SARS-CoV-2 Mutations: B.1.1.7, B.1.351 & D614G Research

In summary, the new SARS-CoV-2 variants are more transmissible and more deadly than the original variants.
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Ygggdrasil
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TL;DR Summary
A general thread to collect the latest research on mutations to the SARS-CoV-2 virus.
Given the seeming increased transmissibility of the new SARS-CoV-2 variants being identified, I thought I'd start a general thread to collect and organize information on the various mutations to the SARS-CoV-2 virus.

B.1.1.7 variant (aka 20B/501Y.V1, VOC 202012/01; originally identified in the UK):
This variant is characterized by 14 lineage-specific amino acid replacements and three deletions. Of most concern are:
  • The N501Y mutation within the receptor binding domain (RBD) of the spike (S) protein, which is thought to increase the binding affinity to human ACE2
  • Deletion of residues 69-70 in the S protein which may be involved in evading the human immune response
  • The P681H mutation in the S protein, which are adjacent to the furin cleavage site
Initial report from COG-UK describing the variant: https://www.cogconsortium.uk/wp-content/uploads/2020/12/Report-1_COG-UK_20-December-2020_SARS-CoV-2-Mutations_final_updated2.pdf
Pre-print manuscript more fully characterizing the vairant: https://virological.org/t/prelimina...defined-by-a-novel-set-of-spike-mutations/563
Report from Imperial College London with epidemiological data suggesting increased transmissibility of the variant: https://www.imperial.ac.uk/media/im...2020-12-31-COVID19-Report-42-Preprint-VOC.pdf

Pre-print showing that the Pfizer vaccine elicits antibodies that recognize viruses containing the N501Y mutation in the S protein: https://www.biorxiv.org/content/10.1101/2021.01.07.425740v1

Pre-print study characterizing the S protein 69-70 deletion: https://www.medrxiv.org/content/10.1101/2020.12.05.20241927v3

B.1.351 variant (aka 20C/501Y.V2; originally identified in South Africa):
This variant is characterized by eight lineage-defining mutations, including the mutation of three important residues in the S protein RBD (K417N, E484K and N501Y).

Pre-print describing the identification of the variant: https://www.krisp.org.za/publications.php?pubid=315

Pre-print suggesting that the E484K mutation could evade immunity: https://www.biorxiv.org/content/10.1101/2020.12.31.425021v1

D614G mutation:
This mutant was observed early in the pandemic and has since become widespread.
Published, peer-reviewed study identifying the spread of the mutation: https://www.sciencedirect.com/science/article/pii/S0092867420308205?via=ihub

Various published, peer-reviewed studies evaluating the role of D614G mutation in affecting the transmissibility of the virus:
SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo: https://science.sciencemag.org/content/370/6523/1464
Spike mutation D614G alters SARS-CoV-2 fitness: https://www.nature.com/articles/s41586-020-2895-3
Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity: https://www.cell.com/cell/fulltext/S0092-8674(20)31537-3

Other resources:
Nice article in JAMA discussing the mutants: https://jamanetwork.com/journals/jama/fullarticle/2775006
CDC page on emerging SARS-CoV-2 variants: https://www.cdc.gov/coronavirus/2019-ncov/more/science-and-research/scientific-brief-emerging-variants.html
 
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Note that widespread transmission of a new variant does not always mean that the new variant is a more transmissible form of the virus. Often, certain variants could be spread more widely by chance (e.g. they happen to get spread at a superspreader event). Here's a good example of the 20A.EU1 variant that emerged in Spain early in the summer and became widespread across Europe, yet researchers subsequently found no evidence that the variant itself had showed increased transmissibility. Rather, the researchers attribute the success of the variant to it being present in the right place at the right time (emerging just as travel and quarantine restrictions were being lifted in Europe).

Emergence and spread of a SARS-CoV-2 variant through Europe in the summer of 2020
Hodcroft et al. medRxiv. Nov 27, 2020
https://www.medrxiv.org/content/10.1101/2020.10.25.20219063v2

