In recent months variants of SARS-CoV-2 have been detected that are unusual in that they have many more genome mutations than previously found. These have been called ‘variants of concern’ (VOC) as it has been suggested that the genome mutations might impact transmission, immune control, and virulence. Below I cover each of these issues separately.
Transmission
The SARS-CoV-2 lineage called B.1.1.7 arose in the United Kingdom in September 2020 and harbors 17 genomic mutations, some of which lead to amino acid changes in the spike protein (pictured). Similar but distinct variants have been detected in other locations, including South Africa (B.1.135) and Brazil, but the B.1.1.7 lineage has been best studied. A good summary of the changes can be found in this manuscript. A number of lines of evidence have led to the conclusion that viruses of the B.1.1.7 lineage may have increased transmissibility compared with previous isolates. These include the rapid displacement of previous variants in the UK within a short period of time; an apparent increase in the R index for such variants; and increased levels of viral RNA in nasopharyngeal washes as measured by PCR or RNA sequencing.
The virological definition of transmission is the movement of viruses from one host to another. In the case of SARS-CoV-2, such transmission occurs when infectious virus particles are exhaled within respiratory droplets and arrive in another host, where they initiate infection. The evidence cited above for increased transmission of the B.1.1.7 lineage are all indirect and do not prove that the variants actually transmit, in a virological sense, better between hosts. The population growth of the variant could, for example, be a consequence of changes in human behavior. The R index, a measure of transmisssibility, is influenced not only by the virus but by human behavior. The finding of increased levels of RNA in nasopharyngeal wash is also inconclusive with respect to transmission. Viral RNA is not the same as infectious virus, and no studies have been done measuring shedding of infectious virus from individuals infected with variants of the B.1.1.7 lineage compared with other variants.
There is no doubt that the B.1.1.7 lineage has rapidly displaced others in the UK. Whether this behavior is due to an increased ability of the virus to be transmitted form one host to another has not been demonstrated. The variant has also been detected in other countries and its dispersion in those locations are not consistent with increased transmission (as I have defined above). For example, we now know that the B.1.1.7 lineage was present in the US 5-6 weeks before its detection in the UK, yet as of January it comprised just 0.3% of cases nationally. After 2 months of circulation in California, the lineage is estimated to account for 0.4% of cases compared with 1.2% at a similar point in the UK. In Florida the lineage is associated with higher spread, 0.7% of cases, but this is not the situation in other US states.
These data emphasize that we cannot conclude that the B.1.1.7 lineage is biologically more transmissible. Multiple factors are likely at play, and this is why it is better to view the B.1.1.7 lineage variants and others in terms of their fitness – the reproductive success of the virus. Many factors can influence fitness, not just transmission. These could include increased physical stability of the particle, increased resistance to immune responses, longer duration of virus presence in the nasopharynx, increased infectious virus produced within the host, more efficient establishment of infection in a host, and more. A slight increase in any of these might drive a particular variant within a population but not actually affect person to person transmission. Whether such mutations are spread by founder effect – being in the right place at the right time – also must be taken into consideration.
The statistical models that have been used to approximate the transmission of SARS-CoV-2 variants cannot prove a biological property because drive through a population can be a consequence of various fitness parameters. Experiments either in animal models (in which case the relevance to humans is unknown) or measurement of infectious virus in humans is needed. So far none of the latter have been done for the current variants.
Immune control
A more immediate concern is whether any of the changes in spike protein within VOC impact the ability of immune response to control infections. This question has been directly addressed for neutralizing antibodies, e.g. those which can block infection. Antibodies recognize specific protein sequences on the virus particle, and specifically the spike protein for those given the mRNA vaccine. Some of the spike changes identified in variants are in regions known to bind antibodies. Consequently an important question is whether vaccination can inhibit infection with the variant viruses.
This question has been addressed for both the Moderna and the Pfizer mRNA vaccines. Sera from persons immunized with mRNA-1273 efficiently neutralized pseudotyped viruses bearing the SARS-CoV-2 spike glycoprotein from the B.1.1.7 lineage. These sera had a reduced (6.4 fold) neutralization titer when the South African B.1.351 lineage was used. However these sera still fully neutralized B.1.351 with a titer of 1:290 which may be sufficient to prevent severe COVID-19. Nevertheless, Moderna has announced that it will advance a modified vaccine (mRNA-1273.351) encoding the B.1.351 amino acid changes.
