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Vaccination Against the New Variants: Real-World Data

We’re definitely not out of the pandemic woods yet, and neither is this blog – so let’s talk some more about antibodies today, in the hopes that we’re getting closer to the time when I (and all of us) can ignore immunology for a while.

But we’re not ignoring it today! There’s a lot of news, a lot of worry, and a lot of speculation about the variant forms of the coronavirus and what that means for the vaccination programs that are underway around the world. The short answer, fortunately, is that the antibody protection you get from the current vaccines still looks solid.

How can I say that, with so much evidence that the antibodies have decreased affinity towards the variant strain proteins? Here’s a new preprint that makes this clear. It shows neutralizing antibody activity in pseudovirus assays against the British (B.1.1.7) and South African (B.1.351) variants, with data versus a panel of monoclonal antibodies, versus convalescent plasma from coronavirus patients, and versus plasma from people who have received the vaccines.

First, the monoclonals. Checking B.1.1.7 against 12 different monoclonals showed that ten of these were equally effective, and two others showed only a small decrease in potency. The B.1.351 variant, though, was tougher. Five of the monoclonals had their activity very significantly impaired, and that includes the Lilly and Regeneron ones that are being used in the clinic right now. B.1.351 seems to evade the Lilly monoclonal outright, although the two-antibody Regeneron cocktail still seems effective as that mixture. This means that anyone using monoclonal antibody therapy with the currently available agents (and those in development as well, also tested in this work) is going to have to keep a close eye out for B.1.351 infections and related strains.

Mapping these activity changes versus single mutations showed that two residues that are trouble are the E484K and K417N mutations. That topic is taken up in more detail in this new paper. It looks at a complete mutational map of the Spike protein’s receptor-binding domain (RBD) and compares the activities of the Lilly and Regeneron antibodies. They picked up on both of the mutations above in the reported variant strains, as well as flagging Y453F, which has shown up in some of the mink-driven variants in Europe. They have also identified some mutations that escape one or the other monoclonal that have not shown up in the wild yet. Mapping all these onto the RBD structure is instructive – there are certainly some patterns that can be rationalized, but as the authors note, there are still mutations in the key RBD binding areas that don’t affect either antibody, and there are also mutations with very noticeable effects that aren’t in direct contact with either antibody at all.

But so far we’re just talking about monoclonals. If you are infected by such a coronavirus, or if you receive any of the current vaccines, you will absolutely not be generating a monoclonal response yourself. No, the whole point of our immune systems is that they come at the problem from a whole set of different directions at once. And in the antibody part of that response, you will make a very long list of different ones, which will in turn be gradually refined and adapted over time. So let’s look at that preprint discussed above and see what happens against convalescent plasma and plasma from vaccinated patients.

Checking plasma from 20 patients who recovered from the coronavirus earlier this year, the authors found that four of them had no loss of potency against either B.1.17 or B.1.351. 16 of the plasma samples showed a drop in potency against B.1.351, and 11 samples showed a drop against B.1.1.7. Those activity drops were 2.7 to 3.8 fold in the latter case, and 11 to 33-fold against the former (more on these numbers in just a moment). Most of that B.1.351 drop seems to be attributable to the E484K mutation. Here’s another preprint that’s just come out looking at convalescent plasma response to the B.1.351 variant and another closely related one, this time using live virus instead of pseudovirus constructs. They also find that the IC50 values are worse in the six patients they examined (more on this below!)

Now to the vaccinated-patient plasma samples, because that’s what a lot of people are really wondering about: how well does being vaccinated with the current agents provide you with protection against the new variants? The authors studied serum from 12 patients that had been given both doses of the Moderna vaccine and 10 patients who had had both doses of the Pfizer/BioNTech one. The activity drop against the B.1.1.7 variant was only about 2-fold in both groups, whereas the overall activity drop against the B.1.351 variant was 6.5-fold in Pfizer vaccinnees and 8.6-fold in Moderna ones.

OK, real-world time. First, those numbers tell us that being vaccinated provides a person with more protection than being infected with the coronavirus itself. That was already thought to be the case for the more common coronavirus forms out there, but it’s good to see that it carries over to these two new variants as well. You will get substantially better protection from being vaccinated, and you don’t have to take your chances with the unpredictable and potentially deadly course of an actual coronavirus infection, either. Now that we have vaccines, the idea of letting the virus just run through a population to achieve immunity by that route looks more obscene than ever. And make no mistake, it has always been an obscene idea as far as I’m concerned. These data also make a case that people who have already been infected naturally and recovered could benefit from being vaccinated, although from a public health standpoint they could be much further back in the line than people who have not yet been exposed.

What about those activity drops, especially the larger ones against the B.1.351 variant? Does that still leave room for protection? Here’s the good news: it very much does. Here’s a graph from the paper I’ve been discussing for most of this post (via Eric Topol on Twitter, who is a solid source for info on this sort of thing), showing activity against the two new variants versus the good ol’ D614G variant that everyone was worked up about a few months ago:

As pointed out by virologist Roberto Burioni this morning on Twitter, it’s important to pay attention to the Y axis on these – it’s a log scale. The bottom of the graph is not a flat-zero no activity line; the bottom is still a hundredfold dilution of the serum from the patients. You have to do that in order to get an assay window to see the differences – straight serum from vaccinated patients should still hammer these viral strains right down. As Burioni says, “There is a decrease, but from extremely high levels. I think these data are very good“. And I agree. It would be very interesting indeed to see this experiment run with plasma from people who have only had the first shot of each of these vaccines, though, wouldn’t it?

The thing we have to watch for, then, are much larger decreases than the sixfold, 11-fold, 30-fold levels. The preprint from the South African team mentioned above is worth considering in that light. It’s a small sample (six patients) of plasma from people who recovered from “first wave” coronavirus, looking at how such antibodies deal with B.1.351 types. Of the six, the activities are 5.7-fold lower, 9.6-fold, 38.1-fold, 53.2-fold, 204-fold, and one that was a complete knockout. Those last two are of concern, for sure, especially the KO. Now, you’d want to see a larger patient sample, to know how common those big drops are. And you’d especially want to see this experiment run versus vaccinated patient plasma, as shown above, which should be better across the board. Update: in response to some questions, yes – one thing the South African data may be telling us is that there will be people who have been through a round of infection who will be more vulnerable to re-infection with one of the new variants. Antibody titers are not the whole story, of course, and there’s always the antibody clonal maturation over time that’s helping out. But I wouldn’t want to take that risk myself, and we shouldn’t take the risk of having these variants spread so much that we find out.

What the data are telling us right now is that it definitely looks like vaccination can still handle the variant forms of the coronavirus that we are seeing – but that we also have to be on our guard, because there is no law that says that this protection can’t be breached. Taking public health measures to decrease the spread of the new variants is critical, as is getting as many people vaccinated as quickly as possible. If we mess either of those up, we are asking for serious trouble.

But there’s even a potential way out of that trouble, although you’d hate to have that emergency and to break that particular glass. As Moderna has said, variant mRNAs can be turned out quickly to be formulated as a new vaccine. Putting one together with the E484K and K417N point mutations (and others) should be basically the same process as what’s been used to make the currently administered ones (both Moderna and Pfizer/BioNTech). You would take a hit in production, of course, because you’d have to stop the current forms and start up the new ones. And you would be taking a small-but-real risk that these might perform differently in adverse events (but this would still be similar to the way that we roll out different flu vaccines every year). So the mRNA technologies offer us a potential counterattack, which is good – but let’s try not to have to use it!

211 comments on “Vaccination Against the New Variants: Real-World Data”

  1. Anon says:

    Derek…..on that graph am I understanding correctly that it should be B.1.351 and not B.1.315 as it erroneously indicates? I am assuming that we are talking about B.1.351 variant and not B.1315(yet!!!!). thanks

  2. passerby says:

    We may indeed end up with a seasonal and recurring covid shot, similar to the flu shots, on the long run. What worries me in the mid term, is that in Brasil, Manaus, after a horrible first wave, almost 70% were found positive in antibody tests. This should have led to herd immunity. But now, in the second wave, the health systems in Manaus have collapsed again… there may be other virus variants at play now. And who knows what happens once everybody is vaccinated? There will be a selective pressure for mutations that evade the immune response….

    1. Novacek says:

      No, they weren’t.

      40% of blood donations were found positive.

      This value was then “corrected” to a higher value.

      It’s very likely that there’s something wrong with the various fudge factors they used to try and compensate. It’s also quite possible that blood donations weren’t representative of the population a whole, especially since it was a way to get a free COVID test.

      1. GM says:

        First, it was 70% in Iquitos too, and that was a properly randomized sampling, so it is not as if 76% is inconceivable for Manaus.

        Second, the second wave is shaping up to end up being larger than the first by more than 1.5X (60:40) so one quickly runs out of space to fit all the deaths in by positing low AR during the first wave.

        Third, there will be a third, and a fourth, and a fifth, and so on waves, and we will see how the “optimists” (the proper words to describe them cannot be printed in polite society) will try to wiggle out of that when it happens. We can have no doubt they will try to do so though — a couple months ago the narrative was “Manaus reached herd immunity without the world ending, see, no problem”, now it has shifted to “Manaus did not reach herd immunity” once the second wave came, and this is often coming from the very same people.

        1. Marko says:

          I’m very concerned about the Manaus situation, and it’s baffling to me why we don’t yet have some firm answers about what’s going on there. I would think that the WHO or CDC or somebody would have dispatched a team there and have it sorted out by now. It seems to me it represents the most critical question we face regarding the pandemic at this moment.

          If reinfections make up a large percentage of the recent surge, that’s bad, but if reinfections make up even a moderate percentage of the deaths, that’s REALLY bad. I’m not convinced that the latter must be true at this point, but I do think it’s urgent that we find out.

          1. Marko says:

            Just today in the WP :

            “Sylvain Aldighieri, a senior official with the Pan American Health Organization who has been tracking the Manaus outbreak, said there is no evidence to suggest that reinfections are driving the health crisis. “We would have many more reports,” he said. “We have to use our common sense at this point. Herd immunity in Manaus was not achieved.”


            Not entirely convincing, but I’m glad that the reports of reinfections are low rather than high.

            One of the things that bothers me about the serosurveys that have been done so far is how obvious it is that they’re using junk antibody assays. Sensitive ELISAs show nearly 100% seropositivity among the previously-infected out to 8 months and probably beyond. With Sars-CoV-1 , the same is true out to 3 years. Use a sensitive ELISA (or two! ) for the serosurveys and stop massaging the data with fudge-factors to account for antibody waning.

          2. GM says:

            One of the things that bothers me about the serosurveys that have been done so far is how obvious it is that they’re using junk antibody assays. Sensitive ELISAs show nearly 100% seropositivity among the previously-infected out to 8 months and probably beyond.

            The Manaus serosurvey did the clinching control — they tested blood from 2019, found one positive out of several hundred.

            It is out of the question it was driven by false positives.

            The only doubt is about the sampling

          3. Marko says:

            “The Manaus serosurvey did the clinching control — they tested blood from 2019, found one positive out of several hundred…..It is out of the question it was driven by false positives….The only doubt is about the sampling”

            Try reading for comprehension next time. Nothing I said remotely suggested a concern with false positives. The problem is false negatives, i.e. using an insensitive assay that requires you to adjust your data for antibody waning. Look at UK serosurvey data for example. They show seropositivity falling by half in some areas from the end of the spring wave to late summer. To make sense of that kind of nonsense requires massive fudging. Assays are available that would have picked up every positive throughout 2020, and probably will through 2021, without sacrificing specificity.

          4. Jose Candido Ferraz says:

            I totally agree with you. I think some serious world health agency must be involved quickly because we brazilians are not being able to deal with it. That is the truth. We do not have a serious (scientific) and competent national health coordination to deal with this pandemic and the Manaus situation will probably extend to the rest of the country (is already hitting hard the neighbouring states). At the government level, we see no one discussing viral mutants and our national vaccination plan has two vaccines (Coronavac and AstraZeneca) but insufficient doses and inefficient rollout. Please, help to press the WHO and CDC. This is the last thing our stupid President will do.

        2. Novacek says:

          Of course it’s possible for a city to reach 70% infected.

          That’s hardly evidence of whether it has actually occurred in different city.

          Yes, a much more rigorous sampling study showed Iquitos at 70%. And unlike Manaus, they haven’t seen a fall wave. That’s of course not a guarantee it won’t happen, but it hasn’t so far.

