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Vaccine Roundup: Merck Wipes Out (and More)

We have a good amount of news in the coronavirus vaccine world, so it’s time for another look over the field. My most recent overview post is here, from late December, with this one from mid-December, and about ten days ago I looked at news from J&J and SinoVac (also summarized below). I’m going to try to round up a lot of lesser-known efforts in this post as well.

Viral vector vaccines:

The big news here this morning is from Merck. They were developing two candidates in this category – with Themis they were working on a measles-based one, and the IAVI a VSV-based one. But the company announced today that they’re dropping both of them after looking at the first human Phase I data. The immunogenicity of both candidates was below the antibody levels seen in convalescent plasma, and below that seen with other reported vaccines. So that’s a good reason to bail out, sadly.

It’s not clear (of course) what led to this lower response. STAT has some interesting statements from IAVI to the effect that the intramuscular administration of the VSV vaccine may not have been the correct route. They seem to believe that different ones may be worth pursuing, especially intranasal, but they’re going to have to round up the money for that idea on their own. Update: turns out that IAVI is going to continue to work with Merck on a possible alternate formuation/route of administration. Hope something works out! But this is a lesson that we have not abrogated the failure rates in drug discovery: there are still plenty of ways to go wrong, and often the only way to find them is to go into clinical trials. It has ever been thus.

There are other viral vector vaccines out there being administered, of course. The UK is pushing ahead with the Oxford/AstraZeneca adenovirus one, of course, but its true efficacy is not any more clear than it was when I last wrote about it in December. This one has been approved in Thailand, Mauritius, Ecuador, and more countries besides, but word has come recently that it will be in much shorter supply than expected due to manufacturing problems.

The CanSino adenovirus vector vaccine is being offered to several countries (such as Pakistan and Indonesia, on an emergency basis) and may be about to be approved in Russia, which I believe would be its first actual regulatory approval outside its use in China. But it’s been very hard to get a read on its actual efficacy – the data are (from what I can see) scattered and incomplete. I honestly don’t see this one being approved in many countries under these conditions.

Similarly, the Gamaleya vaccine from Russia (“Sputnik-V”) continues to be rolled out in a few countries, as I mentioned in December (the latest is emergency use in the Philippines and in the UAE. The full paper on its efficacy trial has not yet published. There’s a report that the combination trial using this one and the Oxford/AZ vaccine may start up in February.

We’re still waiting on clinical trial data from J&J, and it’s still expected any day now. The efficacy numbers on their one-dose protocol are highly anticipated, and the news this morning that Merck’s two vaccine candidates have been shelved just adds to that. Anthony Fauci said on Friday that he would be surprised if a regulatory decision were not made on this one within two weeks. Frankly, it had better work – we need it.

There are other viral vector candidates out there. ReiThera has one going in Italy, and earlier this month the company said that no safety signals had been seen in the first 100 patients in a Phase I trial. It looks like it’ll be a while before we see any efficacy data on this one – you’ll note talk in that article about Italy having “vaccine independence”, but that would involve sitting back and watching most of the rest of the world getting dosed with other candidates. Washington University has been working on a single-dose nasal viral vector candidate, which has now been licensed to Bharat Biotech in India, who say that they hope to start human trials in February. We’ll see if that goes off. Similarly, MediciNova in Japan has been working on an intranasal vaccine, but there’s been no substantial news from them for months. Beijing Wantai has another intranasal candidate – the last thing heard from them was registration of a Phase II trial in China in November. AltImmune has an intranasally-dosed vaccine in development, but in late December the company announced a clinical hold from the FDA (apparently due to manufacturing concerns?), and this has apparently not yet been lifted. Most of the articles you see about this company are about its stock rather than its science, a disconnect that also shows up with Inovio and with Vaxart. They’re another company with a viral vector candidate, this one dosed orally. But I can find no updates at all about its clinical progress – just excited talk about its prospects as an investment. Patrick Soon-Shiong’s ImmunityBio is also working on an oral adenovirus vector vaccine. A Phase I trial is said to have finished up in November, but I have seen no data from it. Further back, Lancaster University and Texas Biomedical have reported animal studies of another intranasal candidate, this one based on a poultry virus (Newcastle Disease).

Finally, there’s a small company called Gritstone that recently announced a Phase I trial of a combination two-dose regimen: one dose of an adenovirus vector and one dose of a self-amplifying RNA. So that takes us to. . .

RNA/DNA vaccines:

Well, the Moderna and Pfizer/BioNTech vaccines are now going into millions of people. The most comprehensive data set we have so far is from Israel, where a vigorous and organized vaccination campaign has been underway with the Pfizer/BioNTech vaccine. So far, so good. The data after the first shot seems to almost exactly recapitulate what was seen in the clinical trials, with a split between vaccinated and unvaccinated people emerging around Day 13 after dosing. The UAE is a country that’s well up there in percent of the population vaccinated, but they have a mixture of SinoPharm, Pfizer/BioNTech, and Gamaleya vaccines being administered, which will be interesting to watch – I hope they’ll be able to collect enough data for a comparison among all three. The Pfizer/BioNTech vaccine has been approved in Australia, and is expected to be approved soon in Japan.

Adverse effects in the US, Israel, and Europe seem to me to be low and consistent with the clinical trial data. There seems to be a headline every time there is a potential AE, which is what I basically expected, but I’m not seeing anything that sets off alarm bells yet. The CDC is monitoring reports of anaphylaxis with both vaccines, but these seem to be at the few-per-million level.

This morning came word of a study from Moderna about the antibodies raised by its vaccine and the new coronavirus variants. It looks like the B.1.1.7 variant doesn’t show much difference compared to “coronavirus classic”, but the South African variant shows about a sixfold reduction in efficacy. That’s not good news, but it’s not horrible news, either: the antibody response that’s still there is expected to be enough. But the company says that they’re working on a modified mRNA to potentially be used as a booster shot, should this be necessary, and describe this as an “insurance policy”. A manuscript on this should be showing up shortly. Update: it’s out now!

Curevac‘s mRNA candidate has gotten a boost with the announcement of a partnership with Bayer. Phase III trials are underway in Mexico; it will be very interesting to see some data from this one, given how well the other two mRNA candidates have worked out.

The other big candidate in this category is Inovio, a DNA construct vaccine that is planned to go into Phase III sometime after March. You’d have to think that the landscape will be quite different by the time this one makes it through trials – for now, we’ll wait on what the Phase II efficacy data look like when those come out. There’s a small company in Vancouver, SymVivo, with an oral DNA vaccine delivery platform – they have announced the start of a Phase I clinical trial in Australia in November, and recently signed a deal with Merck for vaccine development in general (although presumably not coronavirus ones, given today’s news). I mentioned self-amplifying RNA above – a candidate from Imperial College using this technology went into human trials back in the summer, but I have seen no word on any results yet. It does still seem to be alive, though, based on this announcement.

Inactivated virus vaccines:

In India, Bharat Biotech‘s Covaxin has been given emergency approval there while it’s still finishing up Phase III trials. The Phase I data have now appeared in The Lancet, and the results certainly seem worth watching. I wrote last month about the confusion around the SinoVac candidate, and that has not cleared up. I simply have no good idea how effective the vaccine is; the data have come out in a very disorderly fashion. The situation for the SinoPharm vaccine is not a lot better – I wrote about that one in December as well, and although it’s being shipped to more countries now (such as Egypt), to the best of my knowledge no Phase III data set has been released.

Attenuated virus vaccines:

Update: I missed this category before. Codagenix and the Serum Institute in India are working on a live-attenuated coronavirus vaccine that would be dosed intranasally. This is currently in Phase I.

Recombinant protein vaccines:

We’re still waiting on Novavax Phase II data; that’s the most highly anticipated trial readout now behind the J&J one. The NIH/BARDA-funded Phase III started up just before the first of the year; the company’s own Phase 3 trial in the UK started in September. There have been reports that the expected trial difficulties with the availability of other approved vaccines have affected the patient numbers. This candidate is given with the company’s own proprietary adjuvant. Medigen of Taiwan has announced that they’re now dosing patients in Phase II (with an adjuvant from Dynavax). There’s a recombinant subunit vaccine from Baylor, again with a Dynavax adjuvant, that’s now in trials in India with Biological E. Limited of Hyderabad. Meanwhile, I wrote last month about the setbacks in the GSK/Sanofi effort; there’s been no update on their retooling since then. Update: and Medicago’s plant-produced recombinant protein vaccine, which comes in the form of virus-like particles, is now in Phase II/III, partnered with GSK.

Update: In an earlier state is one from the Pirbright Institute, working with Oxford – this is another virus-like particle, in this case decorated with Spike protein that’s attached via the “Spycatcher” protein-protein technology.

You’ll notice the constant mention of adjuvants – the recombinant proteins really need that to get a strong immune response (see this mouse study for a vivid example). But there are plenty of good ones around, and no one (from what I can see) is being so bold as to try to go ahead without one.

