SARS-CoV-2 UK variant: Does it matter?

a new variant of sars co v2 has been identified in the uk and it's causing a lot of fear in this video i want to explain all about that variant and why i'm not concerned about it here's a headline from the new york times this past weekend the coronavirus is mutating what does that mean for us well actually it probably doesn't mean very much i would say this is not a headline because viral genomes are always mutating i think the headline writer needs to bone up on his or her virology so let's do that first before we talk about this variant by the way this headline is in reference to the variant in the uk what is mutation let's define it because most people don't seem to get it right this is a definition of mutation from principles of virology the fifth edition a virology textbook of which i am a co-author and here we go a mutation is a change in dna or rna comprising base changes in nucleotide additions deletions and rearrangements and these changes when these mutations occur in open reading frames they can be manifested as changes in the proteins so one or more base changes can produce a single amino acid substitution a truncated protein or no protein the terms mutation and deletion are used incorrectly or ambiguously to describe alterations in proteins that is what the headline writer did they used mutation to describe changes in protein viruses mutate all the time whether those mutations mean anything is the real question let's take a little bit closer look at that first we know that genome mutation rates vary every genome whether it's a human genome or a fly genome or a virus genome a dna virus an rna virus they all undergo mutations at every reproduction cycle because the enzymes that carry out replication of genomes make mistakes some organisms can correct the mistakes but others can't and this is a very informative graph we're looking at genome mutation rate of different kinds of nucleic acids and the mutation rate here is on the y-axis it's substitutions per nucleotide per generation in other words every time the nucleic acid is copied how many changes do we see per nucleotide coronaviruses of which sars cov2 is a member of course single stranded positive sense rna viruses so those are shown here in yellow circles and in general these plus stranded rna viruses their mutations rate can vary from ten to the minus three that is one in a thousand changes per nucleotide per generation all the way down to about between ten to the minus five and ten to the minus six one and a hundred thousand or one in a million much less and there are others in between as well and you can see that bacteria have very low mutations rates they have dna genomes the dna enzymes can correct mutations and viroids have very high mutation rates so the rna viruses we're talking about today are right in the middle here ranging in mutation rates anywhere from uh one in a thousand to one about one in a million now most rna viruses don't have any ways to correct the mutations that the polymerases make these are viral enzymes of course the chronoviruses are different they have very large rna genomes 30 000 bases and they have an error correction machinery so their mutation rate is slightly less however it is still probably around one mutation per ten thousand or twenty thousand bases per genome replication you know in an infected cell if you make ten thousand genomes let's say ten thousand base rna genome where the frequency is one in ten thousand per reproduction cycle you're going to make easily 10 000 rnas in an infected cell so basically every every base in the viral genome can be substituted that's mutation happens all the time and so look at let's look at it in terms of sars cov2 or coronaviruses you know these viruses get into cells their rna is translated and then among the proteins made are those that are needed to do genome replication you go from a plus strand to a minus strand to more plus strands and of course those plus transit eventually end up in new virus particles every time the genome replicates from plus to minus from minus to plus there's a certain frequency of errors being made so all the viruses come out and there are many thousands of viruses per cell that are made constitute a collection of mutants a collection of mutants which we call a quasi species for sars cov2 again with a grna genome of 30 000 bases all the viruses that come out of a single cell in your upper respiratory tract there are many many different mutants it's a collection of mutants schematized by this diagram on the right where every line is a virus genome and the symbols are different mutations every genome can be different not all of those viruses with mutant genomes make it some of the mutations are lethal they destroy the ability of the virus to reproduce the next time it infects the cell many of them are neutral they do nothing and some of them may have an impact so far with sars cov2 the impacts have been minimal i haven't seen any that really have changed the course of disease if we had one that changed the property would be called a strain but we have no new strains yet in my opinion only variants sars cov2 genome is always mutating does it matter the real question is whether the mutations are causing amino acid changes in proteins that make a difference just to give you a sense of how many mutations we've seen this slide was made i don't know about a month or two ago where in over ninety thousand isolates we have seen twelve thousand mutations and any two of those isolates differ by about 10 bases so 10 out of 30 000 bases differ and many of these have no consequence they're actually just markers that we can use to do contact tracing they have no effect on the way the virus reproduces none of these mutations have led to a new strain a strain is a variant that has a distinct biological property and i mean in people you can look in cells in the laboratory and find all kinds of differences but what matters is in people and as far as i'm concerned none of the isolates so far have proven implications for human transmission or pathogenesis including the latest variant isolated from the uk which we'll get into detail in just a moment it's very difficult to use epidemiological data that is looking at the spread of a virus in a population and conclude that a particular variant is spreading better and here's why it's because of something called the founder effect so here on the left is our original population of viruses reproducing in an individual say and remember because of all the mutations that go on the viruses that come out of that person are a mixture of all different uh viruses like we showed in this slide here every genome is different but when that person transmits to another it may not transmit all of them maybe a subset will be transmitted shown here by the green and orange viruses which have a particular set of mutations and so now that virus is in the population and everyone infected by it will contain those changes as well so that's called the founder effect and they the changes just go along coincidentally they're neutral they have no effect and they seem to spread rapidly to a lot of people that alarms people but in fact it's meaningless and one of the ways you can look at this is because we know that kovi to spreading when it happens is actually done by very few individuals the rapid spread of a virus doesn't have to be a consequence of novel genome mutations we know that transmission of sars cov2 occurs mainly by super spreader events 80 of