Vaccine strategies in light of SARS-CoV-2's ongoing evolution

Jesse Bloom

Fred Hutch Cancer Research Center / HHMI

Slides at https://slides.com/jbloom/sars-cov-2-vaccine-strategy

@jbloom_lab

Disclosures

Scientific advisory boards of Flagship Labs 77 and Oncorus
Consult for Moderna
Inventor on Fred Hutch licensed patents on deep mutational scanning of viral proteins
Unfunded research collaborations with Vir Biotechnology

Outline

Overview of human coronavirus evolution (Jesse, 5 min)
SARS-CoV-2 evolution so far, scenarios for future (Trevor, 15 min)
Assessing specific viral mutations and strains (Jesse, 10 min)

Outline

Overview of human coronavirus evolution (Jesse, 5 min)
SARS-CoV-2 evolution so far, scenarios for future (Trevor, 15 min)
Assessing specific viral mutations and strains (Jesse, 10 min)

Evolution of spike of "common-cold" CoV-229E

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

Note "ladder-like" shape of tree: most variants die out, just one gives rise to future variants

We generated spikes at ~8 year intervals to study them experimentally

Evolution of CoV-229E spike erodes neutralization by human serum antibodies

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

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

Rate that viral evolution erodes CoV-229E neutralization differs among humans

These differences suggest there is potential for different vaccine strategies to elicit antibodies more or less resistant to CoV evolution

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 generally evolves this way too.

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 generally evolves this way too.

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-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 as seen recently for influenza H3N2.

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

CoV-229E has ladder-like tree:

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

Human influenza A generally evolves this way too.

Outline

Overview of human coronavirus evolution (Jesse, 5 min)
SARS-CoV-2 evolution so far, scenarios for future (Trevor, 15 min)
Assessing specific viral mutations and strains (Jesse, 10 min)

Outline

Overview of human coronavirus evolution (Jesse, 5 min)
SARS-CoV-2 evolution so far, scenarios for future (Trevor, 15 min)
Assessing specific viral mutations and strains (Jesse, 10 min)

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 also 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.

A minority of all anti-spike antibodies elicited by current vaccines target RBD.

Omicron's RBD has a lot of mutations

How does Omicron bind ACE2 with so many mutations?

Measurements of mutation effects via deep mutational scanning

Mutations in Omicron have net negative effect on ACE2 binding if summed as single mutants

How does Omicron bind ACE2 with so many mutations?

Measurements of mutation effects via deep mutational scanning

Mutations in Omicron have net negative effect on ACE2 binding if summed as single mutants

However, two mutations (Q498R & N501Y) work together so net effect ~zero when both present

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

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

Plot from escape calculator described in Greaney et al (2020)

Delta only has modest mutations at antigenically important RBD sites

Plot from escape calculator described in Greaney et al (2020)

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

Plot from escape calculator described in Greaney et al (2020)

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. Drop smaller after booster, but not known if that improvement is durable.

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)