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Coronavirus Variants: Down to the Details

It’s my impression that the pace of headlines and tweets, etc. about the many COVID-19 variants has increased recently (and it wasn’t exactly an unexplored topic before). Some of the coverage is just horse-race stuff (here comes this one, around the curve comes that one), but some of it is downright alarmist. And while I’m not here to tell you that everything is peachy, I wanted to add my voice to the folks who are trying to tell everyone not to freak out. Here’s why.

Variants in General

First off, it’s important to remember that variant forms of this virus have been happening constantly, all the way through the pandemic. In fact, it’s a safe bet that every single person who has been infected has had many variant coronavirus forms occur in their own bodies during the course of their infection. The huge, overwhelming number of those possible variations, though, are less competent than the variety that infected a person in the first place, so we never even notice them. They vanish before we even know that they were there, because they don’t have any reproductive advantage (or have outright disadvantages compared to the original type). It’s the same with viruses as it is with us: most point-change mutations are silent, and most of the rest make things either somewhat or greatly worse. Beneficial fitness-enhancing mutations are rare indeed.

But of course, with a cycle time as short as a virus (and a reproduction rate as great as one) any such beneficial mutation (or combination of them) has a chance to stand out pretty quickly against the endless melting-snowflake background of mutations that do nothing or worse. That’s how a variant like B.1.1.7 takes over so quickly. Keep in mind, though, that it’s actually a form with a whole list of changes versus “coronavirus classic”, and that’s surely why it’s taken this long to show up.

Maciej Boni makes that point here. The fitness advantage of the new variants we’re seeing has been built up through several mutations that have piled on top of each other – we are, in fact, seeing evolution at the molecular level going on right in front of our eyes. To that point, this is also a pretty good argument that the coronavirus only recently made the jump into humans – it’s facing a whole new set of selection pressures and heading off into directions that it never was forced to explore in bats, pangolins, or what have you. (Of course, if we had historical examples over a long period in those animals, we’d be able to see what adaptations rose to the top in those species, but they surely wouldn’t be the ones that do the best job against us).

Getting Down to the Tiny Details

There’s a lot of good information out there about all this, but this new paper is a good one-stop-shop. It’s from a large multi-center team in the UK, and it concentrates on the B.1.1.7 variant. That one, the B.1.351, and the P.1 variants all have multiple mutations , with several of them in the Spike protein and indeed in its “business end”, the receptor-binding domain (RBD) that interacts with the ACE-2 protein on the surface of human cells. The N501Y mutation is common to all three of them, and that is a very strong indication that it by itself provides some fitness advantage – you have it as part of three expanding variants in completely different parts of the world, each with their own suite of other mutations.

We’ll look at that one in detail, but first, it’s worth thinking about where these multiple-mutation lines come from. As Maciej Boni says, hitting any beneficial point mutation is like winning the lottery in any genetic sequence, so coming up with a whole list of them means that you have to win the lottery several times over. The only way you’re going to do that in a few months is with something with as fast and numerous a turnover as a virus (bacteria can pull it off, too, for the same reasons). The most likely way that these things happen is for the whole process to take place inside the body of a single patient – one with a grinding long-term coronavirus infection that their immune system is having trouble clearing. This report from December of an immune-compromised patient is exactly that situation: this unfortunate person suffered from at least 154 days of coronavirus before dying from it and his underlying conditions. Sequencing of the virus at different points during this infection shows unmistakeable evidence of its evolution under these forcing conditions – constant immune system attack, but never quite enough to kill the infection off. Those are just the conditions you would use in a lab to generate resistant forms of a virus or bacterium (and it’s just what is done to probe the weak points of a potential new antiviral or antibiotic drug). It’s entirely plausible that these multiple-mutation variants are coming (at least partially) from such patients. In the case of B.1.1.7, it looks like strains with the N501Y mutation and others were already out there last fall, but the addition of a further deletion mutation at residues 69-70 pushed it along a bit further, and that’s the form we’re seeing today.

So what it is about N501Y? The illustration above is from the current Cell paper, and shows (at the bottom of each pane) the N501 form (where the residue is asparagine) and the Y501 form where it’s been mutated to tyrosine. It appears that the new tyrosine of the coronavirus RBD has a chance to form better interactions with two of the amino acid side chains of the human ACE2 receptor, the tyrosine at 41 and the lysine at position 53. You don’t get much more zoomed-in than this – this, in fact, is the level that medicinal chemistry works at (or tries to work at!) all the time. All of our drug potency and selectivity advances, all of our screening hits and promising candidates. . .in the end, they come down to single side chains, functional groups, sometimes single atoms on those groups making slightly better or slightly worse contacts with some protein target. That slight increase in stickiness, the slightly slower off-rate afforded by the interactions with the pi-electrons of the tyrosine ring and the polarity of its phenolic OH group: these are the sorts of things that can alter the course of the pandemic. In fact, that off-rate effect is explicitly demonstrated in this paper through binding experiments using an SPR assay (surface plasmon resonance, the gold standard for this sort of thing), and these show clearly that the tyrosine form parts with the ACE2 protein more reluctantly.

At this level, you’re getting close to what happens when you zoom in so closely on an image that you start seeing the pixels (or the film grain, if you’re around my age or older!) These sorts of molecular interactions are the pixels of medicinal chemistry and of biochemistry in general, added up in their billions and summed up every instant for their positive and negative effects. And if you start to think about how any of those work by themselves, you end up talking about quantum mechanics and the behavior of the actual electrons around the individual atoms and bonds, and that really is a glimpse of the pixel level of reality itself. What a shock it was, about a hundred years ago or a bit more, when it started dawning on people that the universe did indeed have such a granular texture, both in terms of its matter and in terms of its forms of energy, and that indeed the two of those were actually just two sides of the same (almost incomprehensible) coin. It’s worth the occasional reminder that everything, pandemics included, comes down to such things if you pay close enough attention.

In this mutation, the advantage of N501Y is probably not only that it gives slightly better binding to the human cellular target, but that it simultaneously gives slightly worse binding to several types of antibody that were raised to a form of the virus that had an asparagine there rather than that newfangled tyrosine. This change is going to be through the same sorts of interactions, and in this fallen world one should not be surprised to see sins both of omission and of commission. My old biochemistry professor, Bob Schideler (who was indeed old, even in 1982) referred to functional groups on molecules as “peculiar localizations of charge”, and there are surely favorable interactions with the electrons around the asparagine side chain that are no longer there after the switch to tyrosine, and quite likely new unfavorable ones that appear as well (one cloud of electron density banging into another in a negative-charges-repel manner, for example). The Cell paper demonstrates these changes against a large panel of such antibodies, and does a thorough job of showing the binding landscape. It seems very likely that this two-for-one sale (better binding to the target, worse binding to the antibodies that are trying to shut things down) is what’s led to N501Y being a component of so many new strains.

Variants Out in the Real World

But here’s the good news from this paper: there are a lot of neutralizing antibodies out there (present in people both after infection and after vaccination) and not all of them are affected. Even though the paper shows (as does work from many other labs) that overall neutralization is decreased with serum from recovered patients or from vaccinated ones, there is plenty left: “Though much is taken, much abides“. The paper notes explicitly that with B.1.1.7 there is no evidence of vaccine escape. (This is versus the AstraZeneca/Oxford vaccine, and the same statement holds for all the others).

That’s not to say that there can’t be such escape, in some future variant, as I was saying here the other day. It may be that the B.1.351 variant is a step towards this – but on the other hand, it may have gone down a cul-de-sac from which it will have trouble stumbling into further useful changes. That sort of thing happens constantly. The landscape of possible mutations is incomprehensibly vast, and their effects on binding (both to the viral target (ACE-2) and to the antibodies we’re raising against them) is similarly beyond calculation. But we know from observation and from our own experiments in molecular evolution that there are far more blind alleys than ways out of any particular maze.

The key is for us not to find out the hard way. Every single person that gets infected is another chance for the coronavirus to try its mutational landscape against another challenge, and as the B.1.17, B.1.351, and P.1 variants all spread, they’ll be trying their luck against us too. Relentlessly. And remember, those are just the ones we know about. The Cell paper above refers to global sequencing and surveillance for this sort of thing as “wholly inadequate”, and sadly, the authors are right about that.

I was quoting Angela Rasmussen on Twitter the other day, to the effect that if we’re tired of the virus winning evolutionary Powerball drawings, then we should damn well stop selling it so many tickets. We do that by all that stuff everyone’s tired of hearing about, about masks and indoor gatherings and all the rest of it, and also by rolling out effective vaccines as quickly as possible. I am very, very glad to see the way that the case numbers (and hospitalizations) are going down across the US and in many other regions of the world. As best I (or anyone) can tell, this seems to be due to several factors working at once – I would not have predicted such a steep decline, and anyone who tells you that they absolutely saw it coming should be regarded with suspicion and invited to forecast where we go from here. But let’s take it and run with it. The harder these numbers drop, the fewer lottery tickets we sell to the coronavirus, and the better the chance we have to keep beating it down with further vaccination. I would love for us, as in “humanity” us, to actually get out ahead of this virus for once.

225 comments on “Coronavirus Variants: Down to the Details”

  1. Chris says:

    So why don’t more countries do more sequencing?

    1. sgcox says:

      Investment in infrastructure and trained people.
      UK was always a leader in genomics, in big part due to Wellcome Sanger.

    2. Calvin says:

      It’s a rather interesting story. The UK has spent a huge number of money on genomic sequencing generally driven mainly by Wellcome Trust and it’s still considerable funding of the Sanger. It also had the foresight to realize that genomics could be used for infection control and surveillance and about 10 years ago. It started pushing more money in that area and the large number of academics and clinicians who thought that the cost of sequencing would one day allow it to be practical. Sharon Peacock is one such example (among many), although she originally focussed on bacteria. She published some great work showing specific resistant bacteria moving from ward to ward in hospitals.

      So in some ways the UK’s approach was driven by previous expertise, infrastructure and focussed funding. Sanger brought the science. Wellcome brought the cash.

    3. Johnathan Hughes says:

      I honestly don’t know why countries aren’t doing genomic sequencing. This has been one of the real keys to keeping the virus under control in Australia and New Zealand – whenever there’s an outbreak, we very quickly find out where the source of the outbreak was, and often this gives the contact-tracing team evidence they need to find cases that hadn’t been previously detected. It’s such a no-brainer that it’s staggering to realise this isn’t default overseas.

      1. sgcox says:

        Trivial when you have 3 cases and shut down the country because of this 🙂
        Full sequencing be done in one academic lab.
        But when you have 10,000 per day or even 100,000 as in USA, sequencing even a small fraction is a serious business. Even to get all the logistics and equipment and train people is $$$ and takes time.
        There is a youtube illustration in this link

  2. J says:

    “Surface plasmon resonance, the gold standard for this sort of thing” Pun intended?

