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Oxford/AZ Vaccine Efficacy Data

As of this morning, we have a first look at the Oxford/AstraZeneca vaccine’s efficacy in clinical trials via press releases from both organizations. The number in the headlines says about 70% efficacy, but there’s more to the story.

Here’s the landscape so far: we have results from Pfizer and from Moderna, both of them developing mRNA-based coronavirus vaccines, and both showing efficacy in the 90 to 95% range. The Oxford effort is a different platform, though, with key similarities and key differences. It relies on another virus (a chimpanzee-derived adenovirus) that has had its original DNA genetic payload removed and substituted with the appropriate DNA to produce the full-length Spike protein of the coronavirus. In this construct, the original viral “leader sequence” at the beginning of this DNA has been replaced with another, the leader sequence found for the human tissue plasminogen activase (TPA) protein, because this gave better expression and a better immune response. These adenovirus particles can’t replicate – they don’t have the DNA to express the proteins needed to do that. But they do have all the viral machinery needed to infect a human patient’s cells and force them to express the coronavirus Spike protein, which will set off an immune response that should provide protection against later exposure to the real coronavirus.

So both the adenovirus vector and the mRNA vaccines hijack the protein expression capabilities of a vaccinated person’s own cells, making them produce SARS-Cov-2 Spike protein constructs and thus setting off the immune system. The Pfizer and Moderna mRNA vaccines we’ve seen so far actually express a form of the Spike protein that has a couple of proline residues mutated to make it more stable, whereas the Oxford/AZ vaccine is using the straight wild-type Spike sequence – there’s one difference. Another big one is of course that the Oxford/AZ vaccine is using a completely difference virus to deliver a DNA sequence, whereas the mRNA vaccines are skipping up to a later stage in protein production and slipping messenger RNA directly into the cells.

What was announced today is that they have quite different results for two different dosing regimens. This interim analysis was run when 131 cases had been accrued across trials in the UK, Brazil, and South Africa across about 24,000 trial participants (treatment and control groups). In the treatment group, 8,895 participants received two full doses of the vaccine, spaced one month apart, and 2,741 patients got a half dose at first, followed by a full dose a month later. And the efficacy rates for these two dosing regimes were very different: 62% for the two-full-dose group and 90% for the half/full group. I do not see a breakdown of how those 131 cases partitioned across the two groups, but the overall N has to be higher for the first, doesn’t it? I’d like to know what the statistics are for the 90% efficacy number, for sure.

Update: many people had been wondering earlier today why there was a lower-dose initial group at all. Reuters reports that it was a dosing mistake in the UK, that the investigators were then stuck with. Immunology strikes again!

Update: OK, this is getting even worse. Reports are today (Tuesday, 24th) that the 90% efficacy group had an age cap, with no one over 55 in the trial, whereas the other dosing group didn’t. Apparently the confidence intervals on these two efficacy numbers are wide enough to overlap, which is what I was worried about in the update to the next paragraph. Oxford and AstraZeneca should have thought much harder about how they were going to present these numbers.

Why might there be such a significant split in efficacy? My own wild guess is that perhaps the two-full-dose protocol raised too many antibodies to the adenovirus vector itself, and made the second dose less effective. This has always been a concern with the viral-vector idea. It is, in fact, why this effort is using a chimpanzee adenovirus – because humans haven’t been exposed to it yet. Earlier work in this field kicked off with more common human-infective adenoviruses (particularly Ad5), but there are significant numbers of people in most global populations who have already had that viral infection and have immune memory for it. Dosing people with an Ad5 vector would then run into patients whose immune systems slap down the vaccine before it has a chance to work. That’s not the case for a chimpanzee-infecting form, naturally (few if any people have ever been exposed to that one!) but the two-dose regime may have run into just that problem. Immunology being what it is, though, there are surely other explanations, but that’s the one that occurs to me. Update: there’s always the outside nasty chance that the smaller N in the 90% group is giving a number that won’t hold up. I would hope this isn’t the case, but without a better look at the statistics, it’s not possible to rule that out.