        3. Daniel says:

          Iquitos had far higher deaths per million than Manaus though (measured by excess deaths). Manaus reached about 1500 dpm after the first wave (they’re at 3000 dpm now), Iquitos had about 6000 dpm. My guess is Manaus had about 40-50% seroprevalence after the first wave, with a high IFR due to the hospitals running out of oxygen twice.

          1. confused says:

            Ah. I was a bit skeptical of the Manaus numbers in a comment on a previous post based on the apparent low IFR implied (0.2% or a bit less) – sure Brazil has a younger population than Europe, but not so young as most of Latin America (median age ~33, vs. 28 or 29 for Peru and Mexico, and ~25 for Bolivia, also hard-hit by COVID).

            If other places in the Brazilian Amazon show a higher IFR, that’s likely evidence in favor of that.

            Sure, COVID has a very strong risk dependence by age… but Latin American countries with much lower median ages still show high death rates (Peru and Mexico are both over 1 in 1,000 of their total population, and Bolivia is 0.9 in 1,000).

          2. confused says:

            If Manaus was at even 40% seroprevalence with 1500 deaths per million, wouldn’t that imply that Iquitos at 6000 deaths per million actually hit 100%? Or does Iquitos have an older/less healthy population?

          3. GM says:

            If Manaus was at even 40% seroprevalence with 1500 deaths per million, wouldn’t that imply that Iquitos at 6000 deaths per million actually hit 100%? Or does Iquitos have an older/less healthy population?

            The healthcare collapse in Iquitos was much worse than in Manaus. They ran out of oxygen very quickly, and without oxygen people who would otherwise live die, many of them.

            Manaus only ran out of oxygen during the second wave, not the first.

        4. x says:

          We have numerous vaccines, including some viral vaccines, that don’t require any “updates” beyond boosters given decades apart. And yet, somehow, there’s this segment of the population that acts as though it is absolutely certain that we will need annual COVID shots, even though these viruses are not flu viruses and don’t act like flu viruses.

          On what evidence do they base this extraordinary assertion? None whatsoever! No, they’re out here pulling unfounded, nonsensical medical conspiracy theories and science alarmism out of their butts while they have the audacity to accuse “western scientific thought” of being too cocksure.

          Yeah, okay dudes.

          1. JeffC says:

            Sure. But not all viruses are the same. So the mutation rates vary. Flu is a bad example because it’s mechanism of resistance is actually quite specific to flu in the way is swaps it’s surface antigens. SARS CoV2 is different again. It looks like given that it’s become so widespread that we might need multiple vaccines to eventually eliminate it. Or we won’t be able to eliminate it because our immunity is not long lived enough or strong enough. And that would not be unusual. RSV infects us all multiple times. We develop immunity, but it doesn’t last long enough to give us long term protection; we have partial immunity which makes symptoms mild until we get old or our immune system gets weakened ands then we’re more vulnerable again. And there is not vaccine for that one. This is a virus that has been in man for just over a year, so there’s a lot we don’t know. But based on the current data, there’s a good chance we’ll need to be regularly re-vaccinated. Maybe not every year but fairly often. But we’ll collect more data and find out.

          2. John says:

            It’s not completely outrageous, considering we’re pretty close to mutations that evade the current vaccines and it’s been less than one year. OTOH, the mutation rate will go down a lot when the infection rate goes down as the vaccines become more widespread.

          3. Adrian says:

            What you are calling “nonsensical medical conspiracy theories” is actually based on a pretty trivial observation:

            For some viruses a natural infection provides lifetime immunity, and for others it does not.

            When natural infection provides lifetime immunity, it can be expected that a good vaccine achieves the same.

            For the 4 other human coronaviruses that are among the viruses causing the common cold, it is known that immunity after natural infection tends to last less than a year.

          4. jose says:

            I quite agree that the alarmism and assumption that yearly shots will be required seems both unlikely and strangely uninformed, but people love to be scared and scare other people, because it’s such a powerful emotion.

            However, to stick more to the science, it seems to me that we would need at least several locations of significant mutations that independently reduce the effectiveness of vaccination, without significantly reducing infectivity (e.g. r0). We have yet to see a single mutation like that in over a year with well over 100M infections. Even if there is a single mutation that reduces effectiveness by 10x or more, it’s easy to create a booster that targets it (especially for the RNA vaccines). If there were 3 unique mutations that could readily infect and each (and in any combination) also evaded vaccination, that even that wouldn’t be so hard to vaccinate against with a few shots. If they don’t make independent changes to the protein structure then some combinations won’t effectively spread. It’s only when there are 5 or 10 independent effective mutations that there is a real challenge with vaccination. If there were so many effective mutations (independent or not) I’m surprised they haven’t shown up.

            I’d actually worry more that there could be some increase in side effects of the vaccination with more boosters, but they still seem unlikely to be any where near the deadliness of the virus itself.

        5. confused says:

          Has any respiratory pandemic ever had a fifth wave? The 1918 flu is sometimes said to have had a fourth wave, admittedly, but I don’t think it was four waves *in the same location*; I think the 1920 “fourth wave” was in places previously not hard-hit.

          1. Chris Phillips says:

            But didn’t the waves of Spanish flu stop because enough immunity had been acquired through infection to prevent them? Isn’t it because we have limited the number of people infected (in most countries) that we’re still going to be vulnerable to more waves unless and until herd immunity is attained?

          2. GM says:

            This is not a “pandemic” in the conventional 1918 flu sense, i.e. a virus comes and goes, then life goes back to normal.

            This is a new virus that has arrived and is not going to go away.

            Big difference.

            In 1918 it went away because of a combination of built up immunity, possibly thanks to further drift making it less lethal, and due to competition with other flu viruses.

            None of this applies here — this is a coronavirus, and people catch the regular ones dozens of times each over the course of their lives, because there is no lasting immunity to those, there is no selective pressure to make it less harmful because of the asymptomatic and presymptomatic spread, and there is no real competition either, not that it is going to lose it as it is much much more contagious than any of the other respiratory illness viruses.

            P.S. The story that is being slowly developed these days is that the reason it was all bungled in the beginning is that it was incorrectly (but sincerely) assumed that this will be a flu-like pandemic. I don’t buy that — yes, naming it “COVID” rather than “SARS-2” confused the lay public, but it was known that this is SARS from the very beginning, before it got the name “COVID”, and the people who are supposed to make these decisions do know what SARS means, and they did know very well everything I listed before on January 1st 2020.

          3. hardnox fort says:

            As far as I can tell, it is unlikely that it “went away” as such. Tracing of what caused the spanish flu points to a H1N1 from birds. It isn’t too far different from A/sw/Iowa/30, the oldest strain in library. It has likely mutated several times to escape herd immunity, but stayed in the species. However a cloned version has been studied and points to an incredibly potent reproducer, causing massive lung damage in mice.

            Btw. Do not compare a flu and SARS-CoV-2 in that sense. SARS-CoV-2s convalescent plasma seems to do close to squad against the infections, while flu convalescent plasma works well.
            Flu’s are fast at mutating new variants to escape immunity, while SARS-CoV-2 seems to scramble the immune system in other ways too.

          4. confused says:

            @Chris Phillips: >>But didn’t the waves of Spanish flu stop because enough immunity had been acquired through infection to prevent them?

            I don’t know.

            I had thought the virus survived but became “a normal seasonal flu virus”, but whether that was a change in humans’ immunity or virus itself, I don’t know.

            Is the answer to that question even known (to anyone)? They couldn’t sequence the virus back then, flu wasn’t even known to be viral…

            >>This is not a “pandemic” in the conventional 1918 flu sense, i.e. a virus comes and goes, then life goes back to normal. This is a new virus that has arrived and is not going to go away.

            I am not sure there actually IS a difference. It’s a pandemic because we are immunologically naive, it will go endemic when we are not.

            The 1957, 1968, and 2009 flu pandemic viruses didn’t “go away”, they became seasonal flu viruses. But the pandemics ended.

            Isn’t it sometimes said that the 1890s “Russian flu” pandemic might actually have been one of the “common cold” coronaviruses jumping to humans?

            >>there is no lasting immunity to those,

            Is that actually true? There isn’t *sterilizing* immunity, sure, people catch it over and over. But is there no *protective* immunity? (IE, in the sense that what’s “just a common cold” to us might be serious if someone who somehow made it to say 65 without ever being exposed caught it…)

      2. ibraim sued says:

        Yes. Who were the blood donors? They were the guys who were circulating around the city, not afraid of social contacts,

  3. Ross Presser says:

    > straight serum from vaccinated patients should still hammer these viral strains right down

    Does this mean that if you used plasma from vaccinated individuals (perhaps, on a very specific timetable) as a treatment for newly infected patients, it might do even better than convalescent plasma of those recovered from an actual infection?

    1. Derek Lowe says:

      It does make you wonder. On the other hand convalescent plasma has had really disappointing results in the clinic, from what I have seen. So maybe this would push it up to “definitely marginal” instead of “no apparent effect”? I hope that we don’t find ourselves in a situation where we have to find out. . .

      1. Pablo Garibotti says:

        Have you read this study:
        Convalescent plasma showed positive results if applied early

    2. Roland says:

      I really hope if – more likely when – this gets tried some serious care is taken to contain any vaccine escape mutations that get nurtured.

  4. Mic says:

    I apologise for the probably stupid question, but would a vaccine with a variant mRNA need to go through clinical testing before entering in the market?

    1. David E. Young, MD says:

      Yes. Pretty much all of it. Maybe a smaller trial, but not by much

      1. Marko says:

        Not a chance, doc. Updates will be comparable to what occurs with the flu vaccine.

        Watch and learn.

        1. Doug H MD says:

          remember though: we have these vaccines operating under EUA. They are not approved vaccines. whole different ball game. Not that i disagree. the fda is very pliable

          1. Marko says:

            There will probably be a new term entering the lexicon : EUA Stacking.

    2. Derek Lowe says:

      Not a stupid question at all – I believe that’s currently an important matter for discussion with the FDA. I would guess that it would be like the annual flu vaccine update, a much lower regulatory bar.

    3. FrankN says:

      I happen to know someone working with BioNTech who is just discussing this question with PEI and EMA, and I am quite certain similar discussions are ongoing between the FDA and Pfizer and Moderna.

      Short answer: Nobody seems to have a clue yet. All parties involved acknowledge that swift adaptation to new strains might be required to end the pandemy. Equally, everybody understands that SARS-CoV2 isn’t influenza, and procedures for authorising flu vaccine updates might not neccessarily be adequate for corona vaccine updates. Last but not least, they are all aware that the SARS-CoV2 case will set a precedent for any future mRNA vaccine, and as such shape authorization practice for the next 10-15 years.

      So, it is very much work in progress, in dialogue between (hopefully) well informed, and sensitized, researchers and regulators. For the time being, we need to trust in their expertise and professionalism. As far as my BioNTech acquaintance is concerned, I have this trust. Can’t speak for the rest.

  5. Melon says:

    I think this is a bit optimistic. The South African and Brazilian variants are not yet globally relevant, but their descendants in 9 months will be very relevant. In 9 months time we can also expect a large drop in neutralising antibody titers. And if we extrapolate how many more mutations we might see after a few more months in which the virus has been exposed to an environment in which many hosts have some antibodies, we might have to be concerned.

    1. Derek Lowe says:

      Possible – but after several months we will have seen clonal selection in the B cells making the antibodies, and there’s evidence that these have better activity against several of the mutants. It’s going to be a race, though, and I hope that we don’t have to run it that way and find out the answer.

      1. Vlad says:

        What about the inactivated vaccines? They produce a range of antibodies, would they – in theory – start from behind but also have their efficacy decrease less due to be less reliant on S protein?

        1. Melon says:

          Maybe, but people vaccinated with the inactivated vaccines seem to only experience milder/no symptoms but protection from infection is likely very low. If efficacy is 50% for very mild symptomatic disease it must be significantly lower than 50% for asymptomic infection. All of these people will become the perfect incubators for the virus to escape antibodies designed for the original strain

  6. Marko says:

    Derek and others keep hammering away about how the vaccine provides better protection than natural infection, but I have yet to see an apples-to-apples comparison to demonstrate that. What’s being compared are vaccinee sera that are being sampled at or near the peak of antibody response vs. convalescent sera that were collected who knows when in relation to the peak antibody response. And neutralization is still just a proxy for real-world protection, and not a slam-dunk predictor by any means.

    Vaccination is certainly superior in that you don’t have to chance getting a severe disease to get your protection, but beyond that, I don’t think you can say for sure. What you CAN say is that natural infection is much more likely to stimulate a mucosal immune response , and having that response primed could be beneficial in the event of a re-exposure. The SIREN study demonstrates that reinfections, even asymptomatic ones, are quite rare for at least 5 months after a primary infection. We have no data yet that supports a similar level and duration of protection conferred by vaccination.