Others:

I’m sure I’ve missed some candidates as well – there’s a lot of work going on from various organizations, and if some of the major efforts stumble (as Merck did today), they could rise up the charts. I’ll update this post as people send me news over the next few days!

142 comments on “Vaccine Roundup: Merck Wipes Out (and More)”

  1. Jérôme says:

    Hi,
    Stopped after phase I because of insufficient results: the Institut Pasteur in France. This one was based on the measles virus.

    Source (in French): https://www.pasteur.fr/fr/espace-presse/documents-presse/covid-19-point-etape-mobilisation-scientifique-programmes-recherche-candidats-vaccins-issus-institut

    Thanks for your articles.

    1. Derek Lowe says:

      This looks like it’s part of the Merck measles platform, from what I can see. . .thanks!

  2. James says:

    Has anyone seen any data out of Israel (or anywhere else where lots of people are getting Moderna/Pfizer shots) which would indicate how likely vaccinated people are to be asymptomatic carriers? I have been trying to keep an eye on the preprints, but maybe there is something I missed.

    1. Chris Phillips says:

      There have been various figures reported in the press, which seem to vary wildly. The BMJ comments on one of them here:
      https://www.bmj.com/content/372/bmj.n217

      I don’t understand the article, because it seems to be comparing efficacy in the Phase 3 trial (which was based on symptomatic infections only) with efficacy based on blanket testing following vaccination, and expecting them to be the same. In addition, the article points out that the participants of the study in Israel were all over 60, unlike the Phase 3 participants.

      1. James says:

        Thanks for the link!

    2. Sam Weller says:

      One of the HMOs in Israel reported that so far there have been 20 confirmed cases of Covid-19 out of 128,600 people who were at least one week after their second dose of the Pfizer vaccine. Most were above the age of 55, all showed fairly mild symptoms, and none required hospitalization. Similarly, the Israeli ministry of health reported 63 confirmed cases out of 428,000 people that were at least a week after their second dose.

      I have not seen information about asymptomatic carriers.

      1. Marko says:

        That sounds good, but it would have been nice if they’d mentioned the expected number of infections for similar numbers of unvaccinated individuals over the same time span. I guess they figured someone else will do the math. That’s going to be my strategy, too.

        1. Sam Weller says:

          I imagine that stats that may put the above in a proper context will be collected and released at some point, but obviously this is no longer a controlled trial, and all sorts of biases could be introduced. FWIW there have been 110,000 new confirmed cases in the general Israeli population in the past two weeks, which is probably roughly the same period during which the above infections of vaccinated people have been detected.

          1. Marko says:

            Thanks. That provides some perspective, anyway. It looks like whopping efficacy, almost any way you’d slice the data.

          2. confused (now doubly confused) says:

            Yeah, it really does.

            Apparently I’m in optimistic mode today 😉

          3. Some idiot says:

            A member of our family (here in Denmark) is unwittingly part of an “uncontrolled trial” at the moment.

            The family member is in a nursing home. We were celebrating on 31th December when they all (residents and staff) were vaccinated (Pfizer/BioNTech).

            On 2nd January they found out that three people there were infected. I then mentally started counting days as to when the vaccination would start to kick in. Last numbers (around the 20th) was that around 1/3 of all (both staff and residents, similar ratios; total number staff+ residents is around 130 ) had tested positive, with some deaths.

            On 24th January they received their second vaccination. There have been fairly routine mass testing of residents and staff. At the moment, my family member has still tested negative, and (fingers crossed!!!) hopefully now that will stay that way, as will it hopefully stay that way for the rest of the residents and staff (BTW, the staff have done an amazing job trying to stay on top of it all… Hat off to some incredibly dedicated people!!!).

            When the whole thing has settled down, I hope some health experts get a chance to go through the data with a fine-tooth comb. My guess is that there will be some information there about how quickly immunity increases in these at-risk groups, plus possibly maybe some info on whether or not spreading is possible from a vaccinated person.

        2. Andreas says:

          This is a VERY rough guess how many unvaccinated people were infected in comparison:

          With about 7,500 known infections per day, 0.58% of the entire population is infected per week. This means out of random 128.600 people, 746 are expected to be infected per week.

          Now I don’t know how long the phase was within which those 20 infection occurred, but when it was two weeks, then there were 20 infections instead of ~1,500, which sounds pretty compelling. This would mean that 98-99% of all infections are avoided. But of course there are a lot of assumptions in this guess.

  3. Melon says:

    Do we know if any of the symptomatic cases in phase 3 trials were sequenced? The trials done in Brazil might have been biased towards a lower efficacy because of the prevalence of immune escape variants there. Maybe the efficacy of the AstraZeneca vaccine against the original strain and the UK variant is better than we think.

  4. Wilberth says:

    Medicago updated their Ph2/3 COVID19 trial, now enrolling 30K subjects. NCT04636697

    1. Derek Lowe says:

      Just added them – thanks!

  5. Ryan says:

    Is there a possibility that if the Novavax phase II and UK phase III data is fantastic, it could be granted an EUA by the FDA without having to wait for the U.S. phase III trial to read out, which only just began?

  6. Juan says:

    Here is another effort by Oxford for intranasal use that is looking promising in animal studies for a second generation of Covid vaccines. It is a virus-ike protein rather than an actual virus vector, carrying the Spike RBD tagged with Oxford’s SpyCatcher technology: https://www.pirbright.ac.uk/news/2021/01/early-animal-studies-pirbright-and-oxford-yield-promising-results-new-potential-covid

  7. Mandark says:

    I think the vaccine from Codagenix (COVI-VAC), which started its phase 1 trial in the UK this month, is worth mentioning. For one thing, it seems to be the first live-attenuated vaccine for SARS-CoV-2 (and their method of attenuation is interesting, too). It’s also intranasal and single-dose. And they partnered with the Serum Institute of India, so they should be able to actually manufacture it.

    Here’s the trial link:
    https://clinicaltrials.gov/ct2/show/NCT04619628

  8. Jack Ryan says:

    I am surprised the Medicago vaccine candidate has not been discussed. They are currently in their phase 2/3 trial in the US and Canada.

    Their phase 1 study showed that there was ten times higher antibody response over those infected with COVID-19, which would seem quite a bit higher than any other candidate: https://www.medrxiv.org/content/10.1101/2020.11.04.20226282v1.full.pdf+html

    1. Derek Lowe says:

      That one’s in there now – thanks!

  9. Marko says:

    “….the company says that they’re working on a modified mRNA to potentially be used as a booster shot, should this be necessary, and describe this as an “insurance policy”. A manuscript on this should be showing up shortly. Update: it’s out now! ”

    Glancing at the preprint, it looks like this is just a more thorough study of the performance of the approved vaccine, M-1273, against the variants. I see nothing about a modified vaccine, besides the statement that they’re ready to do make one if necessary.

    1. Marko says:

      For some perspective on what an 8-fold average reduction in neutralization titer can look like across a broader population, see this thread by Trevor Bedford :

      https://twitter.com/trvrb/status/1351785356782313473/photo/1

      Here the average in convalescent plasma was around an 8-fold reduction in titer against the SA variant, but ~ half of the samples showed complete knockouts of activity. If you look at the Moderna preprint linked above by Derek, they showed a similar result in their vaccinated non-human primate study.

      I would not expect the Moderna vaccine to perform nearly as well in S.Africa and Brazil, where the immune escape variants are highly prevalent. I suppose we’ll find out soon enough.

  10. John Beamer says:

    Can someone explain in simple language what this means against the South African variant for the mRNA vaccine. If the moderna vaccine is 95% effective against the original Coronavirus what is the implied efficacy against the South African variant? Presumably it is 1/6th ie 16%?

    1. Marko says:

      No, not that bad, but I believe it will show significantly reduced efficiency, perhaps small in magnitude at first, but growing as antibody titers wane. The “buffer” of excess in effective neutralization capacity against the variant will be that much smaller compared to the WT, so protection will be lost sooner.

    2. confused (now doubly confused) says:

      Yeah, I would like to know this too.

      The preprint linked to seems much more promising than that, though some of it is ‘over my head’ — it refers to “reduced but still significant neutralization”, but “all evaluated sera able to fully neutralize”

      and

      “Data from this sample set shows mRNA-1273 maintained activity against all circulating strain variants tested to date, and only the B.1.351 variant showed reduced neutralizing titers, as assessed from vaccinated human and NHP sera. Viral escape was not detected from any sample and neutralizing titers remained above those previously found to be protective in NHP challenge studies.”

      I am not sure what % efficacy “previously found to be protective” refers to, though.

      The sixfold reduction seems to be “neutralization capacity” rather than % protection against infection (the preprint refers to a 6.4x “reduction in neutralization”) — but what does that mean? Titer of antibodies that are neutralizing against that variant, or something else?

