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The New Mutations

OK, time to write about the topic that’s been the talk of the coronavirus world the last day or two: the new strain that has been detected in the UK. I’ll go ahead and put the bottom line right here, and then go into the details: I’m not sounding any alarm bells, but this does bear watching. The signal/noise on this story started out rather low (as has been the case with all the breaking news during the pandemic), but it’s improved. Problem is, the most important questions aren’t going to come into any kind of solid focus for another week or two at best.

I can recommend Kai Kupferschmidt’s article here at Science for background. The short form is that earlier this month, UK authorities noticed that there was an upswing in reported SARS-CoV-2 cases in southeast England, and that sequencing was showing that these seemed to be tied to a new variant of the virus itself. (As Kai’s article notes, there’s a feature of the PCR testing that made it easier to pick this out). There have been cases in several other countries as well.

If you’re counting back to the original Wuhan type, this one has piled up 17 mutations, which is an unusually high number, for sure. Let’s take a look at those in the context of the whole virus’ sequence – below is the “Events” view from Nextstrain.org, which shows you how many reports they’ve had of mutations at particular amino acids.

Virus aficionados will know immediately what they’re looking at here, but if that diagram looks odd to you, here’s how to read it. The vertical-black-line part represents number of reported mutations in that particular three-letter “codon”, which is the unit of DNA/RNA that codes for one amino acid in the resulting protein. That tallest line, for example, represents 70 mutations that have turned up in a particular codon that codes for an amino acid in the viral ORF1a protein. You can see the associated protein by the color of the bar underneath it and its label. That bar is the whole coronavirus genome, laid out in terms of its various proteins. The (in)famous Spike protein is the third biggest, third in line: you go through the ORF1a protein, then ORF1b, and then you have S for Spike (the second green region). And you can see that there are plenty of reported mutations there – more than (say) in the ORF1b protein right before it , which is relatively quiet. So it’s not like we haven’t been seeing Spike mutations; they’re happening all the time.

Now, these lines in the chart are single changes, but as the virus rolls along, it piles mutations on top of mutations. The order that these occur in lets you put together a “tree” diagram based on the branching order in which these took place, and Nextstrain is a great place to see those in all their glory. When you look at the 17-mutation strain that’s of concern in England, several things stand out, as analyzed in this preprint. For one thing, all of these mutations are ones that lead to a different amino acid when that particular codon is read off. The three-letter code has some redundancies in it; some of the changes you can make will lead to the same amino acid in the end, but quite a few of the changes in this latest strain are real change-the-protein ones – there are 14 of those and three that lead to deletions, along with six silent ones that don’t change anything in the end. This strain is in Clade 20B on the Nextstrain charts, and there are charts here that will show you the relationships in detail.

There are three of these amino acid changes in the ORF1a and ORF1b regions, and one deletion, two deletions and six amino acid changes in the Spike protein, three more mutations in Orf8, and two changes in the nucleotide (N) protein. Three of the Spike region mutations have been already described as having significance for its function: the N501Y is on the of the key receptor-binding-domain amino acids at the very tip of the Spike, the part that contacts the human ACE2 protein. (Here are some new data that should make us a bit happier, though: this mutation does not seem to be associated with loss of neutralization when exposed to human antibodies) One of the deletions (69-70del) has shown up several times in other SARS-CoV-2 sequences (including a mink-related outbreak in Denmark), and is speculated to be involved in evading immune response (to some degree). And the P681H is right next to the “furin cleavage” site, which is known to be key for the process of virus going on to enter human cells.

According to that paper last linked above, this list suggests some real selection pressure is at work here, not just random mutational drift and wandering. As mentioned, several of these have shown up independently in the past, but this combination of them is new. The authors speculate that these multiple changes might have occurred, at least some of them, in an individual with long-term infection, where the virus had a chance to deal with the human immune system for an extended period. It’s a plausible idea, because something different had to happen to allow so many mutations to pile up more or less at once, but it remains unproven. It should be noted that not all of the mutations seen in this strain are known to be trouble: there’s a stop codon mutation in ORF8, and something like it was seen earlier in Singapore in a branch of SARS-CoV-2 that later died out thanks to that country’s stringent control measures. It seemed to be associated with milder infection, though its significance when combined with these other mutations in unknown. But as the Kupferschmidt article details, there are still a lot of explanations in play. The increase of this strain in the UK could certainly be down to higher infectiousness, but we’ve thought that about other strains in the past, and it hasn’t panned out. It’s in the “remains to be seen” category, because the vagaries of person-to-person transmission (and the vagaries of human movement!) can produce apparent patterns that aren’t what they appear to be.

I should note here that there’s another strain in South Africa that is bringing on similar concerns. This one has eight mutations in the Spike protein, with three of them (K417N, E484K and N501Y) that may have some functional role. You’ll note the N501Y is also in the UK strain, but the E484K is one that people are particularly watching, because that’s in a region that a number of antibodies seem to recognize. The South African one also seems to be moving up when you look at population sequencing data, suggesting that it might also be more transmissible.

But remember, antibody response (whether through infection or through getting vaccinated) is polyclonal: you raise a number of different antibodies that bind in different ways. That’s one of the key features of the adaptive immune system: hitting a new antigen from a number of directions at once. This makes it harder to slip through for a new pathogen variant – which is good, but at the same time, it’s not impossible, either. Thus the attention being paid to these two new strains.

That leads us to the other big factor that people are worried about: increased transmissibility is not good, of course, but what happens after you’ve been infected? Do these strains produce the same sort of disease in humans? This is completely unclear at this point – so far, no one is associating either of these variants with a notably worse clinical course of disease, though. Many infectious pathogens, in fact, gradually evolve versus a given animal host to be more infectious and less virulent over time. Remember, it’s not the job of a virus to make people deathly ill: it’s the job of a virus to make more virus. Overall, that is generally better served by strains that are easier to catch and that don’t rip into their hosts too viciously. But this is a big-picture statistical effect, and not necessarily at work in any given strain that emerges. There could be a new strain that is both more infectious and more harmful once caught, and we have to keep our guard up against such a thing. Even a more transmissible virus that produces the same level of illness would be (of course) a very bad thing.

So I think the amount of scientific attention being paid to these new strains is completely appropriate. The popular press might be another story. It’s important to remember that (as mentioned) we haven’t even established for sure that these strains are in fact more infectious, and that we don’t know a thing yet for sure about what effect they have in humans compared to the other variants. So if you see any headlines about Relentless March of the Supervirus, go read something else, because that stuff is (fortunately) way out ahead of the facts on the ground. These are by no means the last variants like these that we’re going to be seeing, and we need to learn how to cover them in a responsible way.

So what’s coming next, and when we will know more? We will have animal-model data coming soon to tell us something about infectiousness, and there are already studies underway using human antibody mixtures (from infected patients and vaccinated ones) to see if these new strains are any less susceptible to our immune response. This will be a matter of weeks; I wouldn’t expect to see any clarity before then. And that’s also at least the time scale we would need to start confirming the clinical effects in the human population – you can be sure that medical centers around the world will be monitoring patients who have been confirmed with these variants to see if there are any differences. We’ll also want to know how these look in different age cohorts, in people with pre-existing conditions, and so on, but all of this will take irreducible amounts of time to get a meaningful picture.

My speculations are worth what you’re paying for them. But I think that odds are reasonable that UK strain, based on what we’re seeing so far, may well be more infectious than the existing ones. I hope I’m wrong about that, and I want to re-emphasize that I very well could be. At the same murky level of clarity, I’m not seeing anything so far that makes me think that it causes a worse form of the disease, and I very much hope that I’m not wrong about that. As for vaccine effects, my money is on the antibody response from the vaccines still being protective – and that’s going to be some of the first hard data that we get, because those are some of the most straightforward experiments to run. Updates as we get them.

205 comments on “The New Mutations”

  1. Chris Swain says:

    “We now have high confidence that this variant does have a transmission advantage over other virus variants that are currently in the U.K.,” Peter Horby, an infectious disease expert at the University of Oxford, said Monday, upgrading his assessment from last week of “moderate” confidence. The variant is continuing to overtake other forms of SARS-2 in the country, scientists said. https://www.statnews.com/2020/12/21/looming-questions-new-variant-coronavirus/

  2. Luysii says:

    ” The three-letter code has some redundancies in it; some of the changes you can make will lead to the same amino acid in the end, but quite a few of the changes in this latest strain are real change-the-protein ones – there are 14 of those and three that lead to deletions, along with six silent ones that don’t change anything in the end.”

    14 + 3 = 17 but 14 + 3 + 6 = 23.

    There is an inherent redundancy in the genetic code. We have 20 amino acids coded for by 3 consecutive positions in the genome (the triplet) each of which can be one of 4 things giving 4^3 = 64 possibilities. There are also 3 combinations which tell the ribosome to stop, so there is an inherent 3 fold redundancy in the genetic code. Some amino acids have 6 codons for them others fewer.

    The fact that 14/17 code for a different amino acid given the 3 fold over all redundancy of the genetic code all implies that at least some of the 14 have been selected for. Random mutation is very unlikely to produce this.

    1. luysii says:

      Even if you count the total number of mutations as 23, that 14 of them are nonSynonymous is unexpected. Given purely random mutations one would expect about 1/3 (e.g. 7 – 8) to be nonSynonymous, so this is still pretty good evidence of selection.

      It’s worth looking at the NextStrain map for positions in the genome in which mutations have NOT shown up. They are probably lethal to the virus and should point to juicy drug targets. With a mutable virus like this, we should be looking at further ways to attack it after it penetrates our cells.

    2. Kevin says:

      There’s also some ‘redundancy’ in amino acid replacement. It’s more fuzzy of course, but in many cases the replacement of, say, Glutamine by Asparagine (just one more CH2 group on the sidechain), or Aspartic acid by Glutamic acid (similarly) leads to effectively no change on most occasions (it’s true that this might not be the case right in the active site of an enzyme, but more generally).

      1. luysii says:

        The cell can be incredibly subtle in codon usage, even for synonymous ones. Here is a horrible example — Werdnig Hoffmann disease, in which a change of one synonymous codon to another results in changes in splicing of a gene, with disastrous results.

        https://luysii.wordpress.com/2011/05/03/the-death-of-the-synonymous-codon/

        1. Kevin says:

          Indeed, great link and is which is why I applied caveats – if you’re shoving an extra CH2 into a tight spot then it can make all the difference. But on many (maybe most) proteins you can make substantial changes with no significant biological effect over 80 or 90% of the sequence, even to the degree of chopping out or inserting large sections of alpha-helix – most of it is there just to fold up the chain in such a way that the relatively small area that is the active site is shaped correctly. If you think about it this has to be true as otherwise biology would be so constrained that evolution would look very different.

          1. luysii says:

            Kevin: Oh yes. Some Japanese workers designed proteins stable at 100 C — a designed protein with a Rossmann fold (two pairs of alpha helices sandwiching a beta sheet. Then they mutated 10 of the large hydrophobic amino acids (leucine, isoleucine) in the core to a smaller one (valine) so that 30 of the 34 amino acids in the core were valine. My guess would be that the protein collapsed as the hydrophobic core was smaller. However, basically nothing happened. Here’s the paper Proc. Natl. Acad. Sci. vol. 117 pp. 31149 – 31156 ’20

          2. The eyebrows of some “virus aficionados” are raising. They know that SARS-CoV-2 mutations “having significance for its function” can be more than just the “real change-the-protein ones,” referred to here. We should not dismiss “silent ones that don’t change anything in the end.” They can change function a great deal in the end! There are sites in the genome that are not concerned with protein-encoding. Rather they are concerned with regulation of the expression of proteins and other functions (e.g. recombination) and many can powerfully influence the higher ordered structures the virus can adopt. That there is likely to be “real selection pressure is at work” is suggested by the high conservation of extra-genic and intra-genic regions that are rich in such structure potential. So, yes, there are “a lot of explanations in play”! Yes, we should be hopeful regarding vaccines directed at proteins, but a search is also on for agents that can influence possible viral genome structural Achilles heels.

        2. Oudeis says:

          Wow. I did not not know about that. Thanks for linking.

        3. Timothy D Chase says:

          Rate of translation is known to be affected by choice of synonymous codons, and this can easily affect protein folding:

          Ian M. Walsh, Micayla A. Bowman, Iker F. Soto Santarriaga, Anabel Rodriguez, Patricia L. Clark. Synonymous codon substitutions perturb cotranslational protein folding in vivo and impair cell fitness. Proceedings of the National Academy of Sciences, 2020; 117 (7): 3528 DOI: 10.1073/pnas.1907126117

          https://www.pnas.org/content/117/7/3528

          1. Marko says:

            Indeed, and protein folding can influence epitope display, among other things. Add on epistasis effects, where interactions between multiple mutations (including the “silent” ones) may occur, and the potential for the sudden appearance of an immune escape phenotype is something we have to be concerned about.

            I think many in the scientific community are being awfully cavalier when they point to studies showing that various panels of known mutations have little or no effect on recognition by MAbs or antibodies in convalescent plasma. Show me those same studies that evaluate the combo mutants like we’re seeing in the UK and S. Africa , as a combo , not individually.

            A perfect example of how just a few mutations can make a big difference is staring us in the face in our vaccine technology. Simply replacing two other amino acids with proline and deleting a few arginine residues results in the difference between a pre- and post-fusion spike protein conformation, which is a huge structural transformation. That transformation translates into the difference between a vaccine that confers sterilizing immunity in animal models and one that does not. A few small changes, in the right combination, can make a big difference, for good or for ill.

          2. Luysii says:

            Timothy: It’s exactly how cells make more beta actin than gamma actin

            Actin contains 375 amino acids, beta and gamma actins differ only at 4 of them, all near the amino terminus of the protein. Even the differences aren’t chemically that great –the second amino acid from the amino terminal end of beta actin is aspartic acid, while in gamma actin it’s glutamic acid. Big deal. The other 3 amino acid differences are equally trivial (to the chemist at least). Recall that proteins are synthesized in the ribosome starting with the amino terminal amino acid, adding the next successively. So as a protein is being made, the amino terminal amino acid remains the same, while the carboxy terminal amino acid changes every time a new one is added.

            The beta and gamma actin genes contain different synonymous codons for all but 4 of the amino terminal amino acids (which actually vary between beta and gamma actin). It appears that the choice of codons for gamma actin results in slower synthesis of the protein by the ribosome. Perhaps there is less tRNA or tRNA synthetase around for the codons used by the gamma actin gene. The papers this is taken from don’t say [ Science vol. 329 pp. 1473 – 1474, 1534 – 1537 ’10 ]. The slower synthesis of gamma actin results in exposure of a lysine at codon #18, which is then modified (ubiquitinated) leading to it’s destruction.

            The authors prove this by switching the ‘synonymous’ codons of gamma actin for those of beta actin, and vice versa. What do you think happens?

            After the switch, cells contain more gamma actin than beta actin. So synonymous codons are far from synonymous. This also shows the exquisite forms of biochemical control (and subtlety) found in the cell.

            For details see — https://luysii.wordpress.com/2011/05/09/the-death-of-the-synonymous-codon-ii/

            It’s a triumph of chemical reductionism.

            But it isn’t, because it is only HOW the cell produces more beta than gamma actin, but not WHY the cell would ‘want’ such a thing, which is the other side of the Cartesian dichotomy between flesh and spirit.

  3. Bob Lacatena says:

    Bad link at “as analyzed in this preprint”.

  4. Matt Gruner (not a virologist) says:

    A significant component of this viruses spread seems to involve super-spreaders who infect far more individuals than most. Another way to look at a super-spreader is as an evolutionary bottle neck. Whatever variant succeeds in that host will get spread to a lot more people. Even if most of its allelic variation has no impact on the phenotype ie neutral mutations. You can’t assume a new variant does something different just because its becoming more abundant in a given area. Bench work is critical here to do controlled experiments that can tell us if the virus has changed its cell molecular behavior as well. The animal models are great but a plaque assay would take a couple days and I can’t find this kind of data anywhere.

