Trevor Bedford Profile picture
Feb 3, 2021 19 tweets 7 min read
With emerging variants of SARS-CoV-2 and initial evidence of antigenic evolution, I've seen comparisons here to seasonal influenza and its rate of evolution. In this thread, I want to ground these comparisons with some data. 1/18
If we follow a transmission chain of SARS-CoV-2 from person to person, we'll generally see one mutation occur across the viral genome roughly every two weeks. 2/18
Here I use data from @nextstrain and @GISAID to compare sampling date to the number of mutations across the SARS-CoV-2 genome relative to initial genomes from Wuhan. This shows a steady accumulation of mutations through time with the average virus now bearing ~24 mutations. 3/18 Image
However, this is a random process and some viral lineages accumulate more mutations than others. In fact we see that the variants of concern (B.1.1.7 from the UK, 501Y.V2 from South Africa and P.1 from Brazil) possess more mutations than most circulating viruses. 4/18
The majority of mutations occurring in SARS-CoV-2 don't affect viral function and accumulate because the virus, as an RNA virus, undergoes error-prone copying. However, mutations that alter amino acids in the S1 portion of spike protein will often be functionally relevant. 5/18
This is a plot comparing sampling date to the number of amino acid changes in spike S1 subunit. Here we see a striking pattern where variant of concern (VOC) viruses show significantly more amino acid changes in spike S1 than other circulating viruses. 6/18 Image
With VOCs included, on average SARS-CoV-2 is evolving at a rate of ~2.9 amino acid substitutions in spike S1 per year. This rate can be compared to the rate of amino acid changes in the HA1 domain of the surface protein HA in seasonal influenza. 7/18
There is a caveat in that these are different viruses and one amino acid change in spike S1 of SARS-CoV-2 may be more (or less) functionally relevant than one amino acid change in HA1 of seasonal influenza, but at least this gives a basis for a comparison. 8/18
And importantly the spike S1 subunit is 671 amino acids to HA1's 328 amino acids and so we might expect a ~2X rate difference just based on protein length as target for mutations. 9/18
For the fastest evolving seasonal influenza virus A/H3N2 we see a steady accumulation of ~2.5 amino acid substitutions per year over the past 12 years, which is slightly slower than what we're seeing now in SARS-CoV-2. 10/18 Image
Other seasonal influenza viruses evolve more slowly with A/H1N1pdm showing ~1.5 substitutions per year in HA1, B/Vic showing ~0.5 substitutions per year in HA1 and B/Yam showing ~0.7 substitutions per year in HA1. 11/18 ImageImageImage
These rates of HA amino acid substitutions mirror experimentally determined rates of antigenic evolution. This is a figure from a 2014 paper by myself, @arambaut and others (bedford.io/papers/bedford…) showing faster antigenic drift in H3N2 than H1N1 than B/Vic and B/Yam. 12/18 Image
The rate of antigenic drift in influenza can be quantified by per-year fold-reduction in serological assays. For influenza H3N2, this rate averages ~1 two-fold titer reduction per-year. 13/18
The comparable datapoint for SARS-CoV-2 is work by Wibmer et al (biorxiv.org/content/10.110…) and Cele et al (medrxiv.org/content/10.110…) showing an ~8-fold titer reduction in neutralization assays to the 501Y.V2 variant from South Africa. 14/18
This titer reduction is very roughly what is seen in an average of 3 years of influenza H3N2 evolution, but yearly jumps of 8-fold titer reductions in H3N2 are historically not uncommon, with H3N2 showing a staccato pace to its antigenic evolution. 15/18
Both simple rate of amino acid substitutions in spike S1 and titer drops in serological assays suggest that SARS-CoV-2 might be in the same ballpark as influenza A in terms of capacity for antigenic evolution. 16/18
That said, the evolution that we've seen with the recent variants of concern may represent an unusual circumstance in which the virus has made a large evolutionary jump to a new "fitness peak" and that won't be seen year-after-year. 17/18
Additionally, with new vaccine technologies (and particularly mRNA vaccines) we'll have the ability to more effectively chase the virus than we do with the seasonal influenza vaccine, which suffers from lower immunogenicity and longer lead times for strain updates. 18/18
Follow up #1: From March () until December, my expectation was antigenic evolution like in seasonal CoVs which are roughly as fast as flu B (see bedford.io/papers/kistler…). With VOCs, I now expect more like flu A, but this could be pace that's not sustained.