In a separate study, sera from individuals vaccinated with the Pfizer BNT162b2 mRNA vaccine was tested in neutralization assays using SARS-CoV-2 viruses with selected spike amino acid changes from the B.1.1.7 (deletion of amino acids 69/70, N501Y, D614G) or B.1.351 (E484K + N501Y + D614G) lineages. These changes had small effects on neutralization with the sera. However, the engineered viruses do not contain the full set of changes found in the B.1.1.7 and B.1.351 viruses, which might explain the different results compared sera with antibodies induced by mRNA-1273.
These observations provide confidence that the two mRNA vaccines will provide protection against COVID-19 caused by currently circulating variants. However genomic surveillance must be increased to ensure that any new spike changes that might arise are detected quickly and their effects on neutralization determined.
Disease severity
A previous study did not show evidence that viruses of the B.1.1.7 lineage were associated with an increased risk of hospitalization or death. However upon examination of additional data from three separate studies NERVTAG concludes that there is a ‘realistic possibility that infection with VOC B.1.1.7 is associated with an increased risk of death compared to infection with non-VOC viruses’. This conclusion was reached by statistical analyses of reported death rates among individuals infected with VOC B.1.1.7 or non-VOC viruses. For example, in one study the relative hazard of death was 1.35 (with a 95% confidence interval of 1.08-1.68). In another study the mean ratio of case fatality ratios between cases caused by VOC or non-VOC viruses was 1.36 (95% CI 1.18-1.56). These are small differences with large confidence intervals ranging from no effect to more effect, and the authors note that the absolute risk of death remains low. The statistics are computed by analyzing a limited dataset of all COVID-19 related deaths (8%) and consequently might be in error. Furthermore, there does not appear to be an increased risk of hospitalization associated with infection by VOC viruses. My reading of this report is that it mainly serves as a warning to continue genomic surveillance of variants with respect to death risk and does not come to a conclusion on causality.
Update: Novavax just released the first results of their phase 3, spike-protein based COVID-19 vaccine. Efficacy was nearly 90% in the UK, but in a smaller trial in South Africa it was 50% against the B.1.135 variant.
Thank you for this post.
Thank you for this informative article. The fact that the UK variant did not increase in California is support for my hypothesis that in Europe, the so-called UK variant has escaped the PCR test. We know that the S gene mutations causes S gene dropout during PCR testing. This mathematically and necessarily reduces the sensitivity of the European test – for the UK variant. Therefore, during the time prior to the discovery that it had increased, it’s increase was most likely due to selection by testing and isolating those with the other variants. Sadly, I predict that eventually in every country viral lineages will emerge that have escaped PCR testing. The selection coefficient for mutations that occur in the primer sites must be immense. A study recently reported that 8.5% of all the emerging variants are found in primer sites. The genome of the virus is 29000 bases – all else being equal, there should be far fewer mutations in the primer sites.
I am deeply grateful for the article. Here in Brazil, as is well known, we have a new variant detected in Manaus, Amazonas. I believe that the line of reasoning followed by the article can be adopted for some aspects in the Brazilian variant. But I would like to raise some questions: Did a type of adaptation to higher ambient temperatures occur in the Brazilian variant? Manaus is very hot and humid, and as infection rates are so high that the health system has collapsed, is the hypothesis plausible?
My best wishes to everyone.
This will pass!
Hello Vincent thanks for your podcasts and blogs. Re B117. reference paper states it arrived in USA in November, whereas firs detected in England in September. If that is correct then USA is 2 months behind the UK.
Thanks Vincent for these elucidations. I have been waiting for your comments, in full, to combat the fear coming from alarmist news articles ad nauseum.
You say that “we now know that the B.1.1.7 lineage was present in the US 5-6 weeks before its detection in the UK”. That’s not true: the publication you refer to says that this variant was present in the US since November, while the the earliest sample with B.1.1.7 in the UK was from September.
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Take James Lyons-Weiler (above) w/ grain of salt. Antivaxxer / COVID denier. DOn’t know if his particular comment above has merit.
https://www.thrivetimeshow.com/business-podcasts/biomedical-research-scientist-doctor-james-lyons-weiler/
https://sciencebasedmedicine.org/james-lyons-weiler-coronavirus-conspiracy-vaccine/
Thanks again, for these hype free looks at the evidence.
One thing that might further reduce the hype would be to stop saying that a new variant ‘displaced’ an older one. I don’t see how there can be any competitive ‘motive force’ by which one variant could ‘drive out’ an earlier one: they are also arriving in different cohorts of ‘infectable’ people–that is, if we are to believe that few people are as yet suffering reinfection.