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    2. Nile says:

      In a given area, one super-spreader can make a significant difference; and your one, single, sample may have an entirely insignificant mutation that looks as if it originated in or close to that individual.

      However, displacing other strains of the virus, over a larger geographical area than the ‘reach’ of a handful of ‘super-spreaders’, points strongly towards a strain with increased transmissibility.

      The evidence is now pointing in that direction.

  5. Daniel says:

    According to some of the members of NERVTAG (New Emerging Respiratory Viral Threats Action Group, the UK governments’ main advisors on these kind of diseases), the mechanism through which the virus is more transmissible is that it may infect children more easily.

    https://www.bbc.co.uk/news/uk-55406939

  6. Jack says:

    Isn’t the quickest way to help solve this problem to track if people are getting re-infected?

    1. Marko says:

      If the variant is more transmissible , it’s still a problem even if it doesn’t have any additional capacity for reinfection. It is important to look for reinfections by this variant, of course, as we want to be on the lookout for any immune escape mutations.

      It is the case, though, that one of the mechanisms by which you might see an apparent transmissibility increase is if the pool of susceptible individuals expands due to an immune escape mutation. It should be easy enough to sort this out over time by comparing the rate of spread of the variant in areas with high levels of seropositivity vs areas with low levels.

      1. Stroodle says:

        This was my immediate concern, especially given that London had increasing cases prior to the end of the second lockdown, alongside an already high number infected in the first wave (17% by the end of May alone). Of course, lack of compliance is a factor, and I’m not aware of any anecdotal reports of reinfection. It doesn’t seem to change too much given the current rollout of the vaccine, however I must say it’s pretty grim in London right now with the knowledge that we need to keep put until then.

        1. Marko says:

          I can imagine a scenario where the reinfection story constitutes the entire story regarding “increased transmissibility”.

          Imagine a case where the affected areas currently have 1/3 of the population previously-infected and 2/3 never infected. Now, the previously infected were largely in groups that were at high risk of becoming infected, whether because of their jobs, bar-hopping behaviors, whatever. That’s largely why they were infected in the first place. Add on top of that the fact that with knowledge of their previous infection, they may engage in even more risky behavior than before, believing they’re holders of “immunity passports”. Combine all this and assume that they have a tendency to expose themselves to infected people at 2x the rate of the never-infected, creating an equivalent infection probability between previously-infected vs noninfected ( 2 x 1/3=2/3 ). In this scenario , an immune escape phenotype would be all that was needed to explain the apparent increased transmissibility that has been observed.

          I don’t really expect this to be the outcome, but it wouldn’t surprise me if reinfections turn out to be an important part of what’s going on.

          1. Keith says:

            If the variant evolved in an immunocompromised patient who was treated with convalescent plasma, then the selection pressure was more towards immune escape than increased transmission. That could make it more likely three mechanism you outline is driving the increased R.

          2. Marko says:

            Yes, that was the possibility I was describing, but it seems unlikely based on the figures revealed by Chris Phillips just below. If less than .5% of the new variant cases are appearing in the previously-infected population, they can’t contribute very much to an estimated transmission rate increase of >50% attributed to the new variant.

    2. Chris Phillips says:

      On reinfection, the NERVTAG summary document says:
      “Four probable reinfections have been identified amongst 915 subjects with this variant but further work is needed to compare this reinfection rate with comparable data sets.”
      https://khub.net/documents/135939561/338928724/SARS-CoV-2+variant+under+investigation%2C+meeting+minutes.pdf/962e866b-161f-2fd5-1030-32b6ab467896?t=1608470511452

      1. Marko says:

        Ah, thanks, I missed that. I guess that reinfections are not likely to be a big factor, unless one or more of those few reinfections provided the environment for evolution, and then spread, of the variant. The paper that gave me the feeling that reinfections might play a role was the one where the immunocompromised patient with a long-running infection showed two rapid rises and falls in prevalence of the 69-70del plus one other mutation that corresponded to two treatments with convalescent plasma.

        I take it that when they say “probable” it means they don’t have the sequence data on the first infection to allow them to say with certainty that all four cases are “confirmed” reinfections.

        1. Chris Phillips says:

          Like a lot of the other things in that summary, it’s difficult to know what “probable” might mean. But I would guess that well over 20% of the population of London has been infected with COVID-19 by this time (though many of them may not know it), so it seems a pretty low figure for reinfections.

          1. Adrian says:

            Estimating based on deaths (around 10k in London) with a CFR between 0.5% and 1% gives an estimate that between 10% and 20% of the population of London have been infected so far.

          2. Chris Phillips says:

            That seems like an underestimate to me. Excess deaths for the UK are now 80k, which is 0.12% of the population. And according to antibody testing London is 50% higher than the figure for England as a whole. On that basis you’d get to 18% for London even using an infection fatality rate of 1%, but I think 0.5% will be closer to the mark.

          3. Adrian says:

            Your excess death number matches the 80k with COVID-19 on the death certificate, this means there is no significant number of hidden COVID-19 deaths in the UK.

            You are making a mistake when mixing antibody testing data for earlier phases of the pandemic with death figures dominated by recent developments.

            Since the new variant was spreading quickly in and around Kent in recent months, London might actually have had below-average numbers during that time.

            Looking at deaths for the whole pandemic so far, London was not hit harder by COVID-19 than the UK on average.

          4. Chris Phillips says:

            Adrian

            No – the antibody figures have been higher for London throughout. Nor are the death figures dominated by recent events. I don’t know where your 10k death figure from London came from, but obviously a lower death rate in combination with a higher infection rate in London means that the infection fatality rate was lower for London.

          5. Adrian says:

            Chris, antibody tests show the situation of all infections up to one point in the past.
            What exactly are the studies you are basing your theories on?
            When did they collect antibodies?
            How much delay is there before an infection is visible in antibody tests?

            One third of all COVID-19 deaths in the UK so far were after October, an antibody study that collected antibodies in November might not have data for the latest one third of all infections in the UK.

            10k deaths for London is based on the official numbers:
            https://data.london.gov.uk/dataset/coronavirus–covid-19–deaths
            Based on your excess death number the official statistics should be accurate on COVID-19 deaths, without hidden deaths outside the statistics.

            One constant of this pandemic is that claims like your “the infection fatality rate was lower for London” have always turned out to be wrong.
            When a government succeeds in protecting vulnerable people the fatality rate ends up being 0.5%.
            If COVID-19 also enters retirement homes you end up with 1%.

            Based on death numbers, 10% of the population of London infected so far is a more realistic estimate.
            But if some estimates of 2% of the population of London currently infected turn out to be true, we might be only one month and 10k deaths in London away from your 20% estimate…

          6. Chris Phillips says:

            Adrian

            I’m quoting figures from the ONS for antibody testing. They give percentages both for England and the regions. The percentage for London has been much higher than that for England for months. I just checked back to August, and December is the first time it has been less than 50% higher (at 47%).

            If you think the infection rate has really been lower in London than for England as a whole, you need to explain why the rate of positive antibody tests has been consistently much higher.

          7. Adrian says:

            Chris, the latest published ONS data is based on antibody results from November.

            If you would bother to read what I wrote, you would understand why at least a third of all COVID-19 infections in the UK so far are not yet visible in antibody results collected last month and published this month.

            Death rates are more up-to-date, according to them London did have only slightly more infections than the UK as a whole.

            And your attempt to explain the latter by claiming that London had a much lower death rate than the rest of the UK cannot be taken seriously, such a hugely surprising result would have had a lot of publicity already.

          8. Chris Phillips says:

            Adrian

            I won’t pursue this further. Rest assured, I have read your comments carefully, but I am not persuaded by them. All things considered, I still think the estimate of 20% already infected in London is a conservative one. Of course there is uncertainty, but we have to take all the data into account and make the best sense we can of them.

          9. Adrian says:

            Latest antibody data from the ONS for London is closer to 10% than to your very high guesses, and back in November the Southern and Eastern parts of England had the lowest antibody numbers – since these are now the most affected areas it would be plausible that this had moved London closer to the national average before the latest explosion of case numbers.

          10. Chris Phillips says:

            Adrian

            As I said, I won’t pursue the discussion further, but in case anyone is misled by your comments, I’ll just point out that the percentage of people now testing positive for antibodies certainly can’t be taken as an accurate estimate of the percentage who have been infected with the coronavirus as much as 9 months ago.

            If only we knew what fraction that represented, we would have the answers to a lot of the pressing questions that face us.

  7. Juan Nadie says:

    I was told that, fortunately, those are not new strains, just new variants.

    As for the apparent increase on transmissibility, speaking as a Maths & Statistics guy, there are mundane mechanisms that could explain it, although I agree that this does bear watching, and Britain’s virologists (as Denmark’s) are watching intensily, which could have something to do with the apparent absence of such alarming events elsewhere. I mean: if for *whatever* reason, a new strain becomes popular, they will notice. Ahem.

  8. sgcox says:

    Unless I am missing something, this particular lineage is missing the infamous D614G mutation. This is very odd as it was presumed (many, many papers and discussed here) that D614G becomes the absolutely dominant strain in UK and the rest of Europe as earlier as April or May.
    So how B.1.1.7 evolved if it lacks D614G ? Could it be indeed imported from other part of world where “wt” is still prevalent and catch up very fast in London ?

    1. Marko says:

      “So how B.1.1.7 evolved if it lacks D614G ?”

      You may have answered your own question – it evolved. The fitness of the new lineage may be higher in the absence of D614G than in its presence.

      What we do know is that if the transmissibilty of the new variant is indeed higher than other circulating lineages, it’s also higher than that of D614G, which displaced D614 globally because of greater transmissibility.

    2. Marko says:

      I gather from this Public Health England document that D614G is present in the new variant :

      https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/947048/Technical_Briefing_VOC_SH_NJL2_SH2.pdf

      “…Much less is known about the other spike variants present in this cluster, with the
      exception of D614G which is well characterised and already highly prevalent in the UK….”

      1. sgcox says:

        The document is a bit muddled here. As I read it, D614G is present in Kent cluster of Covid cases among other variants and get progressively squeezed out by B1.1.7 which lacks D614G and thus of different origin. Unless of course it somehow muted back to D… Fascinating science if it was not so deadly.

        1. Marko says:

          Try this one :

          ” The new variant is defined by multiple spike protein mutations (deletion 69-70, deletion 144, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H) present as well as mutations in other genomic regions. ”

          https://www.ecdc.europa.eu/sites/default/files/documents/SARS-CoV-2-variant-multiple-spike-protein-mutations-United-Kingdom.pdf

          1. luysii says:

            Marko: The fact that none of the changes mentioned are contiguous implies separate acts of mutation with subsequent selection.

          2. Marko says:

            Agreed. I’d just clarify that the presence of D614G suggests a greater likelihood that the new lineage arose from an existing, D614G precursor lineage rather than some far-off and less-common D614 lineage.

  9. Jpo234 says:

    About vaccine escape: As I understand it, it will be straightforward to add a new version of the spike protein to the authorized RNA vaccines. Would such a change be covered by the current EUA or would a modification require completely new clinical trials?

    1. Klagenfurt says:

      Uh, sorry, but it’d need new clinical trials for sure. You can’t assume safety and efficacy.

      1. Igor says:

        Serious Q: do we do new clinical trials for each year’s flu vaccine?

        1. Clindevtea says:

          No because of how it is made, and because it isn’t a targeting therapeutic, it is inherently safe. The risk there is just the lack of efficacy if you pick the wrong H_N_ combo.

          To the note above, yes you would need new trial for mRNA vaccines. The wrong sequence could cause toxicities in people. The best analogy would be testing a new antibody in oncology.

          1. Kamil says:

            It is of course only an n ~ 1 experiment, but given the success of almost every vaccine candidate trialed so far in phase III, this does at least suggest that this conservative regulatory climate has inflicted great harm on society. We need to discuss more aggressive conditional approval with an open mind. I do not know the answer, but it is worth thinking about.

      2. jpo234 says:

        Safety I understand, but efficacy wouldn’t be worse, would it? The vaccine would still protect against the original variant.
        The trials for the current vaccines took months, because the companies had to wait until enough people got sick to establish efficacy. Would we have to wait months again to establish just safety?

      3. FrankN says:

        My understanding is that regulators (or at least the EMA, not sure about the FDA) discern between a “vaccination platform” and a “vaccine”. Altering the former requires a new cycle of clinical trials. For the latter, the only thing needed is some proof of efficacy, which, at least for flu vaccines, may be delivered by lab studies demonstrating adequate stimulation of antibody production.

        Since mRNA vaccines are novel, the line between “vaccination platform” and “vaccine” hasn’t been drawn for them yet. However, I assume it may eventually be drawn alongside the declaration of ingredients. I.e., if anything related to the nanolipid formulation is changed, it means an alteration of the “vaccination platform”. If, OTOH, just the “mRNA extracted from SARS-CoV2” is being varied, we stay inside “new vaccine based on authorized platform” territory.

  10. theasdgamer says:

    Old business

    “Chloroquine is a diprotic weak base (pKa1 = 8.1, pKa2 = 10.2 at 37°C) that can exist in both protonated and unprotonated forms (Figure 2 and Table 2). Unprotonated chloroquine can diffuse freely and rapidly across the membranes of cells and organelles to acidic cytoplasmic vesicles”

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537707/

  11. Calvin says:

    If you want to watch some in depth science presentations on all the genomic work that is being done by COG UK to track these variants check out https://www.youtube.com/watch?v=G3CT9N89L-c

    Barrett and Robertson talk are particularly interesting. Robertson has some susceptibility data and some lovely slides.

    The UK is miles ahead (for once) on this stuff having invested a lot in this over the last decade in particular.

    I must admit that given the sheer number of people getting this it’s inevitable that we’ll see some vaccine escape at some point unless we can get the numbers down. There’s just too much opportunity to for it to evolve, although on the plus side SARS CoV2 does appear to be fairly stable compared to other viruses. So we could get lucky.

  12. Jason P says:

    I kinda wish mamilianscaleupperson was still around and could provide us with some insight as to the length of time it takes to make these vaccines. I know the chemists are taking their victory lap as their job is done and its up to the engineers and logistics people to get this stuff made and out there. But what is the process? How long does it take? How long till we make and distribute 600+ Million does in the USA? Thought there was pre-manufacturing at risk and a bunch of contract production going on?

    1. Frank Richards and RHB says:

      We’ve already said our party pieces elsewhere, being aware we’re nowadays generally in a minority of two rolled into one in these parts hereabouts:

      https://blogs.sciencemag.org/pipeline/archives/2020/12/10/the-latest-on-coronavirus-mutations

      22 December, 2020 at 4:21 am
      22 December, 2020 at 9:28 am
      22 December, 2020 at 12:37 pm
      21 December, 2020 at 6:07 am

      …Been a long year. Frank says highlight by country mile buried in preceding links is Led Id Growwww:

      https://www.youtube.com/watch?v=YIP961nxobQ

      And Frank says as well, might be time fast comin’ long time stayin’ for a blast from The Nobel Laureate, digitality low, fidelity high…

      https://www.youtube.com/watch?v=e7qQ6_RV4VQ

      And Frank also says, here it is Merry Christmas Everyone, look to the future ‘cos it’s only just begun…

      https://www.youtube.com/watch?v=0A8KT365wlA

      And last but not least, Frank says, God speed Pipeline and all who sail on her, thank you as ever O Captain! my Captain! For Taking the Helm and Steering the Ship. Choppy waters but as little to waters our fathers, grandfathers, great grandfathers, and maybe even an occasional great great grandfather, once upon a time sailed eastward or westward upon. Blow The Wind Southerly.