Abstract:
Following its emergence in late 2019, SARS-CoV-2 has caused a global pandemic resulting in unprecedented efforts to reduce transmission and develop therapies and vaccines (WHO Emergency Committee, 2020; Zhu et al., 2020). Rapidly generated viral genome sequences have allowed the spread of the virus to be tracked via phylogenetic analysis (Hadfield et al., 2018; Pybus et al., 2020; Worobey et al., 2020). While the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced, allowing continent-specific variants to emerge. However, within Europe travel resumed in the summer of 2020, and the impact of this travel on the epidemic is not well understood. Here we report on a novel SARS-CoV-2 variant, 20A.EU1, that emerged in Spain in early summer, and subsequently spread to multiple locations in Europe, accounting for the majority of sequences by autumn. We find no evidence of increased transmissibility of this variant, but instead demonstrate how rising incidence in Spain, resumption of travel across Europe, and lack of effective screening and containment may explain the variant’s success. Despite travel restrictions and quarantine requirements, we estimate 20A.EU1 was introduced hundreds of times to countries across Europe by summertime travellers, likely undermining local efforts to keep SARS-CoV-2 cases low. Our results demonstrate how genomic surveillance is critical to understanding how travel can impact SARS-CoV-2 transmission, and thus for informing future containment strategies as travel resumes.
 
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  • #3
This paper may be of interest: https://www.biorxiv.org/content/10.1101/2021.01.07.425740v1.full.pdf

It is a pre-publication of data about the effectiveness of the Pfizer vaccine against the N501Y variant.

I've also made some Youtube videos on my channel going through the literature on many of these subjects:
 
  • #4
Ygggdrasil said:
Summary:: A general thread to collect the latest research on mutations to the SARS-CoV-2 virus.
I hope it's not a hijack, then. As far as I understand PCR is about multiplying a possibly present target sequence up to a detectable level.

How sensitive this method to different strains? I mean, when the mutation making the strain makes the 'reference' part of viral genome different than the 'target'?
 
  • #5
Rive said:
I hope it's not a hijack, then. As far as I understand PCR is about multiplying a possibly present target sequence up to a detectable level.

How sensitive this method to different strains? I mean, when the mutation making the strain makes the 'reference' part of viral genome different than the 'target'?

Yes, the RT-qPCR tests for COVID-19 rely on detecting specific RNA sequences in the virus' RNA genome, and mutation of those sequences could cause the test to give a false negative. In fact, this does seem to be the case with the B.1.1.7 variant, where the 69-70del of the S gene prevents some RT-qPCR tests from detecting the presence of the S gene.

However, the RT-qPCR tests were designed with the idea that the virus could mutate in mind. All of the RT-qPCR tests look for multiple, independent regions of the virus, so even if mutation interferes with detection of the virus at one site, the test would still be able to detect the other sites of the virus RNA. Indeed, people have been able to track the B.1.1.7 variant by seeing RT-qPCR tests that are positive for two markers (N and Orf1ab), but negative for the third marker (S).

It is possible to design RT-qPCR tests that are specific for certain strains of the virus, and researchers have developed such tests for the B.1.1.7 variant. It is also possible to design new RT-qPCR tests that will detect all common variants (by making use of existing sequencing data on the various common circulating strains of the virus).
 
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  • #6
Ygggdrasil said:
...
Thank you for the answer, it is really informative. I know about some cases where the symptoms were conclusive but multiple (!) PCR tests were negative. This were buggin' me for some time already :woot:
 
  • #8
Jarvis323 said:
A new strain has been discovered in Japan.

Here's the official report from the Japanese National Institute of Infectious Diseases: https://www.niid.go.jp/niid/en/2019-ncov-e/10108-covid19-33-en.html

Here's a good figure from the report comparing the spike protein mutations found in the B.1.1.248 strain found in Japan to other strains:
covid19-33-en-fig.png


The strain contains the N501Y mutation that is thought to increase the strength of binding of the virus' spike protein to the ACE2 receptor on cells in the body as well as the E484K mutation that could be involved in evading antibody-based immunity.
 
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  • #9
Here's a report of a new strain from Manaus, Brazil called the P.1 lineage. It has 17 unique amino acid changes, 3 deletions, and 4 synonymous mutations, and one 4nt insertion compared to the next most closely related strain (B.1.1.28):

1610558530681.png

https://virological.org/t/genomic-c...-2-lineage-in-manaus-preliminary-findings/586

Of interest are three mutations in the S protein RBD region that are known to be of importance, E484K, K417T and N501Y. The N501Y mutation is also found in the B.1.1.7 lineage from the UK and the B.1.351 lineage from South Africa and is through to potentially increase the transmissibility of the virus by increasing the affinity of the S protein for human ACE2 receptors. The E484K mutation (also found in the B.1.351 lineage) could be involved in evading antibody-based immunity.

The P.1 lineage is very similar to the B.1.1.248 lineage reported above from Japan, which is expected given that the strain was identified in four individuals who had arrived in Tokyo from Amazonas, Brazil.
 