I don’t think it is any more true to say one virus ‘displaces’ another, than it is to say that a wave, breaking on a beach, displaces the one that arrived and dissipated into the sands before it. Virus varieties are being created all the time, and most will only have one point of origin. With lock downs in place, they are likely to run out of infectable hosts, without any intereaction with later variants that arrive at different points and begin their own infiltration and dissipation cycle in a different population of ‘connected’ individuals.
It would also be useful to know what is the meaning of the nomenclature being used to describe new variants–and to distinguish them from strains, should any occur.
Please explain this new article.
https://doi.org/10.5281/zenodo.4477081#.YBlkY7FxZIp.mailto
Please explain this. You and your posse have been dancing (or hiding) from this data for 7 months.
And it really stinks!
What value is your academic standing if you have neither backbone or integrity.
G
“You and your posse have been dancing (or hiding) from this data for 7 months.”
Date on non peer-reviewed report is Jan 29….
Steve
I think the point made is that the insistence that the virus did not come from the lab is based on a known false premise, i.e. that scientists would not have tried to build a virus with the mutations because science (computer modelling) teaches away from pursuing that line.
However, when attempting to obtain a patent on their work (which most scientists opining on this matter have obtained) which has been rejected based on obviousness, they will argue a patent should be awarded because of the very fact that no one would try this route because computer modelling indicates it would fail
A little two faced if you ask me.
Hi Dave,
I think the problem is that people who do not understand any of this are opining on it as thought they do, likely because of politics. I’m a scientist in another field (cog neuro), and I am in no position to adjudicate this question as it is outside my field.
However, I KNOW what I’m lacking here. I understand my limitations from having developed expertise elsewhere.
So let’s drill down a bit.
“based on a known false premise, i.e. that scientists would not have tried to build a virus with the mutations because science (computer modelling) teaches away from pursuing that line.”
Do you really understand what this means? My understanding, from listening to TWIV mostly, is that the changes observed are not ones that there was any science leading up to, and there was no reason to think the changes observed would lead to the phenotypes observed. Again – I’m not expert! But I (and likely you) am in no position to know one way or the other. This woudl require in-depth knowledge re: the direction of the field in a larger sense. Do you have this knowledge? I do not!
If I’m wrong here pls specifically show (to paraphrase your quote above) that:
“scientists WOULD have tried to build a virus with the mutations because science (computer modeling) DOES NOT teach away from pursuing that line”
That is, can you point to some peer reviewed science to show that the statement above is true?
Further:
“However, when attempting to obtain a patent on their work (which most scientists opining on this matter have obtained) which has been rejected based on obviousness,”
This statement says that they both DID and DID NOT obtain a patent for something, but what that something is is not clear. Maybe a type-O (or several) of some kind? Maybe you mean in general? If so, I don’t think it matters to the larger point, and its a red flag that you think its germane.
“They will argue a patent should be awarded because of the very fact that no one would try this route because computer modeling indicates it would fail”
DID they argue this? Or you think they WILL argue this? If the latter, I’m uninterested in the this supposition. However if you had another type-o and its the former, please cite this argument, what it was made in regards to, and what happened. Or maybe you again mean “generally”? Which means you’ve seen enough of these patents to know how microbiologists react to getting / not getting patents? I doubt that honestly. And either way, its not relevant to whether anything in the literature was leading up to the changes observed in SARS-CoV-2 being indicative if its phenotypical properties.
And if you don’t know the answer to my Qs, it means that you’re not an expert in this field and you probably – like me – don’t have a real grasp of the underlying issues.
Steve
I have micro degree, worked in a lab and then became a patent attorney.
I don’t believe there are any patents related to this coronavirus specifically because it is too soon for a patent to be issued. Nevertheless, it is common practice in trying to get a patent in any field, or on any subject, to overcome an obviousness rejection by arguing that the science teaches away from the subject of the invention. No one would try to do the subject of the invention because it doesn’t make sense.
Arguing that in the case of coronavirus no one would build a virus in this way because the computer modelling suggests it wouldn’t work, which is what the argument has been from day one, is a false premise and the scientists making such an argument knew that at the time and know it today.
1. You were speaking generally about the patents and so there’s no evidence to be had there for the proposition that this was man made. OK
2. You cannot speak to the substance – whether the genetic changes observed are ones that could have been anticipated to lead to the phenotypic changes observed. OK.
