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Memory B Cells, Infection, and Vaccination

This new article, I have to say, is rather reassuring about the human immune response to the coronavirus. It’s from a large team centered at Rockefeller University in New York, and it examines 87 people who have previously been infected. We’ve seen many studies of antibody titers and the like over time, but this is going to a deeper level and looking at the actual memory B cells. Those, you may well recall or already know, are the ones that persist and stay on guard should the same antigens reappear. They can go on for decades as an inbuilt surveillance system, ready to expand and start the antibody production process again if a similar immunologic threat shows up again.

At the six-month check-in, the patients in this study were all PCR-negative for the virus – they were no longer infected. Still, 38 of them reported some persistent long-term effects from it (you really, really do not want to catch this if you can avoid it – for more on long-term effects, see this new paper). The more severe the acute infection was, the more likely people were to experience long-term problems. Over a six-month period after recovery from SARS-CoV2, the patients in this work did indeed show lowered antibody levels. The drop in antibody titers was not evenly distributed over the different types (antibodies against the Spike receptor-binding domain (RBD) or the nucleoprotein (N), and IgM for these versus IgA), but overall neutralizing antibody activity was down about five-fold at the six month point as compared to the after-one-month check. But that’s what happens with any infection: the immune system does not crank out high levels of specific antibodies forever. It settles back down to its watch-and-wait mode, and that’s where the memory B cells come in.

And looking at those B cells showed some interesting patterns. There were a variety of them at both the 1-month and 6-month points, but they changed over time. Some of the clonal lines that were present earlier had disappeared, while new ones had continued to show up. The distribution was different as well: at the earlier point, the most common B cell clones were a greater percentage of the whole than at the 6-month point, for example. The authors say: “We conclude that while the magnitude of the RBD-specific memory B cell compartment is conserved between 1.3 and 6.2 months after SARS-CoV-2 infection, there is significant clonal turnover and antibody sequence evolution, consistent with prolonged germinal center reactions.

What’s that antibody evolution look like, then? The good news is that the ones from the six-month check showed both increased potency and an increased range of responses against various protein mutations. That includes many of the ones that are in the news these days, things like R346S, Q493R, and E484K. (As an aside, did anyone ever imagine that amino acid variant notation would creep into major news stories? Strange days). But while the one-month antibody samples were unable to recognize these and bind to them, the six-month ones were.

How does the immune system do this? It comes down to follicular dendritic cells (FDCs), a specialized cohort that displays antigens on their cell surface for an extended time in the “germinal centers” where B cells replicate. You’ll find them in lymph nodes, spleen, bone marrow, and other tissues (here’s a review article on the subject). They’re quite odd, with unusual cellular structures (very few visible organelles in their cytoplasm and an overall large, spread-out net-like structure). They secrete chemokine signals that attract B cells, allowing them to be exposed repeatedly over the long term to the antigens that they present on the FDC surfaces (which are technically in the form of “immune complexes” there).

In severe autoimmune disease, it appears that this process can go wrong and lead to FDCs and B-cells assembling in other parts of the body entirely as part of a sustained (and completely inappropriate) immune response. But when things are working as they’re supposed to, the reservoir of antigen in the FDCs and its continued presentation to the B cells allows for the generation and selection of new and improved antibodies, as seen in this study. We got this system via evolution, too, of course: the viruses that have been attacking us and our phylogenetic ancestors for hundreds of millions of years have always been mutating in real time, so having a system that keeps pace with them after an initial infection is a clear survival advantage. As always, the immune system inspires awe and a bit of terror as well.

What does this mean for people who are vaccinated, instead of getting their immune response by being really infected by the virus? As that last link mentions, “an efficient vaccine should maximize the deposition of immune complexes on FDCs“. You would expect the Spike protein produced in the body via the mRNA or viral vector vaccines to be handled in just this way, as well as the directly-introduced antigen proteins in a vaccine like Novavax is developing. The new paper being discussed also looks into the possibility of persistence of viral antigens in intestinal tissue, which was seen in some (but not all) of the patients studied, and would be expected to drive the evolution of IgA-type antibodies in particular. But overall, the key would be to make sure that the FDCs are displaying the Spike antigen the way that they should be.

How about the variations on the coronavirus that are out there right now? This has a bearing on some very real-time data from Ravi Gupta’s lab at Cambridge. There’s a manuscript that’s on the way to MedrXiv, but this pre-preprint stuff can be found on Twitter here and here. They’re looking at antibodies from the blood of people who were vaccinated three weeks ago, and seeing how these perform against the B.1.1.7 variant. In short, they still have neutralizing activity, but it’s generally lower (at least, in ten of the fifteen patients studied). Now, this doesn’t mean that the vaccine is ineffective in those people – the antibodies still do their job. But it does mean that as mutations continue to pile up, that escape of such a new variant of the coronavirus is not impossible.

But. . .note that Gupta’s lab is (necessarily!) looking at the antibody profile of people who have been recently vaccinated. The paper I’m discussing today raises the strong possibility of continued B-cell and antibody evolution over a period of months, leading to a different set of antibodies that appears to be able to better deal with some of these mutations. It will be very interesting indeed to combine these two studies – clonal B cell changes and antibody evolution with activity against variants like B.1.1.7 – to see if this is indeed the case. It should be, but we’ll want to check!

150 comments on “Memory B Cells, Infection, and Vaccination”

  1. antiaromatic says:

    Interesting work. Would be curious given the long term B-cell maturaiton taking place if you could actually provide a boost vaccine with the mutations that have shown up to get broader coverage. While it does require a separate product, for the mRNA vaccines, this change would be relatively trivial, and the major players in the mRNA field already do this in a personalized way for cancer vaccines that are currently in the clinic.

  2. Very interesting results. Antigen trapping in FDCs is a good marker of long B cell memory.

    For those looking for more information on humoral, and cellular, adaptative immune responses in Covid-19 patients, here there is a comprehensive review: https://doi.org/10.1016/j.cell.2021.01.007
    It contains a very interesting section on antibodies against SARS-CoV-2 variants.

  3. GM says:

    The problem with all this is that empirically it is not what happens in practice.

    I keep seeing these papers showing presence of some kind of antibodies, T cells, B cells, etc. and then that gets picked up by the media as “proof” that immunity is lasting and there is nothing to worry about.

    Which completely ignores what really matters, which is the empirical reality of whether people actually get reinfected.

    We know they do with common cold coronaviruses — it has been known for a long time, and reconfirmed after COVID hit. In that Nature Medicine paper by Edredge et al. (PMID: 32929268) they had an example of someone who caught 229E 12 (twelve) separate times between 1985 and 2020. And 229E is nowhere even in the same league as SARS-CoV-2 in terms of contagiousness, i.e. under similar circumstances with normal life, people would catch SARS-CoV-2 more often than they do 229E, OC43, NL63 and HKU1.

    We also know that we already have tens of thousands of reinfections in the US — only four states have reported data on that (IN, WA, CO, SD), and that is already a few months old, and between them they had more than a thousand cases of people testing positive more than three months apart before the holidays. Those states account for 6% of the US population and they were not even that hard hit during the early phases (and you need to be infected to be reinfected, and it also takes time for immunity to wane). But we can be certain that reinfections know nothing about state lines.

    Then we have the example of what is happening in Manaus right now. We don’t have direct data on reinfections there, but Manaus was supposedly at 75+% seropositivity by October, yet it is experiencing a massive second wave right now that is shaping up to be bigger and more destructive than the first one. How does that happen?

    Even if we assume the seropositivity was overestimated, it is highly doubtful it was overestimated by a huge amount because there is a whole bunch of other cities in that region at or around 50% seropositivity, and at some point you would have to posit an IFR so high that it becomes absurd on its own (based on the data from many many other places and based on the upper limit of it imposed by the CFR).

    We are also seeing second waves ongoing all over the hard hit countries in Latin America, but for those we can assume it was only less than 30-40% infected during the first wave, so it does not mean that much yet.

    Yet.

    When they go through their fourth, fifth, sixth, etc. waves, are we still going to dismiss it?

    And there is in fact one such place already — Iran was the first country outside China to go through a COVID explosion (though they hid it for a while), already back in January-April 2020, then it had a bigger second wave over the summer, then it had an even bigger wave September through November. Supposedly seropositivity was 15-20% already after the first wave.

    Yet the fourth wave is already starting now.

    And we know from the Iranian authorities themselves (which the Western media kept completely silent about for reasons we can speculate quite a bit about) that they were seeing reinfections already during the second wave, and that during the third wave they were seeing a huge number of them (as in 15-20% of hospitalizations in certain areas). We will see how many there will be during the fourth wave.

    A big reason why we are in this mess is that we have stubbornly been looking for the most positive way to look at things. Which is precisely the worst possible approach to managing risk.

    That has to stop.

    1. Hey says:

      Sorry but it seems like you are a lit biased towars an idea that is increasingly being proved wrong. There is very little scientific evidence about SARS-CoV-2 having a short-lived immunity. Papers are continously pointing out to the opposite.

      “Tens of thousands of reinfections”, “Iranian authorities”, sorry but I rather have scientific publications to base my opinion at.
      I don’t think there is any reputable scientist that tries try to be more optimistic than rigourous. They just do their work, for better or worse. For example, look at the preliminary data on E484K mutation, it looks like nAb activity could be affected, and so is reported by the preprints.

      I think you are very far away from having a scientific approach, you just seem worried or scared about reinfections, and you are trying to refute high quality publications with easy conclussions with very little proven data. If reinfections due to immune escape or waning immunity are a common thing, don’t worry that it will be analyzed and published sooner or later, and papers explaining how this virus has short living immunity will pop up. So far, it looks like exactly the opposite.

      1. GM says:

        This is precisely the kind of attitude that got us to this sorry state of affairs.

        — no evidence for human-to-human transmission, I will wait for the studies to show that

        — no evidence for aerosol spread, I will wait for the studies to show that

        — no evidence that children transmit it, I will wait for studies to show that, otherwise schools should stay open.

        Etc. etc. etc.

        Meanwhile the virus spread and killed millions.

        That is absolutely not how you manage risk in fast moving crisis.

        That is how you fail abysmally.

        As we have.

        That there are tens of thousands of reinfections in the US is obvious from the already available public data from public heath authorities. You can go here:

        https://bnonews.com/index.php/reinfection-tracker-suspected-cases/

        And follow the links.

        Again, it is at more than a thousand from four rather small states that weren’t even that hard hit prior to the the Fall wave. You think the virus knows about state lines and just because other states have not reported anything on the matter, no reinfections have happened there? Please…

        Iranian state news agencies have put out many reports about large numbers of reinfections, starting in July-August. Just because you have not seen them that does not mean that they did not. Just because you are going to dismiss anything they say “because it’s Iran” that does not mean it’s false. That’s like dismissing the WHO and the US CDC because you think they are propaganda outlets (which throughout the pandemic they indeed have been — they have been consistently putting out false information painting a much rosier picture of the situation than the facts warranted, which allowed the virus to spread unimpeded) without any consideration for whether the messages you are seeing might be true. In the case of Iran there is really no reason to doubt them — they have been downplaying the seriousness of the situation from the beginning (they completely hid it for more than month initially, then they have been deliberately underreporting deaths by a factor of 3X all throughout — the real death tolls is more than 200K there) so why would they lie that they see mass reinfections? Makes no sense. Plus Iranian opposition groups abroad were reporting the same thing based on reports from doctors on the ground and they have no reason to be colluding with the regime in lying about the situation.

        Once again, this is a real-life situation and a matter of life and death. Not an academic exercise in which you get graded based on your epistemic perfection.

        1. MagickChicken says:

          “Following the link” to your BNONews site, they count 462 “possible” reinfections as the same as the 1 “confirmed” reinfection in Washington.

          There are more reliable sources of data than a guy who got his journalism education by running a Twitter account.

          1. GM says:

            WTF???

            The 461 number is from the Washington State Health Department.