  • #10
Virologist Trevor Bedford had a good thread discussing the emergence of the new Coronavirus strains:


He maintains nextstrain.org which is a good resource for tracking the genomic data available for SARS-CoV-2. Here are some plot from that site showing how the incidence of mutations at E484 (potentially associated with escaping antibody responses) and N501 (potentially increasing transmission) have changed over time:

N501:
1610992560785.png


E484:
1610992447822.png


Both mutation seem to have emerged relatively recently and increased in prevalence, though it seems like the prevalence of the E484K may be going down while the N501Y and related mutations still appear to be increasing in prevalence (though these numbers could be biased by increased efforts to monitor the spread of the B.1.1.7 strain in the UK and elsewhere).

[edit: for comparison here's the plot for the D614G mutation which emerged early on during the pandemic and has become the most prevalent form of the virus:]
1611005761746.png
 
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A few links that people might feel are interesting:

Prof Vincent Racaniello discusses mutation in the SARS-COV 2 virus and why he's unimpressed by the alarmist headlines we see. He frequently makes the point that these changes should be seen as variants they are not new strains.


Then in the Vblog TwiV 708 they discuss a paper that identifies a new type of antibody that has implications for the prevention and treatment of SARS-COV 2 and other viral infections, called nanobodies. These are found naturally in Alpacas and some other animals and seem to offer a range of new possibilities. The discussion on Twiv starts at around 58 minutes and gives rather more information than this discussion at science daily, the paper itself is behind a paywall.
https://www.sciencedaily.com/releases/2021/01/210112110112.htm
 
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  • #12
A non-peer reviewed pre-print reports the emergence of several new variants in the US that have all acquired mutations at position 677 of the spike (S) protein:
1613428949749.png

While it is not yet known whether these mutation affect the transmissibility or ability of the virus to be recognized by the immune system, the mutation does occur near the furin cleavage site of the S protein, suggesting that these mutations could have some effect on the virus.

Surveilance sequencing data from Nextstrain does not seem to show a clear pattern of rapid spread of viruses containing these variants yet, however:
1613429193191.png

https://nextstrain.org/ncov/global?c=gt-S_677

Here's a citation to the study:
Emergence in late 2020 of multiple lineages of SARS-CoV-2 Spike protein variants affecting amino acid position 677
https://www.medrxiv.org/content/10.1101/2021.02.12.21251658v2

Abstract:
The severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) spike protein (S) plays critical roles in host cell entry. Non-synonymous substitutions affecting S are not uncommon and have become fixed in a number of SARS-CoV-2 lineages. A subset of such mutations enable escape from neutralizing antibodies or are thought to enhance transmission through mechanisms such as increased affinity for the cell entry receptor, angiotensin-converting enzyme 2 (ACE2). Independent genomic surveillance programs based in New Mexico and Louisiana contemporaneously detected the rapid rise of numerous clade 20G (lineage B.1.2) infections carrying a Q677P substitution in S. The variant was first detected in the US on October 23, yet between 01 Dec 2020 and 19 Jan 2021 it rose to represent 27.8% and 11.3% of all SARS-CoV-2 genomes sequenced from Louisiana and New Mexico, respectively. Q677P cases have been detected predominantly in the south central and southwest United States; as of 03 Feb 2021, GISAID data show 499 viral sequences of this variant from the USA. Phylogenetic analyses revealed the independent evolution and spread of at least six distinct Q677H sub-lineages, with first collection dates ranging from mid-August to late November 2020. Four 677H clades from clade 20G (B.1.2), 20A (B.1.234), and 20B (B.1.1.220, and B.1.1.222) each contain roughly 100 or fewer sequenced cases, while a distinct pair of clade 20G clusters are represented by 754 and 298 cases, respectively. Although sampling bias and founder effects may have contributed to the rise of S:677 polymorphic variants, the proximity of this position to the polybasic cleavage site at the S1/S2 boundary are consistent with its potential functional relevance during cell entry, suggesting parallel evolution of a trait that may confer an advantage in spread or transmission. Taken together, our findings demonstrate simultaneous convergent evolution, thus providing an impetus to further evaluate S:677 polymorphisms for effects on proteolytic processing, cell tropism, and transmissibility.

Popular press coverage: https://www.nytimes.com/2021/02/14/health/coronavirus-variants-evolution.html
-------------------------------------------------------

Also, the NYTimes has published a nice webpage compiling information on the Coronavirus variants: https://www.nytimes.com/interactive/2021/health/coronavirus-variant-tracker.html
 
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  • #13
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And the New England Journal of Medicine published a preliminary report that the South African variant, B.1.351, is one third as susceptible to vaccine-induced antibodies as the original virus is.

https://nypost.com/2021/02/18/pfize...w-weaker-results-against-south-africa-strain/

However, it’s unclear if reduced antibody response will render the vaccine ineffective against the strain, since it’s not known what level is necessary to neutralize the virus.