Now, I’ve seen people speculating this morning that these numbers may be better than they look, because they believe that these trials monitored patients by PCR tests rather than by symptoms. If that were the case, then yes, that’s a finer net than the Pfizer and Moderna trials used and it would certainly affect the efficacy readouts. But I don’t think it is: looking at the published trial protocol for the US trial, the cases are defined as “SARS-CoV-2 RT-PCR-positive symptomatic illness”, and the patients have to show symptoms of the disease (see Table 13). Update: I have been unable to find published protocols for the UK/Brazil/South Africa trials that went into today’s numbers, but I have no reason to think that they differ on this point. So I don’t think we can explain the lower efficacy by saying that they were finding asymptomatic people as well: the trial excludes asymptomatic people from its endpoint definition. The rate of asymptomatic cases in the treatments and controls will be determined in these trials (see section 8.5.2.1 of the protocol) but those aren’t the numbers we’re seeing today.

So from an efficacy standpoint, the choice is clear: if this vaccine is going to be deployed, the half-dose/full-dose regime is the obvious choice, since otherwise you can do the same amount of work dosing your population, use up more vaccine. doing it, and get notably worse results. How about from the safety side of things? The Oxford release says just that “No serious safety events related to the vaccine have been identified”, and the AZ one says “No serious safety events related to the vaccine have been confirmed”. I would have preferred to hear more about local and systemic reactions, as we did with the Pfizer and Moderna releases, but that seems to be it. Readers will recall that a participant in the UK trial developed transverse myelitis, and that the trial was stopped in the US for about a month. (Note: the US trial is the two-full-dose version). Update: they say now that they’re going to ask to switch to the apparently more effective dosing regime in the US trial.

Overall, I would have to think that Oxford and AZ are disappointed with the results from the two-full-dose regime and will be actively trying to track down the reason for the better performance in the the half/full dosing, which one would expect to be the way the vaccine is eventually used. How many of the other trials that are being run are using that protocol, one wonders? This could still be an effective weapon in the pandemic, but the stories are starting to differentiate. Pfizer (very effective, tough distribution and storage), Moderna (very effective, easier distribution/storage than Pfizer, but perhaps stronger safety reactions), and now Oxford/AZ (widely varying efficacy depending on dosing, easier distribution/storage, safety details TBD). The next vaccine effort to report efficacy will be J&J, another adenovirus vector, and this time with a one-shot dose. The landscape is starting to fill in a bit!

224 comments on “Oxford/AZ Vaccine Efficacy Data”

  1. Claudio Franco says:

    After reading a lot about how hard it is to make vaccines, and how unlikely it is for a vaccine to work in real life, I am a bit amazed that 3/3 (4 if we believe in Sputnik V) vaccine candidate has higher than 90% efficacy!
    It seems that we were on the lucky side to have an easy target!
    Great news for us!

    1. Chris Phillips says:

      The suggestion about an immune reaction to the vector compromising the second dose is interesting. The Russian vaccine uses two different vectors, and as far as can be judged from the figures released, appears to have produced similar results to the half-dose-full-dose Oxford regimen.

    2. Derek Lowe says:

      What we had was a very, very substantial head start due to all the work on the SARS and MERS coronaviruses. Which was indeed fortunate!

      1. Jason P says:

        Nice write up and explanation. Much appreciated.

        1. So how much of that work is “transferable” to the next virus to jump from some animal to humans?

        2. Since mRNA vaccines have never been ‘done’ before is this the wave of the future: “*just*” go into the lab and create an nRNA payload based on the genetic sequencing of the next virus?

  2. daksya says:

    The protocol you link to is for the US trial. I believe, the UK/RSA/Bra trial is single-blind with an active agent in the control arm, so not this one.

    1. Derek Lowe says:

      Updated the post – I have no reason to think that they trials differ on this (rather significant!) point, though. One hopes?

      1. Andy K says:

        Protocol is in the appendix here: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32466-1/fulltext

        what is really remarkable is that the “low-dose/high-dose” group was a CMO-driven mistake! https://www.mirror.co.uk/news/uk-news/oxford-uni-scientists-accidentally-give-22197078

  3. Chris Phillips says:

    The published protocol is for the US trial, and evidently in some respects that differs from the trials in the UK and Brazil. But I don’t think these figures can include asymptomatic cases. The AZ press release said participants in the UK were swabbed regularly but doesn’t mention that happening in Brazil. Surely they can’t be combining data from symptomatic cases only in Brazil and both asymptomatic and symptomatic cases in the UK (can they?).