            That’s “unreliable”?

          2. MagickChicken says:

            461 *possible* infections. The 1 actual infection is actual, reliable data. A website basing its math on the 461 possibilities instead of the 1 actual is NOT reliable.

            Remember, it’s possible God exists and listens to our prayers (since you can’t prove a negative). But I’m not going to base public health policy on that possibility.

        2. Brogie says:

          Even if we assume that all the suspected reinfections are real, then that’s a 0.03% reinfection rate.

        3. Hey says:

          “This is precisely the kind of attitude that got us to this sorry state of affairs.”
          Yes, it’s called the scientific method. We gather evidence that leads us to making conclussions.

          From an epidemiological/desease control point of view, you can assume certain things in order to approach some problem in the safest way. IE: “we will assume this virus has aerosol spread until we can confirm it”. And I admit that from this point of view, some things were done terribly bad.

          But this has nothing to do with immunology, virology or clinical medicine. No respetable academic is advising to stop taking precautionary measures because immunity is long lasting. Or advising us to just get the disease because new antibody treatments look promising.

          Should science lie just to not be “optimistic”?
          Science should be completely neutral about the good/bad bias on the topics being studied. This study proves cellular immunity is present after COVID-19, and based on our knowledge we think this points to longer lasting immunity. The vast majority of other studies also point in this direction. Should scientis “lie” and tell everyone this is not the case because it would be probably “safer” to think this way? And if we se a “negative” paper, just like the one reporting a reinfection in Brazil** apparently due to one of the new variants (pretty solid case IMO) this is ok to believe because is “pesimistic”?

          If that was the case, and science did not tell us the truth, but whatever was convenient to suit a particular epidemiological situation then we will be asking ourselves even more times than now “how can people not trust in science!?”.

          **The Brazil report:
          https://virological.org/t/sars-cov-2-reinfection-by-the-new-variant-of-concern-voc-p-1-in-amazonas-brazil/596

          1. Melon says:

            Following the scientific method, policy makers were advised that there was insufficient evidence that masks are useful, therefore we shouldn’t promote the use of masks. Asian societies implemented universal mask wearing just in case even when the evidence was still weak. The West waited until the evidence was clear and that was a big mistake. It may not feel very scientific, but it may be better to use an AI approach using all the available evidence to make predictions rather than using “no difference” as a null hypothesis until proven otherwise.

          2. Klimax says:

            @Melon
            This is wrong. Mostly western policymakers and reporters were ignorant of scientific evidence on masks, but it was already out there in literature for at least 8 years. (One of first recommendations for mask wearing came from Czech Republic and pointers to scientific evidence were found in Czech news articles)

          3. Marko says:

            “So maybe if you go through 15 reinfections over a span of 15-20 years, only 2 or 3 of them will be severe, while if you infect 15 people for the first time, it will be serious for 5 or 6 of them. But that will be sufficient to make you a physical wreck for the rest of your life, if you survive.

            I don’t want to live in that kind of world.”

            You already do, and it’s not nearly as apocalyptic as you’d like it to be. You get coronavirus common colds throughout your life. Did you know that one of them targets ACE2? Did you know that one of them has been postulated as the cause of the 1890 Russian Flu pandemic? Are you sure that each of the four of them wasn’t deadly when it first crossed into humans? How did we make it? Why aren’t you disabled or dead yet?

            You don’t want to know anything that’s not already in your head. You just want us all to live in fear and for us to lock down forever while you pursue your unworkable “extermination” fantasies. It’s your world that normal people don’t want to live in.

          4. Chris Phillips says:

            “Did you know that one of them has been postulated as the cause of the 1890 Russian Flu pandemic? Are you sure that each of the four of them wasn’t deadly when it first crossed into humans?”

            I think genetic analysis suggests the two before OC43 crossed at times separated by several centuries during the last millennium, and there is a school of thought that believes they would have produced similar pandemics when they did. I don’t know whether much effort has been devoted to looking for them. No doubt the signal-to-noise ratio would be much lower in the early-modern and medieval periods, and descriptions of the symptoms would be much less detailed.

          5. Adam says:

            @Klimax At the time of the pandemic there were a few cloth mask studies. All were inconclusive or negative. Not exactly a high standard of evidence. Not sure what you are talking about with regards to Czech Republic. Do you have a source?

          6. R Hudd says:

            Thank you Marko for informing, “One of the common cold coronaviruses has been postulated as the cause of the 1890 Russian Flu pandemic…”

            And thank you Chris Phillips for speculating… “Genetic analysis suggests… common cold viruses before OC43 crossed… separated by several centuries during the last millennium… they would have produced similar pandemics… don’t know whether much effort has been devoted… the signal-to-noise ratio would be much lower… descriptions of the symptoms would be much less detailed.”

            Courtesy of a late 12th century time traveller, prithee kindly read on for a pott’d and plott’d history…

            *****

            Hail Moderne Tyme Sirrahs, third millenium and first centuryons. Am come foreward in tyme from th’layte twelfth century on th’Equestric Tymeforager to see what thou future Moderne Sirrahs be doing.

            For by now, some two and forty generaytyons later, thou must’ve crack’d th’End of Tyme problem and be ayble to zoom out in tyme and back ag’in pretty much at will?

            Oh… Thou hast not. I’d’ve thought by now thou’d’ve done it. I mean… All I did was mount th’Equestric, fyre up th’old tymeslipstream, kick th’old tymestirrups, put head low an’ foreward an’ ryde onward christyan soldyer into th’oscillating winds of tyme, lookin’ out throu’out for new epochs and eras flashin’ by. Nay hyde nor hair outrageous fortune’s slings an’ arrows seen nor in person met. T’were but a doddle.

            Next thing I know I come poppin’ out of th’ tymeslipstream eight hundred and twenty fyve years later, slap bang in th’middle of thy moderne era. T’was nygh on a millenyum ago I set off. So if we could manage it back then, surely… What? Nay? Thou meanst thou canst not do it at all? Really? Thou all be ryght tyme fogeys!

            Thou canst not travel foreward in tyme? Not even in a Soylent Green Tyme Capsule to make ultimayte escaype from Penultimayte Immune Escaype. What’s been goin’ on for th’last millenyum? What’s thou all been doin’ all those centuries grindin’ by? I DO NOT BELIEVE IT. THOU CAN-NOT BE SERYOUS. Civilysatyon’s actually gone backwards!

            Allegorically speakin’ that is. For th’ Greeks and Romans, th’ Chynese and Persyans, th’ Vykings and Normans, all knew thou canst not travel backward in tyme. Can-not happen. Proven once and for all by Greyt Anglo Saxon King Canute.

            That throne on beach stunte at Clacton Essex commandin’ ye tyde some seven or eight generaytyons afore my tyme. Incomin’ tyde studd still for no man, not even King of End of First Millenyal Ingland. So it were.

            *****

            Now in a quiet century or two on th’way to thy tyme, I did take trouble to read thou moderne era cayse notes compyled by thou Archbishop in person and commented further upon by thy august gatherin’ of moderne day monks, mysteryons and dayta manipulaytors.

            Seryous tymes. Seems thou be troubl’d by playgue. Don’t talk thou to me about playgues. Th’ ravens, th’ jackals, th’ smell. An thou moderne monks, mysteryons and dayta manipulaytors be lookin’ to demystify th’ playgues. Good luck to thee!

            Thou moderne cayse notes tell thou all be consum’d by theorems, detayls and devils therein. Remynds of medieval theologies of olden day monks, who for four generaytyons afore and eight generaytyons after my tyme agonysed unto eternity o’er how many angels could dance upon th’ead o’ a pinn.

            Toward end o’ my tyme journey, an apothecary met late last century hitch’d lift on back o’ th’Equestric and rode foreward in tyme wi’ me. Tell’d me your scyence of ‘ologies about where his scyence of chymical physics was in tyme of aether and plum puddin’ model. Cause und Effekt so very C th’ nineteenth, apothecary said. So very Filosofer Hegel. Ratyonal alone real, sayed Filosofer until silly little Quantum popped out o’ th’unfolding unyverse to kick poor Hegel in th’ cerebrals.

            So where to begin wi’ thy cayse notes? Where else but th’ fyrst payper cyted by Commenter Ye Third re re-infectyon by th’ comm’n cold (NAY ME, far too clever by ha’f, and far too earnest in parts the whole):

            https://www.nature.com/articles/s41591-020-1083-1.pdf

            Th’ payper tells they be four comm’n cold coronavyruses. Big word, co-ro-na-vyr-us. In my tyme three syllables were big, four gynormous, five worde of God via Bishop, Abbot and Monk Six syllable or more divynely unfathomable. Lo such progress thou hast all mayde with thy big wordes, wortles and wordologies.

            Co-ro-na-vyr-us. Vyr-us o’ co-ro-na, which Ye Wizard Translayte tell be Latin for crown. Vyr-us of th’ crown. Hmm. Tell thou truth, headin’ up thro’ tyme on my Tymeforager from tyme o’ Sherwudd Forest, Sherriff of Notting’am and wicked King John, I did wonder what I’ wouldst meet in th’ Brayve New Worlde o’ eight centuries tyme.

            Co-ro-na-vyr-us. Vyr-us of th’ co-ro-na. Vyr-us of th’ crown – Wicked King John be reborn? Surely nay, for Wicked King John be gone in Year o’ Our Lord twelve hundred and nine.

            John be succeeded by son Henry, Ye Child King Henry III. Wicked King John be gone o’ crown fore’er. Amen. Surely not a plot ‘cross centuries planted. Surely not. That be not possible can it? For then thou be talkin’ wicked tyme conspiraycy, which o’ course be four syllable word.

            Gynormous word conspiraycy. Call’d in my tyme a plot. A one syllable worde. Any foole can see a plot full myle off. But a conspiraycy hath four syllables to hyde behynd to foole fooles upon fooles upon fooles.

            Back to th’ payper on th’ comm’n cold mentyon’d by Commenter Ye Third. We knew comm’n cold well back in C th’ twelfth. Winter begat and ha’f or more th’ villayge catch th’ cold lyke drop o’ th’at. In theorem t’were it for t’winter.

            Except some knayve come along from next villayge and give thou an’ thou villayge brethren they villayge cold, so thou send one o’ thy knayves to they villayge in revenge and th’all get thy cold. And afore thou know where thou all are, nygh on all th’ villayges had all common colds doin’ th’ rounds begat that winter.

            Truth tell back then comm’n cold be least o’ winter wurries, what wi’ starvatyon a’ter bad harvest, deadly weather colde, and deadly diseases like raybies from wyld beasts, diseases from vermin that liv’d wi’ thee in thou hovel, and diseases lyke scaybies, scrofula and scurvy, when all thy teeth fell out…

            …And so next winter in deadly colde weather thou couldst not survyve, ‘cause thou couldst not knaw frozen flesh from slaughter’d domestic beasts, ‘cause thou run out of dry fyrewood to cook by and thou had no teeth from thy scurvy.

            An’ talkin’ of domestic beasts, we learn’d full well in my tyme th’ comm’n cold came from thy domestic beasts. T’were obvious. Thy domestic beasts liv’d in thy barns next to thy hovels and thou mixed wi’ thy beasts all thy tyme. In deep midwinter when th’ice were all about, thy lay’d thou head on thy beast for thy sleep, cause thy beast keep thou warm from th’ sharpe colde.

            And in th’ nyght, thy beast myght cough and splutter and slabber and slobber all o’er thee. An’ next day thou might feel unwell and that eve take back to thy bed, instead of lyin’ with thy beast again a’cause thou know thou caught thy cold from thy beast and thou want not to overdo thy vyral loade.

            T’as been goin’ on for centuries nay millenya. Mixin’ wi’ bugs and germs from beasts, and from thy muck, myre and slyme thou lived in all thy tyme around thy hovels.

            *****

            Back to th’ payper on th’ comm’n cold. Scholars travell’d back in tyme near four decaydes. Then come foreward from thereback in tyme found th’ sayme comm’n cold be found re-invented and re-caught winter upon winter.