“We don’t know what the minimum neutralizing number is. We don’t have that cutoff line,” study co-author Pei-Yong Shi said.


https://www.nejm.org/doi/full/10.1056/NEJMc2102017
...neutralization of the B.1.351-spike virus was weaker by approximately two thirds. Our data are also consistent with poorer neutralization of the virus with the full set of B.1.351-spike mutations than virus with either subset of mutations and suggested that virus with mutant residues in the receptor-binding site (K417N, E484K, and N501Y) is more poorly neutralized than virus with Δ242-244, which is located in the N-terminal domain of the spike protein.

Other reports state that all the vaccine manufacturers are willing and ready to modify their vaccines if needed.
 
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  • #15
Astronuc said:
It seams that the new California variant B.1.427/B.1.429 is a much more contagious and deadly strain of the virus.

A Coronavirus variant that emerged in mid-2020 and surged to become the dominant strain in California not only spreads more readily than its predecessors, but also evades antibodies generated by COVID-19 vaccines or prior infection and is associated with severe illness and death, researchers said.

In a study that helps explain the state’s dramatic surge in COVID-19 cases and deaths — and portends further trouble ahead — scientists at UC San Francisco said the cluster of mutations that characterizes the homegrown strain should mark it as a “variant of concern” on par with those from the United Kingdom, South Africa and Brazil.

“The devil is already here,” said Dr. Charles Chiu, who led the UCSF team of geneticists, epidemiologists, statisticians and other scientists in a wide-ranging analysis of the new variant, which they call B.1.427/B.1.429. “I wish it were different. But the science is the science.”

The new analysis is currently under review by the public health departments of San Francisco County and the state, which collaborated in the new research. It is expected to post late this week to MedRxiv, a website that allows new research to be shared before its formal publication.

https://www.yahoo.com/news/californias-coronavirus-strain-looks-increasingly-130055544.html

@Ygggdrasil I know this is an article, but the sources seem credible, there is a lot of information that's new to me, but you may already be familiar with. I'd like your take on the information.

Thanks!
 
  • #16
Evo said:
It seams that the new California variant B.1.427/B.1.429 is a much more contagious and deadly strain of the virus.

@Ygggdrasil I know this is an article, but the sources seem credible, there is a lot of information that's new to me, but you may already be familiar with. I'd like your take on the information.

Given that the Yahoo article says that a pre-print of the study will be posted later in the week, I'll probably reserve judgement until the data are published. In general, it can be difficult to collect data to determine whether a new variant is more transmissible or more deadly.

One paper found that one of the mutations found in the CAL.20C strain, the L452R mutation in the receptor binding domain of the S protein, could potentially allow the virus to escape neutralization by some antibodies. However, most of the antibodies they tested (including convalescent sera) were able to neutralize virus with the L452R mutation and viruses with the L452R mutation did not seem to be more infective than the regular variant. However, L452R is not the only mutation in the CAL.20C strain, so the lab experiments might not be fully indicative of the behavior of the variant.

Data from NextStrain suggests that L452R variants are increasing in prevalence, so it is possible that it could be more contagious.
1614119544698.png

https://nextstrain.org/ncov/global?c=gt-S_452

However, as I noted in post #2, we have seen variants become highly prevalent during major outbreaks of the disease (such as those experienced in California this winter), but those variants became prevalent just by being in the right place at the right time without being inherently more contagious, so we need more data than just seeing a high prevalence of the new variant. For example, for the B.1.1.7 variant (which we do believe to be more highly contagious), researcher were able to see higher viral loads in infected patients and epidemiological modeling suggested that the virus did exhibit greater transmissiblity (along with molecular biology work showing that specific mutations in the B.1.1.7 strain allow the S protein to bind to the ACE2 receptor more strongly).
 
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  • #17
Evo said:
It seams that the new California variant B.1.427/B.1.429 is a much more contagious and deadly strain of the virus.
According to UCSF, they have a number of studies going on in the state.

According to this release, https://www.ucsf.edu/news/2021/02/4...e-coronavirus-variants-san-franciscos-mission, "“The research indicates that the household secondary attack rate of the L452R variant identified in the Mission District appears to be higher than other rates that have been measured within the United States and globally, but more work needs to be done to confirm these findings."

The Yahoo article cites an LA Times article about the CA (homegrown) variant, and various other media outlets are reporting on variants with greater transmissibility.