    1. Roy Badami says:

      Prof Van-Tam seems to be suggesting that only a subset of the trial participants had the regular PCR tests.

    2. Derek Lowe says:

      Updated the post with a mention of this point – thanks!

    3. Justin C says:

      I’m a participant in the AZD12222 trial and can confirm that we are only told to come in if we are symptomatic. I think there is a subgroup getting more tests done, but in the case of the main group (which I’m in), there isn’t routine PCR-testing. They do test on the date of administration of both shots, but I was told that they only run those tests if I should become symptomatic later.

  4. sPh says:

    Three months ago the world would have been jumping for joy at the arrival of a 70% effective vaccine for COVID19. While I would certainly prefer a 93%+ effective shot myself if there is a choice between a 70% effective in March 2021 or the 90%+ in November 2021 which would I take? That is assuming the recipient has a choice, which may not be the case. Vaccination ma be a multi-pronged campaign with some imperfect treatments advanced in favor of speed and availability.

    1. anonnymous says:

      70% is not bad in my opinion! Seasonal flu shots in the USA sometimes tops only 50 -60%. But, AZD offers price advantage to the poor country. Moderna already has indicated it would charge 25-37$/shot.

    2. Walter Sobchak says:

      What I can get. When I can get it. If there are 3, all 3. 10, all 10.
      2 x 95% + 1×30% = 99.925% effective.

      1. AVS-600 says:

        The math probably doesn’t work out like that; there’s no reason to expect that the success probabilities of different vaccines with the same modality are going to be independent from each other. ESPECIALLY if more than one adenovirus-based vaccine ends up working.

      2. David E. Young, MD says:

        AV-S is correct that any two vaccines are probably not independent of each other. If they were independent the math you want is to multiply the risk the vaccine not working for each vaccine. 0.1 x 0.1 is 0.01 which would mean if you had two different vaccines, your chances of catching the virus is 1 in 100. But it doesn’t work that way. If someone gets Covid19 despite the vaccine there probably is a reason that would mean that a second vaccine would not help. So getting both vaccines might still have the same chance or almost the same chance as if you had just one vaccine. This is all speculation, of course. No one really knows unless there is a trial.

        1. Barry says:

          If the first vaccine failed because the subject was already immune to the viral vector used, the second vaccine–using no viral vector, or a different one–has a great chance of working. If the first vaccine failed because the subject has an immune deficiency, the second will likely fail too.

      3. Kevin H says:

        That is what might be politely referred to as a…”naive” approach.

        First, vaccine efficacy doesn’t ‘stack’ the way you think it does. These shots aren’t really what your first-year stats prof would call independent. All the vaccines so far are trying to provoke an immune response to the Spike protein; if your immune system doesn’t catch on after a couple of exposures through one vaccine, it’s not clear that repeated challenges with essentially the same antigen are going to do the job.

        Second, you’re much better off to not hoard the vaccine doses for yourself. Given the choice between taking ten doses yourself, or vaccinating yourself and your nine closest contacts, you’re much better off with the latter. Spreading the vaccines as far and as fast as possible makes it impossible for an outbreak to spread efficiently.

        1. Michael says:

          Agree 100% with Kevin H. Plus, there just isn’t nearly enough global supply at this time for people in the pre-ordering countries to take multiple doses for belt-and-suspenders purposes.

  5. Paolo Gallipoli says:

    Don’t you think possible that because of surveillance swabs in the oxford trial if a participant tested +ve in surveillance he/she was more likely to report a mild cough and be spotted as a case. In other trials people with mild symptoms might not have reported them… it will go with their reported lack of hospitalisation in the vaccine arm in their press release

  6. Eric says:

    Obviously it’s been all over the news here this morning, and two things have been mentioned that are of interest. It has been said that there is a hint that asymptomatic cases are suppressed, which suggests at least some testing has been done on people without symptoms, and the statistics on the half dose/full dose sub- group are strong enough to go through to approval.