    1. lizzy says:

      For those who need a bit of background before reading Derek’s excellent post:

      I am personally interested in Plitidepsin. It has an interesting preprint as well as this article. Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A | Science (

      1. Marko says:

        Care to inform us on what it is in my comment that suggests to you that I need a “bit of background” before commenting on Derek’s “excellent post” , and where, exactly, I might find it in the article you linked?

        No? I didn’t think so.

    2. Doug H MD says:

      you beat me to it.

    3. Roland says:

      > convalescent sera that were collected who knows when in relation to the peak antibody response

      The paper strongly hints when: “We obtained convalescent plasma from 20 patients more than one month after documented SARS-CoV-2 infection in the Spring of 2020.”

      I read that as it’s been on ice since the spring, so it would have been between 1 and approx 3 months after infection. And..

      (Moderna vaccine) “volunteers received two immunizations .. on days 0 and 28, and blood was collected on day 43”
      (Pfizer vaccine) “at the clinical dose on days 0 and 21. Blood was collected on day 28 or later”

      These seem good enough for the purposes of neutralisation comparison, but I agree it’s a stretch to say this definitely means vaccine immunity is better than a real infection overall. It’s just a good hint it is.

      1. Marko says:

        “We obtained convalescent plasma from 20 patients more than one month after documented SARS-CoV-2 infection in the Spring of 2020.”

        I read that as it’s been on ice since the spring, so it would have been between 1 and approx 3 months after infection. ”

        You could just as easily read that as saying they drew the blood a week before they ran the study. It would have been easy enough to tell us ” Convalescent plasma was collected an average of x days post-symptom-onset, with a range of y to z days.”

        It’s an unknown.

    4. sarah says:

      I think this is a key question — is “natural immunity” equivalent, worse, or even superior to “vaccine immunity”?
      Reports in the US estimate that at least 30% of folks have had COVID. Might so-called survivors have BETTER resistance to new variants because their immune systems are primed to respond to more than the targets of the vaccines ?

      1. sgcox says:

        That is my gut feeling too, the real infection should raise a wider spectrum of the immune response than just a single antigenic protein. But then I have gut feelings every morning after strong coffee…

      2. DataWatcher says:

        Does this argument challenge the veracity of the findings from South Africa and the evidence from Manaus that the new variants are capable of sufficient immune escape to re-infect those who have already had, and recovered from, COVID?

        1. sarah says:

          Excellent question. I don’t think we know enough about the situation there to be sure if people are being reinfected or are these new infections altogether. Or, I suppose, immunity may indeed wear off after time, which does not bode well for either vaccination or naturally derived immunity.

  7. Chris Phillips says:

    This also doesn’t look particularly reassuring for the AstraZeneca vaccine.

  8. GM says:

    It’s quite irresponsible to report on these news as “no worries, there is protection”.

    We are seeing major immune escape relative to convalescent plasma evolve with just two or three mutations within just a few months. While things seem to be still above the threshold for the mRNA vaccines (but how many people will be vaccinated with those versus less effective but less logistically challenging vaccines?), who in their right mind would not be expecting complete escape from the vaccines rather soon given that the vaccines are not sterilizing, that there is rampant spread worldwide, that countries are going ahead with plans to half-vaccinated people, and that those variants are probably just another couple mutations away?

    And there is absolutely no guarantee that repeated vaccination against slightly different variants will actually work, quite the opposite, there are all sorts of scenarios under which it does not.

    People in the “West” seem unable to escape this monumentally stupid mode of thinking under which one assumes and plans for the best possible outcome. Which is exactly how one makes sure that risk is not properly managed and various completely preventable (had anyone taken proper precautions) disasters are allowed to happen, . One can speculate why that is — might be because we have basically no people left (aside from the bottom layers of society that have no influence on decision making) who have ever known any real material hardship in their lives and as a society we can therefore not even comprehend that bad things do happen in real life, and we have thus plunged deep into decadence and degeneracy. Whatever the reason, it has to stop.

    The story of COVID is a long unbroken sequence of one boneheaded suicidal decision taken following that approach to life after another.

    And we seem to be set to continue behaving the same way…

    1. luysii says:

      GM — invective aside, you are right

      The B 1.1.7 strain had all sorts of mutations (23 depending on how you count them). This was unprecedented. We now understand how this might have happened due to one very well studied case [ Cell vol. 183 pp. 1901 – 1912 ’20 ] in an immunocompromised patient with chronic lymphatic leukemia, who shed the virus for 70 days. The patients wasn’t symptomatic, but because the patient had enough immune system to fight the virus to a draw, it persisted, and its genome was always changing. Now we worry that infection in people getting just one dose of vaccine might show the same characteristics, being incubators for multiple mutations.

      At least now the data we need is widely available to the people who need it. It also was available a year ago, but the CDC didn’t look. It is exactly one year today since I published “What to do about the Wuhan flu? The short answer is to lay in a month or two of dried food and drink, and have plenty of bottled water around.”

      For more crying over spilt milk please see

      1. Daniel says:

        Why would people who’ve only had one dose of vaccine remain infected for months without clearing the virus? They’re not immunocompromised.

        1. Luysii says:

          Daniel: Certainly most of the millions who will receive the vaccine are not immunocompromised, but among them the ‘silently immunocompromised’ will also be vaccinated. There was a paper ( Science vol. 370, eabd4570 (2020) showing that among those with severe COVID19, 3.5% had inborn errors of TLR3- and IRF7-dependent type I IFN immunity. This was their first sign of immunodeficiency.

          Well that’s severe COVID19 but it is my guess that there are other asymptomatic individuals out there whose immune system is a bit off which will allow the virus to persist.

          A medical school classmate developed severe anemia when he was sent to Vietnam in the 60’s. Why? Because he had a silent deficiency of an enzyme called G6PD which is important to red cells. Malaria was rampant in Vietnam and everyone sent over had a prophylactic dose of an antimalarial which inhibited G6PD, which is OK if you have a normal amount of G6PD — he didn’t probably due to heterozygous deficiency of the enzyme. The point is that it took a particular stress at a particular time to make a silent mutation manifest. I think this is likely to happen with silent immunodeficiency in the general population.

    2. Andy says:

      @GM, you’re not wrong, but exaggerating a bit. First. these mutants didn’t evolve in a “few months”. The mRNA vaccines are based on genome sequences from last January. One year later, the antibodies they elicit still work, albeit 3-fold to 6-fold less, against the newest mutants. This is slower than influenza’s mutation rate, and we know how to work with influenza. We’re still playing catchup with Cov-2, but I see no reason why vaccine updates cannot keep pace with its mutation rate in the long term. The short-term is more an issue because governments really need to roll out the existing vaccine and get that out of the way in order to begin distribution of the booster for the variant(s).

      Second, you said “given that the vaccines are not sterilizing”: Is there any evidence of this or are you just speculating? I have not seen conclusive evidence one way or another. Applying the precautionary principle for the time being should not lead to an inference that the vaccines fail to engender sterilizing immunity.

      Third, you said that complete immune escape is just a “couple mutations away”. This again sounds like speculation. We don’t know that. The dangerous E484K mutation actually has less binding affinity than Cov-2 classic. The N501Y mutation has higher binding ability but is susceptible to antibodies. I’m not saying that there is necessarily a negative correlation here, but there are limits to how much the genome can evolve to escape immunity while still maintaining binding ability as it relates to infectivity. The South African variant clearly hit “the sweet spot” here; perhaps it can’t get any sweeter. Perhaps it can. We don’t know.

      1. Andy says:

        And I should add Fourth: Even if the vaccines don’t create sterilizing immunity, so what? At a population level, immune systems will keep pace with the virus and eventually reach an equilibrium. It is wrong to look at Cov-2 through the lens of smallpox. It is a coronavirus, and we have to look at how other coronaviruses became endemic and in equilibrium with human immunity. Once people have been vaccinated en masse, there is no justification for preventing transmission. This of course rests on the assumption that severe or organ-damaging infections in vaccinated people are very, very rare.

      2. GM says:

        The dangerous E484K mutation actually has less binding affinity than Cov-2 classic.

        This is wrong, E484K+N501 has much higher affinity for ACE2 than N501Y alone, which already has increased affinity.

        So far immune escape has evolved hand in hand with increased affinity (and thus contagiousness too).

        1. Marko says:

          The increased binding affinity with ACE2 could well be part of the immune escape mechanism. Antibodies that might otherwise be neutralizing could be simply brushed aside. There’s an ongoing on/off rate for protein-protein interactions, and to a significant extent, only the strong survive.

          1. GM says:

            Correct, that is exactly what seems to be going on — it is evolving resistance by outcompeting the antibodies.

            Which is a feature of the nightmare scenario.

            You vaccinate with non-sterilizing vaccines (does not even have to be no reduction of transmission, some asymptomatic transmission will do too) and you place enormous selective pressure towards evolving escape mutants.

            Which evolve by becoming better binders.

            Which makes them much more contagious, and quite possibly deadlier too.

            There is a lot of room for that — in those same in vitro evolution papers they found mutants with 600X higher affinity (E484K+501Y is 13x), and that was just one additional mutation.

            Once you reach that level, even an updated vaccine might not have a somewhat reduced efficiency, if this is your only way of neutralizing it. And this is without going into original antigenic sin scenarios, in which vast numbers of people have been vaccinated but the updated vaccines do not actually update their immunity.

            Of course, at some point there might be evolutionary tradeoffs associated with evolving better binding, but there is no knowing how bad things can get before those kick in.

            If the virus is suppressed and you are trying to keep it suppressed, you just might get lucky and not end up in some sort of situation like this. But the plan here is to “go back to normal”, i.e. rampant uncontrolled spread that will not be a problem because people will not get sick due to the vaccine. No flaws in that plan at all…

  9. Masher says:

    Chris Phillips, could you please clarify what you were referring to with your somewhat pessimistic comment about the AZ vaccine? Do the studies indicate lower effectiveness against variants for that one?

    1. Chris Phillips says:

      No, I’m not aware of any data for the AstraZeneca vaccine. It’s just that as its efficacy is quite a bit lower than that of the mRNA vaccines to start with, it seems plausible that it may be significantly less effective against the South African variant.

      1. Mariner says:

        Unless, of course, the claims of 90% protection for the AZ vaccine if the doses are spaced out more up to 12 weeks prove to be accurate. I suppose the only way you could test this would be to run similar tests using sera of those vaccinated with the AZ vaccine a couple of months or more ago. The problem there is that these folk don’t exist yet and most of them that do will be very elderly or with underlying health issues!

        The smalling grouping who received the widely-spaced doses during the trials are likely to have waning protection by this point, I’d have thought, but perhaps worth testing sera from them against these new variants?

        1. Some idiot says:

          The word on the street is that the EU will be approving the Oxford/AZ vaccine tomorrow. I will be interested to see shot dosing regime it approved with…!

  10. sgcox says:

    Regarding mABs and new variants, the “Etanercept” approach of solubilised ACE2 looks looks even more appetising. Whatever mutations buddies come up with, it must still bind to its cognate receptor.
    Any news, updates about it ?

  11. Calvin says:

    While I am partially reassured by the data that the vaccines retain potency, we’re getting into that log loss of potency range with the B.1.315 mutants that gets me very very twitchy. It’s not just about potency, it’s also about the concentration of those antibodies. Assuming the concentration is largely unchanged, then more than a log reductions starts to have an effect very quickly and I’m not sure we know the PK/PD well enough yet to know where the tipping point is. The monoclonals give a hint here given the already heroic doses they are given at.

    What we’re doing right now is immunize a huge number of people with a vaccine that works against Wuhan strain but less well (not by much) against the new strain. Given that we’ve allowed the virus to get into a huge number of people we’ve set up a situation where the pool of possible mutants is getting bigger and bigger. The mutations rate is inherent to the virus so more viral particles equals more mutations. And now we’re applying a selective pressure.

    It’s basically a race now. Can we vaccinate enough people to reduce the number of viral particles and to reduce the number of possible mutations and minimize selection. If we are lucky then we’ll be on the correct side of the stats here and we’ll be OK. If we’re unlucky then we’re bound to select further mutants. Given the vaccine rollout, the nationalistic approach etc, we’re in severe danger of perhaps having success at a country level only be be stuffed by a mutant emerging in a country that isn’t as lucky/good/well resourced.