transmissions are caused by 10 of infectious individuals this has been studied in a number of countries here's a paper out of hong kong where they identified the main transmission events were super spreader events in weddings and churches and bars and restaurants for example and so here on the very left and a is is an example of a superspreader event you have one individual b that went to a bar or a place with a lot of people infected many others who then go on and infect many others and so on and so forth so you can see i think from this that if individual b in this diagram just happened to have a particular mutation in its genome that say led to a spike amino acid change he or she would spread it to a lot of other people who would spread it to a lot of other people and eventually it would be in a lot of people and that's why we get scared when this these kinds of events happen but in fact those changes can be neutral they may not be neutral but you better have some good data to distinguish between them being neutral and not and in my opinion we do not have such data yet so i think anytime a particular amino acid change in the spike which is what we're seeing now for the uk variant whenever they spread in the population it's simply a neutral spread it's by this founder effect combined with super spreader events all right so what about the uk variant what's going on there let's look at the data the first is a place where you should go to look at new sequence data it's called gizaid the global initiative on sharing all influenza data it's basically a website you justade.org where you can go to it was originally established to share influenza data but now of course sars cov2 data are being shared and whenever a new genome or genomes are sequenced they're deposited here so here's the new variant that's the name of it uh and the name comes from variant under investigation year 2020 month 12 variant number one and this variant was defined by multiple spike changes they're not mutations these are the wording from the g state even them get it wrong these are spike protein amino acid changes the mutation is in the genome and you may say oh vinnie you're being pedantic you have to get your terms right otherwise people like headline writers for newspapers get confused here are the spike protein amino acid changes there's there are two different deletions and then one two three four five six seven single amino acid changes so that's the all the changes in the spike protein of this variant and they they've gone further to say an increasing fraction in southern england or share several of these and a handful have been seen through imports in other countries and what i'm going to do now is show you where these are located so remember the the viral particle on the lower left is studded with spike glycoproteins that attach to the cell receptor they're very important we're making antibodies against the spike in our vaccines to prevent infection so the spike is biologically very important for the virus and that spike is a trimer of three polypeptide chains and the structure of that is shown on the right two panels here so we're looking at down from the top at the spike trimer so you can see from the schematic on the lower left it's a trimer and if you look down from the top you have one two three polypeptide chains and on the right we're looking from the side and here in green is ace to the cell receptor so in the light gray is the part of the spike that binds ace2 you can see here okay so we're going to look at these changes the changes in the spike in this variant are in different colors as you can see down here cyan orange or gold and blue let's take a look at where some of these changes are in the spike of what they they might mean for its function so the blue are these single amino acid changes down here there is one n501y which is in gold right there and then in cyan they're the deletions and if you look at the right hand panel here where ace2 is binding to spike you can see that one of these deletions is in the area of where the spike binds so it could change binding in some way based on the evaluation of effect on virus structure and function the most relevant of all these changes might be n501y asparagine to tyrosine at amino acid 501 of the spike that's in orange here and here there's three of them so one two three and you can see this is potentially impacting the spike and then they say in positions contributing to potential spike surface variation and and there's a deletion at why 145 one of these cyan deletions is where some antibodies like one called 4a8 bind all right so the others they think have no apparent interest so the ones they're interested in is n501y that could affect the binding of host receptors in antibodies and then the deletion where one of them in particular could affect an antibody binding site so here they say the other mutations the blue ones so we've focused on cyanine gold so the blue mutations they say their effect on structure and function is less clear and then they also say in another protein called orphate there's a early stop codon that could be relevant this causes a deletion in the orphaned protein and these have been seen before in other viruses isolated from singapore and also other countries they may actually have a role to play in attenuation they may make the virus less virulent which is not something you're hearing at all all you're hearing is increased transmission and finally they they conclude as seen on many occasions before mutations are naturally expected for viruses and are most often simply neutral regional markers useful for contact tracing as i've just told you mutations are naturally expected for viruses the mutations seen have rarely been affecting viral fitness and almost never affect clinical outcome but the detailed effects of these mutations remain to be determined fully and that's a reasonable statement in the past we haven't seen any such changes make a big difference in transmission and disease in humans but we should be aware of of them going forward and make sure we study them and i think that's perfectly fine but what is not fine is all the hype now which is about this strain having higher transmission which simply can't be concluded so far there's one other document i want to refer to and again the the url for it is down here it's from a committee called the noon emerging respiratory virus threats advisory group so they had a meeting on the 20th of december and here the individuals in this meeting some of whom are virologists epidemiologists and so forth and they have looked at the data on this variant and they've made some conclusions so let me go through them with you because i think this document is what's scaring the world at the moment and i don't think it is justified so i'm going to label these nerve tag considerations first within the uk the variant is mostly in london southeast and east of england but has been detected in various parts but it's mostly in those other areas and a few have been reported internationally one confirmed export from the uk to australia i would say it's already out because as they say here a lot of other countries have lower sequencing capability than the uk and other countries so it's not easy to know that the variant is already there because you have to sequence isolates from people to know this now here are the data which lead the committee to be somewhat worried first of all study is a correlation between our values and detection of the variant which suggests an absolute