      1. 이웅견 says:

        A big thank you again to Derek and the reasonable majority of commenters.
        I learned a lot not only from the articles but also the comments, and that’s rare for such public venues.

        Good food and music are among NPIs to keep our mood up and find energy.
        As there is no internet protocol to share *edible* cookies, I will send music instead.

        https://www.youtube.com/watch?v=YwgF3Gylu-0
        https://www.youtube.com/watch?v=C6iHh4yBxCo
        One for Christmas, one for every day. The lady singing is a cancer survivor whose goal is “to use her voice to comfort people who are going through difficult times”.

        https://www.youtube.com/watch?v=1T2gj850zPg
        This one is for the new year. A kind of interdisciplinary work.

  13. Jeff Winsley says:

    ‘UK strain’ seems a bit unfair considering it’s not clear if actually originated in the UK. The UK does 40% of all the genomic sequencing in the world. Perhaps this is akin to calling the cause of the 1918 pandemic the Spanish flu.

    1. dearieme says:

      If its British career really started in Kent, as the newspapers say, I guess that it came in from the Continent.

      Anyway, President Micron’s hysterical reaction suggests that the next time the British researchers find a new variant they should maintain silence,

  14. Carlos Pirez says:

    Sorry to change topics here. But as a concerned Brazilian with the prospect of having SinoVac as the primary vaccine available, there are some concerns as to why SinoVac is not being widely distributed (and prioritized) in China to Chinese citizens. Is this a sign that they rejected it? It seems rather odd. I know other vaccines are also in development but SinoVac seems to have the most data behind it. Yet, reports are saying that only a very small number of people in China are receiving it. One would imagine that there would be a great deal of pressure to prioritize Chinese citizens so the country can open back up. Thanks for any information/insight folks may have.

    1. Adrian says:

      I doubt it is the highest priority for the Chinese government to make that effort on a population of 1.4 billion people just for letting foreigners back into their country.

      China has nearly zero cases now, they have no need to hurry to vaccinate people except those who travel abroad.

      Manufacturing and distributing vaccine for more than a billion people would be a huge challenge, and we do not even know yet for how long immunity would last.

      The urgency exists only in countries where people are currently dying from COVID-19.

      1. stewart says:

        In absolute numbers China and the USA are neck and neck for the number of vaccinations performed.

      2. 이웅견 says:

        Well, China *does* hurry in trying to get 50 million people (high risk + essential personnel) vaccinated before Feb 12, when hundreds of million of people are expected to go on the Chinese New Year trip home, which was a superspreader last year, despite the authorities trying to dissuade people from making it. Now they’re just waiting for the vaccines to get official approval, expected in January.
        But as you rightly said, foreigners are no variable in these plans:-)

  15. Paul Hurley says:

    Is there any evidence of how these mutations affect the current methods of testing, either PCR or Lateral Flow Tests ? I’ve seen some reports that the reason we have so much information about the new variant in the UK is that it does not detect one of the three COVID-19 probes in the PCR test, but does still show on the other two so still gives a positive test. Would the variant also impact the lateral flow test ?

    1. So far, no, at least for antigen LFTs in the later stages of evaluation in the UK. All I believe are N protein-specific, so perhaps no surprise.
      https://www.gov.uk/government/publications/sars-cov-2-lateral-flow-antigen-tests-evaluation-of-vui-20201201/sars-cov-2-lateral-flow-antigen-tests-evaluation-of-vui-20201201

  16. Uncle Steve says:

    As I understand it, the ‘new variant’ has been around since September. And Spring COVID took a month or so to spread through the whole country. If the ‘new variant’ really were ‘70% more transmissible’, wouldn’t it have spread throughout the country weeks ago?

    1. Uncle Rob says:

      Good question, Uncle Steve – Far too sensible for SAGE, NERVTAG and rest of advisery caboodle to think of…

    2. Adrian says:

      You miss that only 70% increase in being transmissible might not even have been enough to compensate for the less welcoming atmosphere compared to spring.

      Wikipedia says:
      ‘On 8 September, the government published new social distancing rules to come into effect in England from 14 September, wherein all gatherings of separate households would be restricted to groups of six or few people (the so-called “rule of six”), excluding work or educational settings.’

      1. stewart says:

        Additionally, in spring, the epidemic was jumpstarted by multiple (several hundred?) under the radar imported cases. With exponential growth the growth from the new strain’s index case to the equivalent of the start of epidemic in the spring would take several weeks.

  17. Paulo Albuquerque Daros says:

    If this level of mutation indicates someone who had COVID-19 for a long time, then this person could be a very important super-spreader. This could explain the high incidence.

    1. J N says:

      I’m intrigued by the “Chinese miner” hypothesis that the virus became so well adapted by incubating and evolving in one or more human hosts while they were hospitalized for an extended period of time.

      One way or another, it’s a heck of an effective “bat virus.”

  18. SanDiegoSean says:

    Derek, I’ve had the pleasure to meet you a few times at drug discovery conferences and I wanted to thank you for all the informative and balanced posts you’ve made during the Covid pandemic. As Medicinal Chemists, we all want to make a positive impact on the world, and you’ve done more than most in the past year! THANK YOU!

  19. stewart says:

    I expect that someone else has already thought of this, but I suggest that when vaccinated people develop COVID-19 disease (at a point when they’re expected to be protected) that the virus be sequenced, so we can tell whether virus strains in that population differ from those in the general population, as a means for monitoring for viral escape from immunity (whether mediated by vaccination or infection by other strains).

    1. Marko says:

      In any population of any species, there’s a replacement rate below which that species will disappear. You either reproduce sufficiently, or your species becomes a historical artifact.

      For CoV-2 (or a particular variant) in an infected person, if that person doesn’t infect at least one other, it would eventually die off, because each infected person is a dead end. Once infected, you’re free of enough viable, infectious virus to infect someone else within 5-10 days or so. So you must infect at least one other person within that period to maintain viability, any less and your virus is finished. This is the famous R<1.0 that almost all governments strive to achieve and maintain (often unsuccessfully) until they're saved by vaccines.

      What happens when you get a new, more infectious variant circulating is that the measures that are then ramped-up to get the overall R to even somewhere close to 1.0 are enough to drive the effective R for the old lineage to less than 1. It falls below its replacement rate and , eventually, disappears.

      In the real world, the old lineages do tend to stick around, somewhere, at some level, for longer than a model might predict , simply because the world is a big place and everything is not happening everywhere at the same time and in the same way.

  20. Iain Flynn says:

    I have a question for the people here who are clearly knowledgeable (from a non-expert sitting alone in locked-down London): how does the one more successful mutant version of the virus edge out others? I get completely the ways in which mutations through selection can create versions which are more infectious, but once it emerges, why do previous less infectious versions disappear (if indeed they do)? I understand fully (I think) that this all taking place at the level of individual virions and their replicants, but by what exact mechanism do the superseded versions of the virus disappear? If they do.

    1. Marko says:

      See just above. I screwed up and hit the wrong reply button.

  21. Larry F says:

    Q: The Modern and Pfizer RNA sequences used for their vaccines. Are they based on the current, predominate G-strain group (which subtype) now circulating as described in the Dec 10 Reuters article & latest Nexstrain maps? Do we need CV lineage maps specific for just the Spike protein sequence to properly track RNA vaccine effectiveness?

  22. Marko says:

    Bill Hanage thread about a new preprint – “Estimated transmissibility and severity
    of novel SARS-CoV-2 Variant of Concern 202012/01 in England” :

    https://twitter.com/BillHanage/status/1341857733633581063

    Bottom line : “increased transmissibility” model better fits the data than “immune escape” or other models.

  23. Blaine White, M.D. says:

    The report on the SARS-CoV-2 multiple mutation variant stated, ”The new variant is defined by multiple spike protein mutations (deletion 69-70, deletion 144, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H) present as well as mutations in other genomic regions.”

    In terms of potential viral immune escape attributable to these mutations, I was interested to compare the mutations to the sites on Spike most frequently bound by patients’ antibodies (Shrock et al. Science 2020; DOI: 10.1126/science.abd4250). Patients’ antibodies have relatively modest frequency of affinity for the Receptor Binding Domain in S:406-520. More frequent antibody footprints were identified in 3 areas –
    S 551-570
    S 766-835
    S 1144-1163
    I note 79% of patients had antibodies against the S:811-830 epitope. However, among the variant virus Spike mutations, only A570D is involved in one of these antibody antigenic epitopes, and that only at the very end of the epitope. It would be interesting to have a similar examination of these mutations against known antigenic epitopes recognized by patients’ T-cells, although those are much more diverse (Grifoni A et al. Cell 2020; https://doi.org/10.1016/j.cell.2020.05.015.) than the predominant humoral immune response against just S and N.

    Of course the variant mutations could alter Spike folding to hide the antigenic epitopes, but the lack of mutations in the dominant antibody antigenic epitopes suggests these mutations are unlikely to provide major resistance to humoral immunity against Spike. That may account for the very low rate of reinfection (0.5%) by the variant. The vaccines against full-length Spike are likely to remain effective against this variant, and the basis of mutational selection may be in viral functions other than resisting adaptive immunity.

    1. steve says:

      Very nice analysis

    2. DataWatcher says:

      Right now, I think the most worrisome aspect is not the possibility of the vaccine being stymied by immune escape, which seems unlikely — it’s the prospect of the rate of transmission becoming so high that no vaccine, even if t’s upwards of 94% efficacious, can keep up with it. Will each new mutation now result in a near-exponential spike in R0? That’s enough to sabotage every positive scientific development we have seen over the past nine or ten months. We could be playing “vaccine catch-up” well-nigh forever.

      It was just about this time last year that COVID first became known. It’s almost diabolically perfect timing: Are we seeing the beginning of a rerun? Was that “light at the end of the tunnel” merely a projector getting ready to screen “COVID Groundhog Day: The Story Continues” for the foreseeable future?

  24. Irene says:

    The popular press has widely reported that this mutation is up to 70% more transmissible. I take it from what Derek says that is not actually known to be the case, but does anyone know where the estimate comes from and what it’s based on?

    1. Chris Phillips says:

      The specific 70% figure seems to come from the model shown at 2:45 in this video:
      https://www.youtube.com/watch?v=G3CT9N89L-c

      I don’t know how that curve was obtained. But it is presented there with great caution and the comment “it’s really too early to tell”. The modelling in the preprint posted by Marko looks more sophisticated than the other calculations to which links have been posted, and produces a figure of 56% with no evidence of a change in severity. It also suggests we need a lockdown more like the one in the Spring than the one in November, which seems like common sense to me.

      1. Chris Phillips says:

        Also noteworthy in the new preprint are the conclusions that a model with increased transmissibility is a much better fit to the data than models representing the alternative explanations of (1) immune escape, (2) increased susceptibility among children and (3) reduction of generation time.

      2. RHB says:

        Lockdown more like the one in spring – No Thanks, I’ll give that one a miss.

        1. J N says:

          Enough people are giving it a miss that you’ll get to watch the science experiment play out over however many months it takes for us to get to herd “mentality,” which given the current tenor I have absolutely no confidence will be July, and wouldn’t bet on December.

          1. RHB says:

            Re: “Enough people are giving it a miss…”

            Not an ‘ologist myself by training, but whether by exposure or vaccine paradigm, come what may:

            Individual/couple/family/household /
            apt block/district/hamlet/village/town/city / region/country/nation/continent/hemisphere/globe / collective/community/herd/school/tribe/workplace…

            …Immunity is where breathing, learning, living, playing, resting and working individuals, couples, families, households, communities and societies large and small are headed (unless SARS 2 just gets bored, gives up and goes away).

            The quicker, with least loss of life, livelihoods, liberties and whatever else detrimental, the better. For what it’s worth, taking UK populace of 67 million as example, hypothesis heretofore put forward that die largely cast throughout month of February 2020, when, via any number of airports, 1.5 million airline passengers entered the country, or returned home, including, by all accounts, significant numbers from SARS 2 hotspots, such as European ski resorts with bustling restuarants, apres ski and night life.

            Back home life had gone on pretty much as old normal throughout February. By early March, UK covertly invaded, contaged by mid-March and colonisation under way within the week. Number Ten Downing Street prime example.

            Not blaming GOV.UK for that (for once). In liberal democracy, not credible option to prospectively close all airports, cancel all tube trains and ban all indoor gatherings from 1st February 2020 onwards, until further notice. Kirkegaard, irony of life and All That.

            GOV.UK, SAGEs, NERVTAGERs, modellers and generalised pestilential controllers may think National Social Distancism saved us, but inclined to think made at best marginal difference.

            So no to more lockdo**s and ritualised distancing. Okay, will give night clubs, LT and Ryanair a miss. Unlike for fair proportion of 20-40somethings, no great loss for a 60something. Different risk-benefit ratio. And, if unwell, all else outside the home given up too, until well again. Pretty simple really. In vivo data are all (as ever).

            And no thanks to hectoring from gov.uk, cabinet ministers, secretaries, junior ministers, assistant secretaries, loyal mps who always vote like sheep, phe, sages, nervtagers, knights of the realm, professors, chiefs, deputy chiefs, chief executives, presidents, experts, mds, bbc stooges, academics dispersing internally moderated mutant plankton on Twitter, discussion forums and sundry other unmoderated wholesale outlets, for bigger fish to gobble and regurgitate…

            …So that out in real world this very evening, as per BBC wholesale news, going free to cheapest bidder: “Hundreds of British skiers flee Swiss quarantine.”

            Bit of a credibility issue all round, you see. Been mounting for some time. Westminster bubble, elite, intellectual and chattering classes, inter alia.

            Have heard your many and varied pieces, all singing pretty much from same hymm sheet. Time for a few canaries to start singing too.

            Oh Ref, I played the ball, honest ref… Okay Ref… I’ll own up. Fair cop. Played the balI first, then played the whole team one by one, off the ball the whole lot. Red card eleven times over. Suspended for rest of the season.

  25. JS says:

    Update from SSI in Denmark:
    https://www.ssi.dk/-/media/cdn/files/engelsk_virusvariant_231220.pdf?la=da
    Now 33 detections of the B.1.1.7 variant from the UK. This represents 0.4% of 7805 sequences from Nov. 14 through Dec. 14. So far 13.5% of positive samples have been sequenced for that period. May increase as it is normally 20-25%. 12 of the 33 were known close contacts who are being preferentially tested, so not trivially scalable.

    We shall see if further countries will decide to restrict travel from Denmark based on this. Despite that it is likely just as prevalent in other countries but not seen due to lack of testing.

    1. JS says:

      Latest update:
      https://www.ssi.dk/aktuelt/nyheder/2020/ny-status-pa-forekomst-af-cluster-b117-i-danmark
      Most interesting is probably the table on page 2. Columns are:
      Week number, total cases (PCR), number sequenced, fraction sequenced, number of B.1.1.7 variant found, fraction
      Not encouraging, but a good thing that they are able to sequence enough samples to track things.

      1. Marko says:

        Looks like it’s doubling in frequency about every week, or less. If this rate of increase continues, the new variant will make up 100% of cases in 5 or 6 wks.

        https://www.ssi.dk/-/media/cdn/files/opdaterede-data-paa-ny-engelsk-virusvariant-sarscov2-cluster-b117–01012021.pdf?la=da

        1. Marko says:

          “”Fortunately, Denmark is virtually closed down now. We hope it also reduces the spread of infection with this virus, but over time it will outcompete the other viruses we have in circulation because it is more contagious. This can mean that the infection flares up quickly when restrictions are lifted, ”says Tyra Grove Krause.”

          Denmark seems pretty certain that the new variant is more transmissible. I guess they haven’t heard of the “founder effect”. Don’t they tune in to TWIV, and listen to “Earth’s Virology Professor” ???