      1. Marko says:

        Remember, “efficacy” as measured in the vaccine trials translates into protection against symptomatic and severe disease. The reduction in neutralization titers would more accurately translate to a real-world effect on protection against infection. I’d expect the vaccines to be somewhat less effective on the latter measure against the immune-escape variants. On protection against disease, we’ll just have to wait for the data. It’s similar to the situation we’re in regarding the protection offered by natural infection.

        1. confused says:

          Maybe I’m just an optimist, but this preprint seems far more positive than what I’d heard previously about the SA variant.

          (Which may just mean that vaccine immunity is better than natural immunity?)

          1. Marko says:

            You’re just an optimist.

          2. confused (now doubly confused) says:

            Quite possible, but that pre-print does say “all available sera able to fully neutralize” and “neutralizing titers remained above those previously found to be protective”. Isn’t that pretty positive?

            I am absolutely not an expert by any stretch, but that seems to mean that activity was, while less, still enough to do the job.

          3. Marko says:

            Yes, one week after the second dose. How about after several months? Even Moderna is wary of this variant, otherwise they wouldn’t have quickly started moving into the clinic to test a new vaccine.

            Also, “all sera fully neutralized” is an overstatement. The NHPs showed neutralization failures in one of the assays used ( lentiviral pseudovirus ) , and even there they only tested a combo of three of the mutations in the cluster, rather than the entirety. With the full mutation repertoire, the results would likely have been even worse, based on the human sera results shown in the study. Finally, these are in vitro , not real-world indicators, and they’re not even the best in vitro tests to use. The South Africans are using the wild variant isolates themselves, rather than pseudoviruses, in their neutralization assays, which is better. Moderna stated in the paper that they intended to do that, at some point. Let’s see if they do.

          4. Not-an-epidemiologist says:

            I don’t think you’re being an optimist — this seems an encouraging result to me. And don’t forget, this isn’t a binary system — even if you lack some degree of neutralising ability when vaccinated, it doesn’t mean that you’re going to experience the same disease trajectory as a naive individual.

            There are too many pessimists out there at present who forget just how well our immune system adapts to challenges. Which is not to say that we shouldn’t approach these variants with caution, but we should have a reasonable expectation that things will be fine.

            Vaccine resistance is in general a very rare thing; and even when it does occur, there is often some degree of protection seen in vaccinated individuals — it’s not like drug resistance.

          5. confused says:

            >>and don’t forget, this isn’t a binary system — even if you lack some degree of neutralising ability when vaccinated, it doesn’t mean that you’re going to experience the same disease trajectory as a naive individual.

            Yes, exactly. This has I think been underemphasized all along, and not just with vaccines, but with reinfections also. People seem to talk like immunity is a binary switch – you’re either 100% protected or 0%.

            I mean, I had chickenpox twice, but that anecdotal example doesn’t undo the *general fact* that infection with chickenpox *usually* prevents reinfection.

          6. Not-an-epidemiologist says:

            If you’re interested, there’s a recent (but pre-covid) perspective in PNAS discussing vaccine resistance, which notes that vaccine resistance is not only unlikely to develop, but even in the rare events when it does it’s generally not disastrous (and that vaccination still confers some benefit):

            https://www.pnas.org/content/115/51/12878.short

            (Note the slight caveat that the scenario of using a vaccine to treat a full-blown pandemic is relatively rare — although it’s obviously been done successfully in the past.)

            But, I mean, this is all old knowledge. And honestly, over the last year it’s felt as though a lot of people who really should have known better have had to re-discover afresh how the immune system works. (Thankfully, this blog has been a rare island of commonsense in the ocean of panic and paranoia. I wish journalists would spend some time here rather than listening to their ill-informed epidemiologist du jour.)

          7. confused says:

            >> honestly, over the last year it’s felt as though a lot of people who really should have known better have had to re-discover afresh how the immune system works.

            A lot of this is probably the fear that they’ll give people an “excuse” not to take it seriously — the awkward fact is that the risk in say the 18-29 age group probably genuinely is not high enough to be frightening to high-risk-tolerance young people, so if people think that if they get it they’ll be immune…

            It’s quite rational, if somewhat selfish, for a young adult to think that a (say) 1/5000 chance of death is pretty insignificant compared to a lost year-plus of opportunities.

            However, the problem is that skewing the evidence to promote one’s desired behavior just makes one seem untrustworthy, at a time when we have a huge crisis of trust in institutions.

          8. hardnox fort says:

            If you want some “escape”-variants, SA is one, California has another so far with partial escape-potential, Scotland/Chech Republic/Sweden has a partial escape variant, Brazil/Japan has a far more serious escape-candidate (Take a look at the current situation in Manaus. That is what looks like real life proof of a convalescent sera hard-escape strain ravaging through a population! Thoughts and prayers!).

            For sourcing on these variants, take a look at:
            https://github.com/hodcroftlab/covariants/blob/master/README.md

          9. confused says:

            I don’t see how SA being a genuine escape variant is compatible with the statement in the linked preprint that “neutralizing titers remained above those previously found to be protective”.

            As for Manaus, my first question would be how solid the estimates of high seroprevalence are…

          10. Chris Phillips says:

            About Manaus, I think the idea that it’s evidence of immune escape does depend on those estimates of the previous infection rate. Which are quite indirect and which prima facie are far higher than a more direct estimate.

            A big second wave that overwhelms health services, despite a large first wave, is not in itself evidence of that. We have been very close to that in London, and are still close (despite some politicians already clamouring for restrictions to be relaxed). But the evidence is suggesting that the new UK variant is not escaping immunity to a great extent.

          11. confused says:

            Those high estimates for Manaus also suggest a rather low IFR (something like 0.2%). Now I don’t know the age distribution for Manaus — but Brazil, while younger than the US, isn’t *that* young (comparable to the younger US states, IIRC) and I would expect healthcare quality to somewhat reduce the effect of age distributions (in general, more developed nations have older populations).

            So if we believe that the US IFR is 0.65% (as the CDC used to say) or something over 0.5% (as implied by the current estimate of 83 million total infections by end of December) – do we really believe it’s like 1/3 of that in Manaus?

            *That would be almost exactly 0.5% compared to current deaths, but given lags in reporting, surely not all deaths resulting from infections by end of December have been counted – some would be just happening now….

          12. hardnox fort says:

            I should of course have called the SA variant escape-candidate.

            As for P.1, the main issue is data. I would love to see if Sinovac or Astrazenecas clinical trials could provide some data on the mutation versus reconvalescent immunity.

            The trials from Novavax and J&J may also improve understanding on the SA reconvalescent situation over time. They have already hinted at it.

            Most important is information on stratification of severity.

  11. confused (now doubly confused) says:

    >>but the South African variant shows about a sixfold reduction in efficacy. That’s not good news, but it’s not horrible news, either: the antibody response that’s still there is expected to be enough

    Sorry if this is a stupid question, but I don’t really understand this: what is the sixfold reduction in? Proportion of antibodies that are still neutralizing to the new variant, or what?

    And does “expected to be enough” mean that the efficacy in terms of protection against actual severe disease will probably still be decent? (IE the antibodies produced against the “basic virus” were “more than needed” so it can be reduced sixfold and still be fairly effective?)

    Or something else?

    1. Jack Komisar says:

      It looks to me as though they took sera from vaccinated humans and nonhuman primates and tested them to see if they neutralized, in vitro, viruses with various mutations. Then they did serial dilutions of the sera and tested them to find the endpoint, the highest dilution of serum that would still cause neutralization. This is the neutralization titer. They already had data on the minimum neutralization titer that correlated with protection in vivo, so they could predict, with some confidence, whether the vaccine would protect against a certain mutant. A “sixfold reduction” is a sixfold reduction in titer, which would not render the vaccine ineffective if it elicited a titer significantly greater than six.

    2. xrayxtals says:

      Looking at the Biorxiv preprint Derek linked in the article, a dilution of 1/290 was still fully protective (using human sera from those vaccinated) against the South African strain.

      This suggests the 6x reduction in antibody binding is not a cause for concern, yet. In combination with more mutations, it could be.

      If this is wrong, someone please correct, thanks!

      1. Michael says:

        I think this is exactly right. The preprint specifically said that all vaccinated sera fully neutralized the South African variant.

        1. confused (now doubly confused) says:

          This seems very promising.

    3. QuarkSpark 9 says:

      I understand the 6x reduction in efficacy, but I don’t understand how they come to the conclusion that the response will be of shorter duration.

      Bancel talks about 6-12 months, but according to William Haseltine, this is already the likely duration of efficacy of mRNA-1273 against the Wuhan isolate because of the absence of cellular response.
      https://www.forbes.com/sites/williamhaseltine/2020/12/22/the-moderna-vaccines-antibodies-may-not-last-as-long-as-we-hoped/

      Is Moderna using the South African variant to hide the possible short duration of protection of their vaccine?

  12. G Carr says:

    It it possible / probable that the Defense Production Act could be used to require pharmaceutical companies, like Merck who have now dropped out of the race of creating their own, to produce effective vaccines like the Pfizer and Moderna vaccine?

