Trevor Bedford Profile picture
14 Jan, 19 tweets, 9 min read
After ~10 months of relative quiescence we've started to see some striking evolution of SARS-CoV-2 with a repeated evolutionary pattern in the SARS-CoV-2 variants of concern emerging from the UK, South Africa and Brazil. 1/19
In SARS-CoV-2, the viral spike protein and in particular the receptor binding domain (RBD) is a locus for important viral evolution and is the primary target for the human immune response (figure from…). 2/19
There had been little evolution in the RBD until ~Oct 2020 when we saw RBD mutations start to spread. Perhaps chief among mutations of interest are E484K and N501Y which mutate nearby sites in the RBD. The evolution of these sites can be seen here:…. 3/19
E484K and N501Y have occurred repeatedly on the evolutionary tree of the virus representing convergent evolution. Many 484K and 501Y instances are due to the three variants of concern, but there are other 484K and 501Y viruses that are not due to these variants. 4/19
The variant emerging in the UK (@nextstrain clade 20I/501Y.V1, lineage B.1.1.7, described at…) possesses 8 mutations in spike, a 3 amino acid deletion in ORF1ab and an ORF8 knockout mutation.… 5/19
The above figure is a "root-to-tip" plot showing number of mutations in sampled viruses against date of collection. The dashed line represents average accumulation of mutations of about 1 mutation every 2 weeks. The 501Y.V1 variant stands out here with additional mutations. 6/19
The variant emerging in South Africa (@nextstrain clade 20H/501Y.V2, lineage B.1.351, described at…) has 7 mutations in spike as well as the same 3 amino acid deletion in ORF1ab.… 7/19
The variant emerging in Brazil (@nextstrain clade 20J/501Y.V3, lineage P.1, described at…) has 10 mutations in spike as well as the same 3 amino acid deletion in ORF1ab.… 8/19
Like 501Y.V1, both 501Y.V2 and 501Y.V3 also appear to possess "extra" mutations beyond what's seen in most circulating viruses. And importantly, these variant viruses show repeated convergent evolution including spike sites 417, 484, 501 and the ORF1ab deletion. 9/19
Extra protein coding mutations localized to spike alongside convergent evolution are hallmarks of adaptive evolution. So, what's going on here? 10/19
My (highly speculative!) hypothesis is that the emergence of these variant viruses arises in cases of chronic infection during which the immune system places great pressure on the virus to escape immunity and the virus does so by getting really good at getting into cells. 11/19
This results in the observed increased viral load (…) and greater transmissibility (…) of 501Y.V1 / B.1.1.7, but importantly this is not due to population-level selection for antigenic drift or faster transmission. 12/19
Instead it's a knock-on effect of the reactor of evolution occurring in rare chronic infections and then spillover from these infections into the greater population. 13/19
This hypothesis of increased binding and cell entry as mechanism for immune evasion was expressed previously in the context of seasonal influenza by @scottehensley in…. 14/19
Hints that these emergence events are related to chronic infections come from multiple sources. First off, we have direct sequencing of viruses from chronic infections that show rapid evolution (figure from @binachoimd et al…). 15/19
Indeed, this particular chronic infection evolved some of the exact same mutations seen in these variant viruses including 484K, 501Y and a 144 deletion. 16/19
Additionally, @K_G_Andersen pointed me to work with coronavirus in mouse models showing that deletions are associated with chronic infections (…). It's striking that the 3 AA deletion in ORF1ab is so far a hallmark of SARS-CoV-2 variant viruses. 17/19
Finally, the exceptionally long branch leading to 501Y.V1 is difficult to explain by a chain of infections given that genomic surveillance by @covidgenomicsuk is sequencing approximately ~5% of cases; surveillance should have picked up intermediates if they existed. 18/19
Again, this hypothesis is highly speculative at this point, but separately, the fact that we've observed 3 variants of concern emerge since September suggests that there are likely more to come. 19/19