    1. sgcox says:

      As it was mentioned before in comments, they used Biolayer Interferometry, not SPR.
      A bit sloppy by Derek, very unusual. And yes, good pun if intended.

  3. Jonathan says:

    Is it possible the emerging new variants with similar mutations are less transmissible, not more?

    I was willing to believe the scientists on this at first, but looking around the world, at COVID cases dramatically dropping, I think many people are left speculating if it is possible the opposite may be the case.

    In the just one month, South Africa’s cases has dropped from a 7 day rolling average of 18,000 to 2,000 per day, even with one of the most concerning variants studied. Why? Same story in many regions where government measures have not appreciably changed in the last month and cannot be explained by vaccination rates.

    1. Patrick says:

      Certainly not for B1.1.7, which has been extensively studied epidemiologically. It also doesn’t match with the US picture – our sequencing rate should be higher but it’s high enough to know that all of the various “variants of concern” listed are a relatively small % of infections at this juncture. (And the drop has been going for a bit now.)

      It’s an interesting idea but I don’t think it really fits the data.

    2. RAD says:

      According to [1] B.1.1.7 has a longer infectious phase vs. the original virus:

      Proliferation: 5.3 days vs. 2.0 days
      Clearance: 8.0 days vs. 6.2 days
      Total Infectious Phase: 13.3 vs. 8.2 days (proliferation + clearance)


      via TWiV Livestream with A&V @1:12:05

    3. DataWatcher says:

      I admit I’ve harbored the thought — based on no data, hence totally unreliable, but undeniably hopeful — that perhaps some kind of natural immunity (whether from seropositivity due to previously uncounted asymptomatic/mildly symptomatic cases, or possibly frim some kind of heretofore undetected genetic/inherent immunity in some people or populations) could be driving at least some of this drop in cases. Certainly what we’ve seen in regions like many parts of India would seem to indicate that some individuals, if not entire populations seem to be unusually resistant to infection. At least arguably, the data from South Africa that Jonathan sites might also indicate something like this. This theory may well come crashing down in flames as B.1.1.7 and/or B.1.351 (and, eventually other mutant variants or even lethal recombinants) gain traction in the U.S. Nonetheless, it could be something to consider.

      1. Sarah James says:

        There’s also the typical seasonality/human cyclical behavioral component. In the US, we had a big surge after the holidays in January, but after the holidays, in the northern hemisphere, it’s cold, the days are long, and people tend to “hibernate”. There are not a lot reasons to gather, people start doing their taxes and their budgets for the new year. They also tend to sleep more in winter, and after the stress of the holidays is over, melatonin levels may possibly be increasing, and melatonin has many antioxidant benefits and could potentially be protective against infection.

        This may not sound scientific, but the combination of vaccinations, cyclical human behavior and a lot of snow in February in many parts of the country have likely kept people from gathering as much, which is a large driver of transmission.

      2. Caron says:

        Fink found that “Inactivated trivalent influenza vaccine is associated with lower mortality among Covid-19 patients in Brazil”. 17% lower, to be precise. Has the SARS-Cov-2 virus run through the non-flu-innoculated population and been slowed by those armed with 2020 flu antibodies?

        1. Marko says:

          Little known fact : The 2020 flu vaccine was actually a Covid-19 vaccine. A trial run, to see if people would start dropping like flies.

          Spread the word….

          1. Marko says:

            OK, it’s been 2 hrs. now, plenty of time for my comment to go viral among the nutjobs, so I can now reveal that it was pure BS. I’m just doing an experiment to see if I can plant a stupid idea into the brains of the stupid people. If it worked, we should see the evidence here over the coming days to weeks.

          2. DataWatcher says:

            Heh — I thought you were sarcastically mocking some of the posters here (maybe including me for my admittedly “non-scientific” brainstorming about the possibilities of as-yet undiscovered or unrecognized sources of natural immunity).

          3. Marko says:

            Actually, I’m open to the idea that non-specific vaccinations might have some beneficial effect. Over the short term, innate stimulation might provide some protection, and longer term, there’s at least a possibility of boosting some antibodies and /or T-cell populations that cross-react with CoV2 and provide some benefit. I don’t think any such effect is major, or else we’d know about it by now.

        2. Micha Elyi says:

          Alternative wild guess: Seasonal flu could be an opportunistic infection of people who come down with CoVID-19.

    4. Roland says:

      “government measures have not appreciably changed in the last month”

      It may be that the relentless worldwide news of scary super-variants has caused many to be more cautious about spreading it, in defiance of official restrictions so to speak, and that’s caused the decline.

      It’s hard to measure but based on some surveys and some indirect data on behavioural changes last year long before governments outside China/Italy put in place any restrictions, there’s a large disconnect between government measures and measures populations actually follow.

      1. DataWatcher says:

        It would be interesting — and, I think, surprising — if people started being MORE careful than their governments required. Every anecdotal example I’ve seen, from the U.S. and elsewhere, suggests the opposite — people are “getting away” with everything they can (gatherings, private parties, etc.), whenever they can. Even in places (e.g., Belgium) where these behaviors carry a significant fine, they’re still doing it.

        1. Roland says:

          It definitely happened back in the early “wash your hands and don’t touch your face” days. Tube use in London was down 20% in the 2nd week of March 2020, before any restrictions. In fact when the official line from an upbeat PM was that there would not be any restrictions at all.

          But it surely also happens in a relative sense with greater or lesser numbers of people ‘getting away with what they can’ or flouting some rules while respecting others, depending on their own assessment of the risk at the time, and the reasons for the restrictions. Finding out the virus is 50-100% more infectious than the one you’ve been dealing with for months is going to cause a re-assessment and behavioural changes for some even in the absence of official rule changes.

          An awful lot of people are staying at home more in any case. Naturally the anecdotes pick up the visible people outside so they don’t give a useful picture of what’s happening.

        2. Kevin Smith says:

          Perhaps when trump-ism was repudiated, covidiot-ism was also repudiated?

      2. stewart says:

        For example, I had decided to abandon public transport (and all travel not on foot) the best part of a month before the first lockdown in the UK.

    5. Charles H says:

      It’s certainly possible. Now why is that an advantage to the virus? Remember, the old version didn’t go away just because a new version showed up.

      One can certainly think of reasons *why* it might be advantageous, but it’s worth remembering that most of those won’t be advantageous to humans.

      FWIW, I suspect that any (pre-vaccination) slow-down in transmission is due to human social adaptations. Being better at keeping social distance, wearing masks, etc. We know those can have an effect.

      That said, a mutation allowing COVID to reside more durably on surfaces could well both slow down transmission, and increase the rate of infection. Perhaps that isn’t quite what you meant, but there are other alternatives. Most of them aren’t beneficial to humans. The only ones that I can think of that would be both decrease the severity of the disease and facilitate it hiding from the immune system, so it can remain resident longer in each host. But, of course, evolution isn’t restricted to only inventing things that I can think of.

  4. Rick Sheridan says:

    That Angie Rasmussen has a funny way of blocking scientific inquiry that she disagrees with when it comes to origin tracing. Just run down the list of block screenshots from:

    Her epidemiology advice might be great, but I’d have an easier time trusting in it if I was assured she was keeping a genuinely open mind across the spectrum of pandemic-relevant subjects.

    1. John Stamos says:

      That account is gold.

  5. AARON says:

    In the Cell paper linked above, biolayer interferometry was used to determine the RBD/ACE-2 off rate, not SPR.

  6. Marko says:

    This thread by Trevor Bedford has info on B117:

    Shows that Florida would the most likely “canary in the coal mine”, followed by California. However, other states, like NY,NJ,CT,Texas, etc. are also possible outbreak sites, as they are also travel hubs but don’t have the same level of genomic surveillance, so B117 could be growing there, undetected.

  7. Marko says:

    Only minutes away from the nail-biting stage for Perseverance :

    1. DataWatcher says:

      If everything goes smoothly, this will be one of those times when I’m really sorry everyone has to wear a mask. I’d love to be able to see all those happy faces (let alone the jubilant hugs and handshakes)!

  8. luysii says:

    “an immune-compromised patient is exactly that situation: this unfortunate person suffered from at least 154 days of coronavirus before dying from it and his underlying conditions. Sequencing of the virus at different points during this infection shows unmistakeable evidence of its evolution under these forcing conditions – constant immune system attack, but never quite enough to kill the infection off. ”

    Unfortunately there are tons of immunocompromised patients around where this can happen. Here is another example [ Cell vol. 183 pp. 1901 – 1912 ’20 ] in an immunocompromised patient with chronic lymphatic leukemia (CLL). She shed the virus for 70 days. Even so, she wasn’t symptomatic, but because the patient had enough immune system to fight the virus to a draw, it persisted, and so its genome was always changing. The authors were smart enough to continually sequence the viral genome throughout the clinical course and watch it change. So that’s very likely how the virus accumulates mutations, it lived for a long time in a patient who lived a long time with a weakened immune system allowing the virus to merrily mutate without being killed and allowing the weakened immune system to effectively select viruses it can’t kill.

    Could this happen again? Of course. There are some 60,000 new cases of CLL each year in the USA. Many of them have abnormal immune systems even before chemotherapy begins.

    Here is an example from my own practice. The patient was a 40 year old high school teacher who presented with severe headache, stiff neck and drowsiness. I did a spinal tap to get cerebrospinal fluid (CSF) for culture so we could find the best possible antibiotic to treat the organism. This was 30+ years ago, and we had no DNA testing to tell us immediately what to do. We had to wait 24 hours while the bugs grew in culture to form enough that we could identify the species and determine the antibiotics it was sensitive to. .

    As the fluid came out, I had a sinking feeling; as it was cloudy, implying lots of white cells fighting the infection. Enough white cells to make CSF cloudy (it normally looks like water) is a very bad sign. So after starting the standard antibiotic to be used in the first 24 hours before the cultures came back, I called the lab for the cell count. They said there weren’t any. I thought they’d seriously screwed up maybe losing what I’d sent or mislabeling it and looking at the wrong sample, and I unpleasantly stormed down to the lab (as only an angry physician can do) to see the spinal fluid. They were right. The cloudiness of the CSF was produced by hordes of bacteria not white cells. This was even worse as clearly the bacteria were winning and the patient’s immune system was losing, and I never expected the patient to survive. But survive he did and even left the hospital.

    Unfortunately, the meningitis turned out to be the first symptom of an abnormal immune system due to a blood malignancy — multiple myeloma.

    That’s probably enough but for more — have a look at this —

  9. Lou Gray says:

    As between B117 and B1351, which would likely over overcome the other to become the dominant strain? Put another way, does the rising prevalence of B117 have any impact on B1351 taking hold?