  7. ghyu says:

    According to the BBC (https://www.bbc.co.uk/news/health-55040635) there were 30 cases in the vaccinated groups and 101 in the placebo. Can you calculate from that how many cases were in each group?
    Even if the 30 were spread equally over both vaccinated groups, there would only be 9 cases in the 2714 people with the 1.5 dose vaccine. With such small numbers, how reliable is the 90% efficacy?

    1. Oz Amram says:

      Based on 30 total cases for those vaccinated and the reported efficacies + sample sizes, you can work back to figure out there were 28 cases in the 2 dose group and 2 cases in the 1.5 dose group. Assuming a poisson uncertainty this would mean the uncertainty on the 2 dose efficacy would be 0.62 +/- 0.08 and the 1.5 dose would be 0.9 +/- 0.07.

      1. Chris Phillips says:

        I don’t think you can make that add up to 101 consistently with the reported efficacies.

        I think it would have to be a 3-30 split in the half-full group and a 27-71 in the full-full group, or something close to that.

        I get much wider confidence intervals, from a simple-minded Bayesian calculation.

  8. Jacky says:

    Remember, just $2.50 per dose for Oxford/AZ vaccine. So this probably help many developing countries!!!

    1. Dick King says:

      The big deal for developing countries is not the cost of the vaccine but the cold chain, which is a lot less demanding for the AZ vaccine.

      -dk

  9. Josh says:

    11,363 participants in the study, 2,741 of whom got the 1/2 dose/full dose regimen.

  10. Alex Beribisky says:

    Hello,

    Just a thought: If the body’s immune system indeed eliminates Ade5 the second time it is administered, would not that be reflected in the SARS-CoV-2 antibody and T-cell levels? A quick look here (a slightly different regimen than in the phase III trial, but still low and high dosages were used):
    https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32466-1/fulltext#seccestitle150
    shows that there is no direct correlation between at least SARS-CoV-2 antibody levels and adenovirus dosage. As I said, just an observation, immune response, is of course, a lot more complex!

  11. James says:

    Hi Derek,

    Do you know when, after receiving their first or second injection, study recruits’ COVID infection can be counted in the results? If it’s after the first shot, the rising level of COVID in the general population would mean that more recent Phase 3 trials will show lower efficacy, as participants didn’t have a low-COVID summer to build up their immune response before exposure.

    That is, if I get the first shot of the vaccine, walk out the door, and immediately get COVID before I’ve produced any antibodies, am I counted as having gotten COVID? Because that seems a lot more likely to happen now than it did when Pfizer and Moderna recruited their Phase 3 cohorts.

    (I’m a J&J trial participant who got the sense this could bias their results vs other trials, given their instructions to me).

    Best wishes,
    James

    1. Derek Lowe says:

      The endpoints are all post-second-dose, according to the AZ trial protocol.

  12. Calvin says:

    The results are fundamentally not a surprise. The earlier data from Phase1/2 was weaker than the Pfizer/Moderna data and also looks weaker than Novavax and JnJ. And that has followed through the Phase 3. ChAdv has always had a habit of not being particularly immunogenic and so this has proved to be the case. I think what we’re also seeing is that COVID is easier to deal with than we hoped. I think we all expected (compared to other respiratory viruses) that it would be extremely hard to generate an efficacious vaccine and we all guessed that 50% efficacy was likely. It turns out (no complaints here), that actually COVID is easier to develop a vaccine against.

    I strongly suspect that vector immunity is the reason for lower efficacy. AZ deserve a bit of a beating here because they are claiming 70% efficacy when in reality most see 60% and a smaller group with a different dosing regime see 90% efficacy. I’ll be interested to see how the regulators feel about approving the regular dose schedule versus the half dose/full dose schedule given the apparent difference but the relatively smaller number of patients in the alternate dosing group. They’d be brave to approve on that many patients.

    Overall, in comparison to Pfizer/Moderna this looks like a mediocre vaccine. While it clearly has cost/scale advantages, anybody getting this one is getting a vaccine with 25-35% less efficacy. And even if we take the best case scenario it is still less efficacious than Modena/Pfizer. I’ll bet the JnJ and Novavax vaccines are superior in terms of efficacy (have a suspicion that the Novavax vaccine might have some more safety issues).