      2. Some idiot says:

        Also interesting to see that they are (a) increasing the number of genomes they can sequence per week, and (b) are setting up a PCR for one of the mutations so that they can screen _every_ positive sample for that mutation… Found in the link from Marko’s post.

      3. JS says:

        Next update from Denmark. Click on the two links.
        https://www.ssi.dk/aktuelt/nyheder/2021/spredning-af-den-engelske-virusvariant_5_1_2021
        With luck the link will not be broken this time.

  26. A N Glosaxon says:

    Minutes of RAGE
    (The UK’s Royal Advisory Group for Emergencies)

    Meeting held 24th December in a year early in the 2020s

    Compiled by Capt A N GLOSAXON
    (Equerry to the Royal Household)

    VENUE: A royal household somewhere in England. Prince George Alexander Louis Mountbatten-Windsor, son of HRH Prince William and Catherine, Duke and Duchess of Cambridge, grandson of HRH Prince Charles, Prince of Wales, and step-grandson of Camilla, Duchess of Cornwall, great grandson of Her Majesty the Queen and HRH Prince Philip, the Duke of Edinburgh, and Heir Apparent but two to the throne of The United Kingdom of Great Britain and Northern Ireland, says…

    “Mummy and Daddy, I’ve been thinking. If the new mutant naughty virus is more transmissible, and it doesn’t make one get any poorlier, isn’t that a good thing, because it will mean the new naughty virus gets round people faster and the epidemic will be over sooner? Maybe that’s what this mutant naughty virus wants to do now, because it’s getting bored being stuck inside our subjects’ support bubbles all the time…”

    So Prince Daddy said… “Problem is Young Prince, as the Prime Minister always says, and his Chief Medical Officer and Chief Scientist always keep reminding us, more people would be poorly in hospital at the same time and the NHS would be overwhelmed, so we all need to do our bit to help in this time of national emergency, so the NHS can stay protected.”

    “You mean,” said Prince George, “Just like one day I will grow up to be a big boy and be Defender of the Faith and Protector of the Realm.”

    “Yes George,” said Duchess Mummy, “That is what you will one day grow up to be.”

    Prince George went over to the third in line to the throne royal armchair and picked up a copy of the Christmas Eve Daily Telegraph, cast aside on the chair earlier by the Great Gramps after breakfast.

    George sat down on the third in line armchair, opened up the Last of the Great British Broadsheets, started turning the pages (no mean feat that for a seven or eight year old, boy should go far), and then, from behind the vast swathes of pages twelve and thirteen, piped up… “Mummy and Daddy, I’ve been thinking again. It says here the nation’s Nightingale Hospitals, especially built in reserve in case the naughty virus became even naughtier, have HARDLY BEEN USED.”

    Duchess Mummy cried out, “George, what a CLEVER little boy you are. We’d completely forgotten about the Nightingale Hospitals, hadn’t we William? How silly of us. All sorted. William – send for that knave, the Prime Minister. At once!”

    Enter perkingly stage right Her Majesty and the Duke of Edinburgh, privately, gloriously, brazenly in defiance of government restrictions on household mixing – not permitted by GOV.UK decree until 24.00 hours this evening, Christmas Day dawning, and then strictly only for one day by order of the Prime Minister, the Health Minister and the whole of GOV.UK.

    “Great Granny, I’ve been such a clever boy,” said Prince George.

    “Oh have you George?” said Her Majesty the Great Granny, “How did you manage that?”

    “He’s banished the virus problem!” exclaimed Duchess Mummy, “At a stroke.”

    “So WHAT’s the ANSWER, clever clogs?” shouted the Duke of Great Gramps, being a near centurion now hard of hearing.

    “Great Gramps,” said Prince George, amplifying through the royal household megaphone, “It’s simple, use the Nightingale Hospitals and have more household mixing.”

    “MORE household mixing?” Queried the Windsors all together out loud, “Oh no, no, no, we can’t possibly have more of household mixing, because the Prime Minister and all his Advisers say so and that must be true, mustn’t it?”

    “They’ve got it all wrong,” said Prince George, “More household mixing of the right sort of people in the right sort of places. Just like they always used to, fit and healthy, young, and older but young of body subjects, mixing at will in places like pubs, cinemas and football matches, in order to spread the virus as benignly as can be done and reach Community Immunity as soon as possible. And this more transmissible very naughty virus should be just the job for that.”

    For an instant, a deathly chilly silence hung over the royal chambers like a miasma…“Ah I see,” said the Queen, feeling obliged to take the lead, “Yes… we thought that all along really, didn’t we Great Gramps?”

    “We did, Old Girl,” said Great Gramps, “Subjects been doin’ it like that for centuries when a virus comes along. Tried and tested method before jabs brought in. Better get that knave the Prime Minister round to remind the troublesome knave what’s what.”

    “He’s already on his way,” said Prince Daddy, “I just texted his fiance.”

    Enter graciously stage left Prince Charles and the Duchess of Cornwall, privately, gloriously, brazenly in defiance of government restrictions on household mixing.

    “Hello Gramps and Step Granny,” said Prince George, “I’ve been a very clever boy. Mummy says so.”

    “Oh have you George, young chap?” said Prince Charles, “How did you manage that?”

    “Pretty simple, Gramps, Old Chap,” said George. “You see, I’ve been thinking and thinking about the latest mutant even naughtier virus and I think it goes like this. Firstly, some of our subjects have prior immunity from catching colds in the past, which should make it easier for the entire realm to reach Community Immunity…”

    “That’s the spirit…” said the Duchess of Cornwall.

    “Secondly, the naughty virus isn’t as easy to catch as The Prime Minister and all his clever advisers fear…”

    “Yes…” said Prince Gramps, “I’ve had my doubts about asymptomatic spread for some time, you know…”

    “And thirdly all this RT-PCR testing, that finds out where the naughty virus is and claims to tell what the naughty virus is up to, in the wrong hands could be a bit dodgy.”

    “YES!” exclaimed the Windsors all together out loud, “We’ve all got a gut feeling about that too!”

    A hushed sense of expectation now hung all around the royal chambers. “But Georgie boy, I have a question,” asked Prince Gramps, “How do we stop fit and healthy little geniuses like you passing on the naughty virus to elderly and conceptually vulnerable old Gramps like me, to Step Granny and to one’s Royal Great Grandparents?

    “That’s OBVIOUS, Boy,” bellowed Prince Great Gramps, “Always was, always has been. If they’ve got serious symptoms, like serious coughing, a serious temperature and serious snot all over the show, then do the rest of us a favour and keep ‘emselves to ‘emselves.”

    “That’s okay for us to say in our royal households with sixty bedrooms and corridors that stretch away for miles…” said the Duchess of Mummy.

    “But what about the family of three or four generations who live in a two storey four bedroom house in three separate units and all use the same single bathroom and kitchen…” said Prince Daddy.

    “Unfortunately in the immediate future there isn’t an answer to that,” said Prince Gramps, “At least not in the timescale of this virus. Housing is a much longer term conundrum. Now Father,” continued Prince Gramps, “When you were talking of bodily excretions, you’re meaning there’s a direct correlation between case severity and viral exposure…”

    “Meaning mild cases usually only lead to other mild cases,” chipped in Prince Daddy.

    Of course I do, you nincompoops,” bawled out Prince Great Gramps, “Don’t give me your correlations. My neurones won’t do correlations any more. Not enough neurones left for that. Got to conserve neurones for more important things like the old bladder control, voluntary arrest or execution thereof. The bleedin’ obvious always was bleedin’ obvious and always will be.”

    “No need for bad language, Philip,” said the Queen, “All means that with a little prior thought and care all one’s subjects can all start seeing their families and elderly relatives again. That would be wonderful, wouldn’t it?”

    “Exactly Dear,” said Prince Philip, “And also all means a load of this new fangled fancy pants science ain’t always what it’s cracked up to be.”

    “INDEED,” said the Windsors all together out loud.

    “Although to be fair,” said Prince William, “New science usually gives new insight, in this case how to deal with epidemics of the future.”

    “And of course,” said the Duchess of Cambridge, ”New science has acted remarkably quickly to give us the vaccines. Looks like they’re going to save the day!”

    “Actually,” said the Queen, “I’m not absolutely convinced. You see, at the Prime Minister’s last audience he said it could be another year before we know for certain if the vaccine protects those most at risk, the elderly like Great Gramps and I…”

    Enter a royal footman with a message for HRH Prince William. Her Majesty paused, while the footman announced, “The Prime Minister has arrived to see the Duke of Cambridge.”

    “Please ask the Prime Minister to await in the main antechamber,” instructed the Duke of Cambridge, “And kindly suggest that he read this morning’s copy of the Daily Telegraph that should be on the table there. Tell the Prime Minister I’ll be along shortly to attend with him.”

    Her Majesty continued in regal splendour… “And then I was on the telephone to that nice man, Lord Sumption, the other day, and he said, for much the same reason, we still can’t rely one hundred percent on the vaccine saving the day, because one’s immune system that needs to be enhanced is at its weakest in the most elderly, like Prince Philip and I.”

    “I’m sure the vaccine will turn out well, Mother,” said Prince Charles. “But going back to the topic of modern science, fact is in the wrong sorts of hands at the wrong time, modern science can lead to all sorts of mischief. And I have to say, this very same epidemic always did seem too early to be parading the latest developments in “The Science” back and forth among the general public, while the “scientific evidence” swung back from one extreme to the other, as I’m told it often does in real-life scientific discovery…”

    Enter a second royal footman with another message. Prince Charles duly paused while the footman announced, “The Chairman of the Conservative Party 1922 Committee has arrived to see The Prince of Wales.”

    “Please ask Sir Graham to await in the second antechamber,” said The Prince of Wales, “There will be no need to mention this morning’s copy of the Daily Telegraph, as I am sure Sir Graham will have already read it. Tell Sir Graham I shall be along shortly to attend with him.”

    Prince Charles continued where he‘d left off… ”Even so, despite all the local difficulties, I personally am heartened by the concommitant reduction in emission of greenhouse gases that has accompanied the MARS epidemic, so maybe without really trying we have all started taking a small step in a greener direction…”

    “HERE, HERE,” said the Windsors all together out loud.

    “Hang on a minute, Boy,” said Prince Philip, “Are you really saying The Chairman, The Chumpster, Pukin’, The Clown Prince and Chancellor DeutschMarkel have planned this out all along? ‘Cos from what I’ve seen of ‘em they ain’t anywhere near clever enough for that.”

    “Right on Grandpops,” said Prince William, “But maybe some physicists, economists and epidemiologists are clever enough…”

    “Well the epidemiologists certainly aren’t,” said the Duchess of Cambridge.

    “But some of those bright young thing economists might just be, and you can be pretty darned sure those clever physicist chappies certainly would be,” said the Duchess of Cornwall.

    “Not a cat in hell’s,” bellowed the Duke of Edinburgh, “If you ask me it’s just history’s macrodrama as one effing thing after another playing out like it always does.”

    “Now, now,” said the Queen, “Language, Philip.”

    By now Prince George was starting to wonder about all sorts of grown up things. Next came that strange fleeting sense of being the same age as Gramps and ten years enthroned as the future King George the Seventh. But never mind sixty five years hence, to a seven or eight year old the next five minutes of life are rightly far more important than that.

    “Thank you, Mummy, Daddy, Gramps, Step Granny, Great Gramps and Your Majesty. Thanks to your inputs, we’re all sorted, working objectives for the day met and not even dinner time yet,” said Prince George. “Great Gramps, please may we play a game of Off With Their Heads?”

    “That’s the spirit, Georgie Boy!” yelled Prince Philip, getting remarkably excited for a near centurion, “You’re talking just like a once and future king. That’s my boy. We haven’t had a good game of OFF WITH THEIR HEADS for years…”

    Meanwhile, Prince Charles and Prince William slipped discreetly away for their respective appointments with the Prime Minister and Sir Graham, leaving an excitable Prince George and a chortling Great Gramps playing together the opening round of Off With Their Heads, the traditional entrée to the Great Royal Board Game that always begins with the grand shout of… OFF WITH HIS HEAD!

    Outside the royal household, the light is starting to fade as Christmas Eve unfolds. In the distance the royal cattle are trailing off for milking at the royal farm, a royal sparrow hawk hovers overhead on the look out for afternoon tea, and dotted around the field the royal sheep alternately nibble and look up, as the first stars of evening come out in a clear Christmas night sky.

    Later Prince George is all tucked up in bed and later still the Royal Family all retired to their chambers. One by one over time lights go off for the night, until one light only lights up the royal bedroom windows.

    As ever, Security is of course discreetly on duty in the background, but if an intruder somehow manages to breach Security and come near the single lit window, from inside through a slighly ajar sash, a habit down the years, might come the faint airs, arias and auras of a long ago dark and bright Lancastrian contralto and a long ago Northumbrian folk song played on a much loved record player, first acquired long ago, “Blow the wind southerly, southerly, southerly, blow the wind south o’er the bonny blue sea. Blow the wind southerly, southerly, southerly, blow bonny breeze…”

  27. mary says:

    I’m sure at least one garage band started up in 2020 has already been calling themselves The New Mutations

    1. Dan Defough says:

      Evocative name. No sign of garage band New Mutations online yet – maybe band is group of biology students.

      New Mutants is X-Men horror movie, looks like released this year…

  28. DataWatcher says:

    This may be why Fauci has upped his “herd immunity” estimate to 90% of Americans getting vaccinated. Given the amount of vax resistance, that’s a pretty pessimistic long shot. Recent surveys have suggested that anywhere from 70 – 80% of Americans may now be in the “possible” category, but I can’t see 90% ever being feasible; even 80% is something of a long shot, although it might be doable. If 90% is what’s necessary, the future may look a lot bleaker than most of us have been trying to believe.

    1. Adrian says:

      There is unfortunately a widespread fake news campaign to distract from actual problems by ignoring the data and then doing fearmongering against an anti-vaxxer strawperson.

      Like the murderous promise from Presiden-elect Biden to reopen schools within 100 days – this would only be safe if there was enough vaccine available in the US for the whole population already by mid-April, which is not realistic.

      The bottleneck is the availability of the half billion vaccine doses the US alone needs.

      Anyone watching the data knows that based on vaccination rates among schoolchildren in the US, > 95% of all parents in the US have their children receive all recommended vaccinations.This data proves clearly that a 90% vaccination rate in the US is not a problem if the vaccines prove in practice that they are both safe and effective.

      1. DataWatcher (AKA "DataSeeker"?) says:

        Let’s hope that’s the case. Given what we saw a year or two ago with that flash measles outbreak in the wake of the Jenny McCarthy-led anti-vax initiative, I’m a little more pessimistic. Social media is more “viral” than even measles, and I fear it will continue to spread anti-science / anti-vax propaganda ever more virulently, especially as allergic reactions and the inevitable rare adverse effects begin to make themselves known.

        I do have a query that I hope isn’t evidence of being horribly uninformed. Technically, the HIT would involve people who have been vaccinated and/or previously infected, not “just” those who get vaccinated. I admit I’ve become confused by the various estimates of how many Americans have now been exposed to the virus, and are thus already in “the herd,” so to speak. In the neighborhood of 10%? Possibly more? Tragically, the more people who get exposed, the fewer who will probably have to be vaccinated for mass immunity to develop. (And no, I’m NOT parroting Atlas’s neo-genocidal theories here, just acknowledging a fact.) Any estimates on this?

        1. Adrian says:

          Assuming a case fatality rate of 1% usually gives a reasonable estimate for past infections when COVID-19 runs through the whole population without working protection for vulnerable groups, and when you look at data like antibody results from New York City after the first wave in spring this way of estimation gives pretty accurate numbers.

