take many mutations to fully evade polyclonal antibodies.

Platform to visualize and download data on how mutations affect antibody binding

Conclusions

Some viruses evolve to erode immunity (influenza), others do not (measles)

Some viruses evolve to erode immunity (influenza), others do not (measles)

Unfortunately, human coronaviruses do evolve to erode immunity

Some viruses evolve to erode immunity (influenza), others do not (measles)

Unfortunately, human coronaviruses do evolve to erode immunity

New SARS-CoV-2 variants contain mutations (eg, E484K, L452R, K417N) that partially erode antibody immunity

 

Some viruses evolve to erode immunity (influenza), others do not (measles)

Unfortunately, human coronaviruses do evolve to erode immunity

New SARS-CoV-2 variants contain mutations (eg, E484K, L452R, K417N) that partially erode antibody immunity

 

However, it will take multiple years (~3-5??) for SARS-CoV-2 to accumulate enough mutations to strongly evade polyclonal antibody neutralization

 

Some viruses evolve to erode immunity (influenza), others do not (measles)

Unfortunately, human coronaviruses do evolve to erode immunity

Therefore, we need to monitor impacts of viral evolution for possible vaccine updates.

New SARS-CoV-2 variants contain mutations (eg, E484K, L452R, K417N) that partially erode antibody immunity

 

However, it will take multiple years (~3-5??) for SARS-CoV-2 to accumulate enough mutations to strongly evade polyclonal antibody neutralization

 

Some viruses evolve to erode immunity (influenza), others do not (measles)

Unfortunately, human coronaviruses do evolve to erode immunity

Therefore, we need to monitor impacts of viral evolution for possible vaccine updates.

Also, it remains unclear whether disease will typically still be severe in re-infections

New SARS-CoV-2 variants contain mutations (eg, E484K, L452R, K417N) that partially erode antibody immunity

 

However, it will take multiple years (~3-5??) for SARS-CoV-2 to accumulate enough mutations to strongly evade polyclonal antibody neutralization

 

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)

  • Adam Dingens

  • Will Hannon

  • Amin Addetia

  • Keara Malone

Tyler Starr

Allie Greaney

Rachel Eguia

Bloom lab (Fred Hutch)

Sarah Hilton

Kate Crawford

Andrea Loes

sars-cov-2-science-advisors

By Jesse Bloom

sars-cov-2-science-advisors

SARS-CoV-2 evolution presentation for May 4 Chief Science Advisors Meeting

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