    If Merck, Sanofi etc can get their trials enrolled then I would not be surprised if they end up being the biggest players here. Pfizer/Moderna is hard to predict, but I think the cold chain advantage of Moderna will win out.

    And of course, if the vector immunity explanation is real, the long term viability of the AZ vaccine is low. If immunity is not long lived, or people need a booster, the AZ vaccine will not be able to do that. And the ChAd platform will be one for the dustbin, unless they re-engineer the vector for each new vaccine (if that’s even possible) which will of course get harder and harder.

    On the plus side we’ve not got three vaccines with 3 different preclinical profiles and we can see how they line up clinically. That is going to be very helpful for the other players to figure out the best profile.

    1. Jacky says:

      The problem is people are rushing back to normal. People can’t wait for Merck, Sanofi’s vaccines which may launch only at the 2nd half of 2021. Many people may already die due to covid-19 or suicide due to bankrupcy.

      The bottom line is even with Oxford/AZ vaccine, you will most likely no need to hospitalized, and die after vaccinated. That’s already great enough. What the problem with such comment is people are unrealistically waiting for a PERFECT vaccine instead of making a choice balancing each factor. You can wait if you are living a village in the mountain. But many people can’t.

      1. A Nonny Mouse says:

        There clearly needs to be a bit of triage in the system; the AZ could be used for the general population where it is “good enough” (and cheap enough) while the Pfizer/Moderna ones could be used more in the high risk population where a 95% effectiveness is most required. This, though, would probably only work in centrally organised healthcare systems.

      2. Calvin says:

        I don’t disagree at all. But when Pfizer/Moderna have 95% efficacy and AZ have 60-90% depending on how you squint I know for certain what vaccine I would take and it’s not AZ!

        My comment around Merck/Sanofi is entirely conditional on them finishing their trial which is not a done deal. But, on balance the AZ vaccine looks like it not well placed. Who wants to take a 90% vaccine when there are two that look better. Despite the cost advantage (which may not be sustained over the long term) unless that 90% efficacy holds up, I can’t see AZ being able to compete. And then if JnJ, Novavax and Merck etc come through with 95% efficacy, a single shot and easier cold chain than Pfizer, then AZ have the weakest product. Somebody has got to lose in the race and right now that is AZ.

        1. A Nonny Mouse says:

          A very US-centric point of view.

          While it may not be the best of the bunch, for the RoW it is a cheap, readily available option in comparison to the others which will help alleviate much of the problem.

          1. Calvin says:

            That’s not an unfair comment (although I’m based in the US I’m not from there), I wouldn’t underestimate the importance of the FDA/EMEA in setting the tone for the rest of the globe, particularly in resource poor settings. Often other parts of the globe will look to the US/EU for their regulatory guidance and an indication on the appropriate standards. I think the AZ vaccine will be approved in the US/EU, but other parts of the globe will look to see what happens before they make their decision. And if they see what they might perceive as the weaker vaccine being pushed their way while the rich countries hold onto the “better” vaccines that will not be a good look.

            Once the next batch of vaccine data comes in, then that will play out. I stand by my thought that the AZ vaccine will probably become less used compared to the other vaccines, unless they can home in on that 90% efficacy with the split dose setup.

            And of course, we’re comparing press releases here which is hardly the best way to do things. But we’re all fairly adept at reading between the lines. AZ are cherry picking a subset (which doesn’t seem unfair), but we’ve got to acknowledge that that approach is not without risk of getting egg on your face.

        2. Joseph says:

          I also have some serious questions about the 90% group if this article is even remotely accurate:
          https://www.reuters.com/article/us-health-coronavirus-astrazeneca-dosing-idUSKBN28327Q

          If it was a dosing error then it is clearly a post-hoc sub-group analysis. It might hold up but it makes me much more concerned about multiple testing issues, which suggests that additional trial work is going to be needed. I like the low cost, and at 70% it might be worth trying, but I am wary about 90%.

          1. A Nonny Mouse says:

            ALL of the UK people were dosed like this, it seems, as they did not want to change once they had started. All others were given the 2 full doses

          2. AQR says:

            It seems that AZ ran a triple blind trial. The patients didn’t know what group they were in, the docs didn’t know whether they were administering the active vaccine or the placebo and AZ wasn’t quite sure what they were manufacturing.