            So be-it. We knew that back in C th’ twelfth from th’ colours, forms and odours of th’ phlegms o’ th’ more seryous colds, for all thy phlegms be in difference somewhat that can be perceiv’d wi’ naked eye and naked nostril if thou be lookin’ and smellin’ close enough.

            An’ we knew back in C th’ twelfth that a seryous winter cold could take thy greyt and thy greyt greyt grandfathers and grandmothers at drop o’ hat, altho’ back then these Elders be exceedin’ rare on account o’ all th’other diseases, perils an’ pestilences thou could die o’ afore thou becomest anywhere near greyt or greyt greyt.

            T’were sad, but t’were so. Ask not for whom th’ bell tolls. We put ‘em in th’ cemetary wi’ all rest gone afore, said our prayers and life went on lyke it always do. So were it.

            Now ye payper on th’ comm’n cold that Commenter th’ third unfurl’d do tell there be four comm’n cold co-ro-na-vyr-us-es that be known. O’ Lord Divyne. Co-ro-na-vyr-us-es be plural and be six syllables and that be well known to be divynely unfathomable.

            But do stick wi’ me, tyme fogeys. Let’s try fathom th’unfathomable. Th’ payper tells there be four comm’n cold co-ro-na-vyr-us-es. Let’s we simplify th’ divynely unfathomable six syllables and call th’ vyruses CV1, CV2, CV3 an’ CV4.

            Which if I be countin’ ryght, makes thy moderne tyme playgue thou be all work’d up about be call’d CV7. That be a start. Don’t be soundin’ quite so bad already, do it? Or if thou must, call thy moderne playgue MARS, that be short for Mark’d Acute Respiratory Syndrome.

            Which nayme fit more apt wi’ SARS that were CV5 and MERS that were CV6. Which for ignorant among thou were Severe Acute Respiratory Syndrome and Middle Eastern Respiratory Syndrome. Pair o’ nastyes those two. But e’en back in C th’ twelfth we all knew full well worse th’ disease, th’ lesser th’ disease spredd, for thou were dead afore thou couldst spredd th’ disease. So t’were then, so it be now.

            So while thou bring out thy daily dead, hear ye, hear ye. For on my tyme foragin’ heretofore, I stoppeth off a few tymes and playces on th’ way. And as thy Cryer Forbes sayeth, thou CV4 were fyrst come upon in Year o’ Thy Lord nineteen hundred and sixty fyve…

            https://www.forbes.com/sites/alexknapp/2020/04/11/the-secret-history-of-the-first-coronavirus-229e/?sh=381d74e571d6

            As thou can readest therein if thou so wish, thy CV4 were mostly w’out harm, except for a lady o’ some manor in mere forty fifth year of her age, t’were not. For her, t’were deadly seryous.

            Her presenteth wi’ fever, dry cough and severe ache o’ th’head. W’thin days her breathin’ begat to go all awry. Her were sav’d wi’ thou moderne day miracle call’d oxygen. Her were tested for all sort dread disease, yet in th’end were found to be vyrus o’ thy comm’n cold, thy co-ro-na-vyr-us CV4.

            By mercy of our Lord, lady surviv’d. Yet were she yet older, she myght not hath surviv’d. So t’were ever thus wi’ e’en ye comm’n cold. An’ Ye Cryer Forbes e’en sayeth CV4 might hath origineth in C th’eighteenth. Seemeth plausible, for as I sayeth afore, we knew full well such things in my tyme eight hundred an’ twenty fyve year ago.

            *****

            Now readin’ behynd thy cayse notes, on my tyme foragin’ heretofore I call’d in on Saint Petersburg, Russia, in autumn o’ Year of Our Lord eighteen hundred and eight nine. Playgue call’d COVID-1889, like worst cold playgues of my an’ thy tymes, that spredd thro’ th’entyre Continent and theretofrom by ship on to th’ New Worlde.

            Thousand thousand dead all told by th’ end, out of thousand and a half thousand thousand then alyve in entyre worlde. And now thy Cryer Bloomberg tells, maybe playgue COVID-1889 were co-ro-na-vyr-us CV3 that since descend’d thro’ tyme to becomest one o’ thy moderne tyme comm’n colds…

            https://www.bloomberg.com/opinion/articles/2020-05-15/coronavirus-of-today-eerily-similar-to-1889-russian-flu-pandemic

            Sufferin’ o’ COVID-1889 sound somewhat sayme to thou moderne playgue, eh, tyme fogeys? But worlde were not sayme playce back one hundred and thirty year ago. So I lingere’d awhile in those tymes and saw that in all th’ landes th’ worlde kept calme and carried on in spyte o’ th’ playgue call’ed COVID-1889. Truth tell, t’were no WHO, thee see.

            So children o’ England be stay’d a’ schools and universityes be greyt houses of learnin’ unabated. Inglish football league be beginnin’ in Ye North and Ye Midlands. Fyrst seasons be watch’d by dense crowdes of thousands upon thousands, who clapp’d, cheer’d and swapp’d ye bugs, germs and myasmas, ignorant of th’advances, fancies and sofistries of nowadays gloryous tyme of natyonal socyal distancysm.

            Even C th’ nineteenth deity of Noble Gayme call’d cricket, Ye Greyt Doctor W G Grayce, play’d out Noble Gayme untroubl’d by moderne tyme knowledge that cricket ball be vector o’ disease and may not be touch’d ha’f an entyre summer, whence th’ sun shyne lyke n’other ha’f summer afore.

            An’ if ask’d about vector o’ disease, Medycal Doctor Grayce, “The Doctor” himself in person, founder o’ Grayce, Bradman & Sobers & Co. Ltd, Cricket Deities Inc, would a sayed out loud, “‘Tis bollox, utter bollox and hogwash. We carry on undaunted wi’ Th’ Noble Game. I’m battin’ for myse’f, Shire of Gloucester and Merrie England. I’m on strike, you bat th’other end, run when I tell thee and keep out o’ my way!”

            *****

            So I underdid more stoppin’ off on my tyme foragin’ foreward. Fyrst stop year thirteen hundred an’ twenty five in Ysle of Olde Errin, some fyve generaytyons a’ter my tyme. Th’istorie can be trac’d, track’d and test’d thro’ collected wordes onlyne o’ thy Sage Wikypedya an’ thy Arkivist Googley…

            https://archive.org/details/animalplaguesth00flemgoog/page/n8/mode/2up

            Thy Sage an’ thy Arkivist tell o’ worke of th’ Greyt Victoryan Veterinary Natur’l Filosofer George Flemyng o’ London, who in Year of Our Lord eighteen hundred and seventy one did compyle learned and scholarly treatise tytl’d, “Animal Playgues; Their History, Nature and Prevention,” and who did sagely say…

            “I have always been impressed with the idea that the history of many of the animal ‘murrains’ that have travelled across countries, often in company with or preceding human pestilences, would prove a most valuable aid to the student of comparative pathology, and be of service to the busy practitioner whose leisure is more limited…”

            An’ Natural Filsofer Flemyng did track, “A.D. 1325. An epidemical disease … common throughout all Erinn…. prostration influenza… affected, during three or four days, every person…”

            Which Ye Natural Filosofer did trace upon by visitatyon to Greyt Library of Dublyn where habiteth Annals of Ireland, which thy Sage Wikypedya now attests do say in translaytion from C th’ fifteenth scribe of Errin, Ruaidhrí Ó Luinín…

            https://celt.ucc.ie/published/T100001B/
            “A plague of general disease throughout all Ireland, which was called a Cold: for the space of three days or four it continu’d on each person, so that he was nigh unto death.”

            An’ earlier in th’ learn’d treatise, Filsofer Flemyng did record that in year afore epydemic o’ Erinn was, “A general plague of cows and also other animals, which was called in Ireland ‘maldrow.’ This was probably the same epizooty that prevailed in England in 1319.”

            An’ Filosofer did earlier still say o’ year thirteen hundred an’ nineteen in England, “A great murrain and death of cattle chanced through the whole of the realm. It is rumoured, what is most unusual, and what will perhaps be incredible to future ages, that dogs died from eating the dead bodies of the cattle… On account of which circumstance, no man dared to eat the flesh of oxen, because this pest prevailed chiefly in oxen.”

            So thou canst see how per’aps Ireland’s first recorded flu epydemic come out o’ cattle, which as we all knew full well could be cayse in my tyme fyve generaytyons precedin.’ An’ if that be cayse, then can per’aps also be cayse that Erinn epydemic be COVID-1325 an’ be fyrst e’er outbreak of th’ vyrus that later become th’ comm’n cold co-ro-na-vyr-us CV1 that thou canst still catch some thirty seven generaytyons layter.

            Next year thirteen hundred an’ twenty six scribe Ruaidhrí Ó Luinín tells Erinn back to usual. Lyfe went on. “Cathal, son of Domnall Ua Ruairc… son of a king… killed along with other persons by the Foreigners in treachery… War arose between Toirdelbach Ua Concobuir and the Muinter-Mailruanaigh… Augustine, abbot of Lis-gabhail upon Loch-Erne, died on the 2nd of the Kalends of November…”

            *****

            My tyme wi’ thee be now almost up. I flash’d foreward from C th’ fourteenth, passin’ through th’ greyt battles o’ second millenyal historie. An’ afore Battles o’ Tornow an’ Austerlitz I did see swabs tak’n from th’ noses o’ th’ soldiers, an I saw horsemen takin’ swabs to tents behind th’lynes for army physicyans to examine wi’ naked eye an’ naked nose for colours, forms and odours.

            An’ I did think maybe Tornow an’ Austerlitz were COVID-1758 that begat comm’n cold CV4 and COVID-1805 that begat CV2, an’ were both spredd by armies maraudin’ round Europe in Seven Years and Napoleonic Wars, except that no-one ev’n much notic’d at those deadly seryous tymes a’cause were too much else deadly seryous to be wurried about.

            An’ to be sure no-one thought to tell th’infected soldiers to isolate ‘emselves for nygh on fourteen days, to sanityse they weapons and to avoyd mortal combat a’ distance o’ less than two payces. Ryght mug’s gayme that would’ve been, tryin’ to stop th’istorie unfoldin’ and make it ne’er ev’n happen.

            So those were th’ greyt historical playgues o’ COVID-1325, COVID-1758, COVID-1805 and COVID-1889, that I been and saw on my tyme foragin’ up thro’ eight hundred and twenty fyve year from my tyme in layte C the twelfth.

            *****

            Now, moderne tyme monks, mysteryons and dayta manipulaytors, to be really seryous, do please permyt man of my tyme to thinke – some tyme in clymate of thy tyme thou dost think thou can get thy king to abolish th’ grim reaper. An’ to abolish grim reaper, th’ young must mayke sacrifyce for th’ancient greyts an’ greyt greyts. T’is a falsehood. Just lyke t’were wi’ ancient peoples lyke th’Aztecs and th’Incas.

            An’ do second permyt man of C th’ twelfth to thinke in clymate of thy tyme thou wurry overly about commandin’, nay controllin’, all things greyt and small, for eternal truth be command an’ control be at tymes but an illusion in face o’ slings and arrows o’ outrageous fortune.

            An’ do third permyt man of my tyme to thinke in thy tyme thou be obsess’d wi’ ev’ry detayl o’ thy laytest dayta manipulayted in thy almyghty computer an’ tweeted on thy myghty twitter, or disclos’d in thy latest payper seen afore only by thy friends, an’ thou thinketh thy laytest dayta must be thy eternal truth and mayde w’thin days policie of thy king.

            An’ last do please permyt man of ancyent tyme to think thou all be wurryin’ too much about wrong thing. ‘Tis literally th’ clymate of thy tyme that t’is thy greytest wurry, yet for decayde upon decayde thou been puttin’ off thy wurry yet ‘nother decayde upon decayde unto thy future.

