Adaptation and immune escape of SARS-CoV-2

Richard Neher @ SSM in Lausanne

Pathogen evolution

Epidemiology

Immunology

Never before have we followed this dynamics at this resolution

SSM Lausanne – 2023-08-31

Waves and variants from the past 3 years

covariants.org

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SSM Lausanne – 2023-08-31

Tracking spread and change of SARS-CoV-2

• Similar sequences imply they are closely related
• Allows to resolve dynamics on the scale of a month
• Most mutations hurt the virus, some increase transmissibility or lead to immune escape

covariants.org

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SSM Lausanne – 2023-08-31

Early 2020: Little population immunity, selection for transmissibility

Outbreak in Europe rapidly dominated by more transmissible D614G variants

SSM Lausanne – 2023-08-31

December 2020: Variants of Concern

• Sudden emergence of variants with a large number of mutations�In Spike: Delta 69/70, N501Y, A570D, P681H, T716I, S982A, D1118H, E1202Q
• No observed intermediates
• Almost simultaneous occurrence of
• Alpha
• Beta
• Gamma
• They share several mutations, suggesting they are adaptive

Hill et al, 2022

Alpha

• Doubling every 1-2 weeks
• Mostly regional, not global
• Moderately more severe
• Beta was immune evasive

SSM Lausanne – 2023-08-31

Ancestral Alpha Beta Delta Omicron

Ancestral

Alpha

Beta

Delta

Omicron

❌

✅

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2021: Delta – global dominance

• A number of mutations that increase transmissibility
• Moderately reduce immune recognition (less than Beta)

SSM Lausanne – 2023-08-31

Seroprevalence: by end of 2021 most people had immunity

• In some places, most immunity stemmed from infection, in other from vaccination
• Since Nov 2021, most have experienced one or several Omicron infections

November 2021: Omicron

Omicron

Delta

Alpha

2019 origin

• Heavily mutated sister variant of previous VOCs
• Several distinct variants
• High rate of reinfections
• Very rapid spread

SSM Lausanne – 2023-08-31

Emergence of VOCs: probably chronic infections

• Chronic infections are common in immunocompromised
• Immune suppression
• Advanced HIV
• Often hardly symptomatic
• Rapid evolution is common�some times very diverse variants
• Likely the source of Alpha and �Omicron, maybe more�

2023, the first recombinant variant, XBB, �rose to high frequency and now dominates.

Chaguza et al, 2023

SSM Lausanne – 2023-08-31

2022 and ongoing: Variant soup

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From waves to more continuous circulation

Hospitalization numbers in England (via Our World in Data)

SSM Lausanne – 2023-08-31

SARS-CoV-2 vaccine strains

X

X

X

X

ancestral vaccine

2022 boosters

Fall 2023 vaccine

BA.2.86 – surprise variant

Highly diverged – unclear whether it is competitive against XBB-type viruses

What can we do with 15 million genomes?

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Publicly available viral genomes

Genomes per quarter

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15M genomes span around a million years of replication

• 15 million genomes�→ each contributing a few weeks�→ “~million years of evolution”

• Million years of evolution �→ 1000 mutations per position if neutral�→ deviations allow to quantify costs

SSM Lausanne – 2023-08-31

SSM Lausanne – 2023-08-31

Interactive plots:��jbloomlab.github.io/SARS2-mut-fitness/

SSM Lausanne – 2023-08-31

Example: Fitness costs of mutations in the E protein

SSM Lausanne – 2023-08-31

Acknowledgements

• Nextstrain team (my lab and Trevor Bedford’s lab)
• Ivan Aksamentov, Cornelius Roemer, Emma Hodcroft, Moira Zuber
• John Huddleston, Jover Lee, Tom Sibley, James Hadfield
• Jesse Bloom
• Sequence data contributors around the world (shared via GISAID or INSDC)

SSM Lausanne – 2023-08-31

Mutation rates and their clade dependence

Bloom et al, 2023

SSM Lausanne – 2023-08-31

Mutation rates and their background dependence

Bloom et al, 2023

SSM Lausanne – 2023-08-31