Also - https://www.ucsf.edu/news/2021/01/419561/how-worried-should-you-be-about-new-coronavirus-variant
 
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  • #18
Yet another variant, B.1.526, "which first appeared in samples collected in the city in November. By the middle of this month, it accounted for about one in four viral sequences appearing in a database shared by scientists."

One study of the new variant, led by a group at Caltech, was posted online on Tuesday. The other, by researchers at Columbia University, has been submitted to a preprint server but is not yet public.

Neither study has been vetted by peer review nor published in a scientific journal. But the consistent results suggest that the variant’s spread is real, experts said.
. . .
The E484K mutation has independently cropped up in many different parts of the world, an indication that it offers the virus a significant advantage.

“Variants that have an advantage are going to rise pretty fast in frequency, especially when numbers are coming down over all,” said Andrew Read, an evolutionary microbiologist at Penn State University.

Dr. Ho's team reported in January that the monoclonal antibodies made by Eli Lilly, and one of the monoclonal antibodies in a cocktail made by Regeneron, are powerless against the variant identified in South Africa.

And several studies have now shown that variants containing the E484K mutation are less susceptible to the vaccines than was the original form of the virus. . . .
https://www.nytimes.com/2021/02/24/health/coronavirus-variant-nyc.html

Caltech - SARS-CoV-2 lineage B.1.526 emerging in the New York region detected by software utility created to query the spike mutational landscape
The most common sets of spike mutations in this lineage (now designated as B.1.526) are L5F, T95I, D253G, E484K or S477N, D614G, and A701V. This lineage appeared in late November 2020, and isolates from this lineage account for ~25% of Coronavirus genomes sequenced and deposited from New York during February 2021.
https://www.biorxiv.org/content/10.1101/2021.02.14.431043v2.full.pdf
 
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  • #19
A few recent papers studying Coronavirus variants:

Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity
https://www.cell.com/cell/fulltext/S0092-8674(21)00080-5

Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine induced sera
https://www.cell.com/cell/fulltext/S0092-8674(21)00226-9

No higher infectivity but immune escape of SARS-CoV-2 501Y.V2 variants
https://www.cell.com/cell/fulltext/S0092-8674(21)00231-2

Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape
https://science.sciencemag.org/content/early/2021/02/02/science.abf6950

Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera
https://www.cell.com/cell/fulltext/S0092-8674(21)00222-1

Neutralization of SARS-CoV-2 lineage B.1.1.7 pseudovirus by BNT162b2 vaccine–elicited human sera
https://science.sciencemag.org/content/early/2021/01/28/science.abg6105

SARS-CoV-2 spike D614G change enhances replication and transmission
https://www.nature.com/articles/s41586-021-03361-1

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants
https://www.nature.com/articles/s41586-021-03324-6
 
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  • #20
New paper with more data supporting increased transmissibility of the B.1.1.7 variant:

Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England
https://science.sciencemag.org/content/early/2021/03/03/science.abg3055

Abstract:
A novel SARS-CoV-2 variant, VOC 202012/01 (lineage B.1.1.7), emerged in southeast England in November 2020 and is rapidly spreading toward fixation. Using a variety of statistical and dynamic modelling approaches, we estimate that this variant has a 43–90% (range of 95% credible intervals 38–130%) higher reproduction number than preexisting variants. A fitted two-strain dynamic transmission model shows that VOC 202012/01 will lead to large resurgences of COVID-19 cases. Without stringent control measures, including limited closure of educational institutions and a greatly accelerated vaccine roll-out, COVID-19 hospitalisations and deaths across England in 2021 will exceed those in 2020. Concerningly, VOC 202012/01 has spread globally and exhibits a similar transmission increase (59–74%) in Denmark, Switzerland, and the United States.
 
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  • #21
Like most of these early reports, people can get a bit carried away, it does seem that B.1.1.7 is more transmissable, but this is surprisingly difficult to be sure about. In certain areas it has become the most common variant but in others, where it is clearly present it doesn't seem to be out competing the established variant. Of course reguardless, it doesn't change much, we will still be trying to control the spread using the current behavioural strategies until vaccines prevent its spread.
The variants with changes in the spike protien are of more concern (B.1.427/B.1.429) but again headlines which describe them as more deadly are alarmist nonsense. These variants have altered one or more of the protien antigens targeted by current vaccines, this means that antibodies produced in reaction to infection or vaccination based on the original variants have fewer binding sites and so offer less protection. For a virus to become totally resistant to these antibodies requires multiple changes and takes time though it is the case that when the infection is so common there is a much greater opportunity for mutations to occur.
So while these variants do reduce the effectiveness of vaccines there is no evidence that they are rendered totally ineffective and vaccination is still indicated. There are already several vaccine manufacturers adapting their vaccines in order to address these problems, there are also some vaccines still in development that target a wider range of epitomes that may help. Its likely that they will need to do this several times, the virus will continue to change, that's what viruses do.
 