increase in the r value of between point three nine to point nine three so r of course is the reproductive index the likelihood that an infected person on average will infect so many other people right so for sars cov2 we think it's between two and three without mitigation without doing any lockdown or any kind of masking or distancing and so forth you can you can reduce the reproductive index obviously by interfering with transmission and so they're saying that um in places where they see this variant there the the r value is increasing however i would say and again this is my theme you can't use epidemiological data to prove a biological effect of a amino acid change in a virus you have to do experiments to do that and that's what they're doing here they're saying ah there is an increase in the transmissibility it must be because of the variant well obviously that's a flawed argument that's not how we do science the other piece of data is the ct value for the pcr right they take nasal swabs from patients they do pcr they get a ct value which is reflective of how many rna copies are present in the sample they say there's a decrease of ct of around two associated with the new very now you know the ct values can go anywhere from 11 to 35 or so that's the range 11 being a lot of rna and 35 very little and probably not infectious so they're saying and people infected with this variant we're seeing the ct value decrease they have more rna so that must mean that the virus is reproducing better in them and they also cite viral load experiments in other words they take a nasopharyngeal swab extract the nucleic acid sequence it they have to convert it to dna and amplify it then they sequence it and then you can calculate the number of rna copies originally present and they see they're seeing more rna copies so those are mainly the three pieces of data that they use to conclude that they have moderate confidence that this variant demonstrates a substantial increase in transmissibility compared to other variants so there are two adjectives in this sentence that i disagree with moderate i don't agree moderate confidence and substantial don't agree at all i think these are all circumstantial evidences that do not prove anything you can imagine that our value could change by other things that are affecting transmission and so you can't conclude it's the actual virus and as i said if the virus is introduced into a population by founder effect and it's neutral it's not going to have any effect on the r value and the pcr is flawed in itself you cannot use pcr to measure infectious virus and that's really what matters if you want to conclude that this virus is more transmissible you need to measure infectious virus and i'll get back to that later pcr doesn't measure infectious virus and i can imagine for example you have a variant that makes more smaller pieces of rna in the infected cells so the pcr shows a lower ct value completely flawed argument to indicate that this is uh leading to increased transmissibility uh but they then say we we don't have enough data to draw any conclusions about the following first the mechanism of increased transmissibility i would say we don't yet know that there is increased transmissibility caused by these particular amino acid changes and so they say for example increased viral load well you have to measure infectious virus you can't use pcr to do that age distribution disease severity i think if anything this variant is going to cause less severe disease because of the or fate deletion and then finally antigenic escape so as i said earlier the location of these amino acid changes they're using the wrong terminology as well the location of the amino acid changes in the receptor binding domain of the spike raises the possibility that this is antigenically distinct and they've identified four reinfections among 15 people with this variant but tell me how many reinfections you see with the other variants as well is it not different this is one antigenic site one epitope of the spike and there are about 20 b and t cell epitopes on the spike i really don't think that one change one epitope change is going to make much of a difference and so they want more data on reinfection readmission and case fatality rates which are apparently being collected more on the age distribution and then this one this third one i think is important to look at in vitro data on the ability of convalescent sierra to neutralize the variant to see if the amino acid change in the antigenic site impacts the ability of convalescent serum to block infection which would have of course implications for vaccines but i don't think there are any as i said this is one out of many epitopes it is unlikely that it would make the virus unable to be neutralized say by antibodies that are induced by vaccination and finally they want to know if lateral flow assays to detect this variant these would be antigen assays would be compromised in any way i think it depends on how you've set up the lateral flow assay of course if you're using more than one antibody you're you're probably better off now here's what i think about this whole story i would say i have low confidence that this variant demonstrates a substantial increase in transmissibility i don't see any evidence for that i i don't see shedding evidence for increased transmission so if you think of viruses transmitting better one possibility is that it's more stable in the environment and that can be tested another possibility is that the infected people shed more virus and respiratory secretions that can be tested so measure shedding and compare it to people infected with the other variants that are circulating in these areas not everyone is infected with this variant however nerve tag doesn't have this on their list of experiments and as i said pcr and sequencing cannot answer this question nucleic acid is not infectious virus this experiment is not going to be easy because you have to have a cohort of people infected with this variant and a variant that's different predecessor for example and compare shedding by isolating virus and you have to do that in cell culture in a bsl3 laboratory of course and the confounding problem is that when you take a nasopharyngeal swab for example you get this slightly different volume from each person so you have to somehow normalize them when you do your infectivity calculation not an easy thing to do and remember that not too long ago another variant d614g arose and propagated throughout the world and similar scary stories were told about that one increased transmissibility but it was nothing was ever done in humans to really address that including the experiments that i'm suggesting but in the end i object to the use of epidemiological data to prove the biological properties of a virus you need to do experiments with the virus to prove that you have increased transmissibility or at least properties that are consistent with increased transmissibility and that simply has not been done in my opinion all the hype about this variant is unwarranted certainly we have to pay attention to it we have to study it but so far i see no reason why this variant is any different from any others that have arisen i think we should move on from the scary headlines and get ahead with vaccination programs which are underway and that is going to be the way that we get away from this pandemic i hope you found that explanation useful i'm vincent draconiello and i'm earth's virology professor thanks for watching [Music] you

