Can mapping viral antibody escape mutations inform vaccines?

 

Jesse Bloom

Fred Hutch Cancer Center / HHMI

 

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

 

@jbloom_lab

Recap of basic principles of human coronavirus evolution

SARS-CoV-2 imprinting and antibody responses

Possible future evolutionary steps in XBB

Predictive cocktail vaccines?

Recap of basic principles of human coronavirus evolution

SARS-CoV-2 imprinting and antibody responses

Possible future evolutionary steps in XBB

Predictive cocktail vaccines?

Other human CoVs cause annual waves

  • 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

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

Recap of basic principles of human coronavirus evolution

SARS-CoV-2 imprinting and antibody responses

Possible future evolutionary steps in XBB

Predictive cocktail vaccines?

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?

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.

Recap of basic principles of human coronavirus evolution

SARS-CoV-2 imprinting and antibody responses

Possible future evolutionary steps in XBB

Predictive cocktail vaccines?

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?

Deep mutational scanning to map RBD mutations that escape antibody binding

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.

Sites of escape in XBB

Clear differences between one and two Omicron infections: eg, site 498 only major site of escape after two Omicron infections

We will probably see viral evolution at many of these sites of escape

 

See here for summary of how deep mutational scanning has predicted many of sites of antigenic evolution in the SARS-CoV-2 RBD over last few years

Recap of basic principles of human coronavirus evolution

SARS-CoV-2 imprinting and antibody responses

Possible future evolutionary steps in XBB

Predictive cocktail vaccines?

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:

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

 

Thanks

escape-calc-for-vax

By Jesse Bloom

escape-calc-for-vax

Mapping escape mutations to inform vaccines

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