            Tyme be passin’, and meantyme thou be wurried about summat else inste’d. I humbly put to thee it be a surrogayte wurry, that thou delude thyselves thou can deal wi’. An’ yet in dealin’ wi th’ surrogate wurry thou art all takin’ small steps that help wi’ th’ real wurry – less flyin’ ‘an drivin’ for a start. Maybe t’all be a plot by thy King? Or ‘tis just historie unfoldin’ as one effing’ thing a’ter ‘nother? Either or, Sieze th’ Day.

            Ryght tyme fogeys, that be enough o’ tree stumpin’, a pressin’ assignaytyon calls. Robin Hudd must mount th’old Equestric Tymeforager, kick start th’old tymestirrups and head back down century upon century to tyme of Sherwudd Forest and Sherriff o’ Notting’am, where deep in th’ forest Maid Marion in her greensleeves awayts upon a greensward cleared from w’thin th’ greyt green treescape.

            Be devil to pay if R Hudd layte. No good sayin’ been busie o’er eight centuries ahead in tyme – Robin Hudd, Maid’ll say, thou been in th’ale house wi’ that Little John, that Fryar Tuck and thy Merrie Men, I can smell th’ale on thee. Thy an’ thy tall tayles be tell’d by too much ale. Get thee out o’ my syght, Robin Hudd. Go thee forthwith ryght this minute now!

            Adieu et au revoir. Fayre thee well, thou Moderne Tyme Sirrahs!

        4. Wkw says:

          Bravo
          Totally agree
          Hopium has been out of control
          Understandable Fauci and folks like Gottlieb had to mention light at end of tunnel — but the excessive cheerleading will only come back to haunt, Ie, Vax not affected by Variants, until they are — 60% covergage to get herd immunity — oops now maybe we need 80-90% (if we can… Brasíl Ex)
          Biden and team best to speak truth to the likely long term fight we’re in

        5. Marko says:

          I’m grateful that BNO News is at least making an effort to track reinfections globally. That’s more than you can say about our supposedly world-class medical institutions that expect us to hang on their every word. Heard anything lately from the JHU reinfection tracker? Me neither.

          An intriguing tidbit from the BNO site, though perhaps meaningless given the data uncertainty: the calculated CFR using their death figures associated with suspected reinfections comes to only ~0.28%, far removed from the global CFR of ~2%. That’s a trend I’d like to see confirmed as more data accrues, though it’s hard to imagine that the data out of Manaus will be very encouraging in this regard.

          1. GM says:

            An intriguing tidbit from the BNO site, though perhaps meaningless given the data uncertainty: the calculated CFR using their death figures associated with suspected reinfections comes to only ~0.28%, far removed from the global CFR of ~2%.

            You are not calculating it right.

            A lot of those are cases of reporting of reinfection but no outcome. Most of them in fact are exactly like that in the “suspected” section.

            So your actual denominator should be much lower, because “no outcome reported” does not mean “recovery”

            Symptomatic reinfections (and I have this from other sources that are actually tracking reinfections over a much larger sample size) tend towards the more severe the second time.

            This is counterbalanced by reinfections being asymptomatic more often.

            Which in turn is itself counterbalanced by damage to internal organs being cumulative.

            So maybe if you go through 15 reinfections over a span of 15-20 years, only 2 or 3 of them will be severe, while if you infect 15 people for the first time, it will be serious for 5 or 6 of them. But that will be sufficient to make you a physical wreck for the rest of your life, if you survive.

            I don’t want to live in that kind of world.

          2. Marko says:

            I calculated it right using the data given, and stipulated that it might be meaningless. You seem to be willing to accept their “cases” without question but don’t accept the deaths because it doesn’t fit your gloom-and-doom narrative. I could as easily argue that the deaths are more accurate because deaths from reinfections are more likely to be reported, while the cases are understated because unremarkable reinfections are no longer remarkable.

            Yeah, yeah, my secret sources say so-and-so. Provide a link or they don’t exist.

      2. JF says:

        “… papers explaining how this virus has short living immunity will pop up. So far, it looks like exactly the opposite.”

        There seem to be papers of this sort:
        https://www.biorxiv.org/content/10.1101/2021.01.18.427166v1

    2. Marko says:

      Reinfections and/or infections following vaccination, whether resulting from waning immunity or from escape mutations, are only of concern to me if they carry a significant risk of severe disease and death. For example, if the current IFR for a primary infection is 0.5%, and that drops by a factor of ten, to 0.05%, for reinfections or post-vaccine infections, the pandemic is officially over for me once everyone is vaccinated. I’m heading straight to the bar, without a mask. No, that’s not a zero risk scenario, but neither is getting out of bed, nor, for that matter, going to bed.

      What’s infuriating to me is that we don’t have these answers yet. What are all the leading scientists doing when they’re not tweeting? I think I answered my own question. They’re never not tweeting.

      Reinfections are undoubtedly occurring in sufficient numbers around the world to do the comparative IFR and “severe outcome” calculations, for wild type as well as the possible immune-escape variant strains in places like S.Africa and Brazil. Why aren’t we getting these numbers? Will we ever get them?

      One possible explanation for the lack of such data is a lack of funding for such studies. The vaccine manufacturers won’t fund them, you can be sure. They want the 25% or more ( and ever-growing ) of the population that has been previously-infected to believe that they, too, must get the vaccine to be truly saved. Governments won’t fund the studies for precisely the same reason, because, in most countries, there is no discernible difference between corporate interests and gov’t interests.

      1. Mykro says:

        “One possible explanation for the lack of such data is a lack of funding for such studies.”

        As is true for a great many research topics, I think you’re conclusion is likely on target; although, I’m rather skeptical of the ‘BIG pharma’ – ‘BIG government’ conspiracy being the cause. Far more likely is that funding was stymied on account of the ‘leadership’ denying that the virus was even real and thinking that it would just go ‘poof’ and be gone after election day. I for one am looking forward to seeing the sign hanging from Lady Liberty that reads “Under New Management.”

        1. Charles H. says:

          Yes, expect the new administration to be better about following scientific advice.

          OTOH, the House is less overwhelmingly Dem than before and the Senate is evenly divided. Nothing too controversial will get through the legislature. So “rule by decree” is going to have to continue. They will be different decrees, more concerned with what’s happening to the country, but it will still be rule by decree. (Which isn’t even really constitutional, though the Supreme Court has allowed it, because they sort of must. Amending the constitution is a real hassle and takes, IIRC, at best seven years.)

          So Biden has immediately proclaimed that masks will be worn on federal lands and by federal employees and contractors. That’s good. That’s beneficial. But it doesn’t directly touch those people at your local grocery store who won’t wear masks, and occasionally lick the goods.

          Hope. Hope is good for you. But don’t gamble on expectations.

        1. Marko says:

          Enjoy what? That study does not even mention risk of severe disease or death once reinfected.

    3. K says:

      Your comment is that we should avoid being too optimistic and you explain the reasons for your concern. There is a good back and forth discussion about the reasons you present (numbers, reports of reinfections, Brazil etc). However, I am wondering what the changes would be in terms of policy or other areas of we were to avoid that too optimistic approach.
      I have not read all the papers and reports you mention so I cannot form an educated opinion of them. I just want to understand what you are cautioning against. I too am cautious of being too optimistic. In your opinion, what would be the real world applications of health officials etc taking a less optimistic approach?

  4. Steve Scott says:

    What about the B-cell response for the 65+ group? I gather it’s not that great:

    “Both humoral and cellular immune responses are impaired in aged individuals, leading to decreased vaccine responses. Although T cell defects occur, defects in B cells play a significant role in age-related humoral immune changes.”

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3040253/

  5. Some idiot says:

    Wow… Thanks for another astounding dive into immunology… I am quite in awe regarding how it manages to do what it does…

    But I have a (possibly stupid) question: ok, the FDCs display antigens for a period of time. But how? Do they trap antigen fragments, or do they somehow work out how to make it themselves, and then display it on the surface?

    I assume the former, because the latter would be the weirdest of two weirds… But how does it decide what to be presented? How does it “ignore” self, and focus on “what is important”? And what determines how long it sits there on display, as it were?

    Pardon the stupid questions, but I am a process chemist. I think I want to be an immunologist if there is such thing as a next life…!

    1. johnnyboy says:

      It’s the former. The FDCs capture antigens that are trickling through the lymph node, spleen or other sites of germinal centre formation. These antigens would have been covered with antibodies and/or complement from the body’s immune reaction to them; FDCs have antibody and complement receptors, which is how they capture antigens.

      1. Some idiot says:

        Ah… That makes heaps of sense… Thanks!

        Still “wow” though…! 🙂

  6. Michael says:

    Derek, just pointing out that the Gupta Lab data is after only one dose. The second dose of Pfizer is obviously really important in generating antibodies, which will be the more interesting comparison regarding the variant.

    1. GM says:

      The Gupta lab data is kind of irrelevant at this point.

      It’s for B.1.1.7.

      This is not the one people were worried about, though even it shows decreased neutralization.

      Yesterday there was data posted about the South Africa variant that showed complete immune escape in half of the samples and decreased neutralization in practically all subjects. This not with the vaccine, it was in people who had it in the first wave, but when you are getting complete immune escape, and the vaccine uses the same antigen, it is quite clear where this is going.

      The Manaus strain will likely be the same as it shares the key mutations.

      So all this freaking out over B.1.1.7 is at this point silly. And has been for over a month (when the initial reports from SA came out) — B.1.1.7 will come and go, the strains like those two (and who knows what is being selected for during the second waves in SA and Brazil right now) will take over.

      1. Marko says:

        Yes, B.1.1.7 is so 2020. The NYT just did an encyclopedic overview of it yesterday. I’m sure it will hit the cover of Time next. In short, all signs point to B.1.1.7 being dead, rotting meat.

        https://www.nytimes.com/interactive/2021/health/coronavirus-mutations-B117-variant.html?action=click&module=Top%20Stories&pgtype=Homepage

      2. Roland says:

        “complete immune escape”

        This isn’t the case. It’s in vitro neutralising activity of blood samples which was measured. Half of samples didn’t display activity to the new variant. However unless I missed it we haven’t been told what percentage showed no activity to the old variant, and we know antibody activity drops off very rapidly so it’s expected convalescent plasma devoid of t-cells and outside the context of a functioning immune system is going to perform worse if it’s say 6 months post-infection. The half figure was first mentioned a month ago and the fact nothing more convincing has been published since seems to me quite promising.

        Comparing to the situation in the UK I haven’t seen anything so far in Brazil or South Africa that can’t be explained by higher infectivity alone. In London seropositivity rates were somewhere around 15% and infection rates remained low going into the autumn even as other parts of the UK more lightly hit in the first spike suffered a strong second spike in infections, so there was clearly some decent reinfection protection at that point. That all changed very rapidly when the new variant got going and the second spike is shaping up to be as bad or worse than the first. However if you combine a ~90% protection rate due to previous infections with a 60% increased infectivity, and some extra multiplier to account for a cold winter and NPI fatigue, that’s pretty much expected. Since there’s good evidence of no significant antibody issues with B.1.1.7 variant, seeing the same explosion of cases with other N501Y-variants isn’t evidence of reinfections.

        Definitely we should be wary. Not optimistic or pessimistic but scientific!

        1. GM says:

          This is the latest from SA:

          Professor Kholeka Mlisana, of the National Health Laboratory Services, said more than 4,000 possible reinfections were recorded as of January 6, 2021. All of the cases had at least 90 days or longer between the two episodes.

          As a reminder, if there was absolutely no immunity left (which we would not expect for a homologous strain so soon) we would expect to see ~5K PCR-tested reinfections based on the number positives in the first and the second wave (assuming random infections and homogenous population).