    2. Nitin says:

      i’ve been wondering about this quite a bit – if you assume that a) these vaccines are unlikely to confer life-long immunity, and b) COVID is likely to stick around as an endemic infectious disease, you’re naturally left with a world where people need routine revaccinations. in which case, why would you go into development with a vaccine built on a vector with immunogenicity issues that prevent effective revaccination? it’s one thing to build a “one-and-done” pediatric vaccine on an adeno vector – but seems like a shortsighted approach to something like this.

      1. TWS says:

        Good point if your assumptions about a) and b) are true. Still, quite a bit of what’s being said give the impression that we can’t really make those assumptions yet. Call me overoptimistic, but I’m at least a little hopefully that at least one of those assumptions will turn out not to be correct.

  13. David Matthews says:

    Thanks for another great summary. Minor typo – it’s tissue plasminogen activator (Activase is the Genentech brand name…)

  14. JIM OTTO says:

    My back of the envelope math, assuming there were 12000 people in the control arm, 8895 in the full dose arm and 2714 in the half dose arm. 101 cases in the control arm computes to an expected 75 cases in the full dose arm and 23 cases in the half dose arm. A 62% efficacy rate means 28 cases in the full dose arm and the 90% rate means 2 cases in the half dose arm. I don’t know how confident they can be of maintaining 90% efficacy, but probably safe to be confident half dose is better.

    1. eub says:

      Starting from your number, boneheaded application of Poisson 95% CIs says:

      No, they really can’t be too sure of 90%; the CI around that goes down to 70%.

      But yes, the two dosing schedules look probably different; the CI on the full-full goes to 76%, so they overlap, but the sigmas are adding up.

  15. Bryon says:

    As far as I can tell, the trial protocol for the half dose/full dose did weekly PCR testing of everyone but the trial protocol for the full dose/full dose did not (see link and text below).

    Also, one trial (full doses/full dose) was in Brazil and the other (full dose/half dose) was in the UK. I have seen some suggestion that there may be some circulating adenovirus in Brazil that made the subjects resistant to the vaccine.

    https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/azd1222hlr.html

    COV002

    COV002 is a single-blinded, multi-centre, randomised, controlled Phase II/III trial assessing the safety, efficacy and immunogenicity of AZD1222 in 12,390 participants in the UK. Trial participants to date are aged 18 years or over, who are healthy or have medically stable chronic diseases and are at increased risk for being exposed to the SARS-CoV-2 virus. Participants receive one or two intramuscular doses of a half dose (~2.5 x1010 viral particles) or full dose (~5×1010 viral particles) of AZD1222 or comparator, meningococcal vaccine MenACWY. Participants have blood samples drawn and clinical assessments for safety as well as immunogenicity at multiple timepoints up to one year post-vaccination. Suspected cases presenting with compatible symptoms were tested for virological confirmation by COVID-19 PCR. In addition, weekly swabbing are done for detection of infection and assessment of vaccine efficacy against infection.

    COV003

    COV003 is a single-blinded, multi-centre, randomised, controlled Phase III trial assessing the safety, efficacy, and immunogenicity of AZD1222 in 10,300 participants in Brazil. Trial participants to date are aged 18 years or over, who are healthy or have medically stable chronic diseases and are at increased risk for being exposed to the SARS-CoV-2 virus. Participants are randomised to receive two intramuscular doses of a full dose (~5×1010 viral particles) of AZD1222 or comparator, meningococcal vaccine MenACWY as first dose and a saline placebo as second dose. Participants have blood samples drawn and clinical assessments for safety as well as immunogenicity at multiple timepoints up to one year post-vaccination. Suspected cases presenting with compatible symptoms were tested for virological confirmation by COVID-19 PCR.

