Possible future evolution of XBB SARS-CoV-2 variants

Jesse Bloom

Fred Hutch Cancer Center / HHMI

These slides at https://slides.com/jbloom/future-sars2-escape-xbb

@jbloom_lab

Recap of basic principles of human coronavirus evolution

SARS-CoV-2 imprinting and antibody responses

Possible future evolutionary steps in XBB

Recap of basic principles of human coronavirus evolution

SARS-CoV-2 imprinting and antibody responses

Possible future evolutionary steps in XBB

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

 RBD does not run out of evolutionary space

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

Recap of basic principles of human coronavirus evolution

SARS-CoV-2 imprinting and antibody responses

Possible future evolutionary steps in XBB

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 they are infected by, 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

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

Sites of escape in XBB

Interactive escape calculator: https://jbloomlab.github.io/SARS2-RBD-escape-calc/

ACE2 affinity from: https://jbloomlab.github.io/SARS-CoV-2-RBD_DMS_Omicron/RBD-heatmaps/

Fitness effects from: https://jbloomlab.github.io/SARS2-mut-fitness/S.html

Interactive escape calculator: https://jbloomlab.github.io/SARS2-RBD-escape-calc/

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