20 Dec 2020

New COVID19 Variant in UK exposes Strategic Risk of Failing to Contain & Eradicate Pandemic

Posted in InfoMullets By Science Decoded On December 20, 2020

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InfoMullet is collaborating with Science Decoded to bring a series of articles on COVID19. To view more of Science Decoded’s content including live-updates, Ask Me Anything videos, and even a few COVID19 related memes check them out on Facebook. Timothy Clancy also contributed.

TLDRUpFront: TLDRUpFront: Pandemic response consists of tactical responses to contain the virus while we gain a strategic advantage through vaccines. But a failure to contain the pandemic increases global viral load leading to new variants and strategic risk. The risk is that one of these variants will be more contagious, more deadly, or resistant to current vaccines. In the last month, this strategic risk has emerged in the United Kingdom.

In analogy: D-Day was a tactical effort to reach Berlin before the strategic risk of a Nazi atomic weapon emerged.

FullContextInTheBack:

Consider the pandemic as a war between the virus and humanity and the mathematics of a global conflict strategy are simple. Reduce the viral load of the current COVID19 strain globally until we can deploy enough effective vaccines to enough people globally to create herd immunity against this variant, which we then eradicate. The more people who get infected, the sicker they are, and the longer we fail to contain – the higher the global viral load in aggregate becomes. Our strategy is to trade space for time. Space in keeping the viral load low while buying time to develop and deploy vaccines.

This strategy of ‘trade space for time’ employs tactics we’re now familiar with: developing test & trace capabilities, social distancing, mask use, temporary lockdowns and closures. The tactical risks of failing to implement these correctly are significant. Massive loss of life, lingering conditions for the recovered, economic devastation, and upended social order. “Tactical” here is not meant to under-play the significance of these risks, but to put them in context versus strategic risk.

The strategic risk of a pandemic is that a persistently high global viral load leads to a virus mutation that is more contagious, deadly, or resistant to our vaccines. Or, a combination of if not all three of those. If that happens, then we could lose the strategic initiative and go back to square one starting over.

And Call Off Christmas!

RIP GOAT

One of these conditions has emerged now in the United Kingdom. Prime Minister Johnson in the United Kingdom has cancelled the 4-day Christmas easement of some parts of the country’s Tier 3 COVID-19 restrictions (mostly London and East England), and instead moved much of southern England to Tier 4 restrictions (one step shy of lockdown) starting Saturday night. He did this because of a new variant of COVID-19 that has been detected, believed to be more contagious than existing forms. Fortunately, this variant does not appear to be resistant to the current vaccines.

But if this variant is not stamped out through the actions taking place in the UK right now, then the rest of the world will have to deal with it. That variant will come to the United States. It will come to France. It will come to Germany. It will come to Sweden. It will come to Brazil. It will come to India. Viruses spread, and this one is no different. If it is especially contagious or especially virulent, then we will have to deal with the consequences of that fact. And, if it reaches a much larger population, the global mathematics of pandemic conflicts kick in and the chances of additional mutations creating greater strategic risk rise exponentially.

The Big 3 Strategic Risk Questions of the New COVID19 Variant

Word of a new of SARS-COV-2, detected in nearly 1000 samples in the UK over the last month has rocked the world. Named VUI-202012/01 the variant is also known as “Variant B.1.1.7”, which is a real snappy name there chaps. People are asking many questions. The big three are how this impacts among existing COVID-19 diagnostics, therapeutics, and/or vaccinations. Those get answered here. Below that is the science behind those answers which also responds to the next set of questions people ask: what the variant is, what the existence of this variant means, and is this a new strain scientifically? Finally – was the Prime Minister’s action is justified. Lets go through those in turn.

Does the new variant impact existing COVID-19 diagnostics?

Maybe. Certain mutations – especially the Δ69-70 mutation – seem to increase the rate of false negative results on certain COVID-19 tests. Specifically, this one seems to affect the TheroFisher-brand TaqPath test and the BioFired-brand BioFire test, both of which are qPCR tests and the former of which is very, very common in the United States. That happens because the amino acid deleted corresponds to three RNA base pairs being deleted, and those three are in one of the spots those tests bind to in order to identify the virus. So, it is possible that if this becomes common then those companies will have to update their test method to account for that. Doing so is not a complicated process, but it will take some time for the new reagents and updated software to disseminate throughout all labs and in the mean time error rates might go up.

Does the new variant impact existing COVID-19 therapeutics?