    1. Madge Hirsch says:

      Healthy- that is the operative word. I read the Participant Information sheet for volunteers for the phase III Oxford / Astra Zeneca trial and excluded from the trial were people who had severe/poorly controlled chronic conditions – cardiovascular , respiratory , renal , liver, endocrine etc etc. So there will be no data at all on how such people respond to the vaccine. Yet a substantial proportion of the elderly population ( those at most risk from the disease ) will suffer from one or more of these conditions. So giving them the vaccine will be treating them as guinea pigs. Also excluded from the trial were all those on anticoagulants – both DOACs and vit K antagonists. Being on Apixaban I find this concerning. I would also like to know why taking this class of drugs led to exclusion. If the other vaccine trials have similar exclusion protocols then data on vaccinating the general population will be incomplete. Normally people who are immunocompromised are warned they have a much greater risk of having adverse reactions and many are advised not to be vaccinated. Will the unhealthy in the population be warned there is no data for people like them? No they will be told their comorbidities put them at greater risk and they should definitely be vaccinated.

  16. arcsix says:

    I’m seeing multiple news sources reporting that before getting FDA approval, the modified half/full dose regimen would need to be trialled in the US. Is this true?

    1. Steve Scott says:

      The company plans to ask (U.S.) regulators whether it can modify the trial to include the more efficacious dosing regimen, Mene Pangalos, AstraZeneca’s vice-president of biopharmaceuticals research, said at a press briefing.

      “It would be madness to use more vaccine than you needed to get less efficacy,” says Ewer. “I think we will see a move towards rollout of the ‘low dose, standard dose’ regime.”
      https://www.nature.com/articles/d41586-020-03326-w

  17. daksya says:

    Two questions:

    1) What are all the input variables in computing the efficacy analysis: is it just the number of cases in both arms?

    2) How does the analysis work for a single-blinded trial? As each new COVID case is recorded, don’t investigators have an open tally in real-time of the partition of the cases across arms? If yes, can’t that bias the timing of the analysis?

    1. Ian Malone says:

      1) What are all the input variables in computing the efficacy analysis: is it just the number of cases in both arms?

      You need the arm sizes as well, which is what makes guessing this one complex. The efficacy is estimated 1 – treated infection rate / placebo infection rate = 1 – (cases in treatment / treatment arm size)/(cases in placebo / placebo arm size). It’s why I’m not going to try and guess on the numbers here. By definition in this trial the 0.5+1, 1+1 and placebo groups are all different sizes (in fact they’ve got three different placebo groups if I’m reading the protocol right; single dose MenACWY and two dose MenACWY with different intervals), and because of amendments they might have been introduced at different times, so you probably have to take account of subject time in the different arms to do the comparison right (whereas with a simple treatment/placebo randomisation you don’t need to worry about that).

      2) How does the analysis work for a single-blinded trial? As each new COVID case is recorded, don’t investigators have an open tally in real-time of the partition of the cases across arms? If yes, can’t that bias the timing of the analysis?

      Good question. I don’t know, however as you acquire more cases you become statistically less likely to have an unbalanced outcome, this is regression to the mean working for you. Like trying to best-out-of-N+1 someone who is better than you at tennis/pool/any game of skill, you might get lucky while N is low, but as you keep doubling down the deficit you have to catch up just gets longer.

      1. David G says:

        On the single blind nature of the trial: For this trial protocol, as far as I understand it the total number of infections for the intermediate analysis is decided in advance. Hence there’s no prospect of trying to bias the trial by timing the analysis: You wait for a set number of cases, and then do the analysis.

        1. daksya says:

          That number was supposed to be 73. But this interim analysis has 131. Hence my question.

          1. Chris Phillips says:

            Is that number not from the US protocol?

            The results they have just reported are from different trials in the UK and Brazil. As far as I know, the protocols for those have not been published.

  18. Roy Badami says:

    N=3000 approx, apparently.

    The Guardian writes “Those given the half dose and then full dose four weeks later were in a smaller group of 3,000 people, of whom 90% were protected against Covid.”

    I’m sure I saw a more precise figure quoted somewhere, but I’m not sure where…

    1. Druid says:

      try Derek’s blog, above

  19. Jonathan says:

    Could this vaccine be as preventative, or more preventative, of serious disease than the Pfizer vaccine? Pfizer reported at least one case of severe COVID in their vaccine arm (which I assume meant hospitalization). Oxford vaccine had zero hospitalizations, according to this: https://ca.sports.yahoo.com/news/end-coronavirus-tunnel-scientists-oxford-university-vaccine-120356521.html

    Similar to the vaccine challenge of the rhesus macaque, perhaps this vaccine is not as effective in preventing URTI, but more protective of LRTI. Just a thought I haven’t seen discussed.