          1. Marko says:

            ” As a reminder, if there was absolutely no immunity left (which we would not expect for a homologous strain so soon) we would expect to see ~5K PCR-tested reinfections based on the number positives in the first and the second wave (assuming random infections and homogenous population). ”

            You’re either terrible at math or terribly confused, or both. Reinfections are infections that occur beyond 3 months from the first infection. As of early Oct. , seroprevalence was estimated at ~ at least 25%, and perhaps considerably higher (link below). If prior immunity provided no protection, you’d expect about 20% (or more) of the reported PCR+ cases since early Oct to be from reinfections, or 0.25 x ~650,000 = 162,500. Instead , we see about 2.5% of that amount, consistent with >95% “efficacy” of natural immunity in S. Africa.

            https://www.bbc.com/news/world-africa-55333126

            “As South Africa confronts a second wave of Covid-19 infections, scientists say new evidence indicates that at least a quarter of the country’s population – and possibly more than a third – may already have been infected by the virus during its first wave, which peaked in July.”

          2. Marko says:

            BTW, I used the early Oct cutoff simply because it cuts the cases about in half, making for easy calcs. Use instead a date of late Nov. , or whenever, in which case you’d have a higher seroprevalence times a somewhat smaller number of cases to come up with a similar result. The first wave, accounting for the bulk of the seroprevalence estimate used, was over by the end of August. Add 3 months and that puts you at end of Nov.

          3. GM says:

            You’re either terrible at math or terribly confused, or both

            I can’t believe what I am seeing here.

            Learn to read. And to think.

            They can only have PCR confirmed reinfections among the pool of already registered cases. The seropositivity is entirely irrelevant — we are only talking about the people PCR-tested during the first wave and PCR-tested again during the second wave, >90 days apart.

            It was ~600K positives in the first wave and ~500K positives in the second up until January 6th (which is their cutoff in that announcement; there has been another 150-200K positives since then, but they don’t count).

            Population is 60M.

          4. Marko says:

            You’re right. My bad. I’ve been thinking too much about the SIREN study. Also drinking.

          5. eub says:

            Cheers, all. Or something situationally appropriate. Bottoms up, these days, whatever it may be the bottom of.

          6. Roland says:

            “This is the latest from SA:
            Professor Kholeka Mlisana, of the National Health Laboratory Services, said more than 4,000 possible reinfections were recorded”

            And she says…
            “However, based on an analysis of the data, Mlisana said that the re-infections do not appear to be increasing alongside the new variant.

            She added that the number of recorded re-infections has increased, but that this is in line with the increase of Covid-19 cases being seen across the country.”

            It’s naive to think infections, reinfections, and PCR tests will be distributed homogeneously through any population, and some (possibly large) fraction of these ‘possible reinfections’ will be chronic infections or false positives, so we would expect hugely more than 5,000 if fully half infected with the old variant had no protection whatsoever from the new one.

          7. GM says:

            However, based on an analysis of the data, Mlisana said that the re-infections do not appear to be increasing alongside the new variant.

            That is supposed to be a positive how?

            They have had 1.2M confirmed cases.

            The PCR-confirmed reinfections have to be within roughly the first half of that, and then within the second half of that.

            Basic math shows we expect about 5,000 such reinfections from that pool if we assume very short-lived immunity.

            If those are not all with the new variant, which very clearly has immune escape properties, that means what?

            It means that they already were seeing rampant homologous reinfections with the old strain.

            Which is a reason not to worry because….?

          8. Roland says:

            You said above you weren’t worried about the old variants or B.1.1.7. I’m arguing there’s no credible evidence of significantly greater reinfections with the variants you are worried about. The evidence for reinfections with the old variant is necessarily time limited. We can only speculate how long it will last.

            How many false reinfections do you expect to detect among 6.7million tests if the test has 99% specificity, and the true positives in each wave were roughly the 600K and 500K you mentioned above?

        2. Marko says:

          ” “complete immune escape”……This isn’t the case. It’s in vitro neutralising activity of blood samples which was measured. Half of samples didn’t display activity to the new variant. However unless I missed it we haven’t been told what percentage showed no activity to the old variant…”

          Some samples had zero neutralization activity, some had reduced activity. So “reduced” compared to what ? Compared to activity vs the WT virus, that’s what. That’s how the mutation studies are done.

          1. Roland says:

            Well they published the details last night, so we can wonder no more: https://www.biorxiv.org/content/10.1101/2021.01.18.427166v1

            The half with no activity all had activity against the ‘original’ variant (D614G) but at the lower end of the spectrum. They do a really good breakdown of the mutations and different antibody types and argue most of the therapeutic monoclonal antibodies in development/emergency use will be useless against the new variants.

            On the other hand they note non-neutralising antibody activity was much less affected, and of course they can’t say anything about t-cell activity, so there are good reasons to hope substantial reinfections and vaccine escape aren’t an immediate consequence of these mutations.

        3. Chris Phillips says:

          Our (UK) esteemed health secretary’s (private) take on these experimental data:
          “There is evidence in the public domain, although we are not sure of this data so I wouldn’t say this in public, but that the South African variant reduces by about 50% the vaccine [sic] efficacy.”

          Not saying it in public, but saying it “during a webinar with business leaders and travel agents”. (Revelation courtesy of Sky News.)

  7. G Carr says:

    Does anyone know whether or not Pfizer and Moderna have begun reprogramming their vaccines to combat the new South African variant? I’ve read, probably in this forum, that it takes about six weeks for these companies to reengineer their vaccines. I would love to hear that new, updated vaccines will be produced in the not too distant future.

    But given that the technology for mRNA vaccines is so new, would the new versions need to go through the approval process again?

    1. Aleksei Besogonov says:

      They can technically start making a new vaccine within a couple of days or so. It’s completely tuneable on the fly.

      The problem is that this new vaccine has to be tested somehow. And currently trials are not at all a simple thing.

  8. Pablo says:

    If the virus mutates and/or immunity turns out not that long (e.g 2 years or less), which of the different vaccine types would be the safest one to take every year or every 2 years (perhaps in slightly changed form)? By safest I actually mean both safe and keeping efficacy?
    The mRNA vaccines, the viral vector vaccines or maybe protein vaccines?

    1. stewart says:

      Immunity to the vector is liable to be a problem with repeat use of virus-vector vaccines. Oxford/AstraZeneca used a chimpanzee adenovirus which humans are less likely to have been exposed to, and Sputnik V used different vectors for the two doses to reduce problems with preexisting and induced vector immunity, but when it comes to boosters that doesn’t help. You could swap between those two vaccines for the first round of vaccination for new strains, but new vectors would need a whole new development.

  9. Mister B. says:

    I have a very naive question.
    Assuming vaccinated people are “release in the wild”, they will face the Sars-cov in every variant there is. Will that boost their immunity too ?

    Basically, if the sars-cov keeps running, will it continue to stimulate those already vaccined / healed from a first contamination ?

    (Yes, it is naive but from a very optimistic person, it would be awesome !)

    1. GM says:

      Assuming vaccinated people are “release in the wild”, they will face the Sars-cov in every variant there is. Will that boost their immunity too

      It will select for further escape variants, which will also be yet more contagious. The vaccines are not sterilizing, i.e. you can catch it and spread it, you just don’t get seriously sick.

      Which is why vaccination should be halted and we should move towards elimination. Which is what any sane person knew was the only out of this from the beginning.

      1. KB says:

        I don’t think any serious scientist thinks eradication is plausible at this point. It’s simply too contagious and too deceptive with the incubation period.

        Endemicity seems to be the likeliest outcome: https://science.sciencemag.org/content/early/2021/01/11/science.abe6522

        1. GM says:

          Under a bunch of incorrect assumptions.

          Also, smallpox was “endemic” too, and so are things like malaria today.

          1. Marko says:

            How do you propose we achieve lasting “elimination” ?

            I can’t wait to hear this one…..

          2. GM says:

            How do you propose we achieve lasting “elimination” ?

            Following the well established rulebook for how to do it, and the well trodden recently by others path.

            1. Segment countries into units, and stop travel between them. Shut the borders of the countries themselves to prevent reintroduction.

            2. Lock down hard. No “essential activity” that is in fact not at all essential open. Give proper gas masks to everyone who is truly essential and has to go out. Everyone else is sealed inside their homes, under real threat of jail and fines. Everyone gets a fixed sum every month to live on. Rent and mortgages are cancelled for the duration.

            3. Test everyone regularly. Mobilize all available resource to do that, i.e. don’t have molecular biology PhDs sitting at home and not doing anything because the lab is shut as we had for much of last year.

            4. Isolate those who test positive. And that means proper rigidly enforced isolation, none of that “please, would you, if you don’t mind and it’s not too inconvenient” BS

            5. You keep this going until you get to zero cases for at least a month.

            6. Then you merge adjacent units that are COVID-free, and proceed from there.

            Eventually you merge adjacent countries into COVID-free blocks. Eventually those who refuse to do what has to be done become pariahs that can’t travel and will be forced to join the effort.

            It can be done. We have the technological capability.

            The only obstacle is the fact that members of the business elites and the politicians that serve them are mass murderers who refuse to do what has to be done because it threatens there economic interests.

          3. Marko says:

            Haha. Yes, that’s about what I expected. You’re going to coordinate every country, across the globe – including all those whose people are so poor that if they don’t go out and work for or find food every day, they starve – to shut down air-tight for a month, after which all will be hunky dory. You forgot to mention the global extermination of every possible animal reservoir, like minks, which could potentially reinfect the human race. And if you miss just a handful of people or animals who can start the cycle again, and you let down your guard for just a bit, you’re back in the soup again, and have to start all over.

            I gotta admit, it’s brilliant, in a way. It’s the most brilliantly stupid plan I’ve heard to date.

            “Crushing the curve” – for a time ,while waiting for cure or a vaccine – made good sense for the countries rich enough to afford to do it. However, no country , and certainly not every country in the world, can do that repeatedly and indefinitely as your proposal would require.

          4. JF says:

            What you recommend in your 9:15PM post sounds reasonable for me. It seems to be what China has been doing and what should have been done by other countries in early 2020. But for me (not being an expert at all) is whether this is too late now because the virus has been transmitted to animal vectors. I would expect most species of apes to be hosts from which humans will be re-infected after eradication along yours lines has succeeded. And it has been transmitted to minks as well as several species of cats, if I remember correctly.

          5. GM says:

            And it has been transmitted to minks as well as several species of cats, if I remember correctly.

            It’s not going to last in most of those hosts, they are solitary animals with insufficient population density to maintain it.

            Gorillas and chimps are a concern, that is true.

            As are humans themselves — let’s say we do get our act together and somehow eliminate it from the population. But it will still be in thousands of labs all around the world, and everyone with basic molecular biology expertise will be able to recreate it and release it back in a matter of days. Much nastier derivatives of it too. How you finish the job there is going to be really tricky.

            It has also by now been frozen in countless cold storage units all around the world, into which various people have coughed, where it will be stable pretty much indefinitely.

            But in general, the argument “it is spreading to other species” is not an argument to just give up, exactly the opposite — we need to stop giving it such opportunities ASAP.

          6. eub says:

            It’s a high-grade test, really. Basic human decency, that implies people should share what they need to live, or no?

          7. Dr. Symour Tushi says:

            It’s pretty remarkable that immediately following your argument for halting vaccination you use smallpox, a disease for which population-level vaccine distribution was wildly effective, as support.

      2. Brogie says:

        There is no evidence that vaccinated people can spread Covid. There is no evidence they can’t, on,y that it has never been the norm with previous vaccines.

        1. Doug H MD says:

          Well, actually no. There are lots of widely used vaccines that do not create sterilizing immunity
          Polio, Pertussis come to mind right away. Influenza for most vaccines.

          1. Novacek says:

            One of the two common polio vaccines does create sterilizing immunity.

            All the more reason that an affirmative claim that the current covid vaccines do not, based on 0 evidence, should be treated with skepticism.

      3. 13enster says:

        “Which is why vaccination should be halted and we should move towards elimination.”

        How exactly do you propose to eliminate a virus without vaccination?