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  • #22
The new version that surfaced in Portland has the same backbone as B.1.1.7, and the mutation it carries — E484K, or “Eek” — is one seen in variants of the virus circulating in South Africa, Brazil and New York City.
https://www.nytimes.com/live/2021/0...rsion-of-a-variant-first-identified-in-the-uk

The B.1.1.7 variant with Eek also has emerged in Britain, but the virus identified in Oregon seems to have evolved independently, Dr. O’Roak said.

Dr. O’Roak and his colleagues found the B.1.1.7 variant with Eek among Coronavirus samples collected by the Oregon State Public Health Lab from an outbreak in a health care setting. Of the 13 test results they analyzed, 10 turned out to be B.1.1.7 alone, and one the combination.
Did B.1.1.7 variant with Eek develop independently, or it was community spread without evidence of the transmission? Portland has an international population.

Nature, March 05 - Multitude of Coronavirus variants found in the US — but the threat is unclear
Ramped-up sequencing efforts are helping to identify mutations that might boost transmission or help a virus evade immune responses.
https://www.nature.com/articles/d41586-021-00564-4
 
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  • #23
The New York Times reports that cases of B.1.1.7 infections in the US seem to be rising while overall COVID-19 cases have been falling, which adds more evidence for the increased infectivity of the B.1.1.7 variant:
1615138771999.png

https://www.nytimes.com/interactive/2021/03/06/us/coronavirus-variant-sequencing.html

This trend also seems to be apparent in most of the states they analyzed. Luckily, most studies suggest that the B.1.1.7 variant can be controlled by the current set of vaccines authorized for use in the US. However, if this variant begins gaining mutations such as E484K ("eek") that seem to lower vaccine efficiency, this could pose problems for containment (though this depends on the extent to which the vaccines still protect against severe disease and hospitalization even if they are less effective at preventing symptomatic disease).
 
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  • #25
Astronuc said:
I was wondering - is the E484K mutation unique to SARS-Cov-2? Is it something that develops from the host?

E484 of the spike protein falls within the receptor binding domain, which is a fairly variable region within the protein (likely b/c it need to evolve new mutations as it the virus moves to new hosts). For example, the equivalent position in the original SARS-CoV virus (which caused the 2002-2003 outbreaks) has a proline instead of a glutamic acid at the equivalent position. Given the evidence that the E484K mutation helps the virus escape antibody-based immunity, it is likely that the mutation arose as an adaptation to transmitting in human hosts.

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Although various studies suggest that the E484K and other mutations could help the new variants escape antibody-based immunity, it is important to remember that there is another arm to the adaptive immune response that involves T-cells. Anew, non-peer reviewed pre-print study suggests that the T-cells which develop in response to either COVID-19 infection or vaccination all seem to still be effective against the various new variants:

Negligible impact of SARS-CoV-2 variants on CD4+ and CD8+ T cell reactivity in COVID-19 exposed donors and vaccinees
https://www.biorxiv.org/content/10.1101/2021.02.27.433180v1

Abstract:
The emergence of SARS-CoV-2 variants highlighted the need to better understand adaptive immune responses to this virus. It is important to address whether also CD4+ and CD8+ T cell responses are affected, because of the role they play in disease resolution and modulation of COVID-19 disease severity. Here we performed a comprehensive analysis of SARS-CoV-2-specific CD4+ and CD8+ T cell responses from COVID-19 convalescent subjects recognizing the ancestral strain, compared to variant lineages B.1.1.7, B.1.351, P.1, and CAL.20C as well as recipients of the Moderna (mRNA-1273) or Pfizer/BioNTech (BNT162b2) COVID-19 vaccines. Similarly, we demonstrate that the sequences of the vast majority of SARS-CoV-2 T cell epitopes are not affected by the mutations found in the variants analyzed. Overall, the results demonstrate that CD4+ and CD8+ T cell responses in convalescent COVID-19 subjects or COVID-19 mRNA vaccinees are not substantially affected by mutations found in the SARS-CoV-2 variants.

This result is very positive news if true. The data suggest that, while the new variants may still be able to infect vaccinated individuals, the T-cell response would likely prevent those infections from leading to severe symptoms.
 