    I strongly feel that we need real combination approaches. Multiple binding epitopes to spike are not real combos. This is the story from HIV/HCV. The best combos hit different targets or dramatically different binding sites on the same protein. We need to go after other targets. N looks like a decent target and we know that the immune system does generate antibodies for that protein. That way it is much much harder for the virus to mutate away from a vaccine/mab/small molecule.

    I’m currently quite negative on this and see 2021 as the year of the mutant. We have to stop the spread and have it in fewer people globally while we try to vaccinate. And cross our fingers.

    1. ibraim sued MD says:

      ”It’s basically a race now. Can we vaccinate enough people to reduce the number of viral particles and to reduce the number of possible mutations and minimize selection.”’
      Right to the point.

      1. Doug H MD says:

        not quite as easy as that.
        if we vaccinate more people but it does not block transmission and people let no of NPIs where are we?

  12. Marko says:

    King Lab of U.of Washington moves their nanoparticle candidate into P1 trials :

  13. Marko says:

    Hate the brain biopsy nasal swabs? Be careful what you wish for :

    1. Marko says:

      Sounds like we could dispense with the deep nasal swabs altogether :

      “We just released new data showing great match between shallow nasal and oral fluid swabs with NP in the first 21 days of COVID-19 (while infectious) but that after that NP can test positive for months after recovery while nasal and oral return to negative”

      (link to preprint is in tweet)

  14. Daniel says:

    When people discuss the possibility of vaccine escape, they often frame it as happening through high transmission in areas of high immunity. But haven’t both of the examples we’ve seen so far (Manaus and SA, I won’t count Kent as doesn’t seem to evade immunity) happened through persistant infection in immunocompromised individuals? My understanding was that this allowed for the virus to accumulate a large number of mutations in a much shorter amount of time than it usually does. I don’t think we’ve seen any examples of the virus evading immunity through antigenic drift yet, even though the virus is circulating at reasonably high levels in places like NYC and Lombardy (not to mention developing countries since they don’t have the best surveillance).

    1. Calvin says:

      In my view it’s a numbers game. We know the viruses in inherent mutation rate (actually quite low, phew), but the more people it goes into the more chance there is of a new mutation emerging spontaneously or under some selective pressure (vaccines, partial immune response etc). The UK variant is a great example. It persisted in an individual and kept replicating away in a tug of war with the immune system. So rather than being around in that individual for maybe a few weeks it was there for much longer. To the total number of viral particles was enormous and so, just like a passaging experiment to generate in vitro resistance, the patient did that. At the start of the pandemic the total number of people was, in the grand scheme of things, quite low. Now it’s massive. So now our chances of seeing a mutant with new properties just goes up. What actually surprises me is that we’ve not seen a US-variant yet. Maybe that’s the counter-argument.

      1. luysii says:

        Calvin: Absence of evidence is not evidence of absence. I went down the tubes for exactly that reason as the first case of B. 1.1.7 was appearing (but not reported ) in England — while I happily said with 12,000 known variant genomes out of a possible 90,000 that if something bad was going to happen we’d have already seen it as the other 78,000 mutants were almost certainly out there and hadn’t caused trouble. Sigh.

        1. Calvin says:

          Agreed. Viruses are……tricky. I’ll note from my past non-active site mutations causing small molecules to bind less well. No amount of structural biology (including x-rays on the mutants) could explain what was going on. But the viral data was clear as day.

          So I’m very cautious with mutations because when you get multiple mutations it gets complicated and unpredictable very fast.

          I continue to be surprised that we’ve not seen a US variant, but you are right that that is probably because we’re not really looking.

          1. Charles H. says:

            IIRC, there was a California variant in the news yesterday. Nobody was certain how bad it was, but there were indications that it was more infectious.

    2. Marko says:

      “But haven’t both of the examples we’ve seen so far (Manaus and SA, I won’t count Kent as doesn’t seem to evade immunity) happened through persistant infection in immunocompromised individuals?”

      That’s a theory, but far from proven yet. Antigenic drift still seems a possible explanation in regions like S.Africa and Brazil, where I doubt the genomic sequencing could have been expected to document the complete evolution of the variants. Heck, aside from the UK and a few other countries, nobody is doing enough sequencing to catch everything that’s going on. Animal reservoirs are another possible mixing pot where antigenic “shift” might occur undetected, as happens with some flu strains, and as the mink episode illustrated.

      The difference now as opposed to earlier in the pandemic is that these antigenic shifts now confer a selective advantage by expanding the susceptible population to include some fraction of the previously-infected. That manifests as a “transmissibility” advantage, and even a small such increase will eventually make itself apparent in the form of increasing prevalence.

  15. Doug H MD says:

    ” First, those numbers tell us that being vaccinated provides a person with more protection than being infected with the coronavirus itself.”
    That is a leap isnt it? Do we really know that neutralizing Ab is the be all and end all of protection? seems to me clinical trials alone will show that.

  16. Pablo says:

    These data are encouraging, but they only concern people vaccinated with the nRNA vaccines authorized so far. However, a significant amount of the world population is being vaccinated, or will be vaccinated, with other vaccines that showed a lower efficacy (Brazil is getting the Sinovac and the Astrazeneca one).

    So we should be careful in our optimism because we don’t know how these vaccines will perform. (maybe we can hope that the sinovac vaccine, being an inactivated, will elicit an immune memory targeting other parts of the virus than Spike?)

  17. Marko says:

    “Australian think tank the Lowy Institute has crunched reams of data to produce a new interactive that assesses the coronavirus response of almost 100 nations.

    While New Zealand took top spot, it was closely followed by Vietnam, Taiwan and Thailand, which were ranked second, third and fourth, respectively.

    Australia also performed strongly and was ranked eighth in the world by the Lowy Institute.

    The United States has been ravaged by the pandemic and languishes near the bottom of the table, at number 94….”

    94 out of 100! That’s an “A” , right ?

    USA! USA! U…. Oh crap, who am I kidding?

    1. confused says:

      I am perfectly OK with saying the US had a bad response, which it certainly did – but I am pretty skeptical of a list that’s said to be *quality of response* (rather than *outcomes*) with a bunch of isolated island nations at the top.

      Germany and Canada have done much better than the US, but I don’t really see evidence that doing much better than them is possible through policies alone (as opposed to natural advantages *plus* policies).

      I would feel much better about attributing outcomes primarily to policies if I could see an explanation for the universally low death rates in the Old World tropics. Given that this includes basically every form of government, and both very rich nations and some of the world’s poorest, and even some failed states, it’s IMO hard to attribute it to universally good policy.

      It could be lack of reporting in the less-developed countries… but there are a number of less-developed countries in the New World tropics that report high death rates, so that’s not really convincing either…

      1. Andy says:

        @confused I have been wondering about the low CFR in the developing world. India’s case count graph, now down to a paltry 10K cases a day in a nation of 1.4 billion, paints a compelling picture that something is very different in the developing nations. My best hypothesis is that this relates to T-cell immunity. I read a preprint that pre-existing T-cell immunity is NOT caused by common cold coronaviruses as was originally believed, but by exposure to antigens in general, both by natural infection and vaccination. Bacterial, viral and fungal antigens. The average Indian has a lot more vaccines pumped into them than the average American. I haven’t seen serious studies of this hypothesis. If this hypothesis is true, this means India has attained functional herd immunity already, not directly by infection with SARS-CoV-2, though.

      2. Marko says:

        If you want an answer to your implied query, at least show that you’ve carefully thought about the impact of median age on death rates, and how that might affect the stats re: the “Old World Tropics”.

        Otherwise, you’re just wasting other people’s time.

        1. Craken says:

          The median age in both India and Peru is 28.
          Peru’s excess mortality over the last year is about 90,000 out of a population of 32 million = IFR of 0.3%.
          I can’t find excess mortality stats for India, but its reported Covid deaths are at 150,000 out of 1.4 billion = IFR of 0.01%.
          That would be a 30 fold difference if India’s numbers were reliable. The rest of SE Asia seems to have similar or lower Covid mortality, whilst the rest of Latin America is much closer to Peru’s numbers. As to India’s statistical reliability: there haven’t been any reports of overwhelmed hospitals in India or abandoned bodies, as we’ve heard from Peru and Ecuador. There have been sero-surveys showing very high seropositivity (>50%) in major Indian cities.

          1. Marko says:

            Thanks. A 30-fold difference is indeed striking. It’s hard to imagine that reporting failures could account for that. Maybe genetics ?

          2. GM says:

            PFR/EMR, nor IFR

          3. Marko says:

            Ouch! I didn’t catch that. We still need the numbers.

          4. Craken says:

            Yes, PFR is what I meant. The epidemic appears to be near its end in both Peru and India, suggesting both have attained herd immunity. If you look at the graph of daily deaths in India, it is a Gaussian distribution, starting in March, peaking in September, and presumably ending in March. Given Peru’s high PFR, its low median age, and its currently very low monthly mortality–this is about the level of PFR to be expected at the threshold of herd immunity. But, its PFR is about 30 times India’s. I think the explanation is genetic and/or immunological, with probably some statistical under-reporting by India. I don’t think Peru’s infection rate is anything like 30 times India’s, maybe 2 or 3 times at most. 70% of India is rural and I’ve seen no rural serological data, yet it beggars belief that rural India magically escaped a virus that did not spare other rural areas around the world. None of India’s urban areas had Covid crises in their hospitals, which suggests that the under-reporting isn’t too severe and that India’s IFR is much lower than in other nations.

          5. Marko says:

            This analysis on the IFR in Mumbai suggests that there’s nothing miraculous going on there :


          6. Craken says:

            IFR must be higher than PFR, Peru’s PFR is 0.3%, its IFR must be >0.3%. That analysis of Mumbai’s epidemic suggests a true IFR of 0.2% and shows that official stats undercounted Covid fatalities by about 50%. If you apply that degree of undercount to India at large, Indian fatalities would be 310,000 = PFR of .022%. That’s still 14 fold below Peru. If you assume 310,000 deaths at a nationwide IFR of 0.2%, then the percentage of the population infected would be only 11%. The undercount of deaths may be worse in rural areas. It would have to be far worse to close that 14 fold gap. But, this does nothing to explain the huge range of PFRs in India’s different states. Notably, those states closest to SE Asia have the lowest PFRs. Maybe no miracles, yet some mystery lingers.

          7. confused says:

            @Marko: Yeah, I did think about median age – but as Craken says, median age is comparable in India to hard-hit countries in Latin America. Bolivia’s median age is *25*.

            It could be a factor for sub-Saharan Africa (where many countries have *very* low median age) but cannot explain the difference between tropical Asia and tropical America.

            Some sort of environmental factor seems likely, but what could it be?

          8. GM says:

            The epidemic appears to be near its end in both Peru



  18. Marko says:

    “The SARS-CoV-2 Spike protein needs to be in an open-state conformation to interact with ACE2 as part of the viral entry mechanism. We utilise coarse-grained normal-mode analyses to model the dynamics of Spike and calculate transition probabilities between states for 17081 Spike variants. Our results correctly model an increase in open-state occupancy for the more infectious D614G via an increase in flexibility of the closed-state and decrease of flexibility of the open-state. We predict the same effect for several mutations on Glycine residues (404, 416, 504, 252) as well as residues K417, D467 and N501, including the N501Y mutation, explaining the higher infectivity of the B.1.1.7 and 501.V2 strains…”

    Interesting that the percentage increase in open-state occupancy observed in the UK variant is of similar magnitude to the increased transmissibility observed, i.e. 33%.

  19. sgcox says:

    Oh, yes, of course.
    I would be much more impressed if they did modelling some time ago and say “we predict that N501Y mutation will increase open-state occupancy and hence virus transmissibility by 33%”.
    Typical post-hock computational junk.

    1. Marko says:

      Read the paper. They do suggest mutations that may become problematic that are not yet, so their hypothesis is testable. They’re looking forward as well as backward, so your criticism is unwarranted.

    2. Natalia Teruel says:

      We were modeling it since May, we just wanted to do more complete stuff to publish. The mutations on K417 tho, defended only by us in conferences for months already appeared after the first version of the preprint in two different strains, South African and Brazilian.

    3. Natalia Teruel says:

      And everything we did is opensource if you feel like replicating the results to see that they are legit

  20. Marko says:

    Pfizer vaccine only slightly less effective against key South African mutations – study

  21. An Old Chemist says:

    Testing the effectiveness of the booster vaccines doesn’t require starting from scratch, Fauci said. The booster shots won’t need to go through the same large-scale clinical trials that were required for the original vaccines to receive the U.S. Food and Drug Administration’s emergency use authorization in December, he said, adding that they could get through with a “quick phase one” trial instead.