    From everything that I have read, it appears that vaccine supply is likely to soon be the largest (but not only) impediment to treating the public at large. If that bottleneck could be eliminated, or at least substantially reduced, the decision seems like a easy one to make. I understand, I believe, that Pfizer and Moderna might not want to share their secret sauce recipes, but for the benefit of the entire world, could we not get all appropriately suited phama manufactures to make this stuff just as fast as possible?

    Same with vials, syringes, cold storage and what have you. For the many trillions of dollars being spent supporting businesses and individuals around the world, end the darn pandemic, and then give Pfizer and Moderna a couple hundred billion for their “loss” of intellectual property.

    Can and should the DPA be used this way? If so, what can we do to pressure the adminsitration?

    1. PastTense says:

      “Johnson & Johnson is also in preliminary talks with Merck, a major American pharmaceutical company, about using its production lines, one of several ideas that federal health officials discussed with the Biden transition team. Federal officials are interested in boosting the nation’s vaccine-making power long-term, and Merck’s facilities may be among the few with remaining manufacturing capability.

      But Dr. McClellan, who sits on Johnson & Johnson’s board of directors, said it would take months to adapt Merck’s factory to produce Johnson & Johnson’s vaccine. A senior administration official predicted that it could take until the end of the year.”

      https://www.nytimes.com/2021/01/21/health/biden-covid-vaccine-supply.html

      1. Mammalian scale-up person says:

        I don’t think it would necessarily take until the end of the year – both companies have plenty of established tech transfer documents in place, they definitely have the equipment and the process for manufacturing adenovirus isn’t very different than other biologics methods. The two difficult parts that Merck may not have in place is
        1) adequate containment as it needs different HVAC and personnel + materials flow – this can be addressed with modular construction though, you can get prefab clean rooms complete with the blowers and HVAC pre-installed and put it in shell space. Even a large batch for an adenovirus process fits in a space the size of a couple of RVs.
        2) raw materials and consumables procurement for adenovirus processes have suddenly become very challenging, I give you three guesses why. Lead time on some of the things I routinely use is now 9 months, and it used to be only 2-3 months. That’s not a problem that will be solved before the end of the decade, though – I’ve even looked into vertical integration for the really unreliable consumables, it’s that bad.

        You know what the government could have done to help is, actually rebuild Puerto Rico after Hurricane Maria and renew the tax benefits of manufacturing our consumables and process intermediates there, which expired in 2006.

  13. Jens says:

    Newspapers in Germany reported today that the efficacy of the Astra-Zeneca vaccine seems to be to low in adults < 65 years (less than 10 percent) so the EU will only approve for younger adults.
    If this is true, Great Britain may have "wasted" a huge number of vaccine doses in their attempt to vaccinate the elderly as quickly as possible.

    1. Marko says:

      “If this is true, Great Britain may have “wasted” a huge number of vaccine doses in their attempt to vaccinate the elderly as quickly as possible.

      Boris Johnson just got the news :

      https://ksassets.timeincuk.net/wp/uploads/sites/46/2016/08/Boris-Johnson-wind-1-1.jpg

    2. Melon says:

      Could be the lower bound of the confidence interval because there were so few participants over 65 in the trial?

      1. Chris Phillips says:

        Actually, it sounds plausible that this could be the lower end of a confidence interval for efficacy. The numbers in the Lancet paper are divided at age 70, not 65, but only about 7% of participants were 70 or more.

        It’s worth noting that the lower end of the confidence interval for asymptomatic infections would be 0%!

        1. Chris Phillips says:

          It’s now being reported that the German Health Ministry has denied the claim of 8% efficacy, and even that this figure is actually just the percentage of participants in the Phase 3 trial who were 56-69!
          https://twitter.com/alexwickham/status/1353999453028577280

    3. Derek Lowe says:

      That’s startlingly bad, if true. I see that AZ is saying that it’s completely false, FWIW: https://www.dw.com/en/astrazeneca-german-reports-on-low-efficacy-on-over-65s-completely-incorrect/a-56341198

    4. Chris Phillips says:

      I don’t understand where this is meant to come from. Obviously the AZ vaccine hasn’t been used in Germany yet. Is it based on something that’s been published? Or a leak from AstraZeneca or Oxford? Or a leak from UK monitoring?

      1. Mariner says:

        The Grauniad is saying that “it understands” the story was given to the papers from a leak within the German regulatory agency. Who knows?

  14. Dave says:

    Can you give a reference to that? Also, so you mean >65 years?

    1. Marko says:

      Yes, I’m sure it was supposed to be >65. Here’s one link:

      https://www.heute.at/s/keine-eu-zulassung-von-astrazeneca-fuer-senioren-100124512

      Note that it was reported by Bild, which is a rough equivalent to the National Enquirer. Still, AstarZeneca will have to address this report.

  15. Wilhelm Cody says:

    For G. Carr, my understanding is that Pfizer offered the USA an option for an additional 100 million doses if they assured supply of limiting ingredients. The presumption was that, if necessary, the federal government will use the Defense Procurement Act to get limiting raw materials for increased manufacture” https://thehill.com/policy/healthcare/531398-government-orders-100-million-more-coronavirus-vaccine-doses-pfizer. In Europe, Pfizer said there would be a short (couple of week) hiatus in full distribution of vaccines while they scale anticipated 2021 production from 1.3 billion to 2.0 billion doses. https://www.news10.com/news/pfizer-temporarily-reduces-european-deliveries-of-vaccine/
    My guess is that the supply problems have been rectified and it is full steam ahead by mid February.

  16. Jens says:

    Yes, sorry, > 65 years, of course.
    Ref. (only German Newspapers yet): https://www.rnd.de/politik/astrazeneca-impfstoff-bei-senioren-moglicherweise-kaum-wirksam-6IZI77NQYFABVMZHIPQS7TXPVE.html
    (You may use deepl.com for translation)

  17. John Hasler says:

    Pfizer and Moderna would lose no intellectual property were they to license the vaccines to other companies or contract with them to make it and if doing so resulted in increased production Pfizer and Moderna would make more money. However before such licensees/contractors could produce any vaccine they would have to be taught how to do it and then construct and qualify a manufacturing facility. It’s faster and more efficient for Pfizer and Moderna to just expand their own production. They are not limited by capital which would be the usual reason for licensing. If they are limited by availability of materials either for making vaccine or for expanding their factory licensing obviously would not help.

    A far more likely use of the DPA is to relieve suppliers of contractual obligations. For example a syringe manufacturer might be willing and eager to sell their entire output to the government for vaccination use but be contractually obligate to deliver much of it to a distributor of veterinary supplies. I think that the DPA would permit them to void that contract without penalty.

  18. N says:

    Great info. Would be so much more consumable in table form.

    1. Mariner says:

      It seems peculiar that, on the one hand, we have the EU threatening to block export of the AZ vaccines manufactured within the EU and on the other hand, these German reports that it isn’t efficacious enough!

      I wonder if what we’re seeing in the criticism of efficacy of the AZ vaccine is just a quibble about what counts as effective? If it doesn’t prevent the majority of symptomatic cases in the over-65s, it’s not ideal, but if it still stops almost all of the most serious cases causing hospitalisation and death, then it is still very useful indeed.

      If this is actually the case, it would be helpful to have the information available in the public arena. There hasn’t been enough clarity with the AZ vaccine data as it stands – in part because it appears they are still collecting it!

  19. Marko says:

    Moderna says it’s working on Covid booster shot for variant in South Africa, says current vaccine provides some protection

    https://www.cnbc.com/2021/01/25/covid-vaccine-moderna-working-on-covid-booster-shots-for-south-african-strain.html

    Includes a short video interview with the Moderna CEO.

    1. Marko says:

      Osterholm, singing : “This is the dawning of the age of the variants. The age of the variants….”

  20. Not a Doctor says:

    About that ‘insurance policy’… what sort of steps would be needed to certify an alternate mRNA vaccine, e.g. to target a mutated spike protein? Would any change to the protein require starting over entirely, or do they get to skip steps on the basis that the delivery method seems safe and effective at generating whatever’s in the payload, and that this general approach seems to work effectively on the original spike?

    I’m trying to find the answer to the last question I asked about how this works for the seasonal influenza vaccine…

  21. Marko says:

    “……Biden added that he expects widespread availability of the vaccines for Americans by spring, with the US “well on our way to herd immunity” necessary to end the pandemic by summer. Even so, he warned the nation was going to be “in this for a while, and could see between “600,000 and 660,000 deaths before we begin to turn the corner in a major way.” ”

    https://www.theguardian.com/world/live/2021/jan/26/coronavirus-live-news-biden-warns-deaths-will-pass-600000-before-us-turns-corner?page=with:block-600f5b3e8f086b454d1ebc16#block-600f5b3e8f086b454d1ebc16

    Biden continues to set an unacceptably low bar for his administration. A 50% increase in deaths will take the US from today’s level of 1300 deaths/million of population to ~ 2000 deaths/million. How is this in any way acceptable? Germany has had less than 650 deaths/million overall so far. Is Germany just that much richer and more powerful than the US? Or are they instead smarter, and more caring?