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  • #26
A new peer-reviewed article published in the British Medical Journal provides data from an observational study suggesting that the B.1.1.7 variant is more deadly:

Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study
https://www.bmj.com/content/372/bmj.n579

Abstract:
Objective To establish whether there is any change in mortality from infection with a new variant of SARS-CoV-2, designated a variant of concern (VOC-202012/1) in December 2020, compared with circulating SARS-CoV-2 variants.
Design Matched cohort study.
Setting Community based (pillar 2) Covid-19 testing centres in the UK using the TaqPath assay (a proxy measure of VOC-202012/1 infection).
Participants 54 906 matched pairs of participants who tested positive for SARS-CoV-2 in pillar 2 between 1 October 2020 and 29 January 2021, followed-up until 12 February 2021. Participants were matched on age, sex, ethnicity, index of multiple deprivation, lower tier local authority region, and sample date of positive specimens, and differed only by detectability of the spike protein gene using the TaqPath assay.
Main outcome measure Death within 28 days of the first positive SARS-CoV-2 test result.
Results The mortality hazard ratio associated with infection with VOC-202012/1 compared with infection with previously circulating variants was 1.64 (95% confidence interval 1.32 to 2.04) in patients who tested positive for Covid-19 in the community. In this comparatively low risk group, this represents an increase in deaths from 2.5 to 4.1 per 1000 detected cases.
Conclusions The probability that the risk of mortality is increased by infection with VOC-202012/01 is high. If this finding is generalisable to other populations, infection with VOC-202012/1 has the potential to cause substantial additional mortality compared with previously circulating variants. Healthcare capacity planning and national and international control policies are all impacted by this finding, with increased mortality lending weight to the argument that further coordinated and stringent measures are justified to reduce deaths from SARS-CoV-2.

Popular press coverage: https://www.reuters.com/article/us-health-coronavirus-variant-britain-idUSKBN2B213E
 
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  • #27
To be clear about mutations: exoribonuclease is the enzyme that assembles nucletides using mRNA, to make new viruses, then "Proofreads" the new sequence. A percentage of new RNA synthesized has an an error rate of change, or mutation rate if you prefer.

This is the source of changes to the genome of the virus that makes for variants. It is also the reason why viruses "species" are viewed by virologists as "quasi-species". A measurable fraction of newly minted viruses has nucleotide sequence changes. Eukaryotes may do this but only Very Slowly. It is usually called genetic drift.

Covid-19 does this rapidly.

To give you an idea, here is a link to a downloadable PDF of a phylogenetic tree:
https://www.news-medical.net/health/The-Phylogenetic-Tree-of-the-SARS-CoV-2-Virus.aspx
 
  • #28
COVID-19: Study from 116 countries suggests surgery should be delayed for at least seven weeks following a COVID-19 diagnosis to reduce mortality risk

More than 15,000 co-authors make this largest ever collaborative surgery study

AAGBI

New international research published in Anaesthesia (a journal of the Association of Anaesthetists) concludes that surgery should be delayed for seven weeks after a patient tests positive for SARS-CoV-2, since the data show that surgery that takes place between 0 and 6 weeks after diagnosis is associated with increased mortality.

The study is by the COVIDSurg Collaborative: a global collaboration of over 15,000 surgeons working together to collect a range of data on the COVID-19 pandemic. This study's lead authors are Dr Dmitri Nepogodiev (Public Health) and Dr Aneel Bhangu (Surgeon) of the University of Birmingham, UK.

While it is known that infection with SARS-CoV-2 during surgery increases mortality and international guidelines recommend surgery should be delayed for patients testing positive for COVID-19, there is little evidence regarding the optimal duration of delay.

This international multicentre study included 140,231 patients (1,674 hospitals, 116 countries)* undergoing surgery in October 2020. Participating hospitals included all patients undergoing a surgical procedure. The number of co-authors (more than 15,000) makes this the largest collaborative surgery study ever undertaken globally.

Patients who became infected with SARS-CoV-2 after their surgery were excluded from the study. The primary outcome measure was 30-day postoperative death. Statistical modelling was used to adjust for patient, disease, and operation variables and calculate adjusted 30-day mortality rates for different time periods from SARS-CoV-2 diagnosis to surgery.

[. . . ]
###
https://www.eurekalert.org/pub_releases/2021-03/a-csf030921.php
 
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  • #29
jim mcnamara said:
To be clear about mutations: exoribonuclease is the enzyme that assembles nucletides using mRNA, to make new viruses, then "Proofreads" the new sequence. A percentage of new RNA synthesized has an an error rate of change, or mutation rate if you prefer.

No.

