Interpreting the evolution of

SARS-CoV-2 in context of Omicron

Jesse Bloom

Fred Hutch Cancer Research Center / HHMI

Slides at https://slides.com/jbloom/sars-cov-2-evolution-short

@jbloom_lab

Disclosures

I am on the scientific advisory boards of Flagship Labs 77 and Oncorus
I consult for Moderna
I am an inventor on Fred Hutch licensed patents related to deep mutational scanning of viral proteins
My lab has unfunded research collaborations with Vir Biotechnology

Only some viruses rapidly evolve to escape antibody neutralization

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

Influenza virus: Evolves to escape immunity. People are infected every ~5 years. The vaccine needs to be updated annually.

We decided to look at another human coronavirus: CoV-229E causes common colds and has been circulating in humans since at least 1960s.

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)

Note "ladder-like" shape of tree

Evolution of CoV-229E spike erodes neutralization by human antibody immunity

Serum collected in 1985 neutralizes virus with spike from 1984, but less effective against more recent viruses.

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

Viral evolution erodes antibody immunity of different 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)

Phylogenetic tree shape and vaccine strategy

CoV-229E has ladder-like tree:

new variants displace old ones
new variants descend from recent successful ones

Human influenza A evolves this way too. It's theoretically possible to pick single well-matched vaccine strain.

See Volz et al (2013), Kistler and Bedford (2021), and Kucharski (Twitter, 2022)

Phylogenetic tree shape and vaccine strategy

CoV-229E has ladder-like tree:

new variants displace old ones
new variants descend from recent successful ones

Human influenza A evolves this way too. It's theoretically possible to pick single well-matched vaccine strain.

CoV-OC43 split into two ladder-like lineages. Influenza B evolves this way too. It's theoretically possible to pick well-matched bivalent vaccine.

See Volz et al (2013), Kistler and Bedford (2021), and Kucharski (Twitter, 2022)

Phylogenetic tree shape and vaccine strategy

CoV-229E has ladder-like tree:

new variants displace old ones
new variants descend from recent successful ones

Human influenza A evolves this way too. It's theoretically possible to pick single well-matched vaccine strain.

CoV-OC43 split into two ladder-like lineages. Influenza B evolves this way too. It's theoretically possible to pick well-matched bivalent vaccine.

In non-ladder-like tree, next variant not descended from recent successful one. Makes picking vaccine strains difficult.

See Volz et al (2013), Kistler and Bedford (2021), and Kucharski (Twitter, 2022)

nextstrain.org

After early fixation of D614G, the SARS-CoV-2 tree has not been ladder-like

Strongest evolutionary selection is in RBD

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

Strongest evolutionary selection is in RBD

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

Sites of mutations in SARS-CoV-2 Omicron (BA.1) spike relative to Wuhan-Hu-1

Main difference is SARS-CoV-2 also fixing transmissibility-enhancing spike mutations that affect proteolytic processing and stabilize defects cause by furin-cleavage site

Majority of neutralizing antibody response in vaccinated/infected humans targets RBD

Greaney et al, Science Translational Medicine (2021)

Importance of RBD

Human CoVs, which evolve to escape transmission-blocking immunity, show strongest selection in RBD. So virus is telling us RBD antibodies matter most for blocking transmission. But non-RBD antibodies and T-cells still matter, especially for reducing disease severity while putting less selection on virus.

Most neutralizing activity from RBD antibodies (although antibodies to other domains such as NTD can also be neutralizing).

However, a minority of all anti-spike antibodies elicited by current vaccines target RBD. Given these facts, we should continue to weigh pros / cons of RBD-only vaccines.

Omicron has a lot of mutations, especially in the receptor binding domain (RBD)

RBD will not run out of evolutionary space

25 of 31 residues in CoV-229E RBD that contact receptor varied during virus's evolution in humans over last ~50 years (Li et al, eLife, 2019)

There are lots of mutations to SARS-CoV-2 RBD that retain (and sometimes even enhance) ACE2 affinity (Starr et al, 2020)

We map antibody escape mutations using yeast display deep mutational scanning

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

RBD

fluorescently labeled antibody

yeast

fluorescent tag on RBD

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/

Infection / vaccination elicit polyclonal antibodies that can bind many epitopes

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 know where in RBD antibodies elicited by current Wuhan-Hu-1-like vaccines bind

Plot from escape calculator described in Greaney et al (2021)

Omicron (BA.1) is extensively mutated at important RBD antigenic sites

Plot from escape calculator described in Greaney et al (2021)

Omicron (BA.2) shares most but not all key RBD antigenic mutations with BA.1

Wilks et al (2022)

Current vaccines elicit substantially worse titers to Omicron than Delta

Delta

Omicron (BA.1)

Most other studies find similar ~20-fold drop in Omicron neutralization for sera after two doses of current vaccine.

Netlz et al (2021)

Richardson et al (2022)

Similarly, Omicron infection without prior immunity elicits poor titers to other variants

Serum neutralization titers after primary human infections with Omicron

Omicron infection after current vaccine elicits good neutralization of Omicron

Humans vaccinated with current vaccines then infected with Omicron BA.1 neutralize Omicron BA.1 and BA.2 comparably to Delta and older Wuhan-Hu-1-like viruses

Yamasoba et al (2022)