    The blue-check “experts” and public health talking heads should be absolutely furious about Biden’s statement, but they won’t be. It’s all about “Team Blue, No Matter Who”. All we’ve done is replaced one craven psychopath with another, but you wouldn’t know it by the tongue-baths lavished daily on Biden by the sycophantic commentariat. We’re in for another miserable four years, folks. Brace yourselves.

    1. Chundong Wang says:

      Low bar? yes. Unacceptably? Not quite.
      Being THE most advanced country of virology study and biology at large, get 25 million infected, and 500k dead, is unacceptably low. On that foundation, get 1/3 of populate vaccinated by summary doesn’t seem too terrible.

      Yes it could be better. I wholeheartedly wanted it to be. But let’s face the reality of the anti-science attitude of half of the population. Hence I predict it to be more of a problem to convince people to take the shot than getting enough vaccine in the warehouses.

    2. confused (now doubly confused) says:

      It may be politically more useful to set a bar you expect to meet easily… Certainly the “100 million doses in 100 days” seems like a case of that, as the current vaccination rate is already above 1 million/day.

      Also, that’s a very vague statement. 600,000+ deaths total seems believable, as we’re at something like 415,000-420,000 now and there is significant lag

      But what does Biden mean by “turn the corner in a major way”? Generally I would think that means “go from getting worse to getting better” — but Cases/hospitalizations are dropping now; if vaccination rates are high enough to make up for increased spread due to UK variant etc., we may already have “turned the corner”.

      But maybe he means “hospitalizations low enough that the medical system is ‘business as usual'” or something like that.

      I would judge the Biden administration’s efforts by their results (which we won’t know for months), not by the wording of an early speech.

      (Although I don’t really doubt that some may indeed criticize less due to political party — I think, e.g., governors of some Northeastern states get a lot of credit for doing a good job which I’m not sure is entirely borne out by the results. Sure, you can say they were dealt a bad hand in March, but when you look at what states are vaccinating most quickly…)

      1. Marko says:

        “It may be politically more useful to set a bar you expect to meet easily…”

        That’s exactly the kind of weak rationalization the Biden sycophants will use in the coming days to excuse his failures. Just be honest with yourself and try to imagine the reaction if Trump had been re-elected and then suggested that we should expect 50% more deaths, even with a vaccine in hand. People would have gone ballistic.

        There is one campaign promise that Biden made that I feel certain he will stand behind : “Nothing will fundamentally change” :

        https://www.salon.com/2019/06/19/joe-biden-to-rich-donors-nothing-would-fundamentally-change-if-hes-elected/

        1. confused says:

          Eh, I prefer Biden to Trump but am far from a “sycophant” for ANY politician.

          I question how much any President could actually do to change things. I mean, I think Trump made it (somewhat) worse by promoting “oh it’s no big deal” … but
          (a) public health in the US is primarily state-level,
          (b) the US is very individualist/anti-conformist (and has been so since long before Trump),
          (c) most of the vaccine stuff is being done by companies and hospitals; the bottlenecks are production and getting shots in arms, which is not the CDC’s part of the process.

          I think the improvement to be expected from a new administration is real, but pretty marginal.

    3. Chris Phoenix says:

      The right wing turned masks into a political wedge issue; told their base that COVID is just the flu; got extremists carrying guns to “free speech” events to protest lockdowns; muzzled and censored their experts; for almost a year.

      Then Marko blames Biden for the fact that some dying will continue for a few months after the transition. Do the math, Marko, if you can. If we get an R of 0.5 starting now (which would be amazingly good), then each transmission cycle will have about half as many deaths as the previous one. 1/2 + 1/4 + 1/8 +… = 1. In fact, we’ll be lucky if we get R much below 1 – especially since so many people have been marinating in deadly propaganda for so long.

      So, you know, you could take any innumerate excuse to attack Biden, making it clear that that’s what you’re really here for. Or you could, you know, engage with actual facts and produce actual insights instead of more propaganda and talking points.

      1. Marko says:

        Ok, Mr. Numeracy, explain to me what is stopping us from doing a hard lockdown for a month, and thereafter simply replicating the past success of a country like Germany, that is , halving our death rate from one month out ? Yes, deaths are baked in for the next few weeks, so maybe that’s 70k that we can’t prevent, but hard lockdowns, even as ineffective as what the UK is doing right now, rapidly drop case loads. It’s been demonstrated over and over. And lower case loads will proportionately reduce future deaths.

        And that’s without even considering what an intelligent vaccine rollout could do to reduce deaths going forward. The only constraint on vaccinations should be supply of the vaccine itself. We have the capability and capacities to vaccinate people, what we lack is the desire and determination to get it done. What Israel is doing is scalable, but it requires federal direction, planning, and money. One million doses a day was a pathetic goal, and when confronted with that fact, Biden’s response was his go-to : ” C’mon, man, give me a break! “. You call that leadership?

        Look, I’m neither a fan of Trump nor the Republicans. I despise both parties with similar levels of intensity. My complaint is that nothing has , or will, change for the better, and that those who delusionally believe that it has, or will, are contributing to the continuation of a long-running status quo that, quite frankly, sucks balls.

        1. Mariner says:

          As the saying goes, “Politics is the Art of the Possible”. Given the political atmosphere in the US at present, with a hefty chunk of the populace believing the election has been ‘stolen’ from their guy, in addition to a mass of wingnuttery about the pandemic which has been fomented by senior politicians, just how would a heavy nationwide lockdown actually be feasible? There is enough paranoia out there to cause real problems if such a move was made. I’m talking shootouts, mass demonstrations etc etc.

          Here in the UK, we’re now in the 3rd week of our lockdown with schools closed to most kids, hospitality closed down and non-vital shops closed, yet the R0 is still only believed to be a smidgeon under 1 at present.

          Everything taken into account, I doubt that Biden could do much to improve the situation. Not a particularly supportive comment about his administration as I doubt he’ll get much done overall, but just noting that his hands are tied a great deal by the political situation in the US.

          1. confused says:

            All this is true, plus the President (probably) does not actually have the legal power to do a national lockdown – those sorts of mandatory public health measures are generally a state thing.

        2. Anon says:

          “One million doses a day was a pathetic goal”
          I think the bottleneck lies in available supply of vaccines. If by some magic, 200 million doses suddenly became available, the CVS’s and Walgreens of the world would rapidly put them into arms.

          1. Marko says:

            “The two companies with authorized vaccines, Moderna and Pfizer, have each promised to provide the United States with 100 million vaccine doses by the end of March, or enough for 100 million people to get the necessary two shots.”

            https://www.nytimes.com/2021/01/21/health/covid-vaccine-supply-biden.html

            Biden’s stated ambition was to get half the supply expected by the end of March into people’s arms by the end of April. The Big Labowsky was less of a slacker.

      2. SamUSA says:

        This is all pure rubbish.

    4. eub says:

      “All we’ve done is replaced one craven psychopath with another”

      Look, that’s dumb. If that’s how you’re going to roll, expect people to take you as you present yourself.

      Much of what Biden or any President can immediately do is to signal “take this shit seriously, yo.” The substantive Federal changes are legislative. And the real hardass public-health powers are at the state level in the U.S. system [linked from my name], if only states were willing to use them in the current disinformation environment. Yell at your governor.

      1. Bill says:

        <<>>

        I agree with that, and Trump was a fail. But Biden trying to convince us that 1M/day is a huge undertaking shows me another fail. Anyone who tracks the data know we were already at that point when handed off. Recently “hoping for 1.5M/day” is not progress.
        Anyone who cares to apply high school math knows that we need perhaps 3M/day to get the country where they want it to be by Fall. Either Biden is not taking this seriously, or he has incompetent advisers who don’t keep him properly informed.

        1. confused says:

          I wouldn’t be surprised if Biden’s team expected the situation to be even worse than it (likely) actually is when he took over, given the *huge* issues w/transition.

          If the supply chain doesn’t hit huge problems in the next week or two, the goal will likely go up.

          3M … might not be within production capacity though.

    5. debinski says:

      “Come on, give me a break, man. It’s a good start — 100 million.” says Joe.
      After all, they are “starting from scratch”.

    6. 이웅견 says:

      I don’t think that Germany (I happen to live there) really provides a bar to look up to.
      South Korea are currently struggling but still are at less than 27 dead/Million for now.
      You could also try New Zealand if Korea sounds too non-western for you.

      1. Marko says:

        I picked Germany because getting to their level of success would be a relative baby step compared to trying to emulate the really successful countries. It would still represent a halving of the per capita death rate for countries like the US and UK, based on Germany’s numbers to date. That’s not to say that Germany won’t screw up going forward.