    1. Marko says:

      B1351 is believed to have significant immune escape potential, unlike B117, so even in a background of high B117 prevalence, B1351 could be expected to spread among the seropositive population where it would have the advantage.

      1. DataWatcher says:

        Hypothetical query: If B.1.351 did become prevalent, and vaccines did still prove to be very efficacious against serious disease and death (but not as much against mild/moderate disease), would this necessarily be a major roadblock against the eventual goal of reducing COV-2 to a flu-like endemic virus that would not severely impact economic and social well-being?

        1. Marko says:

          This is how your question reads : If vaccines reduce CoV2 disease to something like a flu-like illness would this necessarily be a major roadblock against the eventual goal of reducing COV-2 to a flu-like endemic virus that would not severely impact economic and social well-being?

          1. DataWatcher says:

            I’m just thinking about all the dire predictions of what will happen when/if the mutant strains become dominant. Most of what we hear still emphasizes “number of cases” or “case-positivity rates” rather than severity. I suppose that with a mutant like B.1.351, with significant immune escape potential, the question is also whether a seropositive individual who gets infected will be at high risk for suffering severe disease. The same question holds for p.1, I think, especially in light of what has happened in Manaus.

          2. confused says:

            If vaccines remain at least mostly effective against severe disease (and I think they will), then those “dire predictions” turn out to be totally wrong.

            With vaccination plus natural immunity (CDC estimates 83 million infections through December… given case rates in January, probably more like 90-100 million now) there will be few immunologically naive people in the US by the time next fall comes along.

          3. DataWatcher says:

            This is an honest question — if a person is “immunologically naive” to either the “original” COV-2 virus or B.1.1.7,, can he or she really be considered immunologically naive to B.1.351, p.1, or further mutations that develop? What about recombinants? I think there remain a lot of uncertainties concerning exactly how robust immunological “naivete” will prove to be.

          4. confused says:

            Being “immunologically naive” again would mean that the antibodies, T-cells, etc. against COVID do *nothing useful* – not just don’t prevent infection.

            I think the data on this blog before about vaccine efficacy against the South Africa variant showed that’s far from being the case? Still pretty good efficacy, esp against severe disease, and (maybe) especially for the mRNA vaccines?

      2. Chris Phillips says:

        The thing is, though, if the efficacy does turn out to be around 90% for infection acquired through immunity and the mRNA vaccines, doesn’t a variant have to jump an extremely high hurdle to get a significant advantage from spread in the immunised population?

        For example, if half the population had this kind of immunity, and immune escape allowed 50% more infections of a new variant to get through in the part of the population with immunity, that would still only enhance the overall rate of spread of the variant by about 5%.

  10. JS says:

    I thought that one of the most interesting tests they describe in the Cell paper cited by Derek was that they used plasma from patients infected by B.1.1.7 and tested how well that neutralizes the regular variant and B.1.1.7. Result were summarized like this:

    “For these samples as a whole there was a no significant difference between the neutralization titres for the two viruses (Figure 6B) meaning that infection with B.1.1.7 will afford protection from infection with earlier variants.”

    This is extremely encouraging. Unfortunately they did not check it against B.1.351 or P.1.

    Still, this begs the obvious question: Should we start changing the vaccines to target B.1.1.7 ASAP or even just change to 501Y? Wait and include further changes? Has the FDA or EMA made up their mind about what tests will be required before approving a modified vaccine? What about a test in a few people of changed vaccine to see how well they neutralize the different variants? If all they want to do is change 501N to 501Y, they can borrow my arm.

    1. Blaine White, M.D. says:

      Come on my friends. T-CELLS, T-CELLS, T-CELLS (grin). Here again is the link to the just released preprint from NIH-Bethesda and Hopkins ( They studied the CD8 T-CELLS’ targets from 30 subjects post C19 infection. They identified at least 52 target amino-acid sequences in the viral proteome – “52 unique epitope responses were found and were directed against several structural and non-structural viral proteins.” They reference still more CD4 targets. And even for just CD8s and Spike, there is a beautiful AA-sequence map (Figure 1) with the CD8 “KILLER T-CELLS” targets from those people in “gunner green” highlight and the known amino acid mutations in red. There are at least the 8 CD8 target sequences shown in Spike. Only one of them has a red letter in it, and that in a position predicted not to affect the T-CELL affinity. These variants are not going to escape either post-infection T-CELL immunity or mRNA -> translation -> Spike -> MHC1 presentation -> CD8 T-CELL immunity. And then there’s still some effective antibody. I would happily make Marko’s bet if we want to have some fun like Kipp Thorn and Steven Hawking; clinically significant viral immune escape in people with immunity post-infection or post-vaccine is going to remain at the rare order of magnitude (10^-3) seen in the 43,000 studied in Qatar.

      1. JS says:

        I think that most of us are very well aware that there is also a T-cell component to the response. Which may also save you in the end.

        But I would still like to also have good antibodies. As in neutralizing ones with good margins and acting on more than one site.

        So the questions remain. Should we change the vaccine ASAP to target the faster spreading variants? How ready are we for a change from safety and regulatory points of view?

  11. stewart says:

    There at least a 4th N501Y strain – the “Columbus” strain in Ohio. (The original report I saw said that there were two independent N501Y strains in Ohio.)

  12. Jonathan B says:

    Did anyone spot the pre-print giving an explanation for the greater transmissability of B117?

    They utilised the fact that a professional sports team and staff had daily PCR tests to record the dynamics of Covid infections when they occurred. The duration of viral presence by PCR was 13 days with B117 but only 8 days with the parent strain. Which presumably means a capacity for patients to pass on infections to more recipients.

    I appreciated the link indicating the occurrence of viral recombination events. I had wondered if that was possible, since several of these variants had multiple amino acid changes at first detection, but hadn’t seen any actual reports. However it is presumably what happens when this sort of virus crosses species.

    I was also interested in the reports of successive mutations in immunocompromised patients, and in particular the evidence that mutations happened independently in a finite number of “hot spots”. Does this imply that there might be a limited repertoire of permissible variants, with the benefit that would provide to designing vaccines?

  13. Quin says:

    Preprint of an analysis of Pfizer effectiveness prepared by Pfizer and Israel Ministry of Health. Names of authors not immediately apparent. Contributors listed at the end.

    Results sound very good.

    1. Marko says:

      89.4% efficacy vs infection (symptomatic + asymptomatic). There’s your transmission reduction, even without taking into account the lower viral loads seen in those who were infected post-vaccination.

      What’s odd to me is that the efficacy estimates are essentially constant, from infection to symptomatic to hospitalizations to severe/critical to deaths. That’s not what we expected to see, but I agree it looks good nonetheless.

      I’d expect as the data matures, and the high initial antibody levels wane but potentially-protective cellular responses improve, that protection against infection declines somewhat while protection against severe disease and death remains stable or improves.

      I hope this gets published soon.

      1. Doug H MD says:

        is this available even in preprint yet?

        1. Marko says:

          No, but I think it’s legit. I think what was posted was an advance copy. I suspect we’ll see the preprint very soon.

      2. DataWatcher says:

        If these numbers hold up, that’s closer to actual sterilizing immunity than even a lot of optimists dared hope for — remarkable in a first-generation vaccine. We can probably assume that Moderna is in that same range, as well. It’ll be interesting to see how they fare against B.1.351.

      3. Doug H MD says:

        better at preventing mild illness than severe illness than death unless i am mistaken?

        1. Chris Phillips says:

          No, better at preventing symptomatic infection (and worse) – efficacy 92.9-93.9% – than infection in general – efficacy 89.4%. So although its extremely efficacious throughout, so that the efficacy percentages are close, the fraction of infections that get through is about 60% higher than the fraction of symptomatic cases. (For what it’s worth, that’s nearly the same proportion found in the AstraZeneca trials, on the basis of much lower efficacies, but maybe that’s just a coincidence.)

          The other good thing is that the numbers are high enough that the confidence intervals are very tight compared with those from the Phase 3 trials – for example, 88.8-89.9% for infection.

        2. Chris Phillips says:

          Sorry – I see you were comparing 93.7 (92.9-94.3), 93.3 (91.8-94.5) and 92.9 (87.7-95.9). But looking at the confidence intervals, those numbers aren’t significantly different.

      4. Matt says:

        Could 5-10% of people be failing to produce effective antibodies entirely? That might explain the flat distribution.

    2. Marko says:

      “Due to limited vaccine supply, with an exception for LTCF-residents, MoH does not currently recommend vaccinating persons with prior evidence of SARS-CoV-2 infection”

      It must be nice to live in a country with sensible vaccine rollout policies.

      1. DataWatcher says:

        Especially now that the weather problems have gummed up the rollout in the U.S. even more, and there’s more and more worry that the mutant strains might “outpace” the rollout. If ever there was a time to modify our policy, it’s now.

        1. Marko says:

          To be fair, we could never do things in the US the way Israel does. They have a national health care system, like the vast majority of the civilized world, while we have a decentralized, left-hand-doesn’t-know-what-the-right-hand-is-doing, profit-driven, free-market system.

          It’s just not reasonable to think we could do as well as them, even if we weren’t providing them with a $4 billion/yr “allowance”.

          1. confused says:

            OTOH, I don’t think one can really compare Israel’s national system to a hypothetical US national system – Israel is more similar in population size to a single US state than the entire US. There is no internal disparity like the Great Plains states vs LA or NYC either.

          2. Marko says:

            Keep making lame excuses for the shit-hole country we live in and it will remain a shit–hole country.

            Not a single state in the US replicates the quality and equity of care provided by nationalized health care systems around the world. What distinguishes US healthcare is the huge numbers of people who receive none at all, and the huge numbers that do that go bankrupt for it.

          3. confused says:

            I’m not saying the current system is good.

            However, I *also* don’t believe that the sorts of national systems Israel or much of Europe have would work nearly as well in the US as they do there. IMO scale matters.

            You could argue Germany (which is larger populationwise than many European nations, and does have a federal system) as a more plausible analogue, but even then…

            This is not an argument that the current system should remain – but I think it is an argument to think outside the box rather than just copy other nations with a vastly different set of constraints.

          4. Marko says:

            Dr. Mike Ryan, speaking about what’s happening as the US model operates on a global scale:


          5. confused says:

            I am not sure what environmental problems leading to more potential disease emergences (which is absolutely true, both due to wildlife trade issues and more people moving into rainforest/formerly-rainforest areas) has to do with the US healthcare system.

          6. Marko says:

            The US healthcare system is emblematic of the US economic system, which dominates the world and is the root source of the problems he was addressing :

            “We’re doing so much and we’re doing it in the name of globalisation and some sense of chasing that wonderful thing that people call economic growth. In my view, that’s becoming a malignancy, not growth, because what it’s doing is driving unsustainable practices in terms of how we manage communities, how we manage development, how we manage prosperity….We need a world that is more sustainable, where profit is not put before communities. Where the slavery to economic growth is taken out of the equation.”