        1. GM says:

          The current vaccines are not sterilizing.

          They only prevent severe disease, not infection.

          1. Marko says:

            Answer the question.

          2. Klimax says:

            What’s your evidence for your claim?

          3. Yves Smith says:

            It’s been widely discussed that sterilizing immunity unlikely for a vaccine against a respiratory disease.

            See from The Lancet:

            Challenge studies in vaccinated primates showed reductions in pathology, symptoms, and viral load in the lower respiratory tract, but failed to elicit sterilising immunity in the upper airways. Sterilising immunity in the upper airways has been claimed for one vaccine, but peer-reviewed publication of these data are awaited.

            https://www.thelancet.com/article/S0140-6736(20)31976-0/fulltext

            That “one vaccine” is Novavax, which for unknown reasons had to ‘splain itself to the FDA:

            https://www.fiercepharma.com/manufacturing/novavax-swamped-fda-s-manufacturing-questions-hopes-for-us-trial-within-year

            And even the lay press is cautioning against expecting sterilizing immunity:

            “Sterilizing immunity doesn’t happen very often — that is not the norm,” said Alessandro Sette, an immunologist at the La Jolla Institute of Immunology and co-leader of the study [on Covid-19 antibody levels].

            https://www.nytimes.com/2020/11/17/health/coronavirus-immunity.html

          4. Marko says:

            “It’s been widely discussed that sterilizing immunity unlikely for a vaccine against a respiratory disease.”

            I think the main issue here is one of terminology. I consider the protection conferred by natural infection with a common cold coronavirus, lasting months to a year or more, to be “sterilizing”, with limited duration. CoV2 natural infection provides a similar level of protection, and there’s good reason to believe the vaccines will as well, to a greater or lesser extent. As noted in the NYT piece you cited :

            “….The coronavirus in particular is slow to do harm, giving the immune system plenty of time to kick into gear.

            “It may be terminated fast enough that not only are you not experiencing any symptoms but you are not infectious,” Dr. Sette said. ”

            If “sterilizing” is not quite the right term to use, fine, give me another. How about”pasteurizing” immunity ? Or “refrigerate after opening” immunity ?

  10. Stephanie says:

    More naivety: Does the E484K variant increase risk of ADE in vaccinated or previously-infected people? THIS is my vaccine hesitancy in a nutshell.

    I’m inclined to take an mRNA vaccine if/when I do get vaccinated because I like the idea of less antigen and more specific antibody production, seemingly with less risk of autoimmunity (though I have not seen evidence–doesn’t mean it doesn’t exist).

    Thanks

  11. Melon says:

    The mRNA vaccines are said to cause a very strong immune response. What happens if a vaccinated person gets vaccinated again against a new variant? Will there be an original antigenic sin issue in which such people would never have as strong immunity against the new variant as they did against the original strain?

    1. GM says:

      That’s another serious concern (the original antigenic sin) that I don’t see people talking about because it’s too dark a possibility to contemplate, and we live in a society in which pessimism is not allowed.

    2. Klimax says:

      IIUC for mRNA vaccination, in the worst case you have to change lipids. (There is not much else that immune system could target)

  12. Doug H MD says:

    Derek: your article assumes that the vaccine will work with B cell immunity the same way over time as does natural infection. But do we know that? HTe article looked particulary at the GUT roles in this. As you note, these FDCs re not just in the gut. But what evidence do we have to date that B Cell immunity from the vaccine will be comparable to the live virus?

    1. Derek Lowe says:

      Here’s an article on B cells and vaccines, with some emphasis on FDCs and germinal centers: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318960/

      1. Doug H MD says:

        Thank you for this. Fascinating array of options. Would sure be mice to see some primate studies of the mRNA vaccines in use to see where in fact the distribution IS anatomically. Has that been done?
        We know for certain that different delivery routes and different adjuvants or vectors result in very different sorts of immunity for existing vaccine preventable diseases like influenza.

        Seems only time wil tell us more about that here.

  13. Miles says:

    GM should go off and write a dystopian science fiction book – I can see us now all living in capsule hotels with robots passing us Soylent green through a hatch.

    1. Marko says:

      “….I can see us now all living in capsule hotels with robots passing us Soylent green through a hatch.”

      I’m hoping for something more like Mad Max.

      1. miles says:

        Please not Mad Max, or if it has to be Mad Max, with better fashion sense!

    2. debinski says:

      Haha, yes. And the soylent green is, by nature, infected with SARS-Cov-2, killing the entire human race and allowing robots to take over the world.

  14. Marko says:

    mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

    https://www.biorxiv.org/content/10.1101/2021.01.15.426911v1

    “….Taken together the results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy.”

    They’re getting closer to doing it right, but are not there yet. They tested for neutralization using a combo of three of the mutations found in the variants, but not against the full variant RBD repertoire in combination. Perhaps they were afraid to demonstrate just how easy it is to build a custom CoV-2 in the lab. To me, the Gupta Lab variant studies seem better for real-world applicability.

      1. Marko says:

        A major takeaway for me is that wild-type neutralization titers were so similar, in potency and duration of response, between the mRNA vaccines and that acquired by natural infection.

        If the Moderna vaccine is good for at least a year, as the CEO has bragged, then so is natural immunity. It seems the conversation is shifting, from “The vaccines are better than natural immunity” to ” They’re just as good, we hope. “

        1. GM says:

          About a year of natural immunity is what is expected, except for those 5-10% who don’t seroconvert at all and who are susceptible much earlier.

          The reinfections we see are from that latter pool as well as from the left-hand tail of the distribution of the other 90-95%.

          But ten years from now, if the genocidal sociopaths who rule us have still not come to their senses, and the virus is still out there spreading unimpeded, most infections will be reinfections, as they are for the common cold coronaviruses.

          The reinfections we see in SA and Manaus are through immune escape though, and are coming earlier than expected.

          What happened in Iran we don’t know as nobody sequenced anything there.

          1. Marko says:

            I’m not going to worry too much about the long term until I see the data that suggests that the incidence of severe disease and death among reinfections and, presumably, vaccinees, is anything remotely like what is for primary infections, whether from variant strains or not. Even in the US, I think we’d be hearing about deaths from reinfections on a somewhat regular basis. If someone is admitted for Covid, tells their doc that they were PCR+ months before, then has a severe case or dies, I’m pretty sure that would be a reportable event, and we’d be hearing about it.

            Manaus seems like an obvious case to clear this up, but I don’t know if the data collection is good enough there to tell us much.

          2. Chris Phillips says:

            GM

            “We don’t have direct data on reinfections there, but Manaus was supposedly at 75+% seropositivity by October, yet it is experiencing a massive second wave right now that is shaping up to be bigger and more destructive than the first one.”

            “The reinfections we see [sic] in SA and Manaus are through immune escape though, and are coming earlier than expected.”

            I think that estimate for Manaus (from Buss et al. in Science) needs to be treated with caution. Their modelling produced an estimate of 66% for June, but they also mention a random survey which produced a figure of 14% for June (Hallal et al. in the Lancet). They dismiss that figure in a single sentence, on the grounds of inadequate power and test sensitivity. But they say it was a sample of 250 people, and the previous authors’ estimate of sensitivity was 85%. The discrepancy between the two figures is huge.

          3. Novacek says:

            Not to mention using blood donors for measurement requires them to be a reasonable proxy for the general population.

            While in Manaus, giving blood was apparently the easiest way to get a free covid test if you thought you had it.

            https://www.the-scientist.com/news-opinion/study-estimates-76-percent-of-brazilian-city-exposed-to-sars-cov-2-68272

            The idea that Manaus reached 75% infection in a few months is an extraordinary claim, and really requires more evidence than that. It’s a city of over 2 million people. 1.5 million infections in that short of time would have crushed the health system, and anywhere we’ve seen that the fatality rate has skyrocketed. There was no indication of either mid last year (some indications of the former now, giving doubts that it happened before and was covered up).

          4. GM says:

            Their modelling produced an estimate of 66% for June, but they also mention a random survey which produced a figure of 14% for June (Hallal et al. in the Lancet).

            There is no way it was that low, that would imply the IFR is as high as the CFR.

            Plus you have a whole bunch of other cities in the region around 50% seropositivity, some of them measured truly randomly, not from convenience samples, so it is no way an absurd number.

            Perhaps it wasn’t 76%, it was 40%. But the current wave is bigger than the first, and when it’s over will be bigger than the supposed remaining 60% susceptible can account for.

            Of course, then the third wave will come too, and people will be left squirming trying to explain that without invoking reinfections, which they no doubt will try to do.

            I have no doubt about that given that even though the list of PCR-confirmed reinfections has already grown to 9,000 as of today, you still see people parroting the “there has been only four reinfections” nonsense.

          5. Novacek says:

            What list of 9000 “PCR-confirmed reinfections”?

            The one you posted before?

            https://bnonews.com/index.php/reinfection-tracker-suspected-cases/

            The one that lists suspected cases, in no way confirmed?

          6. Marko says:

            ” But the current wave is bigger than the first, and when it’s over will be bigger than the supposed remaining 60% susceptible can account for.”

            Have you seen any recent data on the Manaus death rates comparing the first and second waves? I saw one article a week or two ago that said the 7-day average was running a fair amount lower than during the peak of the first wave. I suspect that reinfections must be playing a significant role in the current wave, but if it’s mainly serving to increase the rate of severe disease among the remaining vulnerable population, and not so much directly contributing to hospitalizations and deaths, it wouldn’t be quite so bad.

          7. GM says:

            Have you seen any recent data on the Manaus death rates comparing the first and second waves?

            We have cemetery burials:

            https://pbs.twimg.com/media/Er9yZqEXMAAkCPa?format=jpg&name=large

          8. GM says:

            What list of 9000 “PCR-confirmed reinfections”?

            The one you posted before?

            https://bnonews.com/index.php/reinfection-tracker-suspected-cases/

            The one that lists suspected cases, in no way confirmed?

            How exactly do you expect those to be sequencing-confirmed when nobody keeps the samples from the first wave so there is nothing to go back to?

            That’s goalpost moving at its slimiest best.

            For all practical purposes two positive PCR tests 90+ days apart plus a return of symptoms (which is true for most of these, that’s why they had the second test) means reinfection.

            The alternative is to propose some absurdly high levels of chronic infection.

          9. Novacek says:

            Goal post moving?

            You’re the one who literally said “PCR-confirmed reinfections”.

            “list of PCR-confirmed reinfections has already grown to 9,000 as of today”

            The confirmed reinfections, from your own source, is 39

            https://bnonews.com/index.php/2020/08/covid-19-reinfection-tracker/

          10. GM says:

            You’re the one who literally said “PCR-confirmed reinfections”.

            “list of PCR-confirmed reinfections has already grown to 9,000 as of today”

            The confirmed reinfections, from your own source, is 39

            https://bnonews.com/index.php/2020/08/covid-19-reinfection-tracker

            You’re losing all credibility by revealing yourself to have absolutely no idea what you are talking about.

            The 39 “confirmed” are confirmed by sequencing beyond all doubt — it’s a different strain in the two episodes.

            This an extremely high bar to clear, and if you insist on that are your criterion for accepting a reinfection, you are setting yourself up for a gigantic failure to understand what is actually happening.

            Those will be always be a tiny number — it is not as if everyone’s probes are kept for months after tested to go back to and sequence, quite the opposite, the vast majority of samples are discarded straight away because labs are inundate with samples and they don’t have the space to keep them around. Even if they are kept, there is no guarantee there is enough RNA to sequence. And then you need to have the infrastructure and resources to sequence, which very few places do. Even wealthy countries are barely sequencing anything.

            In short, it takes an extremely unlikely set of circumstances that have absolutely nothing to do with the actual prevalence of reinfections to end up on that list.

            The ~9,000 “suspected” are PCR-confirmed, i.e. two positive tests more than 90 days apart, typically with no symptoms in between and symptoms either side of the symptom-free period. The more time passes, the more unlikely it becomes that such a situation is a false positive due to persistent virus shedding or something of the sort.