    “You don’t have to do a 30,000 person trial or a 40,000 person trial,” Fauci said. “You work with the FDA and you could bridge information from one trial to another. Bottom line is we’re already on it.”

    1. Marko says:

      So, is the cat out of the bag? I wouldn’t be surprised if Fauci backtracks on that. He may have been too honest, too soon. I’m sure the folks at the FDA would like to maintain the “careful deliberations” theater for a while longer, at least, and preferably right up to the last minute.

      1. confused says:

        Why? We update flu vaccines without full trials, after all. What’s the benefit in sounding more concerned than you really are?

        I actually think the level of publicly-announced caution in development is probably *not* helping vaccine hesitancy, since it gives average people who wouldn’t think of, for example, ADE on their own reason to think there *is something to worry about*.

        1. Doug H MD says:

          you forget; these vaccines are in use under EUAs.. not so the flu

          1. confused says:

            I’m not forgetting – just don’t think that the distinction is very relevant to the average member of the public. I am talking about messaging, not about what the actual decision will be – I am saying that if quick changes are approved, the message being “sure we can do that! no big deal, it’s just like the flu shot!” would be better than showing that they’ve had *concern* over the issue.

            I fear that by trying to bend-over-backwards to ensure everyone knows they’ve “checked all the boxes” they may actually be feeding concern by convincing people that *there is actually something to watch for*.

            I mean before COVID I doubt 1% of the population had ever heard of antibody-dependent enhancement… the public wouldn’t know to be afraid of it. Anti-vaccination sentiment has been around for a while, but it’s disconnected from reality enough that it won’t be affected much by however they do it, IMO.

  22. Chris Phillips says:

    “You vaccinate with non-sterilizing vaccines (does not even have to be no reduction of transmission, some asymptomatic transmission will do too) and you place enormous selective pressure towards evolving escape mutants.
    Which evolve by becoming better binders.
    Which makes them much more contagious, and quite possibly deadlier too”

    Obviously there’s something to that argument. But the weakness is that by applying selective pressure you’re not actually increasing the number of mutations, only selecting ones that are occurring naturally. And mutations that increase transmissibility are always going to have a big selective advantage, even in the absence of any medical intervention, thanks to the magic of exponential growth.

    Perhaps the significant fact is that it’s taken so many infections and so long – and perhaps some unusually favourable conditions within immunocompromised individuals – for these more transmissible variants to emerge?

    1. Marko says:

      “And mutations that increase transmissibility are always going to have a big selective advantage…”

      The virus sees anything that increases the effective R (Re) as a transmissibility increase, whatever mechanism it may use to get there. The UK variant , has, let’s say, 35% increased transmissibility. If the Re is 1.0 with the WT strain, it’s 1.35 with the variant, and let’s assume it’s getting there by some sort of increased receptor binding.

      Now , how else might a variant get such an increase? By immune escape. Let’s use Manaus as an example. Assume the proportion immune ( P ) is .7 (i.e. 70%) , and the original R0 is 3.0, with no NPIs in place. The current Re would be R0 x (1-P) or 3 x .3 = .9 , resulting in a shrinking of case growth.

      Now, imagine that an immune escape mutation effectively reduces P only a bit, to .6 (i.e.70% immune to 60% immune). The current Re would now be 3 x .4 = 1.2 , resulting in growing cases, and a .3/.9 x 100 % = 33% increase in “transmissibility”. So , in the end, it only took about a 14% reduction in the immune population to result in a 33% increase in “transmissibility”.

      In times of high population immunity, selection pressure for immune escape becomes as important, if not more so, than selection for higher transmissibility.

      1. Marko says:

        A good visual representation of the above :

      2. Chris Phillips says:


        Yes, I agree with all that.

        My main point was that GM seemed to be suggesting that vaccination would somehow encourage the development of higher-transmissibility variants. I don’t think that’s true, other things being equal. If higher transmissibility variants arise, they are going to have a selection advantage, and will predominate.

        But the absolute numbers of those variants won’t be increased by vaccination, other things being equal. They’ll be decreased, unless the higher transmissibility variants also happen to exhibit 100% escape from the immunity conferred by the vaccines.

        The same for immune escape in the absence of increased transmissibility. If variants arise that escape immunity but aren’t any more transmissible, the vaccine won’t suppress them as much as the variants that don’t. But the vaccine won’t actually increase their numbers, , other things being equal. They’ll just become predominant in relative terms because the vaccine is eliminating the old variants but not the new ones.

        Of course, if other things aren’t equal – if our political leaders ease restrictions because of vaccination, when it’s not safe to do so – then the net result of all that may be an increase in new variants beyond what would have happened if the restrictions hadn’t been eased. But I don’t see that as any argument for stopping the vaccination programmes, as GM would have us do.

        That way lies madness.

        1. Marko says:

          Yes, stopping vaccination would indeed be nutty. I’m not going to be worried too much about variants of any kind until I find out that people who’ve been infected before or vaccinated are still at considerable risk of severe disease or death from a future infection, whether by WT or variant. We still haven’t seen hard evidence that this is true for more than a tiny fraction of such cases, but that’s why I’m intensely interested in what the final analysis of Manaus will show.

        2. Marko says:

          Comment about “eradication enthusiasts” from someone involved in eradicating smallpox:

          1. GM says:

            Yes, which is why it should never have been a lot to spread in the first place, and the people responsible for that should be in the Hague

            It dos not change the fact that we need to eradicate it though.

            Individual countries, rather large in size too, have done so quite successfully.

            If you do it on a country by country basis and make it so that people from those countries that are outside the expanding COVID-free bubble are not allowed to travel into it, you can go a long way to going back to normal life for much of the world.

            Smallpox was eliminated without any disruption to normal life, and when it showed up in countries that had eradicated it (e.g. 1973 in Yugoslavia), the reaction was lockdowns of the kind we only saw in China last year.

            So this is not a proper comparison — nobody is proposing to try to eliminate COVID under the same no-disruption-of-regular-life conditions that smallpox was eliminated under.

        3. GM says:

          The current variants seem to have evolved most often within individuals battling chronic infections.

          If you rely on vaccination with non-sterilizing vaccines reducing the disease burden and “solving the problem”, you will fix the more contagious variants even faster than they would have otherwise, but you will also create orders of magnitude more situations of chronic prolonged infection within which rapid evolution can take place, and you will, over time be starting those episodes with more contagious variants of the virus (up to a point perhaps).

          All things are not equal — controlling disease but not transmission with vaccination means that you may in fact have a lot more virus than now circulating. The idea is to lift all restrictions and “go back to normal”.

          And the selective pressures imposed by the vaccine may drive the virus in directions it would not have gone otherwise due to other constraints.

          The point here is that we are playing with fire when the sane course of action is to extinguish it.

          So do what is necessary for elimination, and then life will indeed be back to normal, no major risks involved.

          The only argument against that is “economic”, which translated in simple terms means that rich people don’t want to pay higher taxes (and the pandemic is actually making them even better off than before, by killing the small-sized competition), which they would have to do to support the rest of society while that process is finished, so it is better instead for many millions to die and many times that to be disabled for life and for us all to be wearing masks for the rest of our lives. No reasonable person should buy that argument.

          1. DataWatcher says:

            At least in the U.S., the cold hard fact is that it’s not just (or even primarily) the “rich people” who resist even relatively mild restrictions — on business, on personal gatherings, etc. — to slow the spread. Look at the folks demonstrating against masking, against vaccinations, against closing any businesses whatsoever; they’re primarily middle-class and working-class “mainstream” Americans. Look at the militants who threatened to kidnap Gov. Gretchen Whitmer of Michigan. If anything as draconian as what was done in China and other Asian countries — or even what was done in New Zealand — were tried here, we’d have mass insurrections that would make Sept. 6 at the Capitol look like a San Francisco love-in ca. 1967.

          2. DataWatcher says:

            That’s “January 6,” of course. Sorry about the typo, but the point remains the same.

  23. Ancient Briton says:

    School of thought that says the four common cold covs started out as the SARS’s of their day. Another school of thought thinks 1889 Russian flu epidemic might even have been case in point…

    Sounds like petered out 1892-95 depending on where you were. As for gloom and doom out of South America, Manaus and Iquitos ain’t Syngleton Lane, Piper St or 42nd Avenue – yet, although here in Limeyland who can tell, if De Pfeffel keeps on getting his way.

    Day after public penitency over the 100K, school closure can kicked down road to 8 Mar, by implication taking 15 Feb parliamentary review with it. In due course 8 Mar will get kicked on to 31 Mar, when lockdo’n V3 legislation runs out. Another retrospective parliamentary vote will then legitimise lockdo’n V4 to 30 June and end of school and university year.

    Henry VIII rules okay? Watch out Wife-to-Be III and modern day monks, mysteryons and dayta manipulaytors, next stop Dissolution of the Universities. FYI, Henry’s off to do a bit o’ hammerin’ o’ th’ Scots today. No surprise Queen MacFish donna even wanna receive the blaggard…

    1. Chris Phillips says:

      Why on earth do you feel the need to keep posting under different names? The content itself is surely unscientific and silly enough, without any extra clues that people should ignore it.

      1. Ancient Briton says:

        Good morning, Chris Phillips – usual first comment of the day around usual time of day. Although couldn’t help noticing a couple of weeks ago how your first comment posted later in the morning than usual.

        And couldn’t help putting two and two together, but perhaps I was making five. Good to hear pointed out earlier that morning that, “In an open street environment a face mask probably makes little difference.”

        As for being silly, this Briton ancient enough to remember The Ministry of Silly Walks and all the rest of that silly stuff. Seem to recall did make some viewers laugh. Some of those long ago viewers ancient and decrepit now of course, just like me.

        Have sent the occasional Pipeline link in private to the occasional acquaintance of perceived more catholic taste and views than my impression of some Pipeline commenters.

        Maybe recipients all being overly polite, but can’t recall word “silly” being used in reply. No wish to overblow my own trumpet voluntary, but overall feedback rather more positive than that…

        Just curious, Chris Phillips, do you ever read novels? The Machine Stops, Alone in Berlin, WE, Nineteen Eight Four, For Whom the Bell Tolls, The Hunger Games, Brave New World, One Day in the Life of Ivan Denisovich, The Handmaiden’s Tale?

        If above, and/or any other dystopian titles read, do please do feel free to reply. Am always on lookout for new reading.

        1. Chris Phillips says:

          But seriously, why bother? Silly stuff, under a multitude of even sillier names. What’s the point? Nothing better to do?

          1. Ancient Briton says:

            If you don’t get it, I can’t explain it to you…

  24. Quin says:

    Data analysts for the 2 leading Israel health providers are both on Twitter. Both of them write in English sometimes and are being cautious regarding assessments of Pfizer effectiveness until thorough studies are available.

    That said, the analyst of the Maccabi provider thinks that Pfizer efficiency in prevention of severe disease is somewhere between 50%-80%:

    The analyst of the Clalit provider believes that infections and serious disease numbers have continued to increase – despite the vaccine – due to B.1.1.7:

    But he also states that the estimations of the New York Times should not be regarded as authoritative:

  25. Jarndyce and Jarndyce says:

    Preceding posts all very interesting to a simple minded country legal clerk. Trouble is we country folk always fighting battles decade, year or day behind time…

    Last fling of the legal papers. Links deliberately not included as legal clerks who post too many links will know that legal posts can theretofore incur delay. As if, in law, there ain’t enough delay built in a’ready…

    Public Health England cites Ct = 40 as the maximum number of amplification cycles (Ct) in PCR testing (28 January 2020: “Guidance and Standard Operating Procedure COVID-19 Virus Testing in NHS Laboratories”).

    …Chinese and Western academics and Public Health bodies cite Ct = 40 in a paper published 20 November last year (Nature Comms Cao, S., Gan, Y., Wang, C. et al. Post-lockdown SARS-CoV-2 nucleic acid screening in nearly ten million residents of Wuhan, China. Nat Commun 11, 5917 (2020)).

    …Various publications show that Ct = 25 generally corresponds with viable viral growth in cell culture, whereas Ct = 40 doesn’t (e.g. B La Scola et al, Clinical Infectious Diseases, 2020; ciaa1491).

    …The UK Crown Prosecution website cites Ct = 28 as the cut off for PCR testing in UK criminal prosecution cases in which High Sensitivity DNA Analysis is used as evidence, and emphasises the need for ‘clean-room’ laboratories and procedures (“High Sensitivity DNA Analysis: GOV.UK Legal Guidance”).

    Case rested M’Lud. Off back to Chesney Wold to tend the family sheep. Summon me if any new developments in proceedings.