        1. confused says:

          And the countries that did notably better tend to be either islands (Australia, NZ, Taiwan, Iceland), effectively islands (South Korea – its one land border is thoroughly blocked), very small populationwise (Norway, Finland), or have questionably reliable data.

          It will be very interesting, once there is time for data to be finalized once the “crisis mode” is over, whether the same nations look to have done better/worse. Differences in reporting/attribution of deaths between different countries might make a significant difference.

          And it will be very interesting to see whether the very low per-capita deaths essentially everywhere in the tropical Old World, regardless of government forms, public health resources or anything else, “persists” once that data can be looked at. I don’t see a good explanation for that trend.

          (Maybe bad reporting… but there are many less-developed countries in the New World tropics that nonetheless report high deaths; not one in the Old World. India has a high total number but very low per-capita; the highest African nation, South Africa, is outside the tropics.)

  22. Bash says:

    I have been following Derek’s blog for many years, and now recently the comments section more closely. Thanks to everyone for the excellent commentary

    Regarding the South Africa variant;
    On my reading, I am a little confused. The claim is that “monoclonal antibodies from convalescent patients may not be as neutralizing to the SA variant”. I’m paraphrasing. But, aren’t monoclonal antibody therapies mostly ineffective anyway? And, when taking the vaccines, yes we generate antibodies to the spike, but when we encounter the real virus (post vaccination), do we generate the exact same antibodies, or does our immune system make the slight adaptation? I know the immune response is poly-clonal, but much of it is hard to measure…

    Also, the 1/6 reduction in response still seems like a 50x overkill to the 1/290 needed to neutralize the SA variant

    I have to wonder that viral mutation is not a new thing, and we seem to have managed to defeat other mutating RNA viruses in the past with 1950’s technology. Are we suffering from an information overload, with more data to analyze than we have ever had and so more questions to answer than we ever knew to ask?

    1. Andy says:

      I think the reason there is so much focus on antibodies is because they are crucial to sterilizing immunity, and thus inhibition of transmission as well as asymptomatic infections. CD8+ T-cell responses are much less affected by mutations in the S protein, and T-cells are important in preventing disease progression.

      So the real question is, why is there so much focus on transmission? People seem to have a very short-term perspective. In the long term (one year, two years), what is important is that COVID-19 can be downgraded to the level of a common cold. To achieve this, everyone has to be vaccinated. Once that objective has been reached (leaving aside the anti-vaxxers, who can fend for themselves), why does it matter that people are suffering mild COVID-19 infections as a result of poor antibody responses? It doesn’t matter one whit!

      1. Marko says:

        My bet since the outset has been that CoV2 would become the next common cold coronavirus once everyone was either infected or vaccinated. The trouble is, we don’t have the data to accurately predict that outcome just yet. If reinfections occur readily after immunity wanes, and if those reinfections are just half as deadly as primary infections, we’d still have a big problem to deal with, requiring regular vaccine boosters,etc. I don’t believe that will be the case, but we don’t know for sure yet.

        Add rapidly-developing immune escape to the above scenario, as for flu, and you’ve got an ongoing mess on your hands.

        1. Andy says:

          This is exactly why I think the experts (especially the perennially gloomy folks at the WHO) who say that NPIs will last for A Very Long Time need to change their messaging, taking into account both human psychology and epidemiology. Once all those who want a vaccine have received it, society should be opened up fully, sans masks and distancing. The continued transmission and asymptomatic/mild infections this will cause are all good things, as they will serve as ongoing boosters, and also prime immune systems on a continual basis to the evolving viral genome.

          Continuing with transmission mitigation measures in the post-vaccination era is downright dangerous, because it prevents societal immune systems from establishing an equilibrium with the evolving virus.

          The goal of preventing transmission should only be a short-term one, during the period that there are people out there who want the vaccine but have not yet received it. This period will end sooner than we realize, and we need to begin planning for what happens after.

          1. Bash says:

            I’m not sure why there is this expectation of a SARS-COV-2 free world.

          2. Ex UK Pharma R&D says:

            @Andy: “Why is there so much focus on transmission? People seem to have a very short-term perspective. In the long term (one year, two years), what is important is that COVID-19 can be downgraded to the level of a common cold.”

            …Well said, Sir. To go a few steps beyond that sentiment, time to take liberty and post as comment a letter “submitted for consideration,” that’s met with no response whatsoever from UK national, scientific and medical media. Implication – perceived as saying a few publicly unsayables.

            Letter prompted by a recent London Times two-page profile of a member of GOV.UK’s Scientific Advisory Group for Emergencies (SAGE), entitled, “I was having tabloids ring up asking me to explain R rates.”

            https://www.thetimes.co.uk/article/adam-kucharski-sage-interview-qzqnfbj6r

            Pasted below after the letter that never was are links embedded within the draft letter(s). The “links to scientific, public health, media and legal disclosures” mentioned in the letter are too extensive to reasonably cut and paste here as well…

            *****

            I’M PUZZLED TOO

            Sir, “We’re puzzled,” admitted SAGE epidemiological modeller, Dr A*** K*********, in Saturday’s Times. This retired R&D scientist is puzzled too. Not only by the latest mutants, but also by aspects of coronavirus science that puzzlingly seem little debated in public.

            Meanwhile, the UK’s vaccination programme gathers pace. My 90something mother had her first jab last week. Hats off to all involved.

            But government ministers and scientific advisors warn we won’t know for some time how effective vaccinations have been. Timing of ending UK coronavirus restrictions therefore remains uncertain.

            To parallel the vaccination programme, I suggest the UK scientific community review in depth, with open and questioning minds, the following aspects of the science and the scientific evidence (links to scientific, public health, media and legal disclosures supplied separately):

            1) Extent of prior immunity under-regarded?
            2) Extent of asymptomatic spread over-regarded?
            3) Misled by PCR mass testing and “tested positives”?

            In recent months, the stance of government advisory bodies, such as SAGE, ostensibly seems unchanged, namely:

            1) No populace prior immunity.
            2) Significant asymptomatic spread.
            3) PCR protocols and test results taken at face value.

            I call on the spectrum of UK scientific opinion to take stock. Reviewing with some urgency these three inter-related topics could inform how the country moves forward once the vaccination programme is done.

            I call on the UK government to foster, and act upon, such review, bearing in mind that continuing much further into 2021 with “stop-start” policies is likely to become economically, educationally and socially untenable.

            Finally, for healthcare researchers, I’d like to take liberty of invoking the spirit of George Merck, grandfather figure of modern pharmaceutical R&D, who sagely said some 70 years ago, “We try never to forget that medicine is for the people.”

            *****

            …First up (and aptly), links to the one and only George Merck:

            https://www.youtube.com/watch?v=IWeasJJiLAg
            https://www.merck.com/company-overview/history/

            Second up, relatively recent links re points 1), 2) and 3):

            1) 17 September 2020: “Covid-19: Do many people have pre-existing immunity?”
            https://www.bmj.com/content/bmj/370/bmj.m3563.full.pdf

            2) 18 November 2020: “What the data say about asymptomatic COVID infections”
            https://www.nature.com/articles/d41586-020-03141-3

            3) 29 August 2020: “Your Coronavirus Test Is Positive. Maybe It Shouldn’t Be”
            https://www.nytimes.com/2020/08/29/health/coronavirus-testing.html?

            Points 2) and 3) also referred to on pages 11-17 of a document filed 10 January 2021…

            “Request for Expedited Federal Investigation Into Scientific Fraud in COVID-19 Public Health Policies”
            https://www.scribd.com/document/490274322/Request-for-Expedited-Federal-Investigation-Into-Scientific-Fraud-in-COVID-19-Public-Health-Policies#download

            Third up (in passing), a sobering British Medical Journal editorial dated 13 November 2020…

            “Covid-19: politicisation, “corruption,” and suppression of science”
            https://www.bmj.com/content/bmj/371/bmj.m4425.full.pdf

            Over and out. Ahead of a comment posted on an American platform, “Les Barricades Mystérieuses,” by a French composer, heard at 10.15 GMT 2021-01-26 on a UK radio station, while driving along a country lane in Middle England, in a Korean branded car, designed in Germany and built in a factory in Turkey…

            https://www.youtube.com/watch?v=h4nc2LvO6Ow

          3. confused says:

            I pretty much agree. Since March, it’s been clear that SARS-COV-2 won’t disappear. But once the world isn’t immunologically naive, it will probably be just one of many seasonal respiratory viruses.

            And once people have had the chance to get the vaccine, there’s IMO no longer an ethical obligation to restrict your activities to avoid infecting people who *could* but *won’t* be vaccinated.

            And the age-disparity in effects is large enough that the situation may improve drastically with only a relatively small percentage of the population vaccinated, well before “herd immunity” is achieved (there are about 55 million people over 65 in the US – only about 1/6 of the population).

          4. Michael Denyszyn says:

            I agree completely with Andy.