          For the US this estimate would be that 10% of the population have been infected with COVID-19 so far.

          Your implicit assumption of long-term immunity after infection might turn out to not be true.

          Whether infection in spring 2020 would still give immunity in summer 2021 is unknown – reinfections with COVID-19 have been confirmed, and for the other human coronaviruses immunity usually lasts for less than a year.

        2. J N says:

          I’m well into not caring what other people do and waiting for my vaccination.

          I don’t think we’ll have herd “mentality” for quite some time in 2021 if at all, for a plethora of reasons. The COVID deniers and anti vaxxers can get bent, or sick, or whatever suits. I’ll take that jab whenever I can.

          We landed people safely on the moon. We invented PCR. We invented the laser. We invented controlled nuclear fission. We invented the telephone.

          And now we’re a global embarrassment.

          1. DataWatcher says:

            . . . although to be fair, things aren’t looking so rosy in a lot of other countries, either. Even places like Italy and Germany, which made excellent progress in the earlier months, are now in morasses almost as dire as ours in the U.S.

            Maybe most European countries, at any rate, will have less anti-vax hysteria and will be able to get things at least somewhat under control — that is, if these new mutant strains don’t continually develop (another new one has just been identified in Nigeria) and keep COVID a step or two ahead of medical science for the foreseeable future.

          2. Adrian says:

            The whole Western World (including Europe) is a global embarrassment.

            China showed the way, and large parts of East/Southeast-Asia and Oceania followed their successful suppression strategy.
            Leaders in Europe/US were too ignorant for following this path to success.

            People in East Asia are wearing proper surgical masks.
            Already in March Taiwan had ramped up its production to 4 masks per person and week.
            It is a global embarrassment when they see that people in Europe/US are still using pieces of cloth instead of the proper masks they use.

          3. Fairfax says:

            Adrian – Re: “China showed the way…” You mean as per:

            https://www.nature.com/articles/s41467-020-19802-w

            “Post-lockdown SARS-Cov-2 nucleic acid screening in nearly ten million residents of Wuhan, China.” As published in Nature Communications, November 2020. If read right, reports for initial Wuhan epidemic 4-5K deaths, 4-5% IFR, 100-200K cases. Implies wider spread stopped by strictly enforced lockdo*n.

            Important numbers. Get impression plugged into UK epidemiological modelling that predicted worst case 510K UK deaths, 2.2M US deaths and worldwide 40M deaths for unsuppressed SARS 2 pandemic. For the record, officialdom’s epidemical numbers to date ~70K, ~300K and ~1.6M, respectively.

            Over Ides of March weekend (14th/15th), gloom and doom modelling duly changed GOV.UK policy from responding through herd immunity (better called… take your pick from any number of Adjectival Immunities, such as… City, Collective, Community, Local, National or Tribal…

            But GOV.UK comms too busy masterminding… STAY SAFE, SAVE LIVES, PROTECT THE NHS…), to falling in line with rest of Europe we’re now Brexiting got done from… By SUPPRESSING THE VIRUS, CONTROLLING THE VIRUS and STOPPING THE SPREAD.

            Hence out of curiosity, reviewer comments requested 4 December from Nature publishers Springer. 25 Days and 3 fobbing off emails later, still waiting….

            Now to make clear, Adrian, have never set foot in continent of Asia, so all that follows is interpolating and reading between lines, which could have been read all wrong.

            FYI, study out of St Louis, AT&T and Ohio State published online 16 June 2020 queried Wuhan numbers swirling around at time:

            https://www.medrxiv.org/content/10.1101/2020.05.28.20116012v2.full.pdf

            Also FYI, some sources cited for Wuhan crematoria numbers gave, “Page not found,” last time checked.

            Further FYI, study out of Appleton Park postulates absolute minimum several tens of thousands existing cases at time of 23 January Wuhan lockdo*n, then postulates majority remaining 9.9*M Wuhan populace directed into up to thousand apartment blocks to self isolate, and still further postulates immaculately conceived lockdo*n, in order to fit with 4-5K deaths, 4-5% IFR, 100-200K cases.

            Moving on… Nature paper reports 92.9% entire Wuhan populace PCR tested 5-8 weeks after lockdo*n ended. From nearly 10 million nasal jobs taken, around 400 tested positivers found in PCR test, duly run across 63 Biosafety Level 2 labs by 1451 operatives using 701 sets of testing equipment. 40 as negative. 37-40 Cyclers retested and re-assigned accordingly.

            Clear from Supplementary, all testing n = 2 up front. Pretty seriously impressive testing numbers all round (albeit <37 cut off bit highish?). China showing the way, indeed. GOV.UK Test & Trace chums Deloitte, Sodexho et al, please note.

            And while at it, please ask GOV.UK Dept Health and Social Care to respond to Freedom of Information request posted even longer ago than aforementioned Nature reviewer comment request (Pillar 2 Community Testing: number of amplification cycles, false positive rate, SOP, etc, etc, etc).

            ~100 Tested positivers are SARS 2 recoverers. Other 300 are asymptomaticers, who in turn ping 1174 close contacters, who all test negative in PCR. Asymptomaticers’ nasal swabs negative in viral cultures (Biosafety Level 3 labs), indicating positiver asymptomaticers not carrying “viable virus.”

            So conclusion is city of 10 million, from early December 2019 through to early April 2020 racked by disease epidemic in which over four thousand deaths reported by authorities, by late May completely free of infection. Triumph of 11 week city lockdo*n, comprising 5.5 fully suppressed viral infection cycles.

            Pernicious myths of asymptomatic cases and asymptomatic spread also duly nailed? Possible caveat immaculate data all round?? Virus stopped in its tracks, really??? Or epidemic played out – another Appleton postulate is 4M prior immunity, overall IFR 1%, 4M further cases, 40K overall deaths?? Which fits crematoria data that once upon a time were and 80% City Immunity?

            https://www.theblaze.com/op-ed/ready-horowitz-a-severely-symptomatic-lie-about-asymptomatic-spread

            Belt, braces, face masks and safety footwear, 300 asymptomaticers and 1174 contacters all banged up in isolation for 2 weeks minimum until PCR negative. If read right elsewhere, “isolation” may well mean an Isolation Hospital, not comfort of own Xbox, Netflix and Deliveroo.

            In summary… “Findings enabled decision makers to adjust prevention and control strategies…”

            Rest assured My People, “When an epidemic breaks out, a command is issued…”

            http://en.people.cn/n3/2020/0125/c90000-9651799.html

            Assume, Adrian, China showing the way again?

          4. Fairfax (issuing correction) says:

            Correction to error in para 11, thought brought about by IT gremlin when pasting text from Word to Pipeline (possible sporadic issue with pasting less than and greater than symbols)

            RE: Moving on… Nature paper reports 92.9% entire Wuhan populace PCR tested 5-8 weeks after lockdo*n ended. From nearly 10 million nasal jobs taken, around 400 tested positivers found in PCR test, duly run across 63 Biosafety Level 2 labs by 1451 operatives using 701 sets of testing equipment. 40 as negative. 37-40 Cyclers retested and re-assigned accordingly.

            SHOULD READ: Moving on… Nature paper reports 92.9% entire Wuhan populace PCR tested 5-8 weeks after lockdo*n ended. From nearly 10 million nasal jobs taken, around 400 tested positivers found in PCR test, duly run across 63 Biosafety Level 2 labs by 1451 operatives using 701 sets of testing equipment. Less than 37 amplification cycles defined as positive test, greater than 40 as negative. 37-40 Cyclers retested and re-assigned accordingly.

    2. kevin smith says:

      90% immune = X% immune because of disease + Y% immune by way of immunization.
      So, many of the anti-vaxxers and the “hesitant” will contribute to herd immunity by getting COVID, and the rest of us [90%-X% = Y%] will contribute to herd immunity the easy way: by getting immunized.
      So, you don’t need to give shots to 90% of the population.

  29. DataWatcher says:

    Looking more closely at Fauci’s quote, I’m not sure this time where he’s getting his numbers from. According to the report I saw: “He said he’s comfortable drawing the line at 90 percent herd immunity because he doesn’t believe the virus is more infectious than the measles, which falls in that range. ‘I’d bet my house that COVID isn’t as contagious as measles,’ he said.”

    He should KNOW that the R0 for measles is far higher than that for COVID, at least at this point. One wonders whether he has access to data that might suggest this new variant strain is far more contagious than the public estimates have suggested thus far.

    1. Marko says:

      If the original Wuhan strain had an R0 of 3.0, and the D614G mutation conferred a transmissibilty increase of 30%, and then the recent variant confers an increase of of 70% on top of that, you’re at an R0 of 6.63, and it would take only another ~35% increase in transmissibility to land you on an R0 of 10.0, which corresponds to a HIT of 90%. If the original R0 was higher than 3, as many, including myself , believe, the situation only worsens. The recent estimated seropositivity of 76% in Manaus, Brazil suggests a higher HIT than expected for an RO of 3 (i.e. ~67%).

      Nobody knows exactly where we stand today, but a HIT as high as 90% sometime in the near future is well within the realm of possibilities.

      1. Adrian says:

        As of today we do not even have the data to tell whether the vaccines actually reduce transmissions, or whether they only turn symptomatic cases into asymptomatic superspreaders. Many people are optimistic about that, but we do not have data to confirm whether this is actually true.

        Even today the Chinese way of 2-3 months strict lockdown for getting rid of the virus might still be faster and economically cheaper than hoping for herd immunity through vaccines in half a year.

        1. DataWatcher says:

          But politically infeasible. We’d have violence in the streets, and very possibly more threats on the lives of public officials. That could happen even if a mask mandate were attempted, let alone a China-style shutdown.

        2. Marko says:

          True, but we do now have data that tells us that natural infection provides significant levels of sterilizing immunity, at least for a period of months. I’d expect the vaccines to do about the same.

          If incremental vaccination plus natural immunity can slow the spread until everyone is vaccinated ( and presumably protected against severe disease outcomes ) it will contribute to slowing the rate of deaths. However, if the virus keeps mutating towards increased infectiousness, or worse, immune escape, we may find ourselves in a one-step-forward-two-steps-back situation.

          1. DataWatcher says:

            . . . which is why, of course, that rigorously adhering to those “public health practices” (masking, etc.) until the vaccine can be fully administered is even more essential. The best way to reduce possible mutations is to reduce transmissions, and the more effective we are at that, the better the chance that those “two steps backward” could possibly be avoided. (And yes, I know I’m preaching to the choir here.)

          2. DataWatcher says:

            *Sigh* No wonder so many people are so confused . . .

            “”The reality is that about 25 to 50% of Americans have already had the infection and have some natural immunity. “Now, we don’t know if that’s a little better, a little worse, or the same as vaccinated immunity, but we may only need to get an additional 20% of the population immunized by February or March to really hit those 70% herd immunity levels.” (Marty Makary, Johns Hopkins)

          3. Adrian says:

            You are expecting sterilizing immunity from vaccines, looking at the monkey results from the Oxford vaccine I am more skeptical about that.

            These monkeys were also protected from serious disease, but they all got infected in the upper respiratory tract.

            Real infection does require an immune response in the upper respiratory tract, but the current vaccines do not. This would be a plausible explanation for vaccines not providing sterilizing immunity even though real infection does.

            We do not yet have data to settle this question for the current vaccines.

          4. Marko says:

            I don’t have a problem with the gist of the statement by Makary , but I do with the particulars. First, I think we’re probably closer to the 25% infected than the 50% figure. Second, I think the 70% figure for HIT is probably too low. And third, we’re wasting immunization on many people who are already immune via previous infection, which adds very little or no benefit to reaching the HIT in the immediate future.

          5. Adrian says:

            Everytime I read “Johns Hopkins” in the context of COVID-19 I have to think of the country ranking in https://www.ghsindex.org/

            Johns Hopkins claims the countries best prepared for a pandemic are the US and the UK, with China outside the TOP 50.

          6. Marko says:

            “We do not yet have data to settle this question for the current vaccines.”

            Agreed. I’m optimistic that we’ll see some protection from infection by the vaccines, though it wouldn’t surprise me if it’s less than that provided by natural immunity. Even if the vaccine only converts symptomatic into asymptomatic infection, some benefit in reduction of spread would be likely.

          7. DataWatcher says:

            If we’re close to 25% of people who’ve already been exposed, then theoretically a 75% vaccine uptake should be sufficient. On the other hand, Marko, your third point is definitely essential. From my understanding, previously infected people are at *some” (most likely very low) risk of reinfection, which isn’t a good thing but which is a lot less serious than the situation for the 100% immunologically naive. It’s been at least ten months since the first documented cases appeared in the U.S., and so far we haven’t seen any reported spike in reinfections, even among the earliest cases. That could mean that a safety window of at least a year isn’t implausible. So at least until we start seeing reinfections occurring at alarming rates, I’d agree that maybe, at least while we’re still dealing with the highest-risk patients, we should focus on people who have not been previously infected (knowing that we’ll still end up vaccinating some who had been asymptomatic or mildly symptomatic, but never diagnosed).

          8. Adrian says:

            I do consider your ‘“public health practices” (masking, etc.)’ disturbing.

            The only real effective public health distance is social distancing.
            Proper masks (surgical masks used once, not some piece of cloth) are an inferior option in situations where social distancing is not possible,

            It is mask murder when people are reducing social distancing due to masks.

            It was mask murder when the governor of California made masks mandatory at the same time as reopening bars and restaurants. As expected this resulted in increased infections and increased deaths.

            It is mask murder when masked people are sitting in a plane for non-essential travel, like visiting other people for Christmas.

            It is deadly when people are talking as if masks were the most important thing.
            If you look at data from countries like France that were strict on mask mandates but weak on social distancing, the result was another lockdown and even the president getting infected.

          9. DataWatcher says:

            (Apologies for the multiple posts)

            “Even if the vaccine only converts symptomatic into asymptomatic infection, some benefit in reduction of spread would be likely.” And, of course, to the extent that a significant majority of people get vaccinated, even if they are still spreading it they’ll be spreading it mostly to others like themselves — people who are very unlikely to become seriously infected. In time, that would mean significant mass immunity achieved at far less catastrophic human cost than the “herd-immunity-in-the-absence-of-a-vaccine” strategy proposed by Atlas,

          10. Adrian says:

            “Even if the vaccine only converts symptomatic into asymptomatic infection, some benefit in reduction of spread would be likely.”

            My expectation for that is the exact opposite.

            Symptomatic spread was a problem back in the days when you were expected to show up at work even when you have a cold. At least here in Europe with working testing for symptomatic people they are no longer a significant cause of transmission.

            Asymptomatic and presymptomatic infections are now the real source of COVID-19 transmissions, especially clusters of asymptomatic people in groups like college students that might already be huge by the time the first person tests positive.

          11. DataWatcher says:

            I also remain a little unclear as to exactly how many doses will be available. We keep hearing about “ten million doses” or “fifty million” doses or even “100-200 million doses” being available by a certain time, but I assume that we need to divide that number in half to calculate how many people will be vaccinated (two shots per person). I forget whether it was Fauci or Slaoui who estimated about 200 million doses by June, but that would only represent 100 million vaccinated individuals, less than 35% of the population.

            And obviously the assumption is that we won’t be dealing solely with Pfizer and Moderna. Most of these estimates are also assuming significant efficacy and safety from J&J, Oxford-AstraZeneca [problematic?], and Novavax, at the very least. I’m not sure of their timelines, but I’ve seen Novavax promising 100 million doses by the first quarter of 2021, even though they’re just beginning their Phase III trials right now — sounds pretty optimistic. Invio looks promising, but their timeline has been pushed back repeatedly, so they won’t be rolling out until late 2021 at the earliest.