Channel: Vincent Racaniello

Views: 188,024

Rating: 4.9074631 out of 5

Keywords: virus, viruses, viral, virology, coronavirus, pandemic, COVID-19, SARS-CoV-2, UK variant, mutation, spike protein, viral transmission

Id: wC8ObD2W4Rk

Length: 24min 48sec (1488 seconds)

Published: Mon Dec 21 2020

Reddit Comments

[u/north0east]

Calm, rational and detailed explanation. He starts with what a mutation is and how often it happens. For instance this novel virus has had 12,000 identified mutations through 90,000 different isolates. He goes on to explain why one particular strain has become more common and offers an alternate explanation not based on contagion. He argues that this is because of the founder effect

[u/real_CRA_agent]

The UK has just announced another even worse mutant strain from South Africa. This fear mongering is insane!

[u/dankseamonster]

I really appreciate all the rational expert coverage of this mutation - I'm prone to anxiety and the UK media has been non-stop with the fearmongering on this one.

[u/Harryisamazing]

I've just started watching this video and very much so appreciate that he goes through the details in a calm tone and gives us details of why we have nothing to worry about... on the opposite spectrum the MSM makes it out to be the next plague

[u/tosseriffic]

Reminder about the many strains:

https://i.imgur.com/2pOsEhp.png

https://nextstrain.org/ncov/global

"but muh spike protein"

Yeah? What about it?

[u/3dsg3rd1jkstr4]

The media and government are aware that many people are over it and just not complying and in the UK, I feel like our style is more silent noncompliance than big, grand protests which seem more common in the states etc

I think they’re really playing up how much of a disaster the new strain is to try and scare people into complying with the rules. I fear that they’ll successfully manipulate some people (probably people who were doomers anyway) but it won’t sway me, I will not fall for their propaganda and I have faith that lots of people will also not be swayed. We’ll see though, I guess

[u/P22THC]

r/ukantilockdown

[u/ScopeLogic]

Too late now. The twitterfolk have already decided itll kill them all.

[u/loonygecko]

Best i can tell from other sources, the UK new strain scare is the brain child of one guy using 'projections' even though all of his previous projects were horribly wrong and most of his colleagues have already said this new projection did not have enough data to be put out as reliable.