          5. Oudeis says:

            Why is there an expectation of a SARS-CoV-2-free world? I don’t know, but since when has that stopped anybody online? Two guesses:

            First, risk aversion plus availability bias. COVID is constantly in the news, causing lots of problems, killing lots of people, etc. Most people by now probably know somebody who knows somebody who died of it. So the possibility that we might reduce annual COVID deaths to twenty or thirty thousand per year just isn’t adequately comforting to lots of people–yet. It will be eventually. They’ll get used to it, the way people have gotten used to the flu and car crashes.

            Second, the people who still have the megaphone (and should still have it) are monomaniacs by design. Their job is to save people from the coronavirus, period, so that’s what they focus on, to the exclusion of other considerations that do and should matter to everyone else. At some point, as the pandemic comes under control, people will naturally stop paying attention to the experts’ more extreme suggestions the way we already do with monomaniacs who lecture us about health and fitness, diet, personal finance, home safety, etc., etc.

            We’ll reach an equilibrium where people figure out what sort of precautions they’re willing to take and what level of risk they’re comfortable with, and Derek Lowe will finally get to go back to blogging about chemistry.

          6. Charles H. says:

            Unfortunately, you seem to be ignoring “long COVID”. The consequences of even mild infections can be rather staggering. I’m not counting the people who die, but rather those who seem to be incapacitated, perhaps permanently. Damaged hearts, damaged kidneys, damaged brains, etc. Some of that appears to clear itself over time. Others…. If your kidneys have been reduced to half their prior capability, you won’t notice, until something else damages a kidney slightly. Then you’re likely on an external blood filter, until you die.

            OTOH, most people *seem* to recover completely. But, e.g., “brain fog” generally is an indication that a part of your brain has stopped working (e.g. because of a minor stroke) and another part is trying to compensate. I.e., you’re now less intelligent than you were. “Recovery” can just mean that it’s learned to compensate well, and you’ve gotten used to the change.

            I really distrust the idea that everyone should get COVID. I think it’s a prescription for a stupider and more sickly population. I could be wrong, and I’m certainly no medic, but that’s the way I read the evidence.

          7. confused says:

            >>The consequences of even mild infections can be rather staggering.

            “can be”, quite probably. Do we have any idea if that is common, though?

            I have seen a lot of numbers on this, but not a lot that’s very clear; there’s a lot of possibly-unrelated-or-psychosomatic symptoms (I’ve seen headaches and fatigue on lists of neurological effects of COVID, for example), and biomarkers of “damage” may not distinguish (at least in news reports) very well between reversible signs that would be found with “ordinary” viral infections vs. real lasting and significant damage.

            >>. But, e.g., “brain fog” generally is an indication that a part of your brain has stopped working (e.g. because of a minor stroke) and another part is trying to compensate. I.e., you’re now less intelligent than you were.

            Isn’t brain fog common with the flu etc. too though? Or is this a case of a vague term being used to mean two different things? (I’ve seen it used in ways that seem to mean the mental “fogginess” during acute illness – is there a separate meaning?)

            Asking that question differently – is there reason to think that you’d find more lasting/permanent aftereffects in 10,000 mild cases of COVID than 100,000 mild flu cases, *if they were looked at with equal degrees of scrutiny* (ie – sub-clinical effects might be found in COVID cases but not in flu, since no one looks).

            (I mean, I would expect more aftereffects with COVID, because a higher percentage of cases are severe. But if you exclude the severe cases and correct for that…)

            Anyway, if eradication is impossible in practice (and it is, and has been at least since March and probably since ~last December when it first spread beyond China), in one sense it’s not terribly relevant… Some loss of reserve lung capacity or a few IQ points seems far less significant than not being able to date, go to social events, etc.

          8. Andy says:

            @Charles: We have no idea whether vaccinated people who get COVID-19 will get all the severe long-term effects or organ damage as well. Maybe they will, maybe they won’t. I would be very surprised that the rate of “long COVID” (as a proportion of symptomatic disease) is the same among them as for unvaccinated people. Only time will tell. I hope there will be surveillance of this data.

          9. confused says:

            Yeah, tons of long COVID among vaccinated people seems implausible – but I have nothing to base that on except “it sounds implausible”.

            I am not sure how that surveillance will even work, though; is “long COVID” a sufficiently defined entity that one can measure its prevalence? How does one know if post-COVID headaches or fatigue or other “generalized” symptoms are actually related to COVID? And how does one rule out the possibility of psychosomatic effects — it can’t be “blinded”, people will know they had COVID if the researcher knows?

          10. confused says:

            While I’m not able to evaluate this from Science, it certainly sounds optimistic:
            https://science.sciencemag.org/content/early/2021/01/11/science.abe6522?intcmp=trendmd-sci

            This apparently suggests it will become just a common-cold coronavirus (it even seems to suggest that future generations may not need to be vaccinated), even if reinfection is common, because future infections will be milder.

  23. Jonathan says:

    Not mentioned so far, but in the UK at least newspaper reports suggest the regulatory authorities are already working with the vaccine companies to identify what scientific data would be needed to license a modification to ensure efficacy against new variants, presumably with the aim that should this be needed work can proceed without delay.

    https://www.theguardian.com/world/2021/jan/22/mhra-vaccine-makers-covid-variants

  24. debinski says:

    From J&J today:
    “We continue to progress our COVID-19 vaccine candidate and look forward to sharing details from our Phase 3 study soon,” Gorsky said in the company’s fourth-quarter and full-year earnings report.

    Although Gorsky stopped short of revealing exactly when the results will be released, he expressed extreme confidence in J&J’s ability to “deliver lasting value and continued innovation in 2021 and for years to come.”

    Stop with the tease and Show Us the Money!

  25. Marko says:

    J&J CFO Joe Wolk on covid19 vaccine supply: “We’re very confident and on track to meet all of our commitments.”
    -100M doses to US by end of June
    -200M to EU by end of year, w shipments starting April
    -200M to developing countries starting in 2H

    J&J CFO tells CNBC he expects to release vaccine results next week. “We’re optimistic. We think we’re going to have a very robust data set.”

    https://twitter.com/megtirrell/status/1354041623420809217

    Also, J&J results may give us a readout on the impact of the SA and Brazil variants on vaccine efficacy.

  26. Bill says:

    Whatever happened with the mysterious OxAZ 90% @ half-dose thing? No one thought it made sense at the time, but that was a while ago. Any subsequent progress with OxAZ dosing?

    1. Daniel says:

      They now believe that the difference maker was not the half-dose, but the gap between the initial dose and the boost, which was longer in the standard dose-low dose group. Apparently this can be shown from examining the different antibody titers produced in the standard-standard group in people who were boosted at difference intervals, and according to immunologists it makes sense. This is why the UK is now leaving 12 weeks between doses.

      1. Bill says:

        Interesting. Does that mean that all OxAZ results will climb to 90% given enough time?

        1. Daniel says:

          No, it’s just that if you give the boost 12 weeks after the first dose it produces a better immune response than if you give it 3 weeks after.

          1. Bill says:

            I wonder if it’s that sort of uncertainty responsible for the delayed acceptance of OxAZ in the US. A 12 week delay would be welcome from a mass distribution point of view and particularly if it yielded an enhanced outcome.

  27. Daniel says:

    Imperial posted an update today: they’re no longer planning a Phase 3 trial and will instead be aiming to develop their vaccine for use as a booster or against escape mutants. Makes sense given how far behind they are and the likely need for boosters every few years.

    https://www.imperial.ac.uk/news/213313/imperial-vaccine-tech-target-covid-mutations/?utm_source=twitter&utm_medium=social&utm_content=1f6b257c-da19-4216-a05f-3c9c345980d8&utm_campaign=news

  28. Dieles Stolk says:

    @Derek: (or any of the other gentlemen with knowledge on this subject)
    Now that Moderna is looking to make an ´updated´ version of its mRNA vaccine so it would work better against the South-Africa variant of Sars-Cov-2. How would that work out in a vaccine? Would it be possible to ´code´ an mRNA so it would produce different spike-proteins? One for the regular Sars-Cov-2, and one for the South-Africa one?
    Or would it need to be different mRNA’s, each one coded for a different Spike-version? So you would have a vaccine ´loaded´ with a few mRNA´s with different codes of the spike-proteins?

  29. Marko says:

    SARS-CoV-2 recruits a haem metabolite to evade antibody immunity

    https://www.medrxiv.org/content/10.1101/2021.01.21.21249203v1.full.pdf

    So, another reason to question whether in vitro neutralization tells us the story about real-world antibody escape. Researchers will need to start running their assays with and without biliverdin and/or bilirubin to account for this effect.

  30. Marko says:

    One prominent public health expert who hasn’t been afraid to speak out is Peter Hotez :

    https://www.washingtonpost.com/outlook/2021/01/26/biden-vaccine-goal-ambitious/

    “…Hitting 600,000 American deaths later this year would have been viewed as an unacceptable and catastrophic failure by the Trump administration. It would also be an unacceptable and catastrophic failure by the Biden administration.”