            All of which might bode well for the long term, but casts some significant doubt on the projections we’ve been hearing that we’re likely to be getting a handle on this thing by mid-summer or the beginning of fall 2021. And, of course, if we’re racing to stay ahead of the mutations, that longer-term wait could prove disastrous, even if the vaccines that became available by then were truly superior.

        3. J N says:

          I don’t think many people are aware that this is precisely the situation with the current pertussis vaccine: vaccinated subjects become subclinical “carriers” rather than immune. This was difficult to figure out and is apparently significantly responsible for resurgence in pertussis in the US. (I had adult pertussis a while back and I don’t recommend it.)

          This is an uncommon but entirely possible scenario that definitely needs to be considered.

  30. Marko says:

    Wait , Rasmussen is wrong again ? (or Balloux, Racienello, etc.,etc.,etc.)

    I’m shocked! Shocked , I say! :

    https://twitter.com/yaneerbaryam/status/1342143841198092297

  31. Marko says:

    John Burn-Murdoch of the FT : “Cases and positivity rates are still rocketing in London and surrounding areas, the regions where the new B.1.1.7 variant is known to be most prevalent….15% of tests in London now positive. ” (with graphs) :

    https://twitter.com/jburnmurdoch/status/1342181469125537793

    1. Wise Doggerel says:

      Look ye beyond the BBC
      And Boris, Blair and Gates
      Search “Clare Craig Path” and you will see
      A world of truth and light awaits

      Happy Christmas!
      🙂

      1. Marko says:

        Is that you, Riah ? Why should we believe your denialist guru Dr.Craig now , when she was so spectacularly wrong back in Oct. when she declared the pandemic in the UK “all but over” ?
        The body bags piling up in the UK right now tell a believable story. Your gurus do not :

        https://blogs.sciencemag.org/pipeline/archives/2020/10/27/more-antibody-data#comment-331410

        1. Wise Doggerel says:

          Data. Tells. The. Truth. Excess deaths graph at link below, p61. Emergency admissions similarly flat. 111 and 999 too. In most places in England. Still some Covid, sure. But surely much more misdiagnosis now. PCR tests need to be double-checked.
          https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/945502/Weekly_Flu_and_COVID-19_report_w51_FINAL.pdf
          For those interested, check out RealJoelSmalley’s analysis. Has anyone found better?
          PS for anyone commenting, please play the ball not the man

          1. Stroodle says:

            But the document you link DOES show increased excess deaths?! And this is with controlling the pandemic so as not to overwhelm the hospitals. The other main part of the report, as expected, is that influenza deaths are lower than usual, due to distancing measures and a higher vaccine uptake. Hell, Australia had fewer excess deaths last winter than usual for the same reasons. We’re up to 80,000 excess deaths in the UK this year.

          2. Wise Doggerel says:

            Stroodle’s post doesn’t seem to have a reply option… But thanks for the comment. Always good to discuss data 🙂 And yes, there are indeed excess deaths. But the line is broadly flat. Would anyone look at Jul-Dec and conclude we were in the middle of a pandemic? Other indications are the 111/999 calls and emergency admissions.

            For context, I find the following hypothesis plausible. Contrary to popular belief, respiratory viruses don’t do waves as such. Most of England suffered badly with Covid in Spring and reached herd immunity (or something close). A few areas that escaped relatively lightly (e.g. West Yorkshire) were hit in the Autumn. The apparent “second wave/ripple” is actually mainly the first wave in areas previously not much affected. And the current high number of positive PCR test results is largely down to flawed testing (and failing to re-test). Lack of a spike (sorry) in excess deaths in the New Year would confirm this.

            Back to Stroodle’s main point. Some early Autumn excess deaths are thus likely due to Covid. And maybe a few right now. But I think most of the Autumn excess deaths are due to people dying prematurely having missed health appointments due to lockdowns/restrictions earlier in the year. I think the data increasingly tells us that lockdowns are doing far more harm than good. One to watch.

            As to excess deaths for the whole year, we do not have long to wait. It’s important to bear in mind that graphs will vary depending on how they are adjusted for total population and year of birth etc. The website actuaries.org.uk is a good place to look. Note too that 2020 should be considered in the context of two fairly mild previous winters. And that it’s also worth looking at a 20-year period as well as a 5-year one.

          3. Wise Doggerel says:

            PS it seems plausible to me that in England we had significant natural immunity from Covid owing to prior exposure to other coronaviruses (SARS, colds) (think cowpox/smallpox). I wonder whether such immunity was even higher in the Far East.

          4. Marko says:

            Rather than making their usual winter vacation travel, it appears than people in the UK have instead opted for a restful stay in local hospitals :

            https://twitter.com/DrNeilStone/status/1343279099561865216/photo/1

          5. Wise Doggerel says:

            Aren’t hospitals always busiest around this time of year though? The issue of an NHS winter crisis is (quite rightly) an annual concern. Chart at link below is the best I’ve seen for context on this:
            https://data.spectator.co.uk/city/nhs
            All-cause excess mortality data will in due course give us a clearer picture

          6. Wise Doggerel says:

            PS see particularly the chart entitled: “Critical care bed occupancy rates vs 3-year average”
            PPS while there are plenty of people in hospital who have had a positive PCR test, I suspect many (most?) have been misdiagnosed. Why are PCR positives not double-checked, and compared with lateral flow results. And why are we not doing more antibody testing?

          7. David Beckingham says:

            Play the ball not the man. Like it. Class and Respect.

            Starting to follow cricket. Class from Ravi Ashwin down under this morning, after India pulled off stunning win over the Aussies.

            When your back’s against the wall, lean on the wall! Like it. Then just step up and bend it…

          8. Cromwell.Oliver@Lord_Protector1653 says says:

            Good Sir, pray do not expect citizen masses to take in past fact, when all that’s put about by government, vested interests and media is present day hysteria.

            Also Good Sir, I think I do know thou style and who thou might conceivably be. Welcome sound reasoning, measured thought and scientific insight brought to these proceedings.

  32. Marko says:

    The comedy of errors and lies in the Oxford/AstraZeneca vaccine dosage cock-up :

    https://www.reuters.com/article/us-health-coronavirus-britain-vaccine-sp-idUSKBN28Y0XU

    Vaccine nationalism rears its ugly head and then bites your nation right in the ass.

    1. Marko says:

      A snarky tweet by Rasmussen, which would be appropriate if it wasn’t so characteristically dumb :

      https://twitter.com/angie_rasmussen/status/1343027864162107392

      You’d only use a Nanodrop if you had trace amounts to work with. They had liters. The reason they screwed up is because they didn’t account for the uv absorbance of the Polysorbate 80, a rookie error , but one having nothing to do with a Nanodrop.

    2. Chris Phillips says:

      So they were well aware of the discrepancy between the manufacturer’s measurement and their own, and still went ahead on the basis of their own incorrect one, rather than double checking?

      But what I find most incomprehensible is why they recruited so few participants over 65 in the trial as a whole.

      1. Marko says:

        Yes, pretty shoddy all the way around, but reports out tonight are saying they expect UK approval and vaccine rollout to begin by Jan. 4 :

        https://www.msn.com/en-gb/news/coronavirus/oxford-coronavirus-vaccine-to-be-rolled-out-across-country-on-january-4/ar-BB1cfBGP

        “Warp Speed” vs “Warped Regulators” ?

        1. Marko says:

          “…Astra Zeneca’s chief executive, Pascal Soriot, today reveals that new data will show the vaccine is as effective as the Pfizer and Moderna jabs that have already been approved, protecting 95% of patients, and is “100% effective” in preventing severe illness requiring hospital treatment….”

          https://www.thetimes.co.uk/article/covid-vaccine-boost-for-millions-as-hospitals-near-breaking-point-vj7fpj2hr

          Next they’ll be telling us their vaccine makes you smarter, taller , and more attractive…..

        2. Chris Phillips says:

          The conduct of the trial has obviously been shoddy. On the other hand, if the situation in the UK doesn’t qualify as an emergency, it’s difficult to imagine what could. (Cardiff reportedly ran out of intensive care beds before Christmas, and yesterday issued an appeal for anyone with relevant experience to go and help.)

          The former prime minister, Tony Blair, is suggesting throwing the protocol out of the window and giving single doses of vaccine to as many people as possible.

          I think if they’re satisfied about safety, it’s difficult to say the Oxford vaccine shouldn’t be approved for use, but I wouldn’t like to have to make the decision about who and how.

          1. Marko says:

            I agree. I don’t think the screw-ups change the fact that the vaccine is safe and effective. They can approve with something like an EUA and begin a phased rollout without raising eyebrows too much , until the newer data fills in the blanks on the over-65s, low-high vs high-high dosing, etc., to justify full approval. The UK and the rest of the world need vaccines badly , and especially the lower-cost vaccines.

            It would be nice if they stopped the hard sell and showed a little humility, however.

          2. Druid says:

            I’m pretty sure Tony Blair and others were referring to the BioNTech/Pfizer vaccine, not the Oxford/AZ vaccine. Only about 2% of the BioNTech study group received only one dose, not enough for to be sure of the outcomes. It might be sensible to run the idea as a Phase 4 study. At the current rate of infections, a result would soon be evident. It would also test the efficacy of the vaccine in use rather than in a carefully controlled trial, as it would be easy to denature it before injection.
            As for those advocating herd immunity through naturally-acquired infection, I think you might get your wish as the rate of infection is probably faster than the rate of vaccination.

  33. Marko says:

    Good chance that the increased transmissibility of the UK variant is due to higher viral loads:

    “S-variant SARS-CoV-2 is associated with significantly higher viral loads in samples tested by ThermoFisher TaqPath RT-QPCR”

    https://www.medrxiv.org/content/10.1101/2020.12.24.20248834v1.full.pdf

    1. Chris Phillips says:

      Thanks. The NERVTAG meetng summary ten days ago mentioned two indications of higher viral load. Probably that is one of them, and one is meant to be available here, but the link won’t work for me:
      https://www.coronavirus-fraser-group.org/files/files/updated_report_to_nervtag_oxford_20201222.pdf

      There are a few details here on Twitter:
      https://twitter.com/oxfordviromics/status/1341491766915198980

      But they also say samples from London don’t show significantly higher viral load for the new variant. Also that samples from Kent show higher viral load than those for London, for both the new variant and existing lineages.

      1. Devereux says:

        Here we go… Higher viral load, more transmissible in children, surge in UK cases of extreme concern. Any day now, WHO will call Covid-20 (or is it a biennial event?). You read about it first In the Pipeline.

    2. Some idiot says:

      Thanks! Nice take… and good to see how cautious they are in their conclusions. Very refreshing!

    3. Mariner says:

      Hmmm. I wonder if the apparently higher viral loads reported from infections of the new variant will mean there are fewer asymptomatic infections than previously? This might also explain the rocketing numbers of confirmed infections – if people who might have been asymptomatic with previous variants are suddenly coughing/feverish with the higher viral loads of the new one, it might explain such a great increase in numbers.

      On the other hand, a similar proportion of asymptomatic infections allied to higher viral loads could be leading to more spreading by asymptomatic carriers!

      Either would explain the rocketing numbers of reported cases.

      I’m surprised that data about infections in children isn’t available as yet. Surely they have enough data to decide whether the new variant affects children more or not? The schools are due to reopen in little over a week…

      1. Chris Phillips says:

        There doesn’t seem to be any consistent trend in the last few months in the ratio between the ONS estimates of infection rates, based on random swab tests, and the numbers of actual positive tests. Despite the increase in the prevalence of the new variant.

        That ratio is consistently higher in London than elsewhere. I don’t know whether that is because of lower testing rates or demographic differences.

        Looking again at the data, including random antibody testing, I still think 20% is the minimum reasonable estimate for infections in London so far. And given the low infection rates among vaccine trial volunteers, I can’t help thinking that infection rates are also likely to be lower among the volunteers for the random ONS testing.

  34. Uncle Steve says:

    Re vaccines in the UK, I have noticed an intriguing “dog that has not barked”. As far as I can tell, the Queen (94) and Prince Philip (99) have not had a Covid jab…

    1. Mariner says:

      Well, Liz and Phil are somewhat unique compared to most elderly folk in the way that they have live in staff who will undoubtedly be forced to isolate and face multiple tests before being allowed into the presence of the Royal personages.

      Their risk of infection is extremely low in comparison to most nonagenarians.

    2. Marko says:

      They don’t need a vaccine. Known hosts of Sars-CoV-2 do not include the Lizard People.

      1. Buckingham the Palace Cat says:

        No graver insult to Her Majesty and Consort have I ever heard, Sir. You, Sir Marko, are a blaggard and a scoundrel! On Her English Majesty’s behalf, I challenge thee to a duel.

        Her Majesty’s son, grandson and great grandson being next three in line to the throne, so we cannot afford to lose any of them in a petty duel, whereas I, an ageing aristocat albeit with eyesight, claws and feline reactions no longer so acute, won’t be too badly missed at all.

        Name thy weapon, place and second, and I shall see thee there at dawn. My second shall be my younger brother Tom, who will confirm the arrangements with thy second, and may, dependent on your choice of weapon, act as my younger representative in the aforesaid duel, should you choose a weapon at which Tom is more adept than I.

        Likewise I will extend thee similar proxy should need arise. Now as I am challenger and cat of honour, I should warn you of three weapons to avoid, as I was once upon a time Buckingham the Cat at a Royal Laboratory, no less.

        Firstly, the spatula, with which I have won numerous dawn duels with all forms of chemical matter. Secondly the trusty Stanley knife, used for cutting sodium, rubber tubing, buttered toast, dead mice, and, in a couple of unfortunate mishaps, myself.

        And last but not least, the chemical structure, fought over with curly arrow at whiteboard or on hood front, for I have seen enough of structure in my nine lives to know my noradrenaline from my norepinephrine, my testosterone from her progesterone, and my azole from my ar*ehole.

        Prepare thee to stand, deliver and be duly extinguished, Sir Marko! May the better species win. Rest assured, Good Sir, it will most certainly not be whom you think.

        Yours until morrow dawn,

        Buckingham

        1. Marko says:

          You’re rambling again, gramps.

          Eat your applesauce.

          1. McHolyrood the Scottish Palace Cat says:

            Apple sauce, yum, yum, best taken well sloshed wi’ finest Orkney Craft Scottish MacVinegar. Fellow McScotters, let’s enjoy our MacHogmanay that wee lassie Nanny MacFish has taken away from us. Haste ye back across yon bonnie MacBorder that MacNanny’s closed for us. Let’s look forward to our Burns night that Nanny MacF’s going to cancel MacAnnually until further MacNotice for us.

            A wee draft blowin’ down the MacPalace chimney somehow telling McHolyrood the Palace Cat that wee MacNanny’s losing her head, just like wee MacSalmon the smolt did before her.

            Cheer up Fellow McScotties, at least we no got Welsh Ap’ Wizard Nanny Ap’ Drakefford cancelling Ap’ Everything for us…

            Outside meanwhile, Palace lawns and fields beyond covered in snow and palace sheep short of grazing. Palace farmer has difficult juggling act to keep all farm animals fed and watered. His lifetime’s work. Palace knows, and farmer knows, farmer knows what farmer’s doing.

            Farmer off outside for a ramble shortly to check how sheep faring in cold weather, in fields farmer’s been wandering around for decades, like farmer’s paps and gramps before him. Pleasures of the country.

  35. Marko says:

    Adam Kucharski thread explains why , all else being equal , a variant with a transmissibility increase of 50% is worse that a variant that’s 50% more deadly :

    https://twitter.com/AdamJKucharski/status/1343567425107881986

    1. Marko says:

      Some postulate that mutations that increase transmissibility may reduce virulence. Using the same example in Kucharski’s tweet above , you’d need a reduction in CFR of ~87% to offset a 50% increase in transmissibility.