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More from @trvrb

Dec 5, 2022
Currently, the US is reporting about 54k daily cases of COVID-19 (16 per 100k per capita) and the UK is reporting about 4k (6 per 100k). This seems comfortingly low compared to even this summer's BA.5 wave and let alone last winter's BA.1 wave. Figure from @OurWorldInData. 1/16
However, at this point, nearly all infections will be in individuals with prior immunity from vaccination or infection and this combined with a roll back in testing makes it unclear how to interpret current case counts compared to previous time periods. 2/16
We're interested in the case detection rate or the ratio of underlying new infections compared to reported cases. Throughout much of 2020 and 2021, I had a working estimate of 1 infection in ~3.5 getting reported as a case. 3/16
Read 16 tweets
Aug 16, 2022
Largely through partial immune escape, lineage BA.5 viruses resulted in sizable epidemics throughout much of the world. However, in most countries these epidemics are now beginning to wind down. What do we expect after BA.5? 1/10
Lineage BA.2.75 (aka 'Centaurus') has been high on watch lists due to sustained increase in frequency in India combined with the presence of multiple mutations to spike protein. We now have enough sampled BA.2.75 viruses from outside India to make some initial conclusions. 2/10
If we look at frequency data we see sustained logistic growth of BA.2.75 in India, Japan, Singapore and the US. Critically, in India it is clearly displacing BA.5. 3/10
Read 10 tweets
Aug 3, 2022
Based on the experience in winter 2020/2021, seasonal influence on SARS-CoV-2 transmission is quite clear, but much of the Northern Hemisphere is currently experiencing large summer epidemics driven the spread of evolved BA.5 viruses. 1/11
It's necessarily fraught to try to make predictions of seasonal circulation patterns going forwards, but we can gain some intuition from simple epidemiological models. 2/11
In particular, we can use an SIRS system in which individuals go from Susceptible to Infected to Recovered, and then return to the Susceptible class due to immune waning / antigenic drift of the virus. 3/11
Read 12 tweets
Jul 20, 2022
There seems to be a worry that telling people we've exited the "pandemic phase" will lead to further reduced precautions. As always however, I think it's best not to conduct messaging for intended behavioral effect and just try to make scientifically accurate statements. 1/5
Given vaccination and infection, the US and global population now has widespread immunity to SARS-CoV-2 and deaths per-infection are about 10 times lower than they were pre-immunity in 2020 with a ballpark IFR of 0.05% (though this will vary by immunity and age demographics). 2/5
You can see this reduction in mortality rate in looking at projections of deaths from lagged-cases keyed to early case fatality rate. 3/5
Read 5 tweets
Jun 27, 2022
The @US_FDA VRBPAC committee will be meeting tomorrow to discuss variant-specific COVID-19 vaccines (fda.gov/advisory-commi…). Based on present observations, I would argue that the most important metric to optimize are titers against BA.4/BA.5 viruses. 1/10
We've seen repeated replacement of SARS-CoV-2 variants during 2022, first of Delta by Omicron BA.1 and then by sub-lineages of Omicron, with BA.2 replacing BA.1 and now with BA.4/BA.5 replacing BA.2. 2/10
Viruses have been evolving to be higher fitness through both increases in intrinsic transmissibility (seen in BA.2 vs BA.1) as well as escape from existing population immunity (seen in Omicron vs Delta as well as BA.4/BA.5 vs BA.2). 3/10
Read 10 tweets
Jun 3, 2022
Global monkeypox confirmed and suspected cases compiled by @globaldothealth show initial rapid increase as case-based surveillance comes online, followed by slower continued growth. 1/10
This is data from github.com/globaldothealt… and has had a 7-day smoothing applied and all y-axes are shown on a log scale. 2/10
If we focus on the last 11 days, we can see steady exponential growth in global cases with a ~7.7 day doubling. 3/10
Read 11 tweets

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