    Or alternatively, legal clerks please post comments in reply heretofore.

    1. Adam says:

      Uh. What did I just read?

      1. Marko says:

        You read it ? Haha.

        You’ll learn….

        1. Lord Justice Denning says:

          Come across in the comments string of a You Tube posted 19 September 2020 by a Public Health academician, entitled “COVID Diagnosis with PCR | Misinterpreting results | Cycle threshold explained”:

          “Well done! Thank you! I have been making this point to anyone who will listen for several months. 2^40 = 1,099,511,627,776.

          Yes, that’s 1.09 trillion for a Ct=40! One cat hair on a rug amplified 1.09 trillion times is quite a bit of hypothetical cat hair, but no one who is not pandering to Covid fear would seriously argue that the rug is infested with cat hair and should be vacuumed (or quarantined), or that by sitting on the rug one is likely to get a lot of cat hair on one’s clothes.

          And yet people who should know better do this every day! Madness!”

          …Thank you, M’Lud.

      2. Auntie Body says:

        “what did I just read?”

        You just read a legal clerk who saw a Youtube video telling PCR experts how they should run their experiments. Social media is full of twerps who think they know something. It’s Dunning-Kruger in full effect.

        1. Tom Denning (1899-1999) says:

          …Legal clerk who just happens to have a First in Natural Sciences, a PhD in organic chemistry, 40+ scientific publications, 40+ granted patents and 30+ years healthcare R&D experience on the receiving, responding and design-make-test cycle end of R&D biological assay data (good, bad and indifferent).

          …Now 6+ years retired. Maybe science changed out of all recognition in that time, although suspecting not. During said 6+ years become rather concerned by the way PPE, classics and sociology graduates running the UK national show.

          …Latterly also become concerned with spectrum of scientific advice provided by UK experts appointed to advise aforementioned graduates of aforementioned subjects, who seem to have dim as TocH lamp grasp of how science and scientific evidence unfold.

          …As for the PCR experts, by all means, Dr Auntie Body, please go ahead and explain, in the plainest English you can put together, what in principle goes on inside the UK’s Pillar 2 Lighthouse Laboratories, that produce all those “tested positives” from those up to 600K samples tested each day. Legal clerk will be all eyes, ears and neurones.

          …Or instead, please provide link(s) to PCR expert(s) explaining in plain English what goes with mass PCR testing for SARS-CoV-2. Will then compare link(s) with other links from other reputable scientists who’ve expressed doubts about what all those “tested positives” might mean.

          …Legal clerk did try asking various arms of GOV.UK some critical questions via Freedom of Information Requests (amplification cycles, false positive rates, understanding of cross contamination risks, etc), but please take it from me not a productive or recommended course of action. Neither, for the record, was writing to the local Member of Parliament to raise with the UK Cabinet Office. Problem with the TocH lamps, again, I’m afraid.

          Thought for the day: as a 20th century UK High Court Judge, Master of the Rolls and National Treasure used to say, “The spirit of the law is more important than the letter of the law.”

  26. Daniel says:

    I’ve been annoyed by the coverage of the UK variant, which seems to have stuck to the early estimates of 30-70% increased transmissability despite the real world evidence provided by the UK lockdown. When the new variant was discovered, its advantage was estimated by comparing its R to the R of the new variant during the English lockdown in November, with the conclusion that B.1.1.7 had an R of 1.25 compared to 0.85 for the old variant (source: This seemed ominous at the time, since it suggested that a lockdown couldn’t reduce R below 1.

    Since then, however, the UK has entered a new lockdown, which differs from the November version in that schools are mostly closed. R in this new lockdown is about 0.8, with the steepest declines in cases in areas where the new variant is most prevalent (it is declining at roughly the same speed in areas of low and high immunity). Given that R was about 0.6 to 0.7 during the first lockdown in March, this suggests that the impact of less adherance to the rules (far more things are open than in March), it being winter rather than Spring, and a new variant emerging is fairly small. I think B.1.1.7 clearly had an advantage, but it annoys me to see (largely American) writers using the 70% estimate and suggesting that lockdowns don’t work, which I think is now untenable.

    1. Chris Phillips says:

      Given the most recent ONS estimate that about 60% of cases in England are the new variant, and the most recent estimates that the increase in transmissibility is about 35%, there would be no inconsistency in an increase from an “old” lockdown R of 0.6-0.7 to a new one of 0.8. And even if the prevalence of the new variant went up to 100%, the new R number could still remain below 1.

      1. Some idiot says:

        Just saw a press conference here in Denmark a few hours ago. SSI’s data suggests that the British variant’s “share” of new infections (as a percent of new infections) is more or less doubling every week. Having said that, the daily numbers of new infections have been, happily, steadily falling.

        Since they are sequencing essentially all positive samples, they have been able to do some calculations. The reinfection rate of the “standard” variant is now roughly 0.6 (or 0.7; I can’t remember precisely), whereas the reinfection rate for the English variant is around 1.05. Which puts the increased infectiveness at around 50-70 %. Which fits more or less with other data…

        Happily, we haven’t seen the SA variant yet…

        1. Marko says:

          “The reinfection rate of the “standard” variant is now roughly 0.6…”

          That would be the effective reproduction number (Re or Rt) not the reinfection rate.

          1. Some idiot says:

            Yep, you are right… I “failed” just doing a bit too much of a literal translation….!

        2. Chris Phillips says:

          Here is that Danish estimate of 36% increased transmissibility, courtesy of Wikipedia (but it’s in Danish):

          1. Some idiot says:

            Yes, that’s the older one. I had the feeling from his speech today that it was based on newer, more accurate data (the greater volume of data coming that now more sequencing is being done). Just tried to find the newer version:

            In this, it says that the (calculated) re for the “old” variant is now 0.64, and the one for the British variant is 1.07, giving a difference in infectivity of around 65%. They also give confidence intervals. They also say that there is of course a deal of uncertainty in the calculations, but that should improve with more data.

          2. Chris Phillips says:

            Thanks. I thought at least the estimates had been converging, but it appears not.

            The “old one” is only from last week. If it’s changed so radically since then, then perhaps we should treat all the estimates with caution. Sometimes people give confidence intervals that reflect only a fraction of the real uncertainty. I believe the early 70% estimate in the UK had a relatively tight confidence interval related to the mechanics of the specific calculation, even though it had been presented with the comment that it was too early to tell and the data were a very poor fit to the model.

            If anyone is really doubtful whether the UK variant can still be contained by a lockdown, they should look at the figures for positive tests in London – where the new variant is dominant – which are currently at about 30% of the level of three weeks ago.

            I was puzzled by the reports from Denmark, which said there was a “strict lockdown” there and that meetings outdoors were limited to not more than five people. The lockdown in the UK could be tighter, but it’s tighter than that.

          3. Robert James Dancer says:

            I agree 100% with the caution (one can choose how much salt to take with it…!), and they emphasise that themselves. “Unfortunately” I think we will be getting much better number on it soon (mid-late February), since it is there that the British variant is likely to be the biggest at that stage. And they are sequencing almost all positive swabs, so it should be good data, and better over time…

          4. Some idiot says:

            Chris, I agree… with basically everything you say… My feeling (for what it is worth) from the data that is out there is that the actual increased infectiveness of the British variant is probably around 50%, so the latest number from SSI might be on the high side. But I’m sure the numbers should start converging…

            As regards effectiveness of the lockdowns: yes, from when the current (hardest) lockdowns were imposed in Denmark (early-mid December), daily infections have fallen by a factor of 10, which is very positive. Hospital numbers are slowly starting to fall too. Incidentally, the lockdown we have is in practice fairly strict, bearing in mind that a lot of it is actually a combination of “requirements” and “very strong recommendations.” Both are held pretty well, in my experience. The rules say “maximum of 5 people” but preferably not at all, apart from immediate household members. I haven’t seen someone socially for months. At work, we have a series of bubbles, and within each bubble we keep distance all the time. When we move outside our bubble we hold more distance and wear masks. All shops are shut except for food and medicine (and petrol). In some hardware shops you can order online and get it delivered, or queue up outside (with masks and a lot of distance) and pick it up. Works pretty well.

            So on the whole, yes, in practice quite strict. Most people (if at all possible) are working from home, or just the absolute minimum physically at work.

            We’ll get there…! 😊

  27. Ronald Loggers says:

    Derek, thank you. Excellent and relevant blog on variant issues! I notice however that the entire issue of protection is focussed on antibodies and no reference at all is made to T-cells. T-cell memory could be an even more important mechanism (clearing as well as protection) with these viruses. Can you comment on what you expect on immune escape taking T-cells into account as well?

  28. Kasper says:

    Hello readers of this blog,
    I was was wondering what people here are thinking of the following hypothesis.

    Given the (preliminary) reports that Oxford/AZ is suffering from low efficacy problems and the fact that the vaccine is designed using adenovirus technology just like the JNJ candidate, I started looking for reasons why JNJ still might have better odds.
    Besides the specific type of adenovirus platform that is used, the main differences between the two lie in the sequence that is carried in the adenovirus DNA. Where the DNA in the Oxford/AZ vaccine is purely coding for the WT spike sequence that only was codon optimized for translation by humans, JNJ has also incorporated two proline substitutions. Both mutations are improving stability and rigidity of the spike protein (and one is also preventing cleavage of the spike by furin protease). We have seen from Pfizer/BioNtech and Moderna that these substitutions (among others) are resulting in high efficacy numbers.
    Could one therefore argue that low efficacy of Oxford/AZ is likely resulting from the lack of these substitutions and does anyone have an idea why they initially decided to go with the WT sequence?

    Would love to hear what people think of this reasoning!

    1. Marko says:

      “Could one therefore argue that low efficacy of Oxford/AZ is likely resulting from the lack of these substitutions and does anyone have an idea why they initially decided to go with the WT sequence?”

      I’m curious about this as well. The pre-fusion spike technology is NIH property and has to be licensed, so maybe Oxford balked at that aspect, or maybe they tried and NIH told them to stuff it.

      I can imagine a scenario where the Oxford/AZ vaccine works out OK, however. What better way for the virus to evade the pre-fusion vaccine-induced antibodies than to evolve to more of a post-fusion spike configuration ? In that case, the Oxford vaccine may be just the ticket.

      In any event, it would be good to have several different technologies on the shelf. Who knows which ones might come in handy?

  29. Luis says:

    “Vaccine found 92% effective in Israel, in first controlled result outside trials | The Times of Israel”

    1. Quin says:

      The article states: “The Health Ministry reported that there have been 317 infections among 715,425 vaccinees, a rate of 0.044%, or about double the infection rate seen among Maccabi members. However, Maccabi members tend to come from a higher socioeconomic background and live in areas with low infection levels. ”

      So doesn’t that mean that the 92% number is based on a population that has a lower base infection rate than the general population? And thus that it is wrong to use the base rate of the general population?

      There is some speculation that the Israeli authorities are not disclosing the full info that it actually has because it is first sharing it with Pfizer.

      1. WST says:

        The 92% population is also mostly 60+, have seen Maccabi stats but lost the link. So, it’s probably better then Pfizer 95% for 16-85.

        “There is some speculation that the Israeli authorities are not disclosing the full info that it actually has because it is first sharing it with Pfizer”

        Israeli – Pfizer data sharing agreement is public, and all shared data will be public as well.


    2. Quin says:

      For some balanced perspectives on Israeli statistics that have become available, it’s worth following RanBalicer , segal_eran , and kalksteinnir on Twitter.

  30. exGlaxoid says:

    Has anyone seen the paper on bilirubin compounds binding to the spike protein and protecting it from antibodies? I have not been able to get the full paper, but would be curious to know if there is anything to it, and if it gives any clinical useful ideas for fighting covid? There seems to be some interesting data there, but I don;t understand it enough to judge the usefulness.

  31. Marko says:

    The Amazon of variant shopping sites has been updated :

  32. Marko says:

    First US detection of S.Africa variant in South Carolina. Not travel related :

  33. Marko says:

    Rallying cry of the Covid denialists : ” Open Mouth, Insert Both Feet !! ”

    1. Winston Smith says:

      Rallying cry of National Social Distancists: Close Mind, Insert Runes

  34. Marko says:

    Novavax says its Covid-19 vaccine is 90% effective, but far less so against one variant

    “…In its 15,000-volunteer U.K. trial, Novavax said, the vaccine prevented nine in 10 cases, including against a new strain of the virus that is circulating there. But in a 4,400-volunteer study in South Africa, the vaccine proved only 49% effective. In the 94% of the study population that did not have HIV, the efficacy was 60%. ”

    The neutralization studies out of S.Africa were predictive of such a result. The other studies, not so much.