            He did address healthcare in the same speech, and if he wasn’t specifically talking about the US healthcare system, it’s very hard to tell:

            “Covid has laid bare and exploited fundamental inequities in access to public healthcare and the reality that healthcare can be used to empower or curtail the human, civil and political rights…..Access to healthcare during Covid-19 has not been fair. It has been influenced by gender, by age, by social class, by legal status, by ethnicity and by so many other factors…We are prepared to invest trillions of dollars every year of people’s money in the defence against an army that might never come across a border. And we’ve invested almost nothing in the microbes that have brought our civilisation to its knees over the last year.”


          7. confused says:

            We may be getting into broader issues that are a bit off-topic here, but I’ll just say that I don’t believe that economic growth and sustainability/environmental protection are in any sense inherently at odds (and will become ever less so as we move away from more-polluting older technologies e.g. coal).

            In fact, better agricultural technology would mean less land used for agriculture and therefore no need to push into rainforests where many zoonotic spillovers occur.

            The wealthier-per-capita nations also tend to have stronger environmental protection laws, so I don’t think slowing/stopping economic growth would actually have net-positive environmental effects.

          8. David de Marneffe says:

            You cannot have unending exponential economic growth without unending exponential growth of consumption of resources and energy. Thereby, unending economic growth on a finite planet is utterly, fundamentally, mathematically, physically and thermodynamically unsustainable.

            The question is not whether economic growth will end. The question is how.

            Read all of this:

          9. Med Chem says:

            Ryan and dothemath sides of same coin. In principle, I’m with them both all the way. Caveat, as a replier on the Ryan twitterlink feed put it:

            “As always with these sorts of eloquent and seemingly compelling statements, I have to ask: who’s the “we” who is going to be doing this ‘managing of communities’? Who? How democratically decided will it be?”

            Ah, democracratically deciding and ‘managing of communities,’ two interesting concepts. So what’s with this pandemic, the WHO, and come to think of it, World Leaders?

          10. Med Chem also says:

            …And an early 20something son sometimes in effect claims, “If I had to, I’d choose saving the planet over individual liberties.”

            To which gets fired back the old cliche, “Be careful what you wish for.”

    3. Marko says:

      Similar data out of the US :

      “…Administration of two COVID-19 vaccine doses was 88.7% effective in preventing SARS-CoV-2 infection (95% CI: 68.4-97.1%) with onset at least 36 days after the first dose. Furthermore, vaccinated patients who were subsequently diagnosed with COVID-19 had significantly lower 14-day hospital admission rates than propensity-matched unvaccinated COVID-19 patients (3.7% vs. 9.2%; Relative Risk: 0.4; p-value: 0.007).”

      1. Marko says:

        The incidence curves diverge from day 1 of the first vaccination, which is a bit suspicious:×900

        1. Roland says:

          The matching to controls doesn’t seem good in those early days. The incidence appears to define onset as date of positive PCR test. In many cases individuals presumably had symptoms before getting tested, some of those symptoms being at day < 0. (Some could even already be in hospital at day 0). If you have symptoms and a PCR test booked the day after your planned vaccination that's likely to affect whether you go ahead with vaccination and therefore the vaccination group is likely relatively infection free at day 0 compared to the matched group.

          Additionally if you feel ill immediately after vaccination you'll be more likely to put it down to side-effects and delay testing for Covid, while some in the matched group would get tested sooner. That would merely push some of the onsets out a few days for the vaccine group.

          In fact you can see in Figure 3 the 'Distribution of the time from first vaccine dose to first positive PCR test' that there are less positives per day the first 2-3 days following vaccination than on days 4-10.

          Thirdly the act of getting vaccinated and having side-effects may involve days off work and reduce infection opportunities? Overall I don't see how the statistics can possibly be reliable before the 14 days following vaccination graph.

          1. Doug H MD says:

            the statistics cant be reliable period. Too many moving parts here and impossible to control for.

  14. myst_05 says:

    “We do that by all that stuff everyone’s tired of hearing about, about masks and indoor gatherings and all the rest of it, and also by rolling out effective vaccines as quickly as possible”

    Would this actually achieve anything, given that plenty of countries have long abandoned social distancing and even more won’t be vaccinating a large number of people sooner than 2022 (or even 2023)? I.e. India has very few measures in place and won’t reach herd immunity via vaccinations any time soon, which means the virus has 1.2b people to train on.

    Seems to me that in addition to masks/social distancing, experts should be advocating for completely cutting off contacts with any countries that would reach herd immunity later than they do. I.e. once the US vaccinates 75% of the population, it should block off the borders with everyone including Canada until they get their act together. And even then – the US could only let Canadians enter if they promise to block off their borders for everyone except for Americans, otherwise the strategy would fail. But I haven’t heard of plans by the Biden administration on how to *truly* shutdown the borders like China or New Zealand did, banning non-citizens and forcing returning citizens into army-run quarantine hotels. If so, isn’t the US doomed to fall victim to these mutants, regardless of how much masks and social distancing will take place over the next year? What’s the point?

    1. confused says:

      Well e.g. India’s COVID numbers seem surprisingly low given population — same for the entire Old World tropics actually. So the situation may not be that bad.

      Also, historically respiratory pandemics seem to last 2 years or less, so it may not be entirely vaccination that ends it…

      1. Blaine White, M.D. says:

        India is rolling out many million doses of Covaxin (from a very competent vaccine maker). It is an inactivated whole virus vaccine with an adjuvant aimed at assuring a robust TH1 T-cell response as well as antibodies against most of the viral proteome rather than just Spike. It has performed very well in published clinical trials, and I would bet the farm there will be no viral immune escape from that vaccine. We spent 2-1/2 weeks there in 2013, and they have the residual of a very efficient British bureaucracy and excellent medical training. Given their population size, Worldometers shows they’ve done nearly as much testing as the US, and I generally trust their numbers. They’ve also made widespread use of ivermectin to suppress serious infections and death. They have a 1st class scientific base and already manufacture ~50% of vaccines, including many used in US. India isn’t going to be a problem.

      2. DataWatcher says:

        Again, I realize that this doesn’t sound like very “good” science (because it isn’t), but I can’t escape the feeling that there is something else going on. Here in Chicago, we are at a 3.5% positivity rate — the lowest we’ve seen since COVID first appeared here. Some of this can be attributed, no doubt, to folks “cocooning” in February, and/or more vigilant protective behaviors in the wake of all the scary headlines about mutant variants. But it’s difficult to believe that after the Christmas/New Years surge, we’ve all suddenly become so obedient that we’re back doing better than we were at the very beginning, before the mask mandates were in place and before “distancing” became unconscious everyday behavior for most people. Until about a week ago, our weather was relatively mild; the roads were full of cars on weekend nights, and it’s disingenuous to think all of those people were just going grocery shopping. Granted, we haven’t seen a lot of B.1.1.7 yet, and as far as I know, we’ve seen no cases of B.1.351 (and when/if we do, it’s certainly possible — even likely — that a lot of this “good” news will become a thing of the past). Even so, though, I can’t help but wonder . . .

        1. confused says:

          I’ve been saying for a while that historically, at least since the late 19th century*, respiratory pandemics tend to last 1-2 years (and while there was essentially no social distancing during 1957/1968/2009; there certainly was during 1918 – there were even political conflicts over mask-wearing, just like now, eg the “San Francisco Anti-Mask League”).

          The 2009 pandemic second wave was declining before vaccination became available to the general public, IIRC. The vaccine may have prevented a third wave (is there any way to know?) but clearly the ending is not driven by vaccination alone (there was no vaccine in 1890 or 1918).

          *1890 (which may have been a coronavirus, though it was called ‘Russian flu’ at the time), 1918, 1957, 1968, 2009

          We did not have the ability to track variants as we do now (except maybe to some degree in 2009?) so I don’t know what that tells us about comparability to past pandemics.

          1. DataWatcher says:

            Well, to be fair, there was *some* social distancing and masking in 1918-19, but it was far from universal. City streets remained crowded; there were the usual parades and festive events; streetcars were full of people; stadiums, theaters, vaudeville houses, nightclubs, bars, etc. continued to draw heavily (in 1918, Babe Ruth actually suffered two flu episodes — yes, reinfection! — one during spring training, the other in October after the season was over).

            The big question, as you suggested, is how analogous COV-2 is to those other viruses, whether there’s something about it (e.g., mutability) that makes it unique. Offhand, I’d suggest that its insidious ability to spread via asymptomatic carriers is at least one thing that sets it apart and makes it a lot more difficult to contain.

          2. confused says:

            Are there not asymptomatic flu carriers? It’s certainly pre-symptomatic… and people were arguing about whether the true flu IFR was actually less than we thought due to asymptomatics…

  15. Marko says:

    Another Israeli study, in Lancet , lends support to UK strategy :

    Early rate reductions of SARS-CoV-2 infection and COVID-19 in BNT162b2 vaccine recipients

    75% and 85% rate reductions in infections and symptomatic disease, respectively, 15-28 days after one dose.

  16. Ilya Yasny says:

    A good addition to this is a modelling done by my friend Fyodor Kondrashov and team (, showing that the most dangerous period is when most people are vaccinated, the virus is undergoing the highest pressure, and new variants appear faster. This is where the quarantine measures are of utmost importance, contrary to what the people might think.

    1. Gmac says:

      This is why we really should have focused efforts on treatments.

    2. DataWatcher says:

      . . . meaning that “Herd Immunity” might be a viral Trojan Horse?

    3. Chris Phillips says:

      That model seems very odd to me, with vaccinated people being just as susceptible to the resistant variant as unvaccinated and previously uninfected people, but people previously infected with the wild type being as immune to the resistant variant as they are to the wild type.

      1. confused says:

        That does sound very implausible.

  17. gippgig says:

    Clearly immunocompromised people should be close to the top of the priority list for vaccination (more than twice if necessary) & promoting prevention measures.
    If immunocompromised people are a major source of variants shouldn’t there be a lot of variants appearing in Africa (which I believe has lots of AIDS cases)?
    The N501Y variant would only have an advantage from evading 501N antibodies when it first appeared since someone infected with the N501Y variant wouldn’t have antibodies against the 501N form (unless it was a reinfection (rare) or vaccinee (hardly any when these variants appeared) or had cross-reactive neutralizing antibodies from another 501N coronavirus (no evidence at all)). This does raise an interesting question I don’t recall ever having encountered before: Is there any evidence for selection of variants that the immune system is inherently less effective at recognizing? This would include both inherently less recognizable by all immune systems (i.e., antibodies are inherently less able to bind; species independent) & less recognizable by a particular species (i.e., less able to be recognized by the variable regions of that species’ genome; totally species-dependent).

