Potential for antigenic drift in SARS-CoV-2


Trevor Bedford (@trvrb)
11 Dec 2020
HB Friday Faculty Talk
Fred Hutch
Slides at: bedford.io/talks

How likely is it that antigenic variants of SARS-CoV-2 will emerge, circulate and thereby decrease vaccine efficacy?

Integrating genotypes and phenotypes improves long-term forecasts of seasonal influenza A/H3N2 evolution

with John Huddleston, Richard Neher, Dave Wentworth, Becky Kondor, John McCauley, Hideki Hasegawa, Kanta Subbarao and others

Influenza viruses undergo antigenic drift

H3N2 vaccine updates occur every ~2 years

Vaccine strain selection by WHO

Select one strain from circulating diversity

Fitness models project strain frequencies

Future frequency $x_i(t+\Delta t)$ of strain $i$ derives from strain fitness $f_i$ and present day frequency $x_i(t)$, such that

$$\hat{x}_i(t+\Delta t) = x_i(t) \, \mathrm{exp}(f_i \, \Delta t)$$

Total strain frequencies at each timepoint are normalized. This captures clonal interference between competing lineages.

Match strain forecast to retrospective circulation

Train in 6-year sliding windows from 1995 to 2015 with most recent years held out as test

Composite models favor combinations of HI drift, local branching index and non-epitope fitness

Model successfully predicts clade growth and best pick from model is generally close to best possible retrospective pick

Forecasts are live at nextstrain.org/flu, but are currently fraught due to lack of recent isolates

Evidence for adaptive evolution in the receptor-binding domain of seasonal coronaviruses

with Katie Kistler

Four species of seasonal coronavirus (OC43, 229E, NL63, HKU1) cause ~30% of common colds

Seattle Flu Study. 2020.

Focus on spike protein as target for immune response and antigenic escape

Spike gene phylogenies for OC43 and 229E

Substitutions occur more often in S1 subunit than S2

Nonsynonymous substitutions accumulate rapidly in exposed portions of spike

Diversity and divergence used to estimate accumulation of adaptive substitutions

This analysis can be summarized as rate of adaptive substitutions per year (about ~0.5 adaptive subs per year for OC43)

And compared to rates of adaptive substitutions in other viruses

Adaptive evolution in spike is clearly present in OC43 and 229E. It's likely this results in antigenic evolution and contributes to reinfection observed to occur every ~3 years.


Sequencing and data sharing in almost real-time, now with over 250k genomes

Figure by Hadfield and Hodcroft using data from GISAID

SARS-CoV-2 lineages establish globally in February and March

With ongoing mitigation and
decreased international travel,
regional clades have emerged
With ongoing mitigation and
decreased international travel,
regional clades have emerged

Limited early mutations like D614G spread globally during initial wave

More recent variants are confined to regional dominance

Starting to see circulating spike variants

A222V, N439K and S477N spreading in Europe (although may be largely explained by epidemiology)

S477N also spreading in Oceania, having arisen independently

N439K shows evidence of reduced binding and neutralization

Y453F shows associated with passage in farmed mink

I think SARS-CoV-2 will undergo antigenic drift

Strong immune response to mRNA vaccines may help here

Monitoring for antigenic drift

  • Test neutralization of circulating variants against serum panels from
    recovered and vaccinated individuals
  • Combine vaccination records with sequencing of clinical samples


Seasonal flu: WHO Global Influenza Surveillance Network, GISAID, John Huddleston, Richard Neher, Jover Lee, Dave Wentworth, Becky Kondor

Seasonal CoVs: Katie Kistler

SARS-CoV-2 genomic epi: Data producers from all over the world, GISAID and the Nextstrain team

Bedford Lab: Alli Black, John Huddleston, James Hadfield, Katie Kistler, Louise Moncla, Maya Lewinsohn, Thomas Sibley, Jover Lee, Kairsten Fay, Misja Ilcisin, Cassia Wagner, Miguel Paredes, Nicola Müller, Marlin Figgins, Eli Harkins