    1. Marko says:

      “The company also said that about one-third of the trial participants in South Africa had previously developed Covid-19 after being infected by the original form of the virus, and that their results showed those previous infections did not protect them against the new variant. The company said its vaccine did provide some protection for those who had previously contracted the disease, but did not include this group in its analysis.”

      1. Not-an-epidemiologist says:

        I wonder if this is poor reporting — the Novavax press release ( states (my emphasis if the html codes work):

        “Importantly in this trial, approximately 1/3 of the patients enrolled (but not included in the primary analyses described above) were seropositive, demonstrating prior COVID-19 infection at baseline. Based on temporal epidemiology data in the region, the pre-trial infections are thought to have been caused by the original COVID-19 strain (i.e., non-variant), while the subsequent infections during the study were largely variant virus. These data suggest that prior infection with COVID-19 may not completely protect against subsequent infection by the South Africa escape variant, however, vaccination with NVX-CoV2373 provided significant protection.”

        The “may not completely protect” implies that in most cases there *was* protection (it’s maddening that they don’t include numbers here). It’s a very odd paragraph, though, and I hope that we see some raw data at some stage. Honestly, the CI for this SA trial (60% efficacy, 95% CI: 19.9 – 80.1) is so large that it’s not hugely useful data — but I agree it fits the larger trend, and is definitely concerning.

    2. Marko says:

      “…Preliminary analysis indicates that the UK variant strain that was increasingly prevalent was detected in over 50% of the PCR-confirmed symptomatic cases (32 UK variant, 24 non-variant, 6 unknown). Based on PCR performed on strains from 56 of the 62 cases, efficacy by strain was calculated to be 95.6% against the original COVID-19 strain and 85.6% against the UK variant strain [post hoc].”

      This might be a signal of some immune escape potential in the UK variant, which would not be too surprising based on the unbiased neutralization studies.

      1. Mandark says:

        Maybe, but they don’t report CIs for this post-hoc, and for event numbers this small a difference of 10 p.p. is not much.

        1. Marko says:

          Agreed. If there is an immune escape component to the increased transmissibility numbers for the UK variant, it’s probably pretty small. There’s enough evidence for it in neutralization studies however , such that any effect that does show up shouldn’t be surprising.

    3. Mariner says:

      It has to be said, it’s pretty remarkable how many of the vaccines rushed through development have proved to be pretty effective against the virus, though less so against the new variants.

      How long before we have the data to tell us if the infections of the SA variant for those who have been vaccinated (by any of the vaccines) and the reinfections of those who previously tested seropositive only have mild or moderate disease? It would be slightly less worrying if the chances of severe illness with the SA variant were greatly reduced in these cases.

      1. Marko says:

        “It would be slightly less worrying if the chances of severe illness with the SA variant were greatly reduced in these cases.”

        I think it would be hugely less worrying. If it turns out that reinfections and vaccinee infections have greatly reduced incidence of severe disease and death in places like S.Africa and Brazil, that will tell me we’re likely well on the way to CoV2 as the next common cold coronavirus, in which case life will return to normal this year.

        Infections don’t bother me if they don’t kill me or disable me. I get a terrible flu every time I drink heavily, but I bounce right back!

        1. DataWatcher says:

          That would indeed be encouraging news, and its true we don’t have any data on severity in S. Africa, although there is increasing evidence that the U.K. strain may, in fact, be more virulent than its predecessors. From a semi-layman’s perspective, though, I’m a little pessimistic about the possibility that the virus could mutate into significantly less virulent strains anytime soon. Evolutionarily speaking, no pathogen can kill off all its hosts, which would inhibit ongoing mutations into ever-more virulent forms. But this virus (as the anti-vaxxers tirelessly remind us) is not fatal in the vast majority of cases — hence, it seems to have struck the “perfect balance” between contagiousness and virulence. Even if a new strain is significantly more virulent as well as more contagious, it most likely will still result in enough non-fatal and/or asymptomatic cases to enable it to continue spreading, and replicating, in surviving hosts. So, unless I’m missing some nuances here, I don’t know how probable it is that it will “de-evolve” into another flu or common cold anytime soon.

          p.s. I’m a little confused about one detail in the South African data for Novavax: Apparently a significant portion of the participants in the trials were HIV positive. For those who weren’t, efficacy was approximately 60%. Not close to the 90- 95% we’ve been “spoiled” by so far, but still strong enough to make a considerable difference, especially if rollouts and uptake of the current vaccines improve significantly in the coming weeks and months.

          1. Mark says:

            “So, unless I’m missing some nuances here, I don’t know how probable it is that it will “de-evolve” into another flu or common cold anytime soon.”

            No, you’re not missing any nuances. You’re missing the basics. I mentioned nothing about CoV2 evolving to become less virulent. The basic picture you missed is that if an infection that occurs secondary to primary infection or vaccination universally (or very nearly so) results in mild or no symptoms, this pandemic is over just as soon as everyone is either infected once or vaccinated. Infections can still flourish, but if it’s just another common cold , nobody will care. That is, the virus is only dangerous to those who are naive to it, but is harmless to those that have been exposed previously, whether by vaccination or natural infection.

          2. Andy says:

            Continuing Marko’s thoughts a little…it would be interesting to see (but it will take a long time to gather such data) if repeated infection and/or booster vaccinations incrementally reduce the severity of subsequent infections further.

            I really hold out hope that classic vaccines will continue to stave off severe Covid or long Covid or organ-damaging Covid from any variant infection. As long as that is the case, it doesn’t really matter what the overall efficacy against symptoms is. I’d even settle for a flu-level infection post-vaccination; that would still be OK for humanity to deal with.

          3. DataWatcher says:

            Okay, I see my misunderstanding. I apologize. So far, though, the “expert” testimony we’re seeing doesn’t seem to be taking this possibility into consideration —

          4. DataWatcher says:

            Meanwhile, I don’t remember any solid evidence that the relatively few re-infections that have been reported over the past ten months or so have resulted in significantly less serious cases. One would think that if there was evidence pointing in this direction, it would have been discussed.

          5. Marko says:

            There’s not enough evidence available pointing in either direction. That’s why the data to come from areas like Manaus, where reinfections are likely common now, is so important. All we have to date are anecdotes. Somebody dies or has a severe outcome from a reinfection, it probably gets reported somewhere. Ten thousand people never seek medical attention for their reinfection and nobody knows about it. It takes organized data collection.

            I wouldn’t expect any public health types to promote this idea now, when it’s merely a possibility, since if they did and then hopes were dashed by unfavorable data, they’d get pilloried.

          6. DataWatcher says:

            Good point, and I can see their reasoning. My own most troubling doubt about this putatively more optimistic scenario has to do with what GM posted above — the specter of millions of asymptomatic (or mildly symptomatic) carriers nurturing lodes of constantly-mutating strains:

            “If you rely on vaccination with non-sterilizing vaccines reducing the disease burden and ‘solving the problem’ . . . you will also create orders of magnitude more situations of chronic prolonged infection within which rapid evolution can take place, and you will, over time be starting those episodes with more contagious variants of the virus (up to a point perhaps).
            All things are not equal — controlling disease but not transmission with vaccination means that you may in fact have a lot more virus than now circulating. . . And the selective pressures imposed by the vaccine may drive the virus in directions it would not have gone otherwise due to other constraints.”

            According to this scenario, less-virulent cases due to reinfection or infection of vaccinated people could turn out to be Trojan horses of new lethality and pandemic-level infection and spread.

          7. Marko says:

            “My own most troubling doubt about this putatively more optimistic scenario has to do with what GM posted above — the specter of millions of asymptomatic (or mildly symptomatic) carriers nurturing lodes of constantly-mutating strains…”

            That specter is one we live with quite happily in the case of the four common cold coronaviruses. Nobody is suggesting we exterminate them so that we don’t have to worry about new mutations creating more deadly strains.

            I get it though. Catastrophe is a more appealing vision for some. To each his own…

          8. confused says:

            On the previous post, I linked to a Science article suggesting precisely this: coronaviruses don’t provide long-lasting *sterilizing* immunity, but they *do* against *severe disease*, so it will go endemic pretty fast and then not be more dangerous than your average respiratory virus.

            It even said that vaccination might not be necessary long-term, since everyone born post-COVID would be expected to get it in their first few years of life when it’s much less dangerous.

  35. Luis says:

    Marko what is your take about the study carried out in Israel?
    Thank you

    1. Marko says:

      It looks fantastic so far. Better than I would have predicted, but it’s still very early.

      I do think we’ll see the results from their vaccine rollout showing up in hospitalization and death figures before too long, which will provide a lot of encouragement to the rest of the world if favorable, as expected.

  36. An Old Chemist says:

    The New York Times
    Novavax’s Vaccine Works Well — Except on Variant First Found in South Africa

    1. Jack Komisar says:

      I wonder what effect the Novavax vaccine will have on vaccine hesitancy. It is just a protein with an adjuvant. It is not very scary. People will have a hard time arguing that it changes your DNA. Unfortunately, the protein is expressed as a nanoparticle. So we will still be hearing dire warnings about nanotechnology.

  37. Marko says:

    BJ teaches us how to do ELISA pipetting using ten thumbs :

  38. Melon says:

    So the South African mutations turn a 95% efficacy into a 60% efficacy. Do we think the same will apply to Pfizer and Moderna? Novavax also induced a T-cell response btw

    1. DataWatcher says:

      I’m a little unclear as to the extent to which T-Cell responses have been included in these preliminary findings about the efficacy of the vaccines against the S. African variant — all I’ve heard reported about have been antibodies. Is this a flaw in the actual reporting, or are the analyses simply more incomplete at this stage than most of the news reports have led us to believe?

    2. Chris Phillips says:

      I note that the Novavax vaccine is not expected to be available for another six months. Does anyone have an informed opinion about how easy this vaccine would be to modify for new variants?

      I suppose that six months would be plenty of time to test the safety of a new formulation, and perhaps even time for a large-scale trial of efficacy in South Africa, for example.

      1. DataWatcher says:

        Six months is probably enough time. But this does not bode well — we can’t spend our “new normal” future constantly playing catch-up, frantically developing new vaccines against mutations and trying to get them into people’s arms every six months, all the while limping along under semi-lockdown conditions while masking and “distancing” ourselves and avoiding social gatherings.

    1. Moses says:

      The speaker in the above clip is Prof. Adam Finn of Bristol University.

      1. debinski says:

        But not so bad for a one-dose vaccine, especially in the US population. Who knows how Moderna or Pfizer would do vs the S African variant.

      2. Novacek says:

        I don’t see it that way at all. Good numbers in America. Still effective in South Africa (about the same as novovax).

        And the temperature requirements and one shot represent _huge_ logistical advantages.

        Not to mention just having another source of vaccines. 72% effective now is way better than 0% effective because I’m in phase 3 and can’t get any vaccine for 6 months.

      3. Alex Beribisky says:

        Also, it cuts severe disease by 85% (and by 100% after day 49), no hospitalizations or deaths. These numbers are unchanged in South America as well as in South Africa where the worrisome variants are presently circulating in large amounts… Overall, especially given the logistics (one shot, convenient storage conditions) still a very valuable entry!

        1. xrayxtals says:

          Yes, this is actually very promising imo. Prevention of severe disease, especially when viewed with respect to the amount of virus currently circulating, is key. Single dose, stable at fridge temps and should have 100 million doses ready to go.

        2. DataWatcher says:

          Please refresh my memory. Don’t the Moderna and Pfizer/BioNTech vaccines also have virtually a 100% success rate in preventing severe disease? The question, then. in clinical terms, is how we distinguish between “moderate” and “severe.” I’m assuming “severe” means “life-threatening,” but does it mean “requiring hospitalization at all”? If not, then the predictions that the vaccines could reduce COVID to the status of something like a flu could well be accurate (assuming, and this is a big assumption, that further mutations don’t muddy the waters even more). My next question: If the endpoints in S. Africa are the same as here, then the efficacy rate against mild to moderate disease is approximately 60% (for non-HIV patients). But what is the efficacy against severe disease? Do we know that yet?

          1. Alex Beribisky says:

            95% percent, according to their press release. Addressing some of your previous comment regarding T-cells, I really think they are integral in preventing severe disease. Yes, vaccine efficacy against the Brazilian and South African variants is lower in terms of protection from symptomatic Covid due to reduced neutralizing antibody activity. But the T-cell response which the vaccine elicits as well seems to be adequate in protecting your from the more severe Covid symptoms. This is just my hypothesis, but I think it is also supported by studies done on asymptomatics and those with mild covid – many of them had very low or sometimes even non-existent antibody titers. T-cells must have played a pivotal there, probably due to some sort of cross-immunity.