            We are not talking about the people positive for antibodies but never PCR-tested prior to their second infections, of which there are many too.

            Now look at the nonsense you wrote and weep the way I did.

          11. Chris Phillips says:

            GM

            “There is no way it was that low, that would imply the IFR is as high as the CFR.”

            If you have conflicting scientific evidence, you need to try to understand and resolve the discrepancy, not just dismiss the evidence you don’t believe.

            You seem to be admitting that for all you know the 76% figure could be wrong by as much as a factor of two. I don’t know how you arrived at that figure, other than as a wild guess. If it can be wrong by that much, for reasons you don’t understand, why can’t it be wrong by more than that much, for reasons you don’t understand?

            And why do you think the lower estimate is wrong by a factor of three or more? For reasons you don’t understand?

            The data are very inadequate, and there’s a lot we all don’t understand. Dogmatism in the absence of consistent evidence doesn’t help. Otherwise these discussions become more like politics than science.

          12. GM says:

            And why do you think the lower estimate is wrong by a factor of three or more? For reasons you don’t understand?

            What I am saying is based on following these developments very closely from the very beginning (while most of the posters here were sleeping and ignoring the problem until it became impossible to ignore).

            I know very well how many people were actually tested positive in Manaus, what the serosurveys showed elsewhere in Brazil, in Colombia, and in Peru (e.g. there was another one yesterday from Iquitos, which wasn’t convenience samples but properly randomized, and it showed 70% with antibodies), the constraints on the IFR imposed by data from elsewhere, how well the Manaus mortality data agrees with age-stratified IFRs from other regions of the world, etc. etc. etc.

            When I say “There is no way it was less than 40%”, it is based on all of that information.

            So you have all that in your head too, and are ready to dismiss what I am saying based on even better familiarity with the facts than mine? Am I understanding it correctly?

          13. Chris Phillips says:

            GM

            “When I say “There is no way it was less than 40%”, it is based on all of that information.”

            Sorry, but that’s pretty much on a par with somebody who, when challenged about an assertion they are unable to provide evidence for, instead of backing it up, says “Do your own research – the answer is somewhere on the Internet”!

            It’s pretty much the antithesis of the scientific method. That requires testable demonstration, not just an unverifiable claim of superior knowledge or an appeal to authority.

            By all means provide testable evidence for your assertions. By all means demonstrate how the result of random sampling – 14% – could be an underestimate by a factor of four. I mean by pointing to the potential sources of error and giving us evidence that they could account for such a large error. You don’t seem able to do that.

            I’d emphasise that I’m not saying the lower estimate is right. What I’m saying is that the much lower estimate shouldn’t be simply dismissed – and the much higher estimate shouldn’t be simply assumed to be right – without a proper attempt to explain the conflicting evidence.

          14. Novacek says:

            Well there goes your credibility.

            No, absolutely not. Those 9000 are simply a running total of every time somebody, anywhere, merely suggested the possibility of a reinfection. Sometimes with no more data than that

            “South Dakota’s Health Department said 28 suspected cases of reinfection were reported in the state. A spokesman for the agency did not respond to a request for more details.”
            “About 300 people in the state have tested positive a second time.”
            etc.

            There was no such uniformity of diagnostic criteria nor testing.

            What you’re describing is more akin to that site’s _probable_ reinfections. Which are much, much lower than 9k.

          15. Philipp says:

            As you said yourself, 5% don’t seroconvert. With 25 million confirmed infections in the US, that’s 1.25 million people. With the US running at 365 confirmed new infections per 100K per week, this alone could give a re-infection tally way above the numbers you provide as “proof” there is no lasting immunity to speak of.

    1. Marko says:

      Here’s the preprint on the Gupta Lab study :

      https://www.biorxiv.org/content/10.1101/2021.01.15.426849v1

      BTW, above I misstated what the other lab did. They looked only at the RBD cluster of 3 mutations, but failed to look at the full spike cluster like the Gupta Lab did. The N-terminal domain (NTD) mutation cluster is also important, as it’s just a short hop away from the RBD and also plays a role in antibody-mediated neutralization.

  15. Jonesy says:

    This may seem obvious in an answer but could anyone just explain to me. If immunity is 5 months (approx going by recent events) how does 2 year vaccinations work? I cannot get my head around how people now being vaccinated…will be protected the coming Winter? As I said..probably obvious but cannot get head around.

  16. Kyle Weston says:

    unsettling times…. we need to dig in for the long haul
    this virus is showing sign of immune escape already—months not years
    https://www.cnn.com/2021/01/19/health/coronavirus-variant-vaccine-protection/index.html

    1. Alberto J. Villena says:

      I don’t think so. Please, read the section “ SARS-CoV-2 variants” on the review by Sette & Crotty: Adaptive immunity to SARS-CoV-2 and COVID-19. 2021.DOI: https://doi.org/10.1016/j.cell.2021.01.007.
      RBD motif is important for SARS-CoV-2 neutralization, but also other epitopes may elicit neutralizing antibodies.

      1. Kyle Weston says:

        thx – and a couple reads for you

        Molecular dynamic simulation reveals E484K mutation enhances spike RBD-ACE2 affinity and the combination of E484K, K417N and N501Y mutations (501Y.V2 variant) induces conformational change greater than N501Y mutant alone, potentially resulting in an escape mutant
        https://www.biorxiv.org/content/10.1101/2021.01.13.426558v1.full

        https://www.news-medical.net/news/20201223/SARS-CoV-2-mutations-may-evade-T-cell-immunity.aspx

  17. Dr. Seymour Tushi says:

    From above

    >2. Lock down hard. No “essential activity” that is in fact not at all essential open. Give proper gas masks to everyone who is truly essential and has to go out. Everyone else is sealed inside their homes, under real threat of jail and fines. Everyone gets a fixed sum every month to live on. Rent and mortgages are cancelled for the duration.

    >5. You keep this going until you get to zero cases for at least a month.

    GM is right, if scientists would just embrace pessimism we would realize that the real answer to our problem is a months-long global police state and not this unproven foolish idea of “vaccination”

    1. GM says:

      This is not a smallpox vaccine that works near 100% of the time and gives perfect sterilizing immunity.

      More generally, by your logic there can be no emergencies and serious crises that need wartime mobilization to be addressed, ever. By default.

      Do I need to explain how monumentally suicidality stupid such thinking is?

      1. Dr. Seymour Tushi says:

        Congratulations on winning the argument no one was making. There’s a difference between “wartime mobilization” and what you’ve proposed, which is hitting the pause button on society itself, everywhere on the planet, all at the same time, for months. You advocated for this explicitly at the expense of population-level vaccination, an emphasis you assert is catastrophically misguided for reasons few seem to agree with you on, but surely it’s all of them who are acting remarkably stupid.

        The readiness with which you just reverted to a straw man argument and ad hominem attack suggests you’re not having this conversation in good faith. Since you were so ready to name drop malaria earlier, maybe reflect on why the coverage of insecticide treated nets and artemisinin therapies remains remarkably low in many regions in sub-saharan africa, and then ask yourself whether these governments are ready to pay everyone in their countries to stay home for the next 6 months.

  18. Blaine White, M.D. says:

    I read the paper. It’s hard for me to see how there is B-cell clonal evolution to broaden antibody fit to viral mutations occuring in the absence of mutant antigens. This bothered the authors too. Here is the end of their abstract:

    “Analysis of intestinal biopsies obtained from asymptomatic individuals 4 months
    after the onset of coronavirus disease-2019 (COVID-19), using immunofluorescence,
    or polymerase chain reaction, revealed persistence of SARS-CoV-2 nucleic acids and
    immunoreactivity in the small bowel of 7 out of 14 volunteers. We conclude that the
    memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after
    infection in a manner that is consistent with antigen persistence.”

    This evidence is that the virus is hanging around and mutating in individual patients after the acute infection. It probably says nothing about vaccine efficacy in preventing disease in the first place, and it raises the question of whether “reinfection” is movement from bowel back to airway. We need effective antivirals to kill this thing ASAP by early outpatient Rx. “Long haulers” may be “antigen persistence.”

    1. Marko says:

      I can imagine antibody reactivity to a mutant antigen increasing in the absence of the actual mutant antigen simply by affinity maturation. Stronger binding to the unmutated antigen results in cross-over of better reactivity to the mutant form. While the mutant antigen is different than the original, it’s not necessarily THAT different.

      Alos, persistence of Ag is very different from persistence of RNA and/or persistence of virus. I’d guess that FDCs have the capacity to carry and pass around a tiny bit of an Ag protein for quite a while , without any requirement for new synthesis. Maybe not, though. It seems like something that should be known.

      1. Marko says:

        Interpret “alos” as “also” or “alas” , as you please. It’s one of my double-duty words.

    2. x says:

      Call yourself an M.D.? Marko’s got it right, it’s likely affinity maturation. No lingering mutant infections needed.

  19. Blaine White, M.D. says:

    From the paper:

    “Clinically approved nasopharyngeal swab PCR assays were negative in all 14 individuals at the time of biopsy. However, biopsy samples from 3 of the 14 participants produced PCR amplicons that were sequence verified as SARS-CoV-2. In addition, viral RNA was detected by in situ hybridization in biopsy samples from the two participants that were tested.”

    Call myself Professor emeritus and member NASEM emeritus. Four months is a long time for persistent viral RNA in a flushing pipe like the small intestine.

    1. Doug H MD says:

      Thank you for raising this .Shame they did not try to culture the virus.

      1. Marko says:

        You can’t culture from viral RNA fragments, and they never claimed to have detected even a complete viral sequence, only enough of one to identify it as CoV2 as opposed to some other RNA virus.

    2. Marko says:

      “…Four months is a long time for persistent viral RNA in a flushing pipe like the small intestine.”

      Cevik et al :SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis

      https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(20)30172-5/fulltext#seccestitle10

      “The maximum duration of viral shedding reported was 8 weeks in upper respiratory tract, 52 days in lower respiratory tract, 6–7 weeks in serum, and 126 days in stool samples…..Viable SARS-CoV was isolated from stool and respiratory samples up to 4 weeks, and urine specimens up to day 36 from symptom onset.All attempts to isolate virus from RT-PCR-positive stool specimens collected more than 6 weeks after disease onset failed….”

  20. Masher says:

    There seems to be a growing number of people in the scientific/medical community who believe that (given the capacity of the virus to mutate) we may need repeated vaccination programmes across the population in future. How might that be dovetailed in with existing vaccinations such as those for each winter flu season? Could there be a single jab covering all the flu/coronavirus variants for a given year, or would vaccinations have to be administered (say) a few weeks apart?

    I can imagine people happily going along for their annual “one jab for everything” appointment, and that becoming a just an accepted part of life, and fairly straightforward to administer. But an endless round of new jabs to keep chasing after the latest bugs would be pretty hard to sustain.

  21. Marko says:

    Early evidence from Israel suggests that their vaccination campaign will soon show a reduction in death rates . From The Economist :

    https://twitter.com/EricTopol/status/1352317427770482689

    1. Chris Phillips says:

      That dramatic decline in the growth rate of the number of over-60s in intensive care in Israel in the week to 16 January is particularly interesting, as second doses didn’t start to be administered until 9 January. If it’s due to the vaccine, it must be almost entirely a result of the first dose.

      1. Marko says:

        Agreed. I don’t find it particularly surprising. Two doses might be required to start to see evidence of sterilizing immunity, but I can see how the first dose alone, once it kicks in, might reduce severe disease and death incidence. I believe there’s some evidence for this in the trial data.

        1. GM says:

          It’s not sterilizing, first or second dose. Stop with this make-believe nonsense.

          The AZ trial followed infections, and there was little impact on infection. It only makes disease less severe.

          Pfizer and Moderna did not really track them, but there is no obvious mechanism through which those would generate sterilizing immunity in the URT. It’s an intramuscular injection.