    1. Charles H says:

      IF I understand “immunocompromised” properly, I’m not sure the vaccine would help them. Perhaps they need direct infusions of antibodies. But multi-clonal antibodies, not monoclonal. You want to assault the virus from multiple directions at the same time.

      1. aairfccha says:

        Immunocompromised usually does not mean no immune system, vaccinations might be less effective but they should be even more important since the immune system can be expected to be less able to fight the infection on its own. Unfortunately with live vaccines, they can also be riskier.

    2. Marko says:

      “The N501Y variant would only have an advantage from evading 501N antibodies when it first appeared since someone infected with the N501Y variant wouldn’t have antibodies against the 501N form (unless it was a reinfection (rare) or vaccinee (hardly any when these variants appeared) or had cross-reactive neutralizing antibodies from another 501N coronavirus (no evidence at all)). ”

      First of all, if 501Y has immune escape properties, essentially the whole population that had been previously infected would potentially be susceptible, since they would have immunity to the legacy 501N strain. This would also pertain to anyone who had been vaccinated, as the sequence used in the vaccines would be the WT 501N. Second, though, and more important, is that 501Y (as in B.117) has simply not proven to be very problematic as an immune escape variant unless it also has the 484K and other mutations seen in the Brazil and S.Africa variants.

  18. lizzy says:

    What about this data: Seems like prior infection followed by only ONE dose of mRNA vaccine leads to broadly based generalized immunity including SARS CoV 1.

  19. Chris Phillips says:

    Here is yet another paper on the AstraZeneca trial data.

    The emphasis is on (more) “post-hoc exploratory analyses” of what the best interval between doses is. I’m not sure whether/how these differ from the previous ones.

    1. Not-an-epidemiologist says:

      This is the typeset version of the manuscript that’s been linked to in earlier posts. It is indeed a post-hoc bonanza, although there were so many unintended variations in the collection of these Phase III trial data that I’m inclined to suggest it’s not so much post-hoc testing as ad-hoc testing at this point.

      FWIW, my reading of all of this is that:
      (a) the AZ vaccine isn’t performing as well as the others (regardless of dosing scheme or booster timing),
      (b) the advantage conferred by the booster dose is questionable in the short-term,
      (c) related to this, there’s seemingly no disadvantage in delaying the second dose, and possibly — although this is pretty dubious, based on sparse data and some very broad CIs* —
      (d) perhaps even some advantage to delaying the booster until 8+ weeks (so, good job, UK — their gamble turns out to be fully justified by the data so far).

      The very concerning aspect of all of this, in my view, has been Oxford/AZ’s prevarication on the accidental LD-SD dosing scheme, which they over-emphasised in their first interim analysis and are now having to backtrack on at a rapid rate. That desperation to make their data look better than they actually were does not sit well with me.

      It’s still a much better vaccine than nothing, but it would be the last of all the approved ones I’d take if I had a choice (which, sadly, I won’t).

      (* it’s unclear from this paper, but my guess is that the lower efficacy rates from the shorter dosing times are being strongly influenced by the poor performance of the vaccine in SA against B.1.351. The data from the SA trial are included in this analysis — and as the dedicated preprint on that trial makes clear, almost all participants were boosted between 3-6 weeks.)

      1. Chris Phillips says:

        “(* it’s unclear from this paper, but my guess is that the lower efficacy rates from the shorter dosing times are being strongly influenced by the poor performance of the vaccine in SA against B.1.351. The data from the SA trial are included in this analysis — and as the dedicated preprint on that trial makes clear, almost all participants were boosted between 3-6 weeks.)”

        It seems it would be a research project in itself to tease out the different strands of data in these publications, but I thought the conclusions about the interval between doses were essentially already in the analyses of the UK and Brazilian data. Is it possible the Brazilian variant rather than the South African variant could be responsible? It seems difficult to gauge whether it would have been widespread enough to affect these data.

        1. Not-an-epidemiologist says:

          Anything’s possible at this point, and the data are probably reflecting the influence of both variants (although I can’t recall what the dosage intervals were like in the Brazil arm of the study — it would only make a difference if this was also biased towards a <6 week dosage like the SA trial was).

          The "main" interim analysis (Lancet 397: 99–111) also has the =6 weeks analysis, and the <6 weeks indeed has a lower efficacy estimate based on fewer cases (53% vs 65%) but no statistical significance. Not that there appears to be any statistical significance in this later analysis either (except in differences between baseline characteristics in some of the subgroups … #awkward).

          1. Not-an-epidemiologist says:

            (undone by less-than and greater-than symbols and HTML tags, but I think it’s clear what I meant …)

  20. lizzy says:

    Derek – there’s something I really don’t understand. I keep reading that it’s the NTD deletions 69,70 and 144) of the S1 portion of the spike that drive the conformational change allowing the N501Y to bind more closely. Are these deletions just red herrings?
    The Brazil and South African variants have similar substitutions in the N terminal domain.

    Why am I wondering about this? Because many vaccine candidates contain only the RBD, not even the whole S1 part of the spike. If increased binding and vaccine escape is dependent upon 2 hits – one on the NT terminal and the other on the spike, it bodes badly here.

    Am I just barking up some esoteric meaningless tree?

    1. sgcox says:

      AFAIK, all vector vaccines, mRNA or adenovirus encode full length Spike.
      Recombinant protein vaccines – I do not know. Novovax says “derived from Spike sequence”. Probably whole exodomain but may be indeed RBD only.

    2. Marko says:

      I think you’re right that using full-length spike is the way to go, and that the RBD-only candidates currently in trials will probably not make it. Pfizer had an RBD-only candidate as one of their final two choices, and wisely chose the full-length candidate to advance. I don’t believe any of the currently-approved vaccines are RBD-only.

      Still, the problematic variants manage to escape neutralization from convalescent plasma, so even being “vaccinated” with complete, live virus is not a foolproof solution to immune-escape variants, at least as regards sterilizing immunity. For that, you need to be either vaccinated or exposed to the variant of concern, and you probably wouldn’t want to try to use an RBD-only vaccine to address this problem.

      One complicating, but probably irrelevant, factor here is the paper that helped set off a lot of the ADE hysteria, which showed that a certain NTD-specific antibody facilitated viral entry in vitro.

  21. Marko says:

    “We’re relying on Israel for data on vaccine impact.
    We’re relying on India for vaccine production.
    We’re relying on South Africa for data on how vaccines fare against B.1.351.
    We’re relying on UK for data on experimental therapies.”

    We’re relying on the US for the entertaining social media pissing contests between blue-check Covid-19 “experts”.

  22. DataWaatcher says:

    Meanwhile, unless I’m missing something, commentary from most major mainstream public policy types, from Fauci on down, continues to emphasize the number of *cases* as the index of whether or not the vaccines are, and will continue to be, effective, as well as the basic calculus that will determine when/whether/if we can return to a semblance of “normality” at some point. Nothing, as far as I can tell, about the possibility of a significant diminution in severity/hospitalizations and deaths being the primary goal, whether or not cases become diminishingly rare. Am I misinterpreting them?

  23. DataWatcher says:

    “Immunome Discovers Antibodies Capable of Neutralizing Multiple SARS-CoV-2 Variants, Including the South African Variant, in Pseudovirus Testing”

  24. Marko says:

    Graph showing the ratio of life-years lost for CoV2 vs flu, by country :

    For the US, it looks like we’d have to reduce Covid-19 deaths ~7 fold, across the age distribution, to get to a similar level as flu. This seems well within reach based on the vaccine results so far out of Israel.

    An annual loss of life-years from Covid-19 equivalent to what we typically see for flu would still be something we should work to reduce, as we should also do for flu, but it would mean that we’d pretty much go back to normal life.

    1. Not-an-epidemiologist says:

      Hmmm … those numbers would be life-years lost due to covid-19 with current lockdown and social distancing measures in place. We don’t know what the relative numbers would be without any preventative measures, which is what you’d be looking at with a return to “normal life”.

      I still feel that with vaccination it should be possible to reduce covid-related death rates to flu-like death rates; but it will have to be a greater reduction than that.

      (That said — if that graph is accurate, it’s surprising and remarkable how well most countries have contained covid-related deaths. I doubt it’s the take-home Eric Topol was hoping for, but you could even argue that some countries — Norway, most noticeably — have actually been much too restrictive based on those numbers.)

      1. Marko says:

        Don’t make it sound more complicated that it needs to be. If you go by the Israeli results, we’ll easily get to the 7x reduction in life-years lost while reducing the effective R to <1.0 , as long as everyone gets the vaccine.

        If some refuse to get the vaccine, they'll get their immunity, or their burial space, the old-fashioned way.

        Israel will be the proof in the pudding soon enough, one way or another, so I don't know why I even bother debating the point. Let's just wait and see.

        1. Chris Phillips says:

          I think that’s right. If some people want to refuse vaccines, they’re not going to vaccinated against their will, but sooner or later enough of them will be forcibly immunised by the virus to bring the pandemic to an end.

          In fact I suspect disproportionate numbers of those likely to refuse the vaccine will already have been immunised by the virus.

          1. DataWatcher says:

            One hopes, though, that this premature talk of “herd immunity” we’re hearing doesn’t dissuade people from getting vaccinated (i.e., “Oh well, if we’re that close to ending the pandemic anyway, why should I bother?”). At the very least, that could result in needless suffering and — most likely — death. It could also, of course, spur further mutations.

        2. Doug H MD says:

          we have been hearing that for some weeks now. and yet Israel so far is lagging badly . Certainly i think that will change soon.

        3. Not-an-epidemiologist says:

          I agree, and I hope this becomes policy.

          And yes, Israel getting it’s vaccine game on (and now allowing fully vaccinated individuals to regain some semblance of normality) has been a very lucky break in all of this.

          (I remain concerned that AZ + B.1.351 will make some countries relying on AZ — like my own — baulk and lose their nerve here. But I’d be delighted to be wrong about this.)

    2. DataWatcher says:

      “An annual loss of life-years from Covid-19 equivalent to what we typically see for flu would still be something we should work to reduce, as we should also do for flu, but it would mean that we’d pretty much go back to normal life.”

      Well — hopefully, but don’t bet on it. Although I know it’s a stereotype that’s been hijacked by the COVD-denialist / anti-vaxxer crowd, the fact is that some public health policy wonks do, indeed, have a fixation with a Platonic ideal of a risk-free, sterile world; we already see that gestating in some of the comments and predictions we’re getting from various quarters. In Illinois, the ultimate goal of the gradual reopening process will be a Phase 5, defined as ” All sectors of the economy reopen with new health and hygiene practices permanently in place.” Sounds ominously like permanent masking and distancing to me. Even Fauci, when he gushes about how the drop in flu cases we’ve seen this winter proves that “public health measures work!” sounds as if he’s gearing up for the eventuality that since masks seem to have cut flu infection rates so drastically, they might as well become permanent (the usual analogy is seat belts and condoms — we’ve “normalized” them, so why not “normalize” never seeing one another’s faces in everyday life, as well? )

      Again, I know this sounds dangerously close to wingut anti-science paranoia, and I honestly don’t mean it that way. But I do think it’s a very real tendency in the public health world, and I think right now our COVID-phobic environment is a perfect Petri dish for it to grow, mutate, and spread.