    Couldn’t have said it better myself.

    Oh, wait…..

  31. Marko says:

    UK variant in Denmark now up to ~12% frequency, so still appears to be growing at ~8-9% per day, consistent with an increased transmissibility of 50% or so :

    https://twitter.com/kakape/status/1354130730239094790

    1. Chris Phillips says:

      The Danes produced an estimate of increased transmissibility of (from memory) 36% a few days ago, which is in line with the most recent estimates from the UK.

      1. Marko says:

        That’s good that their numbers agree, it increases my confidence that they’re homing in with some certainty now. Assuming the US has upped our sequencing game enough, we should see some similar data from here in coming weeks. I’d think we must be at least in the 1-2% range by now. Portugal is another country with increasing prevalence of the UK variant, but I don’t know how the transmissibility numbers are shaking out there.

        1. Chris Phillips says:

          I read a couple of days ago that the UK variant is up to around 10% in some parts of France. However, the overall numbers of positive tests are continuing to fall steeply in the London and the east and south east of England, where the new variant is most prevalent, so it is certainly not beyond containment by a lockdown.

        2. confused says:

          I wonder if there is much urgency to look for it in the US — it’s not clear what we would *do* with the data…

          I have a feeling most states have their public health measures at the level that is politically viable, and knowing the variant is there probably wouldn’t change “politically viable” until/unless it made a significant impact on cases/hospitalizations/deaths.

        3. Marko says:

          It would be great if the Danes would weigh in on the virulence issue, as well. I’d guess they don’t have the severe stress on the health care system as in the UK, which is one confounding factor to account for when trying to measure any mortality difference, although I suppose a good matched-cohort study should take care of it. The problem there is you have to do the study before the variant takes over completely, otherwise you can’t find a WT cohort to match against.

  32. Marko says:

    “French pharma giant Sanofi will produce more than 100 million doses of the COVID-19 vaccine developed by its competitors Pfizer and BioNTech by the end of the year, CEO Paul Hudson told Le Figaro newspaper in an interview published on Tuesday.”

    https://www.reuters.com/article/health-coronavirus-vaccines-sanofi/sanofi-to-produce-100-million-pfizer-biontech-vaccine-doses-ceo-says-idUSP6N2JG00F

  33. RH says:

    Funny, I remember a conversation on a political blog months ago, in an anonymous comment forum. I had suggested that Pfizer was due to have a vaccine by the end of October, due to indications and rumors from investors. And one commentator replied to me that he worked for Merck, and highly doubted that anything like that was possible, because they were not even achieving a vaccine with 20% efficacy. I doubted at the time that a researcher from Merck would make such a comment on a public blog. I guess I doubted wrong!

  34. RH says:

    I wonder if someone can educate me as to this question. I’ve assumed for some years that Merck has a very good immunology R&D program, due to their work on Mab’s. I guess that doesn’t translate to vaccine development. Is my assumption incorrect about Merck?

    1. sgcox says:

      They do, just check the list of approved vaccines https://www.merckvaccines.com/
      I probably get one of those in my life (not Gardasil)
      No idea why so unsuccessful/unlucky with Covid. May be the choice of viral vectors which are different from AZ or Sputnik and happens to be unsuitable in this case.

      1. DTX says:

        In an interview last summer with Harvard, Merck’s CEO noted that of the 7 vaccines brought into clinical practice over the last 25 years, Merck had created 4 of them. 4 of 7 is quite good if you consider the number of vaccine companies. (

        In addition, in this, he likely wasn’t including Ebola, which was developed only partially in-house and is life saving for a much smaller population (but still of importance). Gardasil was the first vaccine ever for cancer protection. Rotateq protects countless people. Merck’s vaccine successes are legion.

        Merck failed with Covid, but they have the honesty & credibility to readily admit their approach didn’t work. This is important counter to all of the anti-vaxers who assume companies manipulate their data.

        1. Marko says:

          “Gardasil was the first vaccine ever for cancer protection.”

          Not by a long shot. The hepatitis B vaccine claimed that honor long ago.

  35. exGlaxoid says:

    Vaccines are not always easy to develop. They likely just picked some tools that they had, which just happen to not work for Covid. More than hlaf of the vaccines produced so far have not been very good, but since some are great or good, that is enough to start. As has been posted here before, drug discovery is quite tough, most things fail before they get to the clinic, so we have been very lucky to have 2 or 3 work so far out of the first 10 or so. But Merck has some great scientists, and they are working on small molecule drugs that may be more useful.

  36. Richard West says:

    If one is eligible, should they be trying hard to get the first shot of the vaccines available now or wait? Seems like a big risk the second shot won’t be available … or even if it is, will the vaccines coming be better?

    1. paperclip says:

      I would definitely get the vaccine as soon as you can, your protection being one big reason. And the more vaccinations, the fewer virus replications, meaning fewer chances for viral mutations. In the US at least, people are generally getting the second shot as planned. The current vaccines appear so effective and safe that for now at least it’s hard to imagine much of an improvement (although a single-shot vaccine would definitely have an advantage).

  37. Chris Phillips says:

    The BBC reports that the chief executive of AstraZeneca, in an Italian newspaper interview said “AstraZeneca was working on a vaccine with Oxford University that would target the South African variant of the coronavirus”:
    https://www.bbc.co.uk/news/world-europe-55817633

    He also explained that the current problems of delivery to the EU are partly the result of the EU having delayed signing a contract with them until three months after the contract with the UK, leaving less time to deal with practical difficulties.

    Speaking as someone who has always been a pro-European, the behaviour of the EU over this seems bizarre. They haven’t even approved the AZ vaccine yet, and they seem to be threatening to block Pfizer/BioNTech exports to the UK in retaliation for AZ manufacturing problems in Dutch and Belgian plants, just because AZ is partly British owned! It’s difficult to avoid the suspicion that such sabre-rattling is an attempt to deflect criticism of the EU’s own inadequate vaccine provision policy.

    1. Circ says:

      As someone in a similar position, trying to work out what’s happening, I suspect the answer lies a bit further east.

      Hungary has just licenced Russia’s Gamelaya’s Sputnik V (with a very similar to AZ’s), which their government claim is the result of the inability of western vaccine programmes to deliver. (Anyone who’s been following Hungarian politics over the past decade or so will know there’s probably both much more and much less to it than that, but this is their prima facie case).

      If countries where the political sphere is fragmented among pro-western and (usually much smaller) pro-Russian blocs, the appearance of the EU being unable to deliver on the basic health needs of the population in a time of crisis has the potential to rebalance politics in those countries and cause more instability within the EU as a result. The incorrect Bild leak of the supposed 8% efficacy of the AZ vaccine in vulnerable groups is likely “we didn’t want it anyway” political wishful thinking as a way to defuse this issue. While we Brits like to think the world is constantly thinking of us, the reality is that we are out and it will be much more strategically important for the EU to maintain its long term integrity than to score points in any kind of short-term vendetta with a deadbeat ex like the UK.

      1. Mariner says:

        I suspect that the hullabaloo between the EC and AZ is just loudly public negotiations about what to do because of the shortfall in production. The EC know they’ve got the Pfizer vaccine which the UK needs and the plants in the UK are reportedly producing good quantities of the AZ vaccine. Wouldn’t surprise me if some sort of a deal was made where most of the Pfizer vaccine expect in the UK continued to be sent but with a similar number of AZ doses going the other way.

        That is, unless AZ have been a bit naughty and have been shipping some of the vaccines produced in the EU to places which have agreed more lucrative prices such as the UK and the US. The apparent anger would be well-founded then.

  38. Marko says:

    New : “Increased Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7 to Antibody Neutralization”

    https://www.biorxiv.org/content/10.1101/2021.01.25.428137v2.full.pdf

    “…. B.1.351 is markedly more resistant to neutralization by convalescent plasma (~11-33 fold) and vaccinee sera (~6.5-8.6 fold). B.1.351 and emergent variants with similar spike mutations present new challenges for mAb therapy and threaten the protective efficacy of current vaccines”

    The 6.5x reduction applies to the Pfizer vaccinee sera while the 8.6x reduction applies to Moderna.

    1. confused says:

      The other preprint had 6.4x for Moderna, but I’d guess that’s within the margin of error? Or not quite identical tests?

      1. Marko says:

        Neutralization assays are notoriously variable from lab to lab. Badly in need of some standardization, but it’s not an easy thing work out.

        1. confused says:

          OK, so this *is* consistent with the preprint linked in the post then?

  39. Marko says:

    Neutralizing antibody titres in SARS-CoV-2 infections

    https://www.nature.com/articles/s41467-020-20247-4

    1. confused (now doubly confused) says:

      It says “with US pharmaceutical company Merck” and measles-based – is that the same measles-based one that’s one of the two mentioned as being abandoned in the post?

  40. feedaily says:

    What about british virus ?

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