          So the working assumption has to be that it is not sterilizing.

          And this is without the escape mutants we already have.

          1. Marko says:

            “The AZ trial followed infections, and there was little impact on infection.”

            There was an impact. If it reduces the rate of PCR-positivity, that’s sterilizing in my book. The mRNA vaccines likely will do the same, perhaps to a similar limited degree, perhaps a bit better. Duration of such effect is another issue.

            You’re just mad because we may soon begin to see a big reduction in severe disease and death as a result of the vaccines , which will consign your doom-and-gloom narrative to the trash-heap, where it belongs.

          2. Chris Phillips says:

            “The AZ trial followed infections, and there was little impact on infection. It only makes disease less severe.”

            No. According to the paper published in the Lancet in December, in the UK trials the total of the symptomatic and asymptomatic percentages was 3.0% in the placebo arms and 1.4% in the vaccine arms. Clearly the AstraZeneca vaccine was reducing the total number of detectable infections not simply converting symptomatic infections to asymptomatic ones.

            In the low-dose/standard dose arms, the reduction was from 3.7% to 0.8%.

          3. JS says:

            “There was an impact. If it reduces the rate of PCR-positivity, that’s sterilizing in my book. The mRNA vaccines likely will do the same, perhaps to a similar limited degree, perhaps a bit better. Duration of such effect is another issue.”

            Strictly speaking it could also mean that people get infected but test positive for a shorter period of time. Probably still good news as it will likely mean a lower probability of onward transmission.

            As for the mRNA vaccines did Moderna not see 38 PCR positive at the time of the second placebo and 14 at the second vaccine?

          4. Chris Phillips says:

            “Strictly speaking it could also mean that people get infected but test positive for a shorter period of time. Probably still good news as it will likely mean a lower probability of onward transmission.”

            In principle that’s true, but the testing was done weekly, so the reduction in the period of detectable infection would need to be dramatically smaller than the usual one, which is about three weeks if I understand correctly.

  22. Marko says:

    Dr. Fauci: If we get 70-85% of Americans vaccinated by the end of the summer or middle of the summer, we will be approaching a “degree of normality” by around the fall.

    https://twitter.com/Yamiche/status/1352364941970452482

    Fauci needs to have a chat with the boss. A full immunization of 1 million people per day would get you around that target by the end of Aug., but at the rate of Biden’s lame goal of 100 million “doses” in 100 days you’d only be half way there by then.

    Unveil “Turbo Vax” , Mr. Biden.

  23. Marko says:

    It’s too late for the US , I think, but this is what a simple, yet intelligent vaccine rollout would look like :

    “… but mortality and years of life lost were minimized in most scenarios when the vaccine was prioritized to adults over 60 years old. Use of individual-level serological tests to redirect doses to seronegative individuals improved the marginal impact of each dose while potentially reducing existing inequities in COVID-19 impact. ”

    https://science.sciencemag.org/content/early/2021/01/21/science.abe6959

    You could largely eliminate the requirement for a serological test by way of an information campaign informing people that they are as well-protected, if not better, by natural immunity as by vaccination, and that they should just wait, and use their later vaccination as a “booster”.

    The reason we’re not doing it this way now has more to do with elite privilege and profit incentives than it does with science.

    1. Doug H MD says:

      I concur. focus on saving lives now.that will help health care workers A LOT.
      lets not get sidetracked with the one dose strategy too: early indications are it does NOT WORK.

    2. Bill says:

      I try to screw around with the math a bit to get some insight. I’m guessing we may only get 200M vaccinated. That would be 400M shots. At 1M/day that’s over a year.

      To meet the goal of a “normal” Fall we need to up the shot rate to 3M/day. Seems not too great a challenge as I understand 3M/day is typical of flu shots. But then I look at the contract with Pfizer and Moderna and cranking the numbers, they’re only going to deliver 65M/month or 2M/day. And that assumes they hold delivery schedules which have already slipped so good luck with that.

      We need a third supplier now, and OxAZ is approved and going into millions of arms elsewhere. But not here. Fall? I don’t think so.

      BTW, according to Bloomberg News we hit 1.6M shots yesterday. I like Biden’s chances to make a million a day. He’s really got this under control. The media is in awe.

      1. DataWatcher says:

        My math tells me that 1.5 million a day x 30 days a month x 7 months (end of September) = 315 million, or over 95% of the approximately 228 million Americans. No way we can achieve that kind of uptake, but that’s a lot less than 3 million a day. More realistically, perhaps, but still stretch given the amount of vaccine resistance, a 1.5 million a day over 6 months (roughly the end of August) would give us 270 million, or about 82%, which is still within the estimated HIT range.

        1. confused says:

          Also, there should be significant immunity from natural infection, shouldn’t there? CDC’s 83 million by end of December is about 25% of the US population and infections didn’t stop then…

          Now there will be overlap (people both infected and vaccinated) but still…

          I would think things would improve radically well before herd immunity, though, since most of the deaths are in a fairly small part of the population which is being prioritized for vaccination.

        2. Marko says:

          Cut your numbers in half for a 2-dose regimen.

        3. DataWatcher says:

          Okay, I apologize — I forgot to take the two-shot calculus into consideration, so your 3 million is a lot close to the mark. I’m sorry again (although if J&J gets approved soon, that could reduce the necessary number at least to an extent, despite their relatively lower efficacy rate).

          Again, sorry for the brain-f*art.

          1. Data Watcher says:

            But I also think Confused has a valid point, and we might be “pleasantly” (horrible word in this context, I realize) surprised to discover how much lower the HIT might be in terms of vaccinations because of the under-reported number of infections and cases — I’m guessing somewhere between 25-30% of Americans will have been exposed to the virus before long, which would lower the required vaccination rate considerably, I’m guessing . Although, again, we don’t know how strong the immune response is among people who were asymptomatic or mildly symptomatic, or how long immunity from natural infection lasts in general, and of course we have the immune escape problem to worry about now, so there are a lot of unanswered questions there.

          2. confused says:

            >>I’m guessing somewhere between 25-30% of Americans will have been exposed to the virus before long

            CDC suggests we’re there already. 83 million is 25%, and that estimate is for “through December” – given high caseloads in January, 30% seems very reasonable.

            >>so there are a lot of unanswered questions there.

            Oh, absolutely. But I don’t know we really need “herd immunity” or sterilizing immunity – once basically everyone isn’t immuno-naive, just “enough immunity to prevent severe illness” is enough; if it’s reduced to common-cold severity, who cares about transmission?

          3. DataWatcher says:

            Ideally you’re right. However — I’m really sorry to sound like a tape loop, but as long as there’s transmission, there will be more mutations, and I do find that possibility extremely ominous. The virus seems to be evoloving very rapidly toward levels of contagiousness, probably virulence, and definitely immune escape capacity that could re-ignite the entire pandemic and make even the promised “tweaked” Moderna and Pfizer/BioNTech vaccines irrelevant before they’re even rolled ou.

          4. DataWatcher says:

            “. . . out.”

  24. Marko says:

    More on the encouraging vaccine news from Israel :

    https://twitter.com/segal_eran/status/1352696339377885187

    Hard to look at that graph, seeing the dramatic impact starting ~13 days after the first dose, and not believe something good is happening. Caveats be damned.

    1. DataWatcher says:

      Yes, I’ve been flooding my vaccine-skeptic acquaintances with news from Israel over the past few days. If they can manage to get their younger folks on board, summon the political courage to fully open up vaccine access to their Palestinian population, and try to find a way to deal with the vaccine resistance among the Orthodox community, they can be the shining light for the rest of the world to follow.

      1. DataWatcher says:

        Of course, the Israelis’ ace is their public health system — four nationally run not-for-profit HMOs with mandatory membership for all citizens. Imagine the American reaction to such a sane, rational idea! We’d have an insurrection that would dwarf what happened in DC on January 6

  25. Marko says:

    Southern California was not about to let other places steal all the limelight :

    Emergence of a novel SARS-CoV-2 strain in Southern California, USA

    https://www.medrxiv.org/content/10.1101/2021.01.18.21249786v1

    And they had the audacity to call it a “strain”. Racaniello will be livid!

  26. Marko says:

    Israel’s socialized medical care system blows the doors off the privatized, profit-driven system in the US, and it reveals itself in the CoV2 vaccine delivery effort:

    https://www.theatlantic.com/ideas/archive/2021/01/why-israels-vaccine-success-might-be-hard-replicate/617780/

    And Biden is against Medicare for All. The more things change…..

  27. Marko says:

    “….Michael Osterholm, an epidemiologist on President Joe Biden’s COVID-19 transition team, told CNN that the data in the recent U.K. report has “convinced” him the new variant is deadlier.

    “The data is mounting — and some of it I can’t share — that clearly supports that B.1.1.7 is causing more severe illness and increased death,” he said. “Already we know this variant has increased transmission, and so this is more very bad news.”….”

    https://www.masslive.com/coronavirus/2021/01/new-covid-strain-b117-cdc-reviewing-uk-data-suggesting-mutation-is-more-deadly.html

    “The data is mounting — and some of it I can’t share….”

    So Osterholm, the Stuart Smalley of Covid-19, is keeping secrets from us. Sorry, children, this is “adults-only” data.

    Just eyeballing the crude CFRs from the Oct-Nov surge compared to the more recent one, I can see a bit of an increase for the latter, but it’s one I think could be explained simply by extreme stress on the medical system. The daily deaths data seems to be peaking, or close to it, and will likely start heading down during the next week or so. I’ll be surprised if this “30% more deadly” stuff shakes out. There might be something there, but I don’t think it will be 30% or more.

    1. WST says:

      covid severity is 3 orders of magnitude between the really young and really old, so one should also look at demographic data, if more elderly got sick the CFR will increase. A very superficial look at the age analysis (UK 22 January) suggests that infections in groups 70+ and 50-69 peaked later and decreased slower then the younger ones.

      IMHO the second wave stared with the younger then the first wave, while elderly were self isolating or were at protected sites, but such protection is porous and the infection spread up in the age groups.
      I have seen it very well in France and Sweden, there were several accidents that eventually brought the infection inside places that managed to keep it out for months.
      BTW, there is a very interesting paper by two Swedish physicist that try to answer the question about feasibility of keeping two different populations groups apart during an epidemic, the answer is, no, not possible. Without general epidemics suppression effort, there is no way to truly protect the vulnerable.

      “Synchronization in Epidemic Growth and the Impossibility of Selective Containment”
      http://www.medrxiv.org/content/10.1101/2020.11.06.20226894v1?fbclid=IwAR3hQD1RxUH_x3aeDs1kH-I_rZHT2NB106bXDLtWFs-CQS9WvL4gWO7l_Z8

      1. Marko says:

        Agreed. Demographics could have a big impact. Crude CFR is, at best, a very crude measure to use in this case. Still, I want to see the secret data.

        1. Doug H MD says:

          What is up with that ” data i cant share” ?

        2. Some idiot says:

          Also, very importantly, why is the data considered to be secret? Openness in these sorts of situations is key…

  28. Lane Simonian says:

    I try not to dwell on these stories, because even if true they are likely literally one in a million (if we are lucky).

    https://www.nbc4i.com/community/health/coronavirus/investigation-underway-after-man-died-hours-after-getting-covid-19-vaccine/

    My question, though, is why are vaccines being given to people who have already had the coronavirus. If reinfections are rare and immunity likely lasts several months or longer, why add an unneccessary (and perhaps dangerous) immune response.

  29. Patricia L. DAndrea says:

    I have Multiple Sclerosis for which I take a disease modifying therapy called Ocrevus (infusion therapy). Ocrevus has proven to prevent further progression of disease by erradicating 100% of B-cells that house the Epstein-Barr virus causing my autoimmune disease. I get this infusion therapy every 6 months. What are the chances of developing antibodies to the Covid-19 vaccine if I do not have B-cells? Is it possible for T-cells (which are normal) to generate antibodies?

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