      1. George Dorbell says:

        For GS, a world run by wonks, wingnuts and Dr Barr-Charts. Ahead of the long awaited GOV.UK road map for lifting England’s coronavirus restrictions, here’s a take presented by Auntie Beeb from that strange, bizarre and quirky placed quaintly formerly referred to as the real world. Auntie Beeb of all people – pleasantly surprised she’s still got the gumption.

        FYI Scientists – ear and eye protection advisable, as article does mention a “pantomime of scientists against business” during the pandemic…

        Leon boss warns longer lockdown ‘will cost lives’

        1. Chris Phillips says:

          “Leon boss warns longer lockdown ‘will cost lives’”

          Well, even if that does sound rather bizarre, at least he’s realised that “Longer lockdown will cost me money” isn’t going to sound good!

      2. confused says:

        But surely those public health people won’t have much political influence once public fear fades (which will probably happen fairly quickly; I’d say one season/half a year without a significant wave would be enough).

  25. Med Chem says:

    Re: “What a shock it was… when it started dawning on people that the universe did indeed have such a granular texture, both in terms of its matter and in terms of its forms of energy… It’s worth the occasional reminder that everything, pandemics included, comes down to such things if you pay close enough attention.”

    …Indeed. At times almost seems science fiction stuff. What’s with those shadowy leptons, mesons, quarks and spritely particular chums down in that underworld of fundamental ‘articles?

    Maybe they’re busy telling each other trios of short stories, discreetly yet discretely transmitting signals, symbols and metaphors, that get amplified from the pico-femto world down below to the centi-deci world up above of animal, vegetable, mineral and epidemical? And in return signals get sent back for the underworld to decode, interpret and re-encode for onward transmission?

    Maybe chemists – specialist subject the subset of interaction theory that deals with the underlying structure of Matter – as well placed as any to grapple with the metaphysics of it all (if not the Mathematics…)?

    Stuff in long ago Epistle of Seen Through a Glass Darkly and So Abideth These Three? As relayed thrice yearly by a late middle aged orator at a nineteen sixties high school. Stuff of… What can be shown, cannot be said?

    Meanwhile, in the world beyond school, a professional teacher of the science of metrology and amateur reader of The Strange Story of the Quantum, once upon a time known quite well, when in the right mood used to talk along the lines of – if the observer is part of the experiment and the experiment is part of the universe, maybe the universe is somehow like a thought experiment?


    Perhaps in the years after 1953 organic chemistry too overly consumed for its own good in chemical structure determination, total synthesis and small molecules? Narrative, plot and fight duly lost in conceding molecular biology to the ‘ologies and the ‘omics?

    Maths begets physics, physics begets chemistry, chemistry begets the ‘ologies, whereas those pesky ‘ologies sometimes seem not to get what their begetters are getting at? Language plausibly part of the problem – je parle chemistry, mais je ne parle pas les ‘ologies, et vice-versa?

    Conversely, ‘Ologists, perhaps you’ve been honorary chemists all along without even realising? Ah well, back to work putting together that fact-based, epidemical questionnaire for overly zealous, overly judgemental and overly inquisitorial commenters. Compilation ongoing by an innocent physical scientist abroad. To be posted in due course, site moderation permitting…

  26. Marko says:

    “….Offit said he would be concerned if people who already had COVID-19 or who had been vaccinated were being hospitalized due to infections caused by a new variant.

    “That line hasn’t been crossed,” he said. “You just want to keep people out of the hospital and it looks like to date there’s not a variant that has escaped either disease- or vaccine-induced immunity.” ”

    This sounds like another case of what Osterholm told us a while back – they’ve seen data that they’re not allowed to share with the great unwashed just yet.

    Patience, children. We’re being kept completely in the dark for a good reason, I’m sure. Something like “You can’t handle the truth!” , I’m guessing.

    1. DataWatcher says:

      At the very least, if they’re still focused on attaining the HIT, now’s the time to seriously consider delaying vaccinations (or at least second doses) for those who’ve already been infected. If they want to hedge their bets, they could do so for those who’ve been infected within the past six months.

  27. Jose Candido Ferraz says:

    In the matter of selling lottery tickets to the SARS-CoV-2, no one can beat the Brazilians!

  28. Jerry C. says:

    If you’re scratching your head about why the decline in cases has been so steep, it helps to remember that exposure is not evenly distributed in the population. The vast majority of cases are in a subset that is heavily exposed. And now, the same is true of the vast majority of people with immunity. This is by design (vaccination) and by accident (infection).

    1. Micha Elyi says:

      Could enough of the likely superspreaders have acquired immunity to significantly slow the infection rate?

      1. Jerry C. says:

        By “superspreaders” do you mean essential workers and highly exposed people? If so then that’s likely to be part of it. Along with vaccination strategies that have targeted these groups, and also seasonality and increased mask use. None of these factors may have been sufficient by themselves, but they add up.

  29. Marko says:

    “…The risk of illness from COVID-19 dropped 95.8% among people who received both shots of Pfizer’s vaccine, Israel’s Health Ministry said on Saturday. The vaccine was also 98% effective in preventing fever or breathing problems and 98.9% effective in preventing hospitalizations and death, the ministry said….”

  30. DataWatcher says:

    It says “infections” dropped 96.8% — think that’s accurate? This is Reuters, and a lot of mainstream news reports use the words “infection” and “disease interchangeably.

    1. Marko says:

      Reuters made a mistake in the earlier headline. They’ve changed “infections” to “sickness”.

      1. DataWatcher says:

        Ah, okay — although if those earlier numbers from Israel suggesting 89.4% efficacy vs infection hold up, we’re a lot closer to the “gold standard” of sterilizing immunity than anyone expected. Hope this isn’t going to be another “If it sounds too good to be true, it probably is” scenario . . .

        1. Marko says:

          We’ve clearly demonstrated sterilizing immunity in humans now, probably only of limited duration, and not universally obtained in everyone who is vaccinated or infected, but it definitely happens. It’s already been demonstrated in challenge studies of NHPs, so there was no reason not to expect the same in humans.

          This provides no end of irritation to those who proclaimed “parenteral administration can’t give you mucosal immunity”, “the antibodies don’t get to the site of infection”, and on and on. But there it is, and they’re just going to have to live with being wrong, which they should be getting good at by now.

          1. Doug H MD says:

            link to any demonstration of sterilizing immunity please?

          2. Marko says:

            You don’t believe the Israel data? If vaccinated people repeatedly test negative by PCR while unvaccinated people around them are testing positive, that demonstrates sterilizing immunity.

            For NHPs, see the vaccine trial data or find Ralph Baric’s recent paper.

  31. DataWatcher says:

    . . . sorry, typo — that’s “95.8%” . . . (Wish there was an “edit” function here for the prestidigitationally impaired!)

  32. Marko says:

    My prediction is that next week the case count in Florida stops declining, and then begins to head up sharply in the coming weeks. Based on what ? Three things. The B117 variant, the end of the February Effect, and the DeSantis Disadvantage.

    1. confused says:

      What is the February effect? Did Florida have unusually bad weather this week? (Usually, I would think February would be one of the nicer months in South Florida…)

      At this point I think people are pretty fixed in their opinions/actions regardless of what the governor does.

      It certainly could happen, but at this point I don’t think anything is predictable. We will see.

      1. DataWatcher says:

        You’re probably right that it’s difficult to tease out the “February effect” in a state like Florida, but certainly the DeSantis Disaster, in and of itself, remains a pandemic spike waiting to happen. B117 just adds fuel to the fire.

        1. confused says:

          Do you think anything the governor could do would change on-the-ground behavior that much, at this point, though? Would local authorities actually enforce it?

          I think people mostly now are either being careful or not.

          Here in TX, where a mask mandate exists but a lot of people don’t care, I’ve seen people wearing their masks in obviously non-effective ways just to “check the box”.

          Florida may have a new wave, or it may not — current numbers look to be to be flat-to-declining depending on what numbers one looks at: the emergency-department visits are dropping, but positive tests are essentially flat; that could be a sign of the decline ending before a new wave, or not…

          But I am not sure how much policies can change that at this point (vs, say, last March). I think people’s attitudes are fairly established now.

        2. DataWatcher says:

          My main point about DeSantis was that he set a bad tone early on, encouraging the denialists and the anti-maskers and supporting Trump’s non-“policy” in dealing with the pandemic. If, in fact, Florida does start seeing a spike as B.117 takes hold, I seriously doubt whether he’ll be willing to admit his earlier mistakes and begin to try to enforce more strict mandates. And even if he tried to, I’m guessing a good portion of the population wouldn’t follow the directives.

          1. confused says:

            Ah, OK, that I can see. The previous effects of bad policy could very well be “baked in” now.

    2. Micha Elyi says:

      Also toss into the mix the Super Bowl Party and St. Valentine’s Day Socialization effects.

      1. confused says:

        Maybe. But I don’t think holiday effects have really been that obvious in the COVID curves so far (the fall spike was well-along before Thanksgiving).

  33. Doug H MD says:

    I have not seen any published Israel data on random routine PCR testing. Can you link : thanks!

  34. Doug H MD says:

    Barics paper that is about INTRANASAL vaccination, Altogether something different i would venture

    1. DataWatcher says:

      I remember seeing this article some time ago. Any information on whether this intranasal vaccine has been, or will be, tested on humans? I know there were a few early mouse studies on intranasal vaccines last year, but I haven’t heard anything since.

    2. Marko says:

      “Similarly, all RBD207 scNP-vaccinated macaques had undetectable N gene sgRNA in BAL and the nasal swab fluid except one macaque that had 234 copies/mL of N gene sgRNA detected on day 2 in nasal swab fluid. Viral replication was undetectable in this macaque by the fourth day after challenge (Fig. 4d,e). Thus, RBD-scNP-induced immunity prevented virus replication, and likely provided sterilizing immunity, in the upper and lower respiratory tract in all but one macaque. ”

      This was an intramuscular vaccine.

      The Israeli data have been discussed above. One is the advance copy of a preprint released by Ynet, which is unpublished as yet, AFAIK. The other was the Sheba study published in Lancet. And , of course, earlier we had the AstraZeneca report of reduced overall infection.

      I understand if the data is not as lock-tight as some would prefer, but it will be, before too much longer. Then people are going to have to abandon their long-held, ill-informed beliefs about how sterilizing mucosal immunity can arise.

