Other human CoVs cause annual waves

Shah et al (2022)

• Seasonal waves starting late Oct / early Nov, peaking Jan to mid Feb
• Often only one each of the alpha- and beta-coronaviruses cause large wave

Human CoV spikes evolve to escape neutralizing antibodies

Eguia, ..., Bloom (2021)

Human sera from 1985-1990 neutralizes contemporaneous CoV-229E spikes quite well, but as virus evolves into the "future", neutralization is eroded. There is substantial heterogeneity in the rate of erosion across sera from different human individuals.

Antibody selection concentrated in RBD

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

Sites of mutations in SARS-CoV-2 Omicron BQ.1.1 spike relative to Wuhan-Hu-1

Imprinting: even after Omicron infection, neutralization highest against early strain

Imprinting: Omicron infection mostly boosts pre-existing B-cells to old strain

Omicron specific antibodies

Wu cross-reactive antibodies

But in Chinese cohort, two Omicron infections mostly breaks imprinting

Omicron specific antibodies

Wu cross-reactive antibodies

Immunological imprinting and CoV-229E?

Eguia, ..., Bloom (2021)

People imprinted with first CoV-229E that infects them, but still generally neutralize later strains to which they are exposed. Blue shading shows timeframe each individual alive prior to serum collection.

Dominant variant currently is XBB

Current vaccine recommendation is XBB.1.5. But by time vaccine is in use, there will almost certainly be more mutations. Can we forecast what they might be?

Greaney*, Starr*, Gilchuk*, Zost*, ..., Crowe, Bloom

RBD

fluorescently labeled antibody

yeast

fluorescent tag on RBD

Experiments combine flow cytometry and deep sequencing of a library of yeast expressing all RBD mutants

These measurements can be made on ~10,000 to ~100,000 mutants all at once 

Escape map from one antibody (LY-CoV555, ie bamlanivimab)

484

452

490

This turned out be an unfortunate choice of an antibody for Eli Lilly to develop as drug, as mutations at sites 484 and 452 were prevalent by early to mid 2021

Infection / vaccination elicit polyclonal antibodies 

From Yunlong Cao, we have deep mutational scanning data on ~1000s antibodies that neutralize XBB

Text

See here for summary of how successful escape calculator has been so far in pinpointing sites of evolution.

What if we make vaccine that is just mix of a bunch of these predicted future mutants?

Is this a brilliant idea, or a dumb idea? It's hard to tell...

Design of a "future mutant" cocktail vaccine

Design cocktail using the following principle:

• Pick RBD mutations that maximize the product of:
  • antibody escape as quantified by escape calculator
  • ACE2 affinity and RBD expression in yeast display deep mutational scanning
  • fitness effects estimated from all human SARS-CoV-2 and just recent XBB clade
• Design cocktail to favor inclusion of new mutations in each component

Current cocktail vaccine

Current designs are available at https://github.com/jbloomlab/SARS2-cocktail-vax (if you plan to use designs, let me know and I will update)

Current components, not validated for folding are below. For a N-component cocktail, take the first N entries off the list:

1. XBB.1.16
2. XBB.1.16_F456L_K440R_K356T_K444T
3. XBB.1.16_F456L_P445A_S490V_T346K
4. XBB.1.16_K440R_Y453F_F456L_T346S
5. XBB.1.16_K444R_K440Y_Q493L_H505Y
6. XBB.1.16_L452M_S494P_P445A_L455S
7. XBB.1.16_L452R_K440R_A484K_N405G
8. XBB.1.16_S490L_K444M_K460Y_E340D
9. XBB.1.16_A484S_K444T_Y453F_K356R
10. XBB.1.16_A484Q_K444R_K460T_E340Q

Bloom lab

Bernadeta Dadonaite

Kate Crawford

Caelan Radford

Tyler Starr

Allie Greaney

Rachel Eguia

rest of lab

Peking University

Yunlong Cao

Fanchong Jian

Penn

Scott Hensley and Grace Li

Drew Weissman

Slides: https://slides.com/jbloom/escape-calc-for-vax

Thanks