An exoribonuclease is an enzyme that catalyzes the degradation of RNA into nucleosides. I don't think there is an exoribonucease encoded in the SARS-CoV-2 genome. The RNA-dependent RNA polymerase (RdRP) is the enzyme responsible for the synthesis of new viral genomes, and misincorporation errors from the RdRP generate the mutations that help drive evolution of new viral variants. The SARS-CoV-2 RdRP is encoded by the Nsp12 gene in the viral genome.
 
Last edited:
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  • #30
Thank you, what then is the name RNA polymerase that incorporates changes? -

I saw the one above in a discussion several weeks ago - clearly it was misleading. I got the impression the name was specific to Coronaviruses. I will try to find the reference.
 
  • #31
Exonucleases are involved in proofreading replication because they can remove mismatched nucleotides from the end of the nascent RNA molecule. The SARS-CoV-2 Nsp14 gene does encode a protein with exonuclease activity that helps to proofread RNA replication (see https://www.cell.com/molecular-cell/pdf/S1097-2765(20)30518-9.pdf). Maybe this is what you were referring to.
 
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  • #32
Here are the two pre-print articles analyzing infections with the new variants from California, suggesting that the variant may be slightly more transmissible:

Estimation of secondary household attack rates for emergent SARS-CoV-2 variants detected by genomic surveillance at a community-based testing site in San Francisco
https://www.medrxiv.org/content/10.1101/2021.03.01.21252705v1

Transmission, infectivity, and antibody neutralization of an emerging SARS-CoV-2 variant in California carrying a L452R spike protein mutation
https://www.medrxiv.org/content/10.1101/2021.03.07.21252647v1

Popular press summary: https://www.nytimes.com/2021/02/23/health/coronavirus-california-variant.html
 
  • #33
Another observational study published in the peer reviewed journal, Nature, arguing that the B.1.1.7 variant is more deadly than the original SARS-CoV-2 strains. The data are fairly consistent with the findings of the BMJ study I cited earlier:

The B117 COVID-19 variant, which was first identified in the United Kingdom in October 2020, may pose a 61% higher risk of 28-day mortality, according to a study published today in Nature.

The finding is in line with last week's BMJ study that reported B117 had a 64% higher 28-day risk of death among people older than 30, although both studies note absolute 28-day mortality risk remains low for most populations.
https://www.cidrap.umn.edu/news-per...dlier-other-covid-19-strains-more-data-affirm

Here's the study:

Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7
https://www.nature.com/articles/s41586-021-03426-1

Abstract:
SARS-CoV-2 lineage B.1.1.7, a variant first detected in the UK in September 20201, has spread to multiple countries worldwide. Several studies have established that B.1.1.7 is more transmissible than preexisting variants, but have not identified whether it leads to any change in disease severity2. Here we analyse a dataset linking 2,245,263 positive SARS-CoV-2 community tests and 17,452 COVID-19 deaths in England from 1 September 2020 to 14 February 2021. For 1,146,534 (51%) of these tests, the presence or absence of B.1.1.7 can be identified because of mutations in this lineage preventing PCR amplification of the spike gene target (S gene target failure, SGTF1). Based on 4,945 deaths with known SGTF status, we estimate that the hazard of death associated with SGTF is 55% (95% CI 39–72%) higher after adjustment for age, sex, ethnicity, deprivation, care home residence, local authority of residence and test date. This corresponds to the absolute risk of death for a 55–69-year-old male increasing from 0.6% to 0.9% (95% CI 0.8–1.0%) within 28 days after a positive test in the community. Correcting for misclassification of SGTF and missingness in SGTF status, we estimate a 61% (42–82%) higher hazard of death associated with B.1.1.7. Our analysis suggests that B.1.1.7 is not only more transmissible than preexisting SARS-CoV-2 variants, but may also cause more severe illness.
 
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  • #34
Reuters - Virus variants found to be deadlier, more contagious; some may thwart vaccines
https://www.msn.com/en-us/health/medical/virus-variants-found-to-be-deadlier-more-contagious-some-may-thwart-vaccines/ar-BB1eGYzs?li=BBnbfcL
Antibodies induced by the Moderna Inc and Pfizer Inc/BioNTech SE vaccines are dramatically less effective at neutralizing some of the most worrying Coronavirus variants, a new study suggests. Researchers obtained blood samples from 99 individuals who had received one or two doses of either vaccine and tested their vaccine-induced antibodies against virus replicas engineered to mimic 10 globally circulating variants. Five of the 10 variants were "highly resistant to neutralization," even when volunteers had received both doses of the vaccines, the researchers reported on Friday in Cell. All five highly resistant variants had mutations in the spike on the virus surface - known as K417N/T, E484K, and N501Y - that characterize a variant rampant in South Africa and two variants spreading rapidly in Brazil.
 

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