      1. Doug H MD says:

        gentlemans bet on that one.

        1. Marko says:

          Define your bet. Any demonstration of a reduction in transmission, as reflected in reduced levels of PCR-positivity, including among asymptomatics, will prove sterilizing immunity is attained. Whether it turns out that it only reduces transmission by 20-50% instead of 90% is immaterial to my point.

          Look, I’m an advocate for developing oral or nasal vaccines, as they will certainly be more efficient at stimulating a strong mucosal response, and secretory IgA neutralizes more efficiently than the monomeric IgA or IgG that appears in the mucosa as a result of intramuscular vaccination. But those neutralizing antibodies do appear in the mucosa, and it’s irrational to think that they somehow lose their capabilities there.

          1. Doug H MD says:

            if by sterilizing immunity you mean any reduction in transmission I guarantee you will be right.
            If however you mean something along the lines of smallpox you are dreaming.

            Who in their right mind things we wont see SOME reduction in transmission?

          2. Marko says:

            Again, define your bet. If you’re saying that the CoV2 demonstration must equal that seen with smallpox, then there’s no bet worth talking about. Anybody would take your side of the bet in that case.

            I maintain that some amount of sterilizing immunity will be demonstrated in humans, perhaps only during the early period when antibody levels are maximal, but it will be demonstrated, and recognized as such by the experts in the field. If the PCR data is not convincing enough, the serological studies that will eventually be released by the vaccine manufacturers will be.

  35. Jimmy Page says:

    Is it possible that partially effective vaccines accelerate mutations similar to persons with deficient immune systems? I have not find anything about this at all.

    1. Barry says:

      find discussion of the (slim but non-zero) possibility that a partially-effective vaccine might exacerbate infection here:

      Note that the risks of ADE are far lower with vaccines targeting only the SPIKE protein than for whole virus vaccines. All the vaccines (except SinoVac) that have been deployed to date have been SPIKE only, whether as mRNA or via adenovirus vector.

      1. Marko says:

        Baric’s recent preprint (Feb 18) has an extended discussion of infection and disease enhancement associated with anti-spike antibodies :

        The bottom line is that while it’s pretty easy to demonstrate antibody enhancement in vitro, in vivo the same antibodies often seem to provide protection, though there are exceptions. So we should continue to monitor the various vaccines, but no signals of a significant problem yet.

        Studies like this may inform our future usage of convalescent plasma, if we can screen the donor plasma for potentially troublesome antibodies beforehand.

    2. aairfccha says:

      Sounds unlikely. A partially effective vaccine might create selection pressure towards full vaccine escape, but I don’t see a way it increases the mutation rate (a vaccine which is actively mutagenic shouldn’t make it through safety testing).

  36. Marko says:

    Now being reported that the infection-reducing numbers reported in the Ynet scoop are “sketchy at best” :

    It’s the hospitalization and deaths figures that are really important, but it will still be disappointing if infection reduction is not as good as we thought.

    1. Marko says:

      This is the Bloomberg report that prompted the pushback :

      1. Marko says:

        Bloomberg has corrected the report, adding comments from Zoe McLaren :

        “The study compares the number of reported cases between those who had been fully vaccinated and those who hadn’t been vaccinated, but vaccinated people are less likely to get tested so the data will undercount cases, especially asymptomatic cases, in this group, she said……..“That means that the true reduction in transmission is lower than the estimate of 89.4%,” McLaren said. “How much lower? We need more evidence to know for sure. But I expect that, once we account for the bias, we’ll still find that this vaccine does reduce transmission. And that would be very good news.”

        1. Marko says:

          And then, after all her vigorous debunking, she just posted this on twitter :

          “A vaccine that slows transmission by 85-90% is especially good news for Americans who want to travel abroad.”

          Not WOULD BE especially good news, IS especially good news.

          Way to go, Zoe. If you can’t convince ’em, confuse ’em.

    2. Chris Phillips says:

      So the idea is that this will be biased towards symptomatic infections, because most testing is done because people have symptoms?

      It’s actually quite difficult to think of a way of estimating the efficacy for infection that isn’t subject to one problem or another. There is random testing, but I suppose the number of people volunteering for that but refusing the vaccines will be small. And there’s contact tracing, but probably the response rate there will be different from those who refuse the vaccines. Or challenge trials – but obviously those aren’t going to include the most vulnerable groups.

      1. Marko says:

        The best way is probably repeat (monthly or so) serology on vaccinated vs not-vaccinated cohorts. I’m hoping the trial data when it comes out will add clarity here.

        1. Chris Phillips says:

          I suppose any real-world comparison is going to come against the fact that behaviour will differ between vaccinated and non-vaccinated people. And it’s difficult to be sure in what way. Vaccinated people may indulge in risky behaviour because they feel safer. Or non-vaccinated people may indulge in risky behaviour for the same kind of reason that makes them refuse the vaccines.

        2. Ron says:

          Yes, but supplying all those folks with Rapid Test kits (~$5ea–and the FDA has thousands in stock already!)) as Prof Mina advocates so they could self test whenever and wherever they felt a tiny bit symptomatic could work and be a whole lot easier, arguably more accurate and for sure faster.

          1. Marko says:

            Yes, that’s what they do in the SIREN study, in addition to doing PCRs every two weeks. That way they miss few positives, even among asymptomatics.

            Mina is a hero of mine. He’s been fighting a lonely battle many months now, against an army of blockheads.

      2. DataWatcher says:

        Okay, layman’s question — if that original 89% estimate came from testing people with symptomatic infections, can we suggest that they probably carried higher viral loads than asymptomatic carriers, hence if anything the efficacy vs. transmissibility would probably be even higher among asymptomatics? Or am I misunderstanding things entirely?

  37. Marko says:

    I don’t think you need much more than this to explain the increased transmissibility of B.117:

    It’s kind of ironic that this outstanding public health surveillance study arises from the professional sports arena. It could have easily been done anywhere.

    1. confused says:

      When I click on that, it says “This is not available to you.”

      1. Marko says:

        It’s Fig 1-E from this pdf, showing the viral load over time in patients infected with either B.117 or non-B.117 virus :

    1. Marko says:

      What if the public is smarter than the public health experts? Maybe the people who aren’t showing up for the second dose are people who have been previously infected, in which case they’d be making a very reasonable decision. Wait 6 months or more for the second shot and thus get an effective “boost”, which you wouldn’t get with the standard schedule, or just wait until the new variant-capable vaccines roll out, depending on the developing timeline for that.

      1. DataWatcher says:

        If it is mostly people who’ve been previously infected, this could indeed be a positive development. Wish we had more data on exactly who is blowing off their second doses, and why.

        1. Mori says:

          …bad side effects for second dose, Moderna specifically….less risk of priming/ADE if you only take one at a time – if that’s possible to anticipate – maybe wait for the variant booster as number 2?

      2. A Nonny Mouse says:

        New data

        The work led by Public Health Scotland found by the fourth week after the first dose hospitalisations were reduced by 85% and 94% for the Pfizer and AstraZeneca jabs respectively.

        In total, there were just over 8,000 people who ended up in hospital.

        But just 58 of them involved patients who had been vaccinated four weeks previously.

        Among the over 80s, the combined figure was an 81% reduction.

        Possibly doesn’t matter too much about the second dose.

  38. Doug H MD says:

    LOL:” some amount of sterilizing immunity ” is not a bet worth talking about.
    What people want to know is are they relatively certain they can not transmit this virus.

    1. DataWatcher says:

      Well, that original 89% estimate definitely looked “relatively certain” to me. The initial AZ numbers looked promising, too, even though they were pretty confusingly presented. We’ll just have to wait and see what the data look like when they’re more reliable.

    2. Marko says:

      Try thinking ahead just a tiny step or two, doc. If sterilizing immunity is demonstrated in a subset of vaccinees, and this can be correlated with antibody levels, or a specific antibody level, this will be discovered and exploited by the vaccine companies in order to convince us of the need for continual vaccine boosters.

      This sort of “correlate of protection” is critical to understand for any vaccine against an infection that starts in the URT, present or future. You have to show that such sterilizing immunity is possible with parenteral administration , even to a limited degree, in order to be able to improve upon that characteristic going forward.

      Finally, regardless of the impact it has on an individual’s sense of his own immune state, even a 50% reduction in population-level transmission would be a big deal, in anyone’s book, just as a variant’s 50% increase in transmission is a big deal.

  39. Marko says:

    It looks like B.117 and B.1351 are both gaining ground in Germany, both doubling roughly every week :

  40. Marko says:

    “Early data from PHE’s SIREN study shows a promising impact on infection in healthcare workers aged under 65. Healthcare workers in the study are tested for coronavirus (COVID-19) every 2 weeks – whether or not they have symptoms.

    Data shows one dose reduces the risk of catching infection by more than 70%, rising to 85% after the second dose. This suggests the vaccine may also help to interrupt virus transmission, as you cannot spread the virus if you do not have infection.”

    1. Marko says:

      Preprint :

      Effectiveness of BNT162b2 mRNA Vaccine Against Infection and COVID-19 Vaccine Coverage in Healthcare Workers in England, Multicentre Prospective Cohort Study (the SIREN Study)

      1. Marko says:

        With the caveat that the SIREN study is in HCWs, so may not be generalizable to the entire UK population, this further validates the UK delayed-dose strategy, and also adds more support to the argument for not vaccinating seropositives, at least until everyone else has received their vaccine.

        It’s also a slam-dunk for showing reduced transmission. It will be interesting to see how that effect evolves over time. I believe the SIREN study will continue for some months yet.

  41. Marko says:

    Nobody should be surprised about this :

    “The Food and Drug Administration said on Monday that vaccine developers would not need to conduct lengthy randomized controlled trials to evaluate vaccines that have been adapted to target concerning coronavirus variants.

    The recommendations, which call for small trials more like what’s required for annual flu vaccines, would greatly accelerate the review process at a time when scientists are increasingly anxious about how the variants might slow or reverse progress made against the virus.”

    1. JS says:

      Great! Hopefully the tests will start ASAP.

      By the way I notice the 1.5 fold GMT reduction limit. Seems quite conservative.

      1. Marko says:

        Where did you find the reduction limit? I wonder how they could even specify the limit so early. I would hope that we’d be able to specify a variant-specific neutralization titer that needs to be achieved, rather than an overall antibody titer, but maybe we don’t have the time to figure that out.

      2. Marko says:

        Ah, I found it :

        “..The study should be adequately powered for primary immunogenicity analyses to demonstrate statistical non-inferiority of seroresponse rates and GMTs elicited by the modified vaccine against the variant(s) of interest as compared to seroresponse rates and GMTs elicited by the prototype vaccine against the original virus upon which the prototype vaccine was based, using non-inferiority margins of -10% for seroresponse rates and 1.5-fold for GMTs, respectively. Alternate non-inferiority margins may be considered, with adequate justification, on a case-by-case basis….”