Unlikely. There are certain mutations – N439K and Y453F in particular – that seem to allow SARS-COV-2 to escape the neutralizing effect of certain monoclonal antibodies. In addition, the “Cluster 5” variant identified in Denmark may be able to neutralize the effect of convalescent plasma, suggesting that it might compromise the efficacy of certain vaccines. But, “Cluster 5” is not the same variant as “VUI-202012/01” and so the concerns that exist for the former don’t exist for the latter. At least, not right now.

Does the new variant impact existing COVID-19 vaccines?

Almost certainly not. While one set of mutations – the aforementioned “Cluster 5” – seems like it might be able to do that, it only shares one mutation with “VUI-202012/01” and that does not appear to have that effect. While it is possible that as the virus accumulates more and more mutations it at some point will become unrecognizable to antibodies against wild type (“normal”) SARS-COV-2, the 14 mutations accumulated so far are mostly not in the Receptor Binding Domain, and the ones that are account for only a handful of the hundreds or thousands of amino acids present there. There is a non-zero chance that they will be the amino acids that really matter, and so they will have that effect… but it isn’t very likely. More testing will have to be done to know for certain.

Behind the Snappy Name Lies a Certain Science: What VUI-202012/01 really is

To understand the answers above it’s important to understand the science about COVID-19 specifically, and molecular biological nomenclature (I know; I promise to make that easier than it sounds) generally.

First, as an RNA virus, SARS-COV-2 mutates rapidly compared to a DNA virus or to organisms we are more familiar with (cats, camels, earthworms, parrots, fleas or human beings, to name a few), but there are viruses that mutate much more rapidly than it does (Influenza and HIV, to name two). These mutations happen nearly every time that the virus replicates inside of your body, and they are nearly always “silent.” That means they have no effect on the structure or function of the virus itself. But, sometimes, they aren’t silent. Literally thousands of these non-silent mutations have been detected in SARS-COV-2 over the course of the COVID-19 pandemic (out of millions of millions of billions of billions of silent ones), and only a handful of those have any practical effect (i.e. they aren’t just the biochemical equivalent of it being blonde instead of brunette). But, tracking those non-silent mutations of potential practical significance is important… so, we actively examine a subset of COVID-19 swabs collected that generate positive results, to search for those mutations. The COGC (Coronavirus Genomics Consortium) in the UK is one body that tracks these change, and it is from them that we get these snappy names.

Next, molecular biological nomenclature. To start with, you need to understand what’s called the “central dogma” (a better name might be “first law”) of molecular biology: information is stored in DNA, is transcribed into RNA by a one-way process, and is use by turning it into a specific sequence of amino acids (like beads on a string, that then folds up to make a big plate of spaghetti) that makes up a protein. Viruses break this law. A lot of them store their genetic information as RNA, then use that RNA to either make more RNA or to make proteins, or sometimes to make DNA that is then used to make RNA that is then used to make protein. So, they are the anarchists of the tree of life in that way. That is summarized in the pic below about the central dogma, for your convenience.

So, when we are talking about a protein sequence, we are ALSO talking about an RNA sequence, and sometimes about a DNA sequence too. Thus, when changes are said to happen to a protein, what people are really observing is changes to RNA and/or DNA that affects the way the resulting protein is made. When we talk about changes to the sequence of a protein, we use a standard format: [Letter]###[Letter]. The first letter stands for the amino acid that WAS in that position, the ### is the molecular address of that position, and the second letter stands for the amino acid the IS is that position now. So, Y455P means that the Tyrosine that was on position 455 of that protein is changed to a Proline. The single letter codes of the 20 most common amino acids – and the only ones that ever occur in most organisms – are below. If an amino acid is removed- deleted – from a protein entirely, it is listed with the Greek letter delta and the position that it was deleted from: so, Δ149-150 means that the amino acid in position 149 was removed so the one in 150 moved up to accommodate in the new sequence.

With that out of the way, what are the observed mutations (specifically in the spike protein – I have omitted a few outside to simplify this post and this list)? They are:

T1001I – Threonine 1001 was changed to Isoleucine
A1708D – Alanine 1708 was changed to Aspartic Acid
I2230T – Isoleucine 2230 was changed to Threonine
Δ69-70 – The 69th amino acid residue was deleted
Δ144-145 – The Tyrosine at position 144 was deleted
N501Y – The Asparagine in position 501 was changed to Tyrosine
A570D – The Alanine in position 570 was changed to Aspartic Acid
P681H – The Proline in position 681 was changed to Histidine
T716I – The Threonine in position 716 was changed to Isoleucine
S982A – The Serine in position 982 was changed to Alanine
D1118H – The Aspartic Acid in position 1118 was changed to Histidine

What that looks like to the spike protein as a whole is shown in the picture of the Spike protein that is below.

