Jesse Bloom PRO
Scientist studying evolution of proteins and viruses.
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
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
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.
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
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.
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.
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.
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
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
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.
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
Even with an update to Omicron, there will still be a strong effect from immune imprinting with earlier vaccines / variants
If Omicron remains dominant in future, we should probably update vaccine to Omicron
What if Omicron isn't dominant in future?
Data from van der Straten et al (2022); similar results in Wilks et al (2022)
All pre-Omicron variants are more antigenically similar
Continued Omicron circulation will make vaccine strain update more urgent
Effect of any update will be somewhat muted by immune imprinting to current vaccine
Consider cocktail vaccines, which might induce broader response and buffer uncertainly in evolutionary forecasts
Thanks
Data also taken from studies by:
- Katie Kistler / Trevor Bedford
- Derek Smith / David Montefiori groups
- Penny Moore group
- Kei Sato group
- Dan Barouch group
- Colin Russell / Rogier Sanders / Dirk Eggink groups
Tyler Starr
Allie Greaney
Rachel Eguia
Bloom lab data shown here from:
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
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