        “…Of note, the recommendations detailed below are specifically tailored to pandemic COVID19 vaccines that express the S protein and are made under the assumptions that neutralizing antibody to SARS-CoV-2 S is a major component of the vaccine protective response (or for a given vaccine construct, is likely to vary in proportion to the protective response), that an immune marker predictive of protection has not been established, and that it is not feasible to conduct clinical disease endpoint efficacy studies rapidly enough to respond to the emergence of SARS-CoV-2 variants that may escape immunity conferred by prototype vaccines….”

  42. Marko says:

    Good article from yesterday about transmission reduction, but already dated by the new study results out today:

    ” This is what experts say we’re learning:

    • Infection-fighting antibodies are found where we need them to reduce transmission: those mucous membranes that line our nose and respiratory tract, home to gobs of virus that spew out with talking, shouting and singing. Post-vaccine, one important subtype of protective antibody, called Immunoglobulin G (IgG), is found in the blood. But now there’s new evidence that IgG is also found in the nose and throat……”

    Not really that new, but the demonstration of neutralizing activity in nasal swab samples of humans is fairly recent, to my knowledge.

  43. Marko says:

    Good graphics in this thread by Burn-Murdoch summarizing the essentials of the Scotland and PHE studies :

    1. Doug H MD says:

      “The risk of dying is less than half (56%) in vaccinated cases compared to unvaccinated cases, at least 14 days after receiving the first dose.”

      1. Marko says:

        “The risk of dying is less than half (56%) in vaccinated cases compared to unvaccinated cases, at least 14 days after receiving the first dose.”

        That, of course, is the reduced risk of dying in the vaccinated over-80 age group ONCE INFECTED.

        If you combined a 50% reduced risk of infection if vaccinated, with 50% reduced risk of death if infected, you’d have a 75% overall reduced risk of dying if vaccinated compared to the unvaccinated.

  44. Marko says:

    If we have a new spring wave in the US, we will be properly humiliated for not adopting the UK rollout strategy, and for not adopting vaccine-sparing strategies re: seropositives, as the dead bodies continue to pile up unnecessarily. It’s no surprise to me that US-based covid “experts” are strangely silent today regarding the new UK data.

    What the US probably needs right now is widespread distribution of Ex-Lax among our policy-makers. Maybe that would clear their heads….

    1. Ron says:

      Only if they double or triple the doseS 🙂

    2. Marko says:

      I think I can see the coming end of the February Effect, and this while case rates are still at fairly high levels in the US, Europe, and globally :

    3. DataWatcher says:

      “Dr. Fauci Just Said These People May Only Need One Vaccine Dose”

      1. Marko says:

        The deadly “Fauci Foot-Drag”.

        For him, I’m almost certain the Ex-Lax would clear that right up.

      1. Marko says:

        The Scotland data is a little weird. The dropoff in VE with later timepoints shows up in all the age groups except the over-80s, where late VE remains high, which is the last type of pattern I’d expect to see. It’s the over-80s that everyone has agreed should remain on the 2-shot schedule, due to immune senescence, etc.

      2. Chris Phillips says:

        I wonder whether that is a real decline in efficacy after the fifth week.

        From the last column of Table 2 the differences look statistically significant. But there is an awful lot of “adjustment” to get those final figures, and the unadjusted ones (fourth column) don’t look significantly different. Could the difference be an artefact of inappropriate adjustments?

        1. Marko says:

          Maybe so, I don’t know. With only 20 or so events per week after day 28 in the “overall” vaccinated cohort, any attempt to slice and dice by age group, vaccine type, etc., gets you into very low event numbers, where just one event +/– in a subgroup makes a big difference. As big as the study was, it looks like maybe it needed to be bigger.

  45. Marko says:

    The odds of testing positive for COVID-19 was reduced in patients who received an influenza vaccine compared to those who did not by 24%.
    •Vaccinated patients testing positive for COVID-19 were less likely to require hospitalization or mechanical ventilation and had a shorter hospital length of stay.
    •The influenza vaccine should be promoted to reduce the burden of COVID-19.

    It’s probably shorter-term innate immunity stimulation rather than longer-term cross-reactive adaptive immunity, and the same effect would probably be seen with other vaccines. Not a real strong or lasting effect, most likely, but every little bit helps.

    1. Marko says:

      This is what the authors say about the mechanism :

      “….However, emerging data on epigenetic and metabolic reprogramming of innate immune cells suggests that exposure to a second, non-specific stimulus could trigger a targeted and heightened proinflammatory response. This “heterologous immunity” could explain the non-specific cross-reactivity that vaccines have against unrelated pathogens. Trained immunity has been demonstrated with the heterogenous effect of the bacilli Calmette-Guérin (BCG) vaccine against infectious diseases such as yellow fever or malaria, and even certain malignancies.
      Additionally, recent research from the Netherlands found that the quadrivalent inactivated influenza vaccine was able to induce an improved cytokine response after stimulation of immune cells with SARS-CoV-2…..”

      So, maybe this sort of “trained immunity” could last for a while. The median time from flu vaccine to Covid test was 225 days in the study. They then say that “No association was found between the timing of influenza vaccination and COVID-19 clinical outcomes” which would suggest that the noticed effect didn’t wane too rapidly, at least not dramatically.

  46. Doug H MD says:

    or maybe it is really hard to match those vaccinated with those unvaccinated since we know they are going to be REALLY DIFFERENT

  47. Marko says:

    J&J statement to Congress tomorrow :

    “..Assuming necessary regulatory approvals relating to our manufacturing processes, our plan is to begin shipping immediatelyupon emergency use authorization, and deliver enough single-doses by the end of March to enable the vaccination of more than 20 million Americans. We are confident in our plans to deliver 100 million single-dose vaccines to the United States during the first half of 2021…”

  48. Marko says:

    CIDRAP Viewpoint : Reassessing COVID-19 Vaccine Deployment in Anticipation of a US B.1.1.7 Surge: Stay the Course or Pivot?

    1. Chris Phillips says:

      I read a bit of that and I’m a bit baffled by their expectation that a surge will be short-lived. It was in the UK because we went into lockdown, but I’m not clear what they think is going to stop it in the USA.

      1. Marko says:

        Well, given that Osterholm seems to be drawing on Colin Powell for guidance, maybe he figures that when B.117 gets nasty, we’ll dispatch it with another “Shock and Awe” campaign.

        I’m stocking up my bomb shelter, just in case….

      2. confused says:

        Seasonality maybe?

  49. Marko says:

    South Africa Has Found About 4,000 Covid-19 Re-Infections

    Sounds like we may be getting more info on this soon.

  50. DataWatcher says:

    “A third Pfizer dose? The Covid-19 vaccine maker is studying booster shots.”

    1. Gmac says:

      Milking the cash cow

      1. BDBinc says:

        You are on the money these criminals are milking it ( and you can follow the money in the covid pseudo pandemic). Taxpayers funding development and costs while big pharma just profit. Science has been corrupted.
        Talk about vaccines and mrna … but for what???
        Statement On Virus Isolation (SOVI)

        1. David says:

          Has it occurred to you that “Big Pharma” would profit a lot more if we all continued getting sick?

        2. Med Chem says:

          SOVI – interesting read from Beyond the Fringe.

          Big Issue what are millions ill with and dying from?

      2. Chris Phillips says:

        Gmac wrote:
        “Milking the cash cow”

        Comments like that are at least helpful in clarifying the motivation behind people’s posts.

        Thankfully most people here have some interest in the science rather than the politics (in the broad sense).

        1. Gmac says:

          This is in an area where South African variant is widely circulating. You’ll surely remember my concerns as regards the possible mechanism for these events. Might they be attributable to immune complexes with classic antibodies and the variant? More likely than a bad batch.

          What do you think Chris?

  51. Gmac says:
    Variants could be very dangerous indeed. This article is from over a year ago. My last comment awaits moderation.

  52. Gmac says:

    Strange regarding my comment but maybe as it was a reply to Chris Phillips. This is it:
    This is in an area where South African variant is widely circulating. You’ll surely remember my concerns as regards the possible mechanism for these events. Might they be attributable to immune complexes with classic antibodies and the variant? More likely than a bad batch.

    What do you think Chris?

  53. Gmac says:
    This is in an area where the South African variant is widely circulating. This raises my previous concerns as regards the possible mechanism for these events. Might these coagulation related events be attributable to immune complexes with classic antibodies and the variant? More likely explanation than a “bad batch”.

  54. Gmac says:

    Chris Phillips, your expert opinion on this groundless idea would be appreciated
    If I was the EMA I would be thinking along the lines of: Vaccine induced antibodies alone +/- covid classic = no clots. Vaccine induced antibodies + variant = immune complexes and clots.
    Impossible to eliminate in clinical trials (did anybody look hard enough?) but this was predictable

    1. Chris Phillips says:

      My non-expert opinion is still that you’re an anti-vaccine loony trying to twist whatever news you can find to fit with your chosen narrative. And what you’re trying to do will cost people their lives, if people are fool enough to believe you.

      The report you linked to says this:
      “The EU medicines agency has emphasised there is no indication the vaccine had caused blood clots.
      It said the number of cases in vaccinated people was no higher than in the general population.”

      Do you have any evidence to suggest the statements I put in bold are inaccurate?

      Sorry, but I don’t have patience with people using every dishonest trick in the book to dissuade people from accepting a life-saving vaccine. To put it bluntly, I think you’re sick in the head. I hope that’s clear enough.

      1. Gmac says:

        Yup, the over time statements are true and massage the figures. The temporal frequency and geographic clustering of coagulation events of late are the concern. I suspect that there’s something else at play. Many national medicines agencies have now suspended the use of this experimental vaccine (dumb sick in the head anti-vaxxers).

  55. Bill says:

    What we need is more perspective from news media. Headline should read:

    “Woman died of blood clot yesterday. 10,017 more died of Covid”

  56. stewart says:

    A study reports that B1.1.7 is 30%-100% more lethal than other strains circulating in the UK. If I understand correctly that wipes out a year’s improvement in treatment regimes.

    1. Mariner says:

      As people infected with B117 apparently have a high viral load for longer than earlier variants, it certainly wouldn’t be a surprise if it was more deadly. Logically, you’d expect that the auto-immune overload which seems lead to most of the serious illness would be more likely to occur when high viral loads are prolonged.

      I do wonder, however, if this might indicate that the vaccines are actually even more effective than expected from the earlier trial data. We know that B117 is dominating in the UK and Israel where the rollout of vaccines has been very quick, yet deaths are still quickly falling amongst those vaccinated in those two countries. Perhaps they might have been even more effective against the earlier variants?

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