“Arguing that in the case of coronavirus no one would build a virus in this way because the computer modelling [sic] suggests it wouldn’t work, which is what the argument has been from day one, ”
I’ve heard other arguments proffered, so there we are. That if you examine the genetic changes, these would not be the ones that the *previous literature* has indicated would lead to the observed characteristics. The previous literature is not only computer simulations, right? And then here’s the knowledge of the field – to understand the evidence in total. As neither of us do. But the consensus of those who DO know the field feel its incredibly unlikely that this was man made, for the reasons cited above.
“is a false premise and the scientists making such an argument knew that at the time and know it today.”
And here we go! All that which cannot be proven (which here is everything) goes to…CONSPIRACY!!!!.
Do you have direct evidence of a conspiracy?
Hello, Professor Racaniello. Thank you for another great article.
I’d like to offer some suggestions for ideas and questions to discuss (on a future TWiV, or TWiEVO or Q&A):
The selection pressures and how they relate to the co-evolution between SARS-CoV-2 and our various immune responses, and some related ideas. Also a weirdness in the results of the new AstraZeneca preprint.
Selection pressure on SARS-CoV-2:
1. Now that a mutation causing the E484K change has evolved out of B117,
[see: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/957504/Variant_of_Concern_VOC_202012_01_Technical_Briefing_5_England.pdf ]
can we surmise that maybe E484K is the path of least resistance for adapting to our current immune response?
If so, can we use this info to help develop a predictive model for the most likely mutations that would most easily evolve in response to population immunity? If we could predict and not just react to mutations, then we could start preparing vaccines before the more destructive mutations emerge.
2. As a greater proportion of population immunity comes from vaccination rather than infection, especially as a more diverse range of vaccines are implemented, we are creating a more complicated set of pressures on the virus to adapt, and forcing the virus through a kind of obstacle course in its attempts to optimize for spread. Any thoughts on whether this increases the likelihood of the virus developing new unpleasant characteristics along the way of its search for optimality (fitness) ?
—
Also a bit of weirdness in the Latest Oxford/Astrazeneca vaccine study preprint, maybe worth a look:
One of the results looks like an error.
Question: What kind of methodological error might show zero protection in SDSD and 49% protection in LDSD? Seems odd to submit this in the current state.
Personally, I’ve never liked the small sample sizes used in calculating vaccine efficacy, (but I’m just an engineer, not a statistician), so my guess is that it’s in the range of error you can expect with such small samples.
“There were 130 cases of asymptomatic infection occurring more than 14 days after the booster dose (COV002 UK cohort only). In the SDSD cohort there was no evidence of protection with VE of 2.0%, 95%CI (-50.7%, 36.2%, 41 ChAdOx1 nCoV-19 versus 42 control cases). However, in the LDSD cohort there were 47 cases and VE was higher at 49.3%, 95%CI (7.4%, 72.2%, 16 ChAdOx1 nCoV-19 versus 31 control cases).”
https://poseidon01.ssrn.com/delivery.php?ID=908065002113091029031029004116028092034057081068083017073097002123008109020031031080121005029070024024123121020000093004092067107017108057080016040016089012029024061015090120064080002082029044015123030087062015030073022110000024024071086084122004017095106117125088098104074082070007095074082&EXT=pdf&INDEX=TRUE
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Thanks very much,
Howard A Pasternack. P.Eng.
Steve
https://www.livescience.com/coronavirus-not-human-made-in-lab.html
The literature does not say probably not man made. It says it was not engineered. Period. No qualification. The assertion is all based on the false premise that because literature and modelling doesn’t teach it, it didn’t happen.
Dave:
In my last post, I noted that you proposed a conspiracy:
“…is a false premise and the scientists making such an argument knew that at the time and know it today”
I asked for evidence of this conspiracy. You provided none. Please provide.
“The assertion is all based on the false premise that because literature and modelling doesn’t teach it, it didn’t happen.”
The false premise that because there’s no evidence, it’s not true? Always a tough one.
What’s the evidence that it did happen, and how do you know which evidence to believe.
One strong reason for doubting that the SARS-CoV-2 virus was created in a lab is that all RNA viruses mutate at a fearsome rate, as we are now experiencing with the emergence of the UK, SA and Brazilian strains. If someone wanted to make a militarized virus, a better choice would be a DNA virus, which would be much more stable, genetically, and much less likely to throw off mutants that do things you didn’t count on.