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

26 Nov
There have been a number of overview threads on the emerging variant designated as @PangoNetwork lineage B.1.1.529, @nextstrain clade 21K and @WHO Variant of Concern Omicron. I'm not going to attempt to be comprehensive here, but will highlight a few aspects of the data. 1/16
Global systems for identifying novel variants and rapidly sharing data are working well with 91 genomes from Omicron viruses shared to @GISAID from specimens collected between Nov 11 and Nov 23 from Botswana, South Africa and Hong Kong. 2/16
These viruses are visible on @nextstrain as "21K (Omicron)" shown here in red (nextstrain.org/ncov/gisaid/af…). They do not descend from previously identified "variant" viruses and instead their closest evolutionary connection is to mid-2020 viruses. 3/16 Image
Read 16 tweets
22 Nov
Did vaccination drive the evolution of variant (Alpha, Beta, etc...) SARS-CoV-2 viruses? This is a legitimate scientific question, but after looking into it I don't believe this to be the case. 1/19
Grenfell et al. 2004 (science.org/doi/10.1126/sc…) lays out the conceptual foundations for thinking about this problem. This figure is a bit hard to parse, but basically vaccination will increase population immunity and move rightward on the x-axis. 2/19
This will increase the strength of selection for immune escape (blue line), but will decrease viral abundance (red line). The rate of viral adaptation (black line) depends on both selection and abundance and so is maximized at an intermediate level of population immunity. 3/19
Read 19 tweets
17 Nov
I support making boosters broadly available for those 18 and older. Even if breakthrough cases are generally mild in younger age groups, there is significant societal benefit to reducing circulation. 1/6
nytimes.com/2021/11/16/us/…
Currently Washington State is seeing almost 30% of cases as breakthrough cases (doh.wa.gov/Portals/1/Docu…). 2/6
Here, I think of @alexismadrigal's piece on the implications of a positive COVID test (theatlantic.com/health/archive…). It's crazy to me that we're saying to healthy younger individuals they must isolate for 10 days after a positive test, but that they're not eligible for a booster. 3/6
Read 6 tweets
15 Nov
The evolution of SARS-CoV-2 in the past year has been remarkable with Delta increasing transmissibility by perhaps 2.2X over "non-variant" viruses. 1/14
We should expect this evolution to slow as SARS-CoV-2 continues to adapt to the human host, but when should we expect this? Here, I propose that we've already seen slowing between 2020 and today. 2/14
One very important concept here that I keep coming back to in thinking about evolution is @GreatDismal's quote that "the future is already here. It's just not evenly distributed yet". 3/14
Read 14 tweets
13 Oct
I've meaning to write a "COVID endgame" thread for a while and I apologize this is somewhat delayed compared to media interviews like science.org/content/articl… and statnews.com/2021/09/20/win… and to recent seminars like . 1/17
Here, I've been trying to think about what COVID will look like in its endemic state, ie once the (more or less entire) population has immunity to the virus, blunting transmission and disease relative to the pandemic state. 2/17
I expect endemicity to be achieved at different times throughout the world due to inequities in vaccine distribution and I expect this to be a soft transition rather than a sudden flip of a switch. 3/17
Read 17 tweets
11 Oct
I realize this is rather late to the party, but I wanted to provide a look at the prospects of Mu variant virus. I believe we can conclude that Mu appears more transmissible than all circulating variants except for Delta, but Delta is substantially fitter than Mu. 1/9
If we look within Colombia, we see Mu becoming predominant around May 2021, outcompeting other endogenous South American variants Gamma and Lambda. However, recent sequencing suggests that Delta is successfully invading on this Mu background (nextstrain.org/ncov/gisaid/so…). 2/9 Image
In neighboring Ecuador, we see a heterogeneous mix of Alpha, Gamma, Iota, Lambda and Mu by June 2021. Delta has been successfully displacing most of this diversity since July 2021, while Mu has remained relatively stable (nextstrain.org/ncov/gisaid/so…). 3/9 Image
Read 9 tweets

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