  36. Marko says:

    People vacationing in London hospitals are having oxygen-snorting parties, apparently , depleting supplies :

    https://www.independent.co.uk/news/health/coronavirus-london-queen-elizabeth-hospital-oxygen-b1779468.html

    1. A Nonny Mouse says:

      Build the wall…. Again….

  37. Marko says:

    If these graphs are correct and the trends continue, ~90% of new infections in the UK will be with the new variant by Feb 1 :

    https://twitter.com/TWenseleers/status/1343575693544796160

    We should know in a week or two if the trend is confirmed for certain, assuming genomic surveillance keeps up over the holidays.

  38. kevin smith says:

    The increased lethality of the more highly transmissible variants will come about because their increased transmissibility will cause overloading of the hospital and ICU systems, with the result that suboptimal care / no care will lead to increased case-fatality rate.

  39. Marko says:

    Update on the UK variant :

    “…Preliminary results from the cohort study found no statistically significant difference in
    hospitalisation and 28-day case fatality between cases with the variant (VOC
    201212/01) and wild-type comparator cases. There was also no significant difference in
    the likelihood of reinfection between variant cases and the comparator group. ”

    https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/948121/Technical_Briefing_VOC202012-2_Briefing_2_FINAL.pdf

    It would be reasonable to have hopes that the new variant might cause less severe disease, given several deletions that might be expected to impact virulence factors. No such luck, apparently.

  40. Marko says:

    “Perspective: If an American had moved to Denmark, Norway or Finland in January, her or his risk of dying from Covid would have been 5-10 times lower in 2020. South Korea, Liberia, or Hong Kong: 50-60 times lower. New Zealand: 200 times lower. Taiwan: 3,400 times lower.”

    https://twitter.com/DrTomFrieden/status/1343632152580288513

    The denialist gurus told us : ” Oh , just wait a year or so – every country’s numbers will look the same”. Wrong again, as they have been at every step along the way. The differences noted above will still be evident when the pandemic is well and truly over, because the vaccines will curtail the pandemic fatalities in a few months , at roughly the same time in all those countries. The US and the UK will have overseen a needless carnage relative to their peers because , to a disturbing degree, they’ve become nations of morons , led by morons.

    1. A McMoran (born 1916) says:

      As we al’ays used to say back in th’ Gorbals in th’ nineteen twennies when Aye were a wee laddie, “It takes ‘an to ken ‘an…”

  41. Marko says:

    “Hello, I run a network for over 46K doctors. Things are really bad on the frontline and NHS doctors need help getting the word out. If you support the NHS would you tweet this to your followers so I can help get out what is happening on the ground?”

    https://twitter.com/sbattrawden/status/1343652707937243137

    People disparaging docs like this one as being part of some giant hoax are among the lowest life forms on the planet, and a few of them comment regularly here. My fervent prayer for them is that karma really is a bitch , a scorchingly vindictive bitch.

    1. Tony M says:

      I am not a medical person. However, I have been following the debate on outpatient treatment for people initially diagnosed with Covid-19. The NHS hospitals in the UK are currently been overrun with Covid-19 patients. Honest Question: In the UK when an initial diagnoses of Covid-19 is made, are patients prescribed early outpatient treatments by their doctors or are they told to self isolate and then go to the hospital when they deteriorate?
      Example of possible outpatient treatment been discussed in US :

      Outpatient Treatment Guidelines for COVID-19 Aim at Reducing the Risk of Hospitalization and Death
      Source: https://covexit.com/outpatient-treatment-guidelines-for-covid-19-aim-at-reducing-the-risk-of-hospitalization-and-death/

      Regards

    2. Chris Phillips says:

      I agree completely. At this stage, denialism is more than just stupid and perverse. It could cost many lives, and I would shed no tears if some of those lives were the denialists’.

      The politicians in the UK still seem to be pressing on with the reopening of schools in the New Year. In the south east of England hospitals are full and the NHS is at breaking point. How many times can people carry on making the same mistake – over and over again?

      1. Lambchops says:

        It’s just barmy.

        I was expecting an announcement of a nationwide lockdown in England on Boxing day (or soon after) and yet still nothing (other than some vague rumours of yet another “tier” being introduced – I’m assuming that would be back to the initial April lockdown rules or something close to them).

        Inaction and dithering time and time again as cases rise – it beggars belief.

  42. Chris Phillips says:

    From the BBC:

    The number of people being treated for Covid-19 in hospital is now 20,426, which is higher than the previous peak of about 19,000 in April.

    Now, a senior doctor has said that health staff are considering the idea of setting up tents outside hospitals to triage patients.

    Emergency medicine consultant Simon Walsh, who is deputy chair of the British Medical Association’s UK consultants committee, said such plans were normally reserved for dealing with major incidents such as terror attacks or major industrial disasters.

    But he told the PA news agency that many trusts in London and south-east England were “effectively operating in a major incident mode”, with crisis meetings, and staff asked to work on their days off.

    He added: “They are dealing with queues of ambulances outside many emergency departments, often with patients sat in the ambulances for many hours until they can be offloaded into the department because there simply isn’t any space to put them in.”

    https://www.bbc.co.uk/news/live/world-55473196

    1. Bill says:

      At least the UK is vaccinating based on age. Here in the states the hospitals are now filling to capacity, mostly with people over 65.

      But we’re vaccinating young people. Not just doctors and nurses, but administrators, spouses, cops and firemen.

      Population over 65 are scheduled for fourth category as opposed to grocery store box boys who are third category. You can rationalize anything but ignoring the category of people who are actually flooding the hospitals now and in the future is stupid — even criminal.

      1. Marko says:

        Tulsi Gabbard making the same sensible argument regarding vaccination rollout in Hawaii :

        https://www.youtube.com/watch?v=J61nZOfqDTY&list=TLPQMjkxMjIwMjDgc6CrW5bY6A&index=10

        If it looks like a cull and quacks like a cull, it’s probably a freakin’ cull, and it shouldn’t be so surprising to people. We’re led by psychopaths.

      2. DataWatcher says:

        I’ll go along with the cops and firemen, and I also think all healthcare personnel who are likely to have person-to-person contact with high-risk patients should be prioritized. Does this include commissary workers, orderlies, and other service workers? It probably does. It also includes medical assistants and aides, esp. in nursing facilities. In fact, although a lot of people here will probably disagree, I’d also include home healthcare providers who work with elderly people at home.

        Teachers? That’s a tough one, although knowing a few teachers who actually contracted COVID this year while teaching, I’m inclined to believe they should be pretty high-priorit7y, especially as we do our best to re-open classrooms (and especially since we will not be vaccinating children at all, at least not until Fall 2021 at the earliest).

        And we also need to very seriously take into consideration the fact that poor and “minority”
        communities and individuals, regardless of age, are at disproportionate risk of becoming seriously ill and dying. Speaking for myself, I’m over 65, but I’m in pretty robust health and my finances are secure. If I have to wait a little longer to take off my mask and hug my friends so the single mom on the next block who can’t afford health insurance and who is struggling to feed her kids can have access to the vaccine, then I’m ready to do so. My turn will come soon enough.

  43. Chris Phillips says:

    Public Health England technical briefing on the new variant:
    https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/948152/Technical_Briefing_VOC202012-2_Briefing_2_FINAL.pdf

    Few differences from other variants of the virus among the properties examined (including reinfection), but attack rate (percentage of contacts infected) is 15.1% rather than 9.8%, in line with the 50% increase in transmissibility estimated previously.

    1. Marko says:

      Muge Cevik has updated her very good Dec. 21 thread on the UK variant to include the new data:

      https://twitter.com/mugecevik/status/1341094836682838021

    2. Marko says:

      This bit about the sequencing data is interesting :

      https://pbs.twimg.com/media/EqaSdpGW4AIQawJ?format=jpg&name=small

      They collect the PCR sample plates from labs around the UK, then randomly select positive wells from the plates from each region so as to generate a representative genomic survey. Amazingly, it appears they can generate enough of a complete sequence to define the variants out of 98-99% of such PCR+ samples. How do the PCR-bashing denialists explain this?

      Of course, that’s not all they have to explain. We also now know that nearly 100% of PCR+ subjects , including asymptomatics, develop a CoV2-specific antibody response that can be detected with a timely (~30 days post-symptom onset ) and sensitive assay.

      In order to claim that PCR testing is non-specific, you’d have to show that sequencing and antibody assays are also bogus. In other words, you’d have to invoke faith in an anti-science god, rather than science itself, to explain this.

  44. Marko says:

    New from ECDC :

    “Risk related to spread of new SARSCoV-2 variants of concern in the EU/EEA -29 December 2020”

    https://www.ecdc.europa.eu/sites/default/files/documents/COVID-19-risk-related-to-spread-of-new-SARS-CoV-2-variants-EU-EEA.pdf

  45. Marko says:

    “For countries that have not already confirmed high levels of community transmission of a variant of concern, efforts to delay the spread should mirror those made during the earlier stage of the pandemic”

    https://pbs.twimg.com/media/EqbOEEaXMAAVbx4?format=png&name=small

    Boy, is that the wrong advice to give to the US. In the earlier stage of of the pandemic, our strategy was to reduce the spread by not testing ( no tests = no cases ).

    Don’t worry, though. Trump assures us, from the golf course, that we have the UK variant “under control”. Pretty soon it will “just disappear”.

  46. Marko says:

    First detection of the UK variant in the US, in Colorado :

    https://www.colorado.gov/governor/news/3856-gov-polis-and-state-public-health-officials-announce-first-case-covid-variant-covid-19

    No travel history, so probably just one of very many.

  47. Chris Phillips says:

    The Oxford vaccine has been approved for use in the UK. But the tested protocol is indeed going to be abandoned – apparently both for this and the Pfizer vaccine:
    “Having studied evidence on both the Pfizer/BioNTech and Oxford University/AstraZeneca vaccines, the JCVI has advised the priority should be to give as many people in at-risk groups their first dose, rather than providing the required two doses in as short a time as possible.
    Everyone will still receive their second dose and this will be within 12 weeks of their first. The second dose completes the course and is important for longer term protection.”
    https://www.gov.uk/government/news/oxford-universityastrazeneca-vaccine-authorised-by-uk-medicines-regulator

    1. Marko says:

      Good for the UK. Their vaccine rollout strategy will save more lives, though they’ll be criticized for not going “by the book”. I suspect they’ll also do a better job of targeting the truly at-risk population first than what we’re doing in the US.

      1. RHB says:

        Well done, Teams AZ, JCVI, MHRA, NHS, OXFORD and GOV.UK. Team UK leading the way globally. Just like Team British Isles once upon a time did – Newton, Boyle, Brindley, Bridgewater et al. In time, could even play out as PM.UK’s Falklands moment.

        First anniversary tomorrow of first death reported by global media. As history teacher Mr Irwin once first advised The History Boys at the the Royal National Theatre, London, on 18 May 2004…

        “But this is history. Distance yourselves. Our perspective on the past alters. Looking back, immediately in front of us is dead ground. We don’t see it and because we don’t see it this means there is no period so remote as the recent past and one of the historian’s jobs is to anticipate what our perspective of that period will be…”

        https://en.wikipedia.org/wiki/The_History_Boys

        https://en.wikipedia.org/wiki/The_History_Boys

    2. Lambchops says:

      I’m guessing this decision is partly linked to the data being mentioned in the press that the AZ vaccine is supposedly 95% effective when the doses are given 3 months apart: https://www.livemint.com/science/health/efficacy-of-oxford-jabs-at-95-if-given-3-months-apart-sii-11609181643451.html

      While I’ve got some scepticism towards this claim given all the questions around the AZ data so far (it’s hard to believe that these data will be based on anything other than some post-hoc analyses on small subgroups of patients at this stage) given the current situation the fact this approach will allow more people in priority groups to be vaccinated may be a good thing – even if the efficacy turns out lower than claimed. Particularly so if it allows front-line health workers to get vaccinated quicker and potentially relieve some of the pressure on the NHS. I guess we’ll wait and see if the priority groups for vaccination are tweaked slightly as a result of this announcement.

      Still I don’t think AZ’s attitude throwing top-line comments around in the press has been helpful of late and I’d like to hear more from them about what further data they’re planning on collecting to clarify efficacy/safety for this approach.

      We’ll also wait and see what’s happening in terms of restrictions on movements later today but from the sounds of it there will be a lot more messing around with tiers, which just seems the wrong call at this stage – the cynic in me says that Boris is trying to avoid being accused of locking down the whole country when there are problems in London and the south east, whereas in previous options he kept London under lighter controls while imposing tough restrictions on the north of England.

      1. sgcox says:

        From MHRA announcement on BBC today about approval:

        “Results of half dose regiment not borne out by full analysis”

        So once again, post-hock subgroup analysis is PR exercise, nothing more.

        1. Mariner says:

          If I remember correctly, the half-dose group encountered longer delays between receiving their first (half) dose and the second full dose than should have been the case? This could perhaps be where the apparent improved efficacy came from, as opposed to the lower dosage? I could be misremembering, of course.

          Given the rapid spread of the new variant, of the data is good enough to indicate that just one dose will protect enough against serious disease, then I think the plan to roll it out quickly is a good idea. I’ll be getting it myself in a couple of months, no doubt. My wife is a teacher so she’ll probably get it sooner.

          1. A Nonny Mouse says:

            Interesting that it says 3 x more antibodies at 28 days post 12 week delay rather than the <6 week delay. Even 2 x more when at the 9-11 week delay.

            It would have been interesting to see the <6 week delay at the + 6 week time period, though the 9-11 week should be close enough

          2. Lambchops says:

            So is the “95% efficacy” claim based on simply comparing the antibody levels post second dose of the 9-11 week delay group with the post second-dose figures from the Pfizer/Moderna studies? If so that’s a pretty strong claim (that could be valid but needs a lot more caution than claiming a “magic formula” or something along those lines).

            That said, on first glance this does seem to support changing the interval for the roll-out strategy – while 95% efficacy may be a strong claim, it looks like there’s enough there to suggest that efficacy is likely to be better than with a shorter interval and certainly not any worse.

          3. RHB says:

            Agree with Chris Phillips. MHRA “Regulation 174 Information for Healthcare Professionals on COVID-19 Vaccine AstraZeneca” is hard going, especially for vaccine non-expert. As is the AZD1222 Lancet paper with in depth data:

            https://www.thelancet.com/action/showPdf?pii=S0140-6736%2820%2932661-1

            A few things picked out from print out of Regulation 174 Info (preceded by document section number and with poster’s comments/queries in brackets):

            2. “One dose (0.5 ml) contains… 5 × 1010 viral particles” (so occurs to wonder out loud, how many real viral particles needed to kick off real disease?)

            2. “Product contains genetically modified organisms (GMOs)”

            4.2. “The second dose should be administered between 4 and 12 weeks after the first dose”

            4.2. “Efficacy and safety data are currently limited in individuals aged 65 years or older” (highest priority UK age group(s)!)

            4.4. “The duration of protection has not yet been established… vaccination with COVID-19 Vaccine AstraZeneca may not protect all recipients.”

            4.8 “Overall… 9.7% [of participants] were 65 years of age or older” (hence only handful of clinical trial cases in this age group?)

            4.8 “Adverse reactions were generally milder and reported less frequently in older adults aged 65 years and older” (implying potential for less protective effect in this critical age group?)

            Will refrain from comment on Section 5 (“Pharmacodynamic properties”) as too nitty gritty for vaccine non-expert.

            From past experience in Pharma R&D, overall layout has feel of originating from summary document to support transition to next phase of clinical development.

            No wish to nitpick, but evidently done in haste, text referring to “Table 2” and “Table 3”, yet no mention of “Table 1,” and the two tables included are not captioned with a table number.

            Table headed, “COVID-19 Vaccine AstraZeneca efficacy against COVID-19” also rather confusing, as one column not headed and other four columns have two rows of headers – not clear to this reader how these rows relate to each other (may have been a table copy and paste issue from Word to html?).