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More from @trvrb

29 Dec 20
With data that has emerged in the last week, I'm now 80-90% convinced that infections by the UK variant virus (Pangolin lineage B.1.1.7, @nextstrain clade 20B/501Y.V1) result in, on average, more onward infections, ie are more transmissible. 1/10
My thinking primarily comes from three data points:
1. rapid increase in frequency of variant over wildtype
2. higher secondary attack rate of variant than wildtype
3. increased viral loads of variant over wildtype as measured by Ct
For point 1 (increase in frequency) we have pretty much the same data as of a week ago, where we see increasing frequency of variant over wildtype across the UK. This can be readily seen in this analysis by @TWenseleers. 3/10
Read 11 tweets
28 Dec 20
Given that the US has not detected SARS-CoV-2 variant viruses 501Y.V1 or 501Y.V2, what bounds can we place on their current frequency in the US based on sample counts? 1/12
So far, the US has not detected any cases that genetically match either the UK variant virus 501Y.V1 (…) or the South African variant virus 501Y.V2 (…). 2/12
However, because the US is generally slower at turnaround of specimens into SARS-CoV-2 sequences than the UK, we lack confidence that 501Y.V variants are absent from the US. 3/12
Read 13 tweets
23 Dec 20
Given the large discrepancy in specimens collected in Dec that were sequenced and shared between the US and the UK, I wanted to follow up on the relative quality of genomic surveillance in the US and the UK. 1/12
First thing to clarify, in the @nytopinion opinion piece yesterday (…), it's mentioned that "since Dec. 1, Britain has sequenced more than 3,700 coronavirus cases, compared with fewer than 40 cases in the United States, according to Trevor Bedford". 2/12
As of today, the UK has shared to @GISAID 23,377 genomes during Dec and the US has shared 8033 genomes. However, the UK turnaround time has been much faster with 5010 specimens that were collected in Dec shared vs 65 collected in Dec and shared by the US. 3/12
Read 12 tweets
22 Dec 20
Following up on general thoughts on antigenic drift of #COVID19 from this weekend, I wanted to discuss what we know about the new variant of SARS-CoV-2 thats emerged in the UK. 1/17
This variant is referred to as the B.1.1.7 lineage in nomenclature and clade 20B/501Y.V1 in @nextstrain nomenclature and can be seen here within circulating viral diversity, where the variant lineage is highlighted in orange (…). 2/17
Broadly, I'd characterize the source of concern as arising from the combination of:
1. Multiple mutations that from sequence composition alone are suggestive of biological importance
2. Observed rapid epidemic spread
Read 17 tweets
19 Dec 20
With #COVID19 vaccine efficacy of ~95%, I'm looking forward to vaccine distribution in 2021 bringing the pandemic under control. However, I'm concerned that we'll see antigenic drift of SARS-CoV-2 and may need to update the strain used in the vaccine with some regularity. 1/18
First, some background. RNA viruses all evolve extremely rapidly, but some like influenza are able to accept mutations to their surface proteins in such a way that they can partially escape human immunity. This process is known as "antigenic drift". 2/18
For influenza, this necessitates regular vaccine updates to keep up with an evolving virus population. Other RNA viruses like measles mutate quickly but are unable to change protein structure to escape from immunity and so these vaccines don't need updating. 3/18
Read 18 tweets
17 Dec 20
There has been a significant question about the degree to which Thanksgiving holiday and associated travel and social gatherings may have contributed to transmission of #COVID19. Here I try to briefly address this question. 1/8
Based on known incubation periods (…), we expect, on one end, some infections arising on Nov 26 to become symptomatic on Nov 30 and on the other end, for some infections arising on Nov 30 to become symptomatic on Dec 6. 2/8
This brackets the window where we expect most of the increased case load to be. However, most states only list cases based on date of report rather than date the case became symptomatic. This causes jitter that's hard to deal with when looking for a Thanksgiving effect. 3/8
Read 8 tweets

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