Reconstructing, tracking, and predicting viral spread and evolution

Richard Neher
Biozentrum & SIB, University of Basel

slides at neherlab.org/202205_MPGHD.html

Human seasonal influenza viruses

slide by Trevor Bedford

Positive tests for influenza in the USA by week

Data by the US CDC

Genomic analysis to reconstruct pathogen spread and evolution

Track how pathogens spread: clusters, introductions, etc

Link genotypic and phenotypic changes: immune escape, drug resistance, host adaptation

Influenza A/H3N2

Influenza viruses evolve to avoid human immunity
Vaccines need frequent updates

nextflu.org

joint project with Trevor Bedford & his lab

Hemagglutination Inhibition assays

Slide by Trevor Bedford

Antigenic distance tables

Long list of distances between sera and viruses
Tables are sparse, only close by pairs

Slide by Trevor Bedford

Integrating antigenic and molecular evolution -- ferret serology

RN et al, PNAS, 2017

Integrating antigenic and molecular evolution

each branch contributes $d_i$ to antigenic distance
sparse solution for $d_i$ through $l_1$ regularization

RN et al, PNAS, 2016

Beyond tracking: can we predict?

Prediction of the dominating H3N2 influenza strain

Explicit fitness scores based on specific mutations
→ mutations in previously characterized epitopes
→ mutations that likely reduce fitness
→ mostly historically ascertained
Phylogenetic indicators to spot rapidly expanding clades
Laboratory data (antigenicity, virulence)

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Prediction of the dominating H3N2 influenza strain

Predicted "distance to future"

Projection for HA1 mutation 104

RN, Russell, Shraiman, eLife, 2014; Huddleston et al, eLife, 2020

SARS-CoV-2

by Trevor Bedford

Available data on Jan 26 2020

Early genomes differed by only a few mutations, suggesting very recent emergence

nextstrain.org/ncov/2020-01-26

nextstrain.org/ncov/gisaid/global

Tracking diversity and spread of SARS-CoV-2 in Nextstrain

A variant seemed to spread systematically in Summer 2020

Hodcroft et al, Nature, 2021

Diversity patterns suggested a large role of holiday travel

Spanish diversity mirrored in many European countries
Suggested many introduction with clusters of similar size
→ travel
A transmission advantage would result in a few dominating introductions
Screening and quarantine system rather leaky

Hodcroft et al, Nature, 2021

High case numbers in Spain and high travel volume spread the variant

Hodcroft et al, Nature, 2021

EU1 did not have a strong advantage -- unlike later Variants of Concern

High incidence differential and high travel volume can drive a variant to dominance
Travel associated activities and behavior further increases impact
Onward spread in traveling demographics can be higher

Variants of Concern are characterized by many mutations in S1

nextstrain.org/ncov/gisaid/global

Successful variants are characterized by many mutations in S1

nextstrain.org/ncov/gisaid/global, outbreak.info

Delta vs Omicron

So far, independent variants have dominated sequentially

nextstrain.org/ncov/gisaid/global

Current Omicron subvariants of interest

BA.2 (21L) has essentially taken over.
BA.4 (22A) and BA.5 (22B) emerged in Southern Africa. Mutations at positions 452 and 486 lead to immune evasion
BA.2.12.1 (22C) has a mutation at position 452 and is common in the US

nextstrain.org/ncov/gisaid/global

Medium term dynamics of SARS-CoV-2 is very uncertain

Will we start seeing second and third generation variants, as opposed to sister variants?
Will we the saltatory dynamics with heavily diverged variants continue?
Will a more diverse immunity landscape slow down future variant dynamics?
Will waning/antigenic evolution slow down and give rise to annual or even rarer waves?

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