I can hear some of you making comments right now to the effect of “But how can you say this won’t affect vaccine efficacy?!?” – we’ll get to that. But, in the mean time, lets talk about the practical effect some of these changes might have on the protein

Δ69-70 – Might help the virus evade an immune response but appears to have no effect on vaccine efficacy; also might cause a few specific COVID-19 tests to produce erroneous results (that is, false negatives)
N501Y – Increased binding affinity for the human ACE2 receptor, which could result in the virus being more contagious. This is a mutation in the Receptor Binding Domain of the Spike protein, meaning it is of particular interest.

The other changes, while non-silent and potentially significant, have effects which are not fully known at this time. Those changes might have profound implications… but they also might be a lot of sound and fury, signifying nothing.

So the million dollar question after all this, for a lot of people, is: does all this mean it is a new Strain of COVID-19? Ultimately, that depends upon how you define “strain.”

I have used “Strain” to mean a variant of a virus that exhibits a unique pattern of immunity – that is, something you would have to separately vaccinate for. Other people use the term more loosely (usually, “any variant that exhibits differences in immunogenicity, pathogenicity or contagiousness”), but given the fear that term elicits I have chosen to use a narrow definition. I do that so that when I DO call something a new strain, then hopefully people will sit up and take notice of it.

By that definition, this is almost certainly NOT a new strain of COVID-19. It is almost certain that this will have no effect on the vaccines currently being developed against COVID-19, and if it DID have an effect then it would be fairly easy to update the vaccines to account for it. If we have to do that – which we probably won’t, at least not right now – then we can do that over a long weekend some time.

Immediate and Long-term Effects – What VUI-202012/01 Means

If you are in southern England right now, then you will have a very concrete and immediate idea of “what this means.” It means that people are confined to their home except for essential activities and nonessential travel is banned in much of the UK. It means shops have closed. It means Christmas gatherings are forbidden. It means that much of the country is under “near lockdown” conditions. Technically things can get worse, but not much, as illustrated in the chart below.

But, that’s not the whole story.

What this means for the United Kingdom is not the same as what this means for countries like the United States, or what it means for the pandemic more generally. The swift and significant action taken by the UK Government is a good sign, and has a decent chance of allowing this new variant to die out without further action. If that is the case, then that means that the lockdown – which likely will also help ease any holiday bulge that would have happened in the UK – will have paid dividends both immediate and long-term to the United Kingdom. It will mean that the United States never has to face this threat. It will mean that this mutation does not have a change to mix with others – such as the D614G mutation that gained prominence this August, or the “Cluster 5” Variant that was detected in Denmark’s mink farms – and thereby has no chance to synergize with those, combining the worst of all world into a witch’s brew that could be especially dangerous to humanity as a whole. It will also mean that it doesn’t have a chance to develop new mutations, which might make it more dangerous.

See, every mutation is a potential danger. The vast majority of them are silent, and of those that are non-silent the vast majority are insignificant… but if you roll a billion-sided die five billion times, the chances are that eventually you will roll a 1.

Is the Prime Minister’s Action Justified?

In a word: yes.

It was not justified because of an immediate threat, however. This variant does not appear more deadly, and by itself it does not appear as though it would have had grave consequences on the United Kingdom. However the name of the game in public health is prevention, not response. If you act swiftly, act harshly, and act proactively to combat a threat, then you can fight it while it is small enough that you can eradicate it. It might be that this threat is still in those early stages. As was said early in the pandemic: if your reaction appears to be an overreaction, then you are doing it right.

If you don’t act in the prescribed manner, then the threat grows. If you act hesitantly or ineffectively, the threat grows. If you compromise on public health goals in order to meet other needs, the threat grows. Soon, it is too large to fix easily or completely, and you have lost control of your life for the foreseeable future. Unless, you want to risk dying every time you do anything at all out in public. Some people are comfortable with that; most, quite reasonable IMO, are not.

The Prime Minister’s action is justified on that basis, and on the hopes that the United Kingdom’s Christmas gift to the world will be stamping out this threat so that the rest of us don’t have to face it in the new year. That is their challenge right now, and I for one hope they succeed at it.