          2. Alex Beribisky says:

            “The question, then. in clinical terms, is how we distinguish between “moderate” and “severe.”

            Hmm, not sure whether the benchmarks for this are set in stone. Here is the J&J criteria used in their trial: Severe COVID-19 disease included laboratory-confirmed SARS-CoV-2 and one or more of the following: signs consistent with severe systemic illness, admission to an intensive care unit, respiratory failure, shock, organ failure or death, among other factors. Moderate COVID-19 disease was defined as laboratory-confirmed SARS-CoV-2 and one or more of the following: evidence of pneumonia, deep vein thrombosis, shortness of breath or abnormal blood oxygen saturation above 93%, abnormal respiratory rate (≥20); or two or more systemic symptoms suggestive of COVID-19.

            “I’m assuming “severe” means “life-threatening,” but does it mean “requiring hospitalization at all”? If not, then the predictions that the vaccines could reduce COVID to the status of something like a flu could well be accurate (assuming, and this is a big assumption, that further mutations don’t muddy the waters even more). ”

            According to their press release, severe disease does not imply a hospitalization (those did not occur at all among the vaccine group), so I guess the severe cases were not severe enough to warrant a hospital stay. So yes, in general it looks like that if you are vaccinated and do get sick, you will have cold or flu-like symptoms, nothing worse.

          3. DataWatcher says:

            That’s certainly all of our hope. Interesting that this aspect of the entire situation seems to have been downplayed by almost all of the spokespeople, from WHO on down. It would be reassuring for people to hear that, I think.

            This may be a topic for a separate discussion, but it will be interesting to see, when and if this does come to pass, how strict and stringent the requirements will remain in terms of public health measures (gatherings, “distancing,” masks, etc.). Thus far, it seems as if they may still remain pretty strict, at least in the U.S. (e.g., Fauci’s admonition that “constant vigilance” will be the norm in perpetuity, or Gov. Pritzker of Illinois predicting that even when the final “full reopening” of the state can occur, with an effective vaccine and diminishingly low case-positivity numbers, “all sectors of the economy [will] reopen *with new health and hygiene practices permanently in place*”).

          4. DataWatcher says:

            . . . with the caveat that “pneumonia” and “abnormal respiratory rate,” to cite just two examples, could well develop into serious conditions for the elderly and people with pre-existing conditions (as, of course, they already are, along with flu, which kills anywhere from 12,000 – 61,000 people a year in the U.S.).

          5. Marko says:

            “Interesting that this aspect of the entire situation seems to have been downplayed by almost all of the spokespeople, from WHO on down. It would be reassuring for people to hear that, I think.”

            You keep expecting people to risk career suicide just to momentarily comfort you. We don’t know yet how long this protection lasts. At 6 months, does the chance of death if infected rise dramatically? If it does, then all of those comforting spokespersons would be looking for new jobs.

            The reinfection data, if we ever get it, will give us a better handle on this. If we find that those who were infected 8-10 months ago, and whose antibody levels had waned significantly, are still protected against severe disease and death after reinfection, then you may begin to get some of the comforting words you seek.

          6. confused says:

            Yeah, protection against severe disease is what matters, IMO.

            I cannot see the US public, at least, continuing to accept/follow much of any public health measures once basically everyone has been vaccinated who wants it.

          7. DataWatcher says:

            “I cannot see the US public, at least, continuing to accept/follow much of any public health measures once basically everyone has been vaccinated who wants it.”

            I believe you may be right, for the most part, although I won’t be surprised if we still see businesses where clerks and other personnel interact with many people daily mandating masks for employees (and maybe customers) — ditto for most restaurant workers and probably bartenders.

            People who consider themselves especially vulnerable — frail elderly, cancer survivors, the immunocompromised, etc. — will likely continue to mask up, as well (at least some were already doing that during flu season, pre-COVID).

            Not sure about teachers and students, but again they’re in close contact with multiple people every day, and it’s unlikely that children will be required to get vaccinated to go to school, so (as much as it impairs “normal” human interaction and emotional bonding), I think we’ll be seeing masking and distancing in schools for quite some time, also.

            It’ll be interesting to see how it plays out. Fauci, who has occasionally predicted that masks will simply become an everyday cultural norm in the U.S. as they have in many Asian countries, gets a little “fudgy” when he talks about this (“Things can probably get back to *some semblance of normal* by Fall of 2021”) while predicting that “constant vigilance” will be essential in perpetuity. In Illinois, the governor has laid out a five-phase recovery plan; Phase Five, “Illinois Restored,” includes the caveat, “All sectors of the economy reopen *with new health and hygiene practices permanently in place*,” which sounds to me a little like a permanent mask mandate of some kind. So we’ll see . . .

          8. confused says:

            I mean, some concern may remain… but I don’t really think so. I cannot see masks becoming normal in the US, they’ll be too much of a symbol/reminder of the chaos, IMO.

            I don’t think what government figures say *now* is very meaningful for what will actually happen *then*.

            Because certainly some states will get rid of measures as soon as they can (or earlier) and once COVID levels are low enough that that *isn’t* a problem, I don’t think it will be economically or politically viable to maintain them elsewhere. Especially once COVID is “old news”, and in the modern fast-moving world I think that will happen faster than we’re thinking.

      4. DataWatcher says:

        If I recall correctly, the J&J vaccine did not inhibit infection in the nasal passage in the early non-human primate studies, so the chances of any kind of sterilizing immunity are probably very low. No data yet, as far as I know, on Moderna and Pfizer/BioNTech, although I wouldn’t be surprised if they conferred at least *some* sterilizing immunity — whether enough to significantly reduce spread, no way of knowing yet. I think the Novavax vaccine did appear to confer sterilizing immunity in the primates — which, if that pans out for humans, would be a definite factor in their favor, perhaps even given their less-than-stellar performance in South Africa (so far).

  39. Chris Phillips says:

    Here is the Johnson and Johnson press release:

    Initially I thought the headline 66% afficacy didn’t look good. That is for “moderate to severe” disease. But on the other hand, the range is not as large between South Africa (57%) and the USA (72%) as might have expected based on the Novavax numbers.

    Perhaps most significant is no hospitalisations at all beyond 28 days after vaccination, including in South Africa where 95% of cases were from the B.1.351 variant. That sounds like very good news indeed, particularly if it can be taken as an indication for the other vaccines.

    1. hardnox fort says:

      The J&J might turn out to be one of the most underappreciated, because the topline of 66% ain’t that good at 28 days.

      As I understood it, severity at day 28 was about 15% severe infection, which is not that good, but at 49 days no severe infections were found.
      Both interpretations point to day 28 as topline effect may be a bit earlier than peak effect and thus topline underestimating the longer term effect.

      All in all, it is looking fine so far, but we will see when the report lands early next week.

    2. A Nonny Mouse says:

      But aren’t one dose of the currently used vaccines as good after one dose? Maybe I’m mistaken.

    3. confused says:

      Yeah, they really ought to advertise the efficacy against hospitalization / death (which is what really matters). We don’t do public health measures against the common cold, so that should be enough to go totally back to normal.

  40. exGlaxoid says:

    The news is amazing, we have at least 5 decent (> 50% protective) vaccines that appear to prevent most serious illness in people. I agree with many that we can’t yet stop covid completely, but if we can just prevent people from being sick enough to be hospitalized or dying, that will buy us the time to find more treatments, tweak the vaccines, and find other ways to stop this from killing millions of people.

    1. Chris Phillips says:

      “The news is amazing, we have at least 5 decent (> 50% protective) vaccines that appear to prevent most serious illness in people.”

      As of today, apparently we have to start reckoning how many the EU has, and (if we are outside the EU) subtract those.

    2. PastTense says:

      On the other hand I think most people will instead think in terms of will this vaccine allow me to return to a normal lifestyle (going to restaurants, ball games, etc). I think people will decide that a 95% effectiveness does–but that a 66% effectiveness doesn’t.

      1. DataWatcher says:

        Not to sound trite or cliche, but I think it’s all about those “numbers.” When/if case-positivity rates become diminishingly small for a period of time (weeks? months?), people will start to feel more comfortable. If public officials agree, and begin to loosen restrictions, the conversation about what “normal” looks like can begin in earnest. The wild card, of course, is the international nature of the pandemic, and the connectedness of modern life. As long as COVID continues to spread and have serious health consequences in even the poorest countries, the rest of the world will also be at risk. It won’t be like Ebola and the other, all too numerous, so-called “Third World epidemics” which, for the most part, never jumped the borders and traveled very far North and West.

      2. confused says:

        I doubt people would decide that 66% isn’t enough; from what I see around me, maybe half of people are basically going back to normal with no vaccine at all!

        And new risks are more frightening than familiar risks. (I mean, people went about their lives when even more deadly infectious diseases were endemic – the US used to have yellow fever and smallpox, etc.)

  41. JerryC says:

    When a coronavirus vaccine performs more poorly in South Africa, is that because of the local virus variant, or because of high HIV prevalence in SA, or both? Has that been sorted out?

  42. lizzy says:

    I do not see an evolutionary selection advantage for any virus to kill or even maim its host. That only results in a premature loss of substrate for replication without possibility of escape through transmission.

    Severely ill people are hospitalized, transmission blunted by PPE.
    Oropharyangeal swabs become negative as the disease settles into the lungs, further decreasing person to person transmission. Severe disease leads to a dead end whereas presymptomatic and asymptomatic individuals end up being superspreaders.

    I think the above could be a contributing force on Covid 19 variant evolution. Leave the host unscathed, partially vulnerable to repeated infection, and very infectious.

    We don’t fully understand why some people get severely ill while others don’t. Yes, we have a handle on host risk factors such as age and comorbidities. But we have done a very poor job at characterizing and cataloging viral variants, especially in the US. Perhaps there is a variant that contributes to disease severity and as such, is more likely to be selected out. It is even possible that known or unknown viral variants contributed to prior superspreader events, none of which lead to increased lethality.

    Yes, I know, this is my speculation. And yes, I am an optimist. I tend to think that this pandemic will go out “not with a bang but with a wimper”.

    Here’s Paul Offit on variants from JAMA:

    1. Marko says:

      I was disappointed by that piece by Offit et al. All that talk about variants, and not one mention of severe disease or death.

      1. lizzy says:

        In terms of variants, don’t you think it’s too soon and probably too open to conjecture? To my knowledge, no one has data on % of variants in those with severe disease or death compared to % of different variants in that particular population.
        Thus your earlier statement calling for better tracking of variants is indeed warranted and echoed by Paul Offit. (See #2)

        First, SARS-CoV-2 viruses must be immediately isolated and characterized from individuals who have been fully vaccinated but are nonetheless admitted to the hospital with COVID-19. This would likely be the first sign that variant viruses are becoming resistant to vaccine-induced immunity.

        Second, the US should create and maintain an active sequencing and surveillance system to identify these variants quickly once they arise. While the UK has been excellent in this regard, the US and much of the rest of the world has not. International cooperation is essential to do this properly.

        Third, it would be of value to create a central repository of serum samples from people in the US who have been immunized with SARS-CoV-2 vaccines. This resource would enable researchers to test their neutralizing capacities against any new variants as soon as they are identified.

  43. An Old Chemist says:

    What to know about 4 worrisome coronavirus variants, including one that can partially evade vaccines:

    (In the spike protein, Asparagine at residue 501 has been swapped by Tyrosine (N501Y) in these mutations along with a few other amino acid residue swaps e.g. K417T and E484K. Also 69/70 amino acid deletion is seen.)

  44. An Old Chemist says:

    There is some research suggesting that E484K mutation may be a key culprit behind why certain vaccines appear less effective in South Africa.

    Coronavirus strain in UK picks up mutation that could impact vaccines, experts say

  45. Giltil says:

    I am wandering. Couldn’t some of these variants associated with escape from neutralizing antibodies elicit ADE (antibody-dependent enhancement) following vaccination?

    1. Derek Lowe says:

      Man, there are a lot of people worried about ADE. So far there’s been no sign of this, though, even as the variants spread in a number of populations.

  46. JS says:

    A question from someone outside the field:

    It seem plausible that different people have different inherent susceptibility to the virus. Due to differences in the ACE2 receptor or immune system, say. Something so subtle or random that we have not spotted the pattern. Is it possible that the various mutations like D614G, N501Y, E484K and K417N cause some people to become more susceptible and others less? If so, might that explain some of the puzzling results we see in places like Manaus?


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