            Final thought… AZD1222 paper in Lancet “Published: 08 December, 20”, but submission and acceptance dates not cited. Independent review quaint old nicety of the past it increasingly seems in these stressed and urgent times. No doubt just the same for penicillin 76 years ago – but back then there was of course a full blown international conflict going on.

          4. Marko says:

            “2. “One dose (0.5 ml) contains… 5 × 1010 viral particles” (so occurs to wonder out loud, how many real viral particles needed to kick off real disease?)”

            To kick off real disease, probably comparable numbers. To kick off an infection leading to real disease, a disappearingly tiny fraction is required. I hope this is obvious to you.

            The viral vector used in the Oxford vaccine is non-replicating , so what you inject is what you get in terms of viral particles.

          5. RHB says:

            Re, Marko: “To kick off an infection leading to real disease, a disappearingly tiny fraction is required. I hope this is obvious to you.”

            No, not obvious to me. For my education, would you be able to please provide link to definitive article to back up statement?

            Also thinking out loud, dependent on immune status of viral recipient, or maybe that’s a different question?

        2. debinski says:

          Although it’s a little risky to change the dosing interval (efficacy-wise), it really does look like the UK is trying to get vaccine to the most people as quickly as possible and to the most vulnerable to severe disease. Their roll-out is mostly based on age and comorbidities – unlike the US plan. We are vaccinating teenagers who work part time at the grocery store and teachers who are mostly working virtually before elderly (64-75) and people with comorbidities. What happened to preventing hospitalization and death? So glad congress and other federal government workers are at the top of the list!! Hmm, I wonder how that happened?

          Article on UK approval of Astrazeneca vaccine: https://www.bbc.com/news/health-55280671

  48. A Nonny Mouse says:

    To Lambchops….

    Dose Interval – – –
    <6 weeks (N=481) 60.51 (54.1; 67.7) (N=479) 8,734.08 (7,883.1; 9,676.9) (N=443) 22,222.73 (20,360.50; 24,255.3)

    6-8 weeks (N=137) 58.02 (46.3; 72.6) (N=99) 7,295.54 (5,857.4; 9,086.7) (N=116) 24,363.10 (20,088.5, 29547.3)

    9-11 weeks (N=110) 48.79 (39.6; 60.1) (N=87) 7,492.98 (5,885.1; 9,540.2) (N=106) 34,754.10 (30,287.2; 39,879.8)

    ≥12 weeks (N=154) 52.98 (44.4; 63.2) (N=152) 8,618.17 (7,195.4; 10,322.3) (N=154) 63,181.59 (55,180.1; 72,343.4)

    Number, mean age, antibody titre first dose, antibody titre second dose (both + 28 days).

    All A-Z, no Pfizer which is probably why they don't like the fact that theirs may also be given at up to 12 weeks.

  49. Charles Coe says:

    Pretty complete article in Nature Communications on variants and transmissibility:

    https://www.nature.com/articles/s41467-020-19818-2

    1. Marko says:

      Balloux has a well-established reputation for getting Covid-19 stuff wrong. Baric’s subsequent article on D614G, among others, consigned Balloux’s to the trash heap, where it belongs.

      If you’ve noticed, Balloux has been carefully straddling the fence on the issue of transmissibility of the UK variant. He trying to preserve what little credibility he has left.

      1. Dr Sternberg says:

        True to form, Marko, man taken, ball run off with. Past bruised shins and ruptured anterior neuronal network myself to prove it. But when going gets tough…

        Kick another ball against wall… If reading right, Balloux et al (UC London, Radcliffe, Oxford and Reunion, France) state ~47K SARS 2 genomes identified from patients worldwide. Some in silico homophasic black boxery then establishes none of 185 recurrent mutations “more transmissive”?

        Paper found from Farzan et al (Scripps/Emory/Beijing):

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693302/pdf/41467_2020_Article_19808.pdf

        …Showed experimentally that mutant pseudovirus better cellular entry. Okay, more compelling – as far as it goes… but still deep inside team’s own half and nowhere near opponent’s goal.

        For newer visitors and posters, Derek Lowe’s blog goes back 15 years and began life as a blog focussed on medicinal chemistry in drug R&D. For last 9 months, blog understandably rather taken over by the science of a wider event.

        As Derek’s blog posts have alluded to plenty of times over the years, drug R&D is about getting to compounds that meet the many and varied requirements of national regulatory authorities – nowadays, among others, proof of drug target potency and engagement; profiling target selectivity; understanding human drug pharmacokinetics and pharmacodynamics; convenience, reliability and reproducibility of dosage; efficacy, tolerability and safety in human beings, etc, etc.

        As Derek has also pointed out in the past, scientists working in Pharma R&D tend to appreciate better than scientists in academia the multifactorial nature of drug R&D, academic scientists having a tendency to over focus on the early stage data, primarily in vitro, that they work with most of the time.

        So to this retired medicinal chemist, now an eye opener to see how over a period of a couple of weeks, the “in vitro” viral mutational data, summarised with typical elan by Derek in posting “The New Muations”, has already become enshrined in public health policy here in the UK…

        …And, for example, has already led to government-imposed partial school closures for the first two weeks of the forthcoming term (with prospect of more to come, while at same time school teachers and heads grapple with proposed virus testing programme of school children announced by government as the previous term ended, with usual minimal notice that’s come to be expected, as if a war was on).

        Now this medicinal chemist appreciates response to viral epidemics requires urgency, but with every twist and turn of government policy in response to the latest “in vitro” viral data happening almost daily in front of the UK populace’s very eyes, the med chemist also wonders if a load of potentially decision making “in vivo” data are being bypassed here.

        Might be unattainable to gather data in useful timescale, but if med chem anology holds then past medchem experience tells helluva lot of latest “in vitro” viral data could get overtaken by more meaningful “in vivo” data, and make latest twist and turns of policy look very debatable (which gut feel tells some are).

        Thinking scientifically more widely, most med chemists come from pure chemistry background, pure chemistry being oft cited as applied physics. Newly recruited Pharma med chemists (which number falling inexorably over last three decades) then come up against complexities of biology and all the other ‘ologies, and over time come to realise med chemist’s trade is strange hybrid of applied chemistry and applied biology…

        …In which in R&D assay data may have whole range of credibility. Reasonably solid for much of chemistry data, but at any one time some or even most of a project’s biology data could be a case of shifting sands. Frequently occurs in earlier stage projects, but even in later stage projects sinkhole can open up and swallow whole swathes of data, taking chemical equity with it. Kerching! Next project!

        So medchem is applied pure chemistry, which is applied physics. Broadly speaking, the physics of a century ago that wondrously came up with quantum theory. In physics terms, that’s the best medchem can do, although maybe those lead to drug flowcharts that started appearing in medchem papers about two decades ago show a hint of Feynman diagram thinking.

        Which means there’s Physics gone on since quantum theory, that in a century’s time could have filtered down to medchem, if by then there’s any chem left to med (string theory anyone – if only I could work out what it is, unless maybe just a fancy term for information exchange?).

        Which could mean, if medchem seems “solid” compared with biology, maybe all this epidemiology, virology and immunology may not be that solid at all. Which Dr Sternberg, cousin of Dr Leo Sternbach, who once upon a time told the warts and wizards tale of where the first tranquillisers librium and valium came from…

        https://pubs.acs.org/doi/abs/10.1021/jm00187a001

        …Now submits that case for adding to 575 million schooldays lost in UK’s first lockdo*n (with another couple hundred million child self isolator days thrown in since) could turn out debatable, or maybe even counter productive, when looked back at in the future through history’s lens. Time will tell (along with who gets to write the history books…)

        Apologies Marko, elderly gramps Dr S been off rambling again and back for appelsaus…

  50. Marko says:

    Mutations arising in cell culture under selective pressure of convalescent plasma confer antibody resistance :

    https://www.biorxiv.org/content/10.1101/2020.12.28.424451v1

    “…The recent emergence in the United Kingdom and South Africa of natural variants with similar changes suggests that SARS-CoV-2 has the potential to escape an effective immune response and that vaccines and antibodies able to control emerging variants should be developed.”

  51. Marko says:

    New report from Imperial College :

    “Report 42 – Transmission of SARS-CoV-2 Lineage B.1.1.7 in England: insights from linking epidemiological and genetic data”

    https://www.imperial.ac.uk/mrc-global-infectious-disease-analysis/covid-19/report-42-sars-cov-2-variant/

    1. Marko says:

      Also new :

      “Lineage-specific growth of SARS-CoV-2 B.1.1.7 during the English national lockdown”

      https://virological.org/t/lineage-specific-growth-of-sars-cov-2-b-1-1-7-during-the-english-national-lockdown/575

    2. The King’s Royal Alchymist says:

      NEW YEAR’s DAY RECIPE Year of Our LORD 1521: Admixing Frogs & Toads, as told by The King’s Royal Alchymist Baron Nyell de Flummoxyngham to scribe JRR de Tolkien the Younger

      Order two servants to adjourn to ye banks of ye Thames before dawn wyth horse and cart to procure a vast cawldron of swyrling fog sealed withyn ye cawldron by ye tyghtly fitting lyd.

      Order a third servant to adjourn to ye banks of ye Thames at low tyde to procure from ye ryver’s mudflats two parts boxes of frogs. Ye third servant may report an old woman at ye mudflats dressed in dyfferentyially coloured rags, warning – tell thy master nothyng good wyll come of boxes of frogs. Ignore her, lest she be a wytche.

      Retyre to your pryvate laboratorium with aforementyioned vessel of swyrling fog and boxes of frogs. Remove lyd from cawldron and lower two parts boxes of frogs into cawldron below surface of swyrling fog. Replace lyd and leave cawldron to stand in laboratorium at ambient temperature.

      Return to laboratorium nine months later. Order your third servant to adjourn to mudflats on opposyte side of ye River Thames at low tyde to procure two boxes of toads. Ye third servant may this tyme report an old man at ye mudflats dressed in dyfferentyially coloured rags, warning – tell thy master nothyng good wyll come of boxes of toads. Ignore him, lest he be a warlock.

      Remove cawldron lyd and with utmost cawtyion introduce two parts boxes toads below surface of swyrling fog. Replace cawldron lyd wyth utmost haste, ensuring tyght, and retyre from laboratorium forthwyth.

      Return to laboratorium one week later, takyng care to leave laboratorium door wyde open. Forthwyth open all laboratorium wyndows as farly as hynges do permyt.

      Put on appropryate PeePeeEee in form of noble famyly armour, helmet and protectyve colours. With utmost utmost cawtyion, gently lift cawldron lyd and then toss asyde with haste. Retreat yet more hastyly in dyrection of stairs to baronyal battlements, ensuring all baronyal doors withyn baronyal resydence left closed but main resydence door left open to ensure egress of egregious emergences from cawldron.

      Retyre to battlements and observe openyng salvo of four to ye power of nineteen eighty four Gyant Froads descendyng upon Grate Cyty of London and adjacent south eastern envyrons of Ye Realm.

      Summon thy scrybe JRR de Tolkien ye Younger and order thy work enscrybed in two copies, one for thyself and one for Ye King of Ye Realm Hymself in Person. Delyver to Ye Palace wyth thyne own hand for attentyion of Ye King.

      Request audyience with Ye King. In primundum, advyse King to advyse intyre Realm to stay indoors to stay sayfe, save lyves and protect all almshouses from infestatyion by Gyant Froads. In secundum, advyse King to order all alehouses shut to prevent people gatherying, gossipyng and werretying therein about doiyngs of Gyant Froads.

      In triendum, advyse King people wyll be much troubled throughout Realm then confyned thus in dwellyngs and almshouses. In quadrendum, advyse King to proclaym to Inytre Realm War to be declayred upon Enemy of Gyant Froads to reassuyre people of Ye Realm King knows what Ye King be doiyng.

      Fynally, advyse King to commence War by summonyng archers with longest longbows capabyle of dyspatching longest arrows in Ye Intyre Realm in order to guard almshouses and fyght off attaking Gyant Froads thereat.

      Retyre to baronyal battlements to observe Gyant Froads advancyng, notyng expected development that Froads now also joyned by Gyant Trogs egressyng and emergyng egregiously from Laboratorium in droves upon droves. Summon scrybe de Tolkien to send news of Gyant Trogs joyning Gyant Froads dyspatched forthwyth to Ye King.

      Observe Froads and Trogs infestyng Great Cyty of London and keepyng intyre people wythin dwellings and almshouses. Observe agaiyn as vast army of Froads and Trogs spread beyond Ye Cyty, fyrst upon south eastern envyrons of Ye Realm and then throughout Intyre Realm of UnMerrie Ingland.

      Note how, as thou had predycted, people now much feared now throughout Realm confyned wythin dwellyngs and almshouses. Now be moment to summon scrybe de Tolkien to dyspatch sygnal to Ye King to order archers wyth longest longbows sent forth to engage with Gyant Froads and Trogs and to dyspatch longest arrows from longest longbows to dyspatch ye Enemy, in primundum ye Froads and Trogs attakying almshouses and in secundum ye Froads and Trogs infestyng dwellyngs of ye Realm.

      Observe ye battle commence throughout Ye Realm. In primundum, order scrybe de Tolkien to dyspatch sygnal to King to proclaym to Intyre Realm ye war with Gyant Froads and Trogs be over by ye Festyval of Easter and ye moment of Ye Proclamaytyion of Ye Resurrectyion of Ye Realm.

      In secundum, retyre from battlements to Laboratorium and in pryvatio to scrybe de Tolkien, order de Tolkien to enscrybe pryvate sygnal to Ye King.

      Deliver with thyne own hand to Ye King. In pryvatio advyse Ye King ye tyme of Ye Resurrection be not this Year of Our Lord 1521, for be ye Gyant Froads and Trogs so devyous and near overwhelmyng in ye power, ye year of Victory in Name of Our Lord will become to pass… 1524.

      In triendum, in pryvatio with King advyse Ye King to advyse Ye people ye two weeks before Easter, due to ye power and ye devyousness of Froads and Trogs Ye Resurrection be now not at Festyval of Easter. Decree to ye people of Ye Realm Easter be cancelled and ye must confyne unto ye dwellings untyl ye Midsomers’ Day when for certaiyn Ye Resurrectyion be.

      In quadrendum in strictum privatium, advyse Ye King Ye King must repeat ye proscryption quadriannually triennially until Year of Our Lord 1524 attayned. In pentedendum, advyse Ye King Ye King’s reward be unto Heaven and ye people of Ye Realm in ye next electionum officium, which by that tyme passyng may become Ye Referendum Secundum de Parliamentum. Amen.

      Retyre to thy pryvate laboratorium to reflect on ye job well dun. Order thy three servants to adjourn to ye River Thames to duck ye olde wytche in ye festeryng ryver waters and plaster ye old warlock in ye thych oozyng mudflat mud thereof. Contemplayte ye recipe for ye next alchymy, ye admyxing of supposityion, superstityion and ratyional thort in ye lateste gyante cawldrone.

      Reclyne in ye armchayr in ye laboratorium and put ye feet up on ye laboratorium bench. Summon ye pryvate balladeer Dylan of Greenwych and accompanying lyre for ye soothyng pryvate rendityion of ye old ballad Ye Tymes Be ‘a Changyn’. Fall asleep and sleep ye sleep of ye rightyeous and all knowing, as rendityion ends with balladeer Dylan of Greenwych proclayming…

      “And the first one now will later be last
      For the times they are a-changin’…”

      And so, as New Years Day 1521’s twilight draws in, 1521’s New Year’s Day musik fades away. Fallen silent for the early evening, Musik’s resonances set off on long journeys forward into unfolding experimental macrodramas, later referred to as histories…

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