    If this is true, perhaps the efficacy, in terms of danger to human health, is higher than those numbers show.

  20. Pablo Garibotti says:

    Some comments assume they will have the option of choosing what vaccine: up to the second half of 2021 most people will only be able to get what it is available in their country. Even in the US or West Europe.

    So I will get what is available as soon as posible and maybe go for the better one later

    Also very important but not enough data yet: how effective are the different vaccines to prevent hospitalization and death?

    1. T B says:

      I wonder if there are any adverse effects to taking a second vaccine (different type) a few months/years after the first.

      Taking the AZ now and the Moderna next year, if given the choice.

      1. Dark Day says:

        I’ve been considering the scenario of taking either the BioNTech/Pfizer or the Moderna as early as possible next year, and then the Novavax later on, if it proves to be as effective in bringing about sterilizing immunity as some of the early trials suggested. And eventually, if another vaccine that confers longer-lasting protection appears in the meantime, perhaps switching again in 2022 (or whenever it’s time for another booster).

        Problem with that scenario, though, is that I’m not aware that most of us will have the opportunity to “pick and choose” in this way. I don’t see thousands of doses of three or four different vaccines all being delivered to the same provider — whatever our local pharmacy, our local physician’s group, or our local health clinic or hospital gets, is what we’ll end up taking.

        1. Bill says:

          I would think we will indeed be able to pick and choose. Sure your preferred provider might have only one offering, but these vaccines aren’t so expensive that you can’t just go elsewhere and pay out of your pocket.

      2. RB says:

        Sounds a good choice, if given the option. By the year after, vaccination might well be on offer in pharmacists.

  21. Mr T says:

    Just read that the lower dose was due to a dosing error- unbelievable!
    https://www.mirror.co.uk/news/uk-news/oxford-uni-scientists-accidentally-give-22197078

    1. Marko says:

      Serendipity has always been an essential component of scientific progress , painful as it may be to admit.

      1. Mr T says:

        just hope that this type of dosing error does not carry over when it comes to manufacturing the approved product

    2. Wilhelm Cody says:

      there is a phrase for this phenomenon: “the principle of optimum sloppiness.” Molecular biologists in the 1960’s used this term to refer to the occasional error in designing or executing an experiment that resulted in an unexpected and illuminating result.

      1. Barry says:

        Optimal sloppiness is an old concept. Although eukaryotes have extensive error-correction in our DNA replication, evolution depends on the failures. And cancer cells routinely disable error-correction; sloppiness improves their chance of getting genes into a next generation.Likewise, some bacteria modulate their mutation rate under stress
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747772/

    3. stats guy says:

      This is a problem. Took a look at the protocol. Dosing regiment is not a stratification factor and the population of patients receiving the ‘mistaken’ dosing is not pre-specified. This means there may be imbalances in the ‘mistaken’ dosing regiment which may skew or at least affect interpretation of results. So this analysis appears to be post-hoc which may or may not be a problem when it comes up for approval

      1. Dark Day says:

        I’m guessing approval will be problematic, at best. Those early adverse events set off alarm bells; there was at least one death in Brazil that (unless I’m mistaken) was never explained with 100% transparency; and now the uncertainties cited by debinski above only muddy the waters even more. And it’s not as if we’re “desperate” — despite the very real logistical challenges in storage and distribution, we have two very promising candidates likely to win approval soon, and several in the pipeline that had preliminary test results at least as promising as Oxford/AZ’s were. So there should be no pressure on the FDA — quite the opposite, in fact: it would probably encourage public trust if a vaccine candidate with even the appearance of uncertainty in its results were not approved. I’m not suggesting that “p.r.” should be a consideration here, but public health obviously is, and anything that will encourage, instead of discourage, public trust and uptake should be taken into consideration.

        1. Zambo says:

          The death in Brazil was in the placebo group.

    4. Roy Badami says:

      The Guardian quotes AstraZeneca as saying that when they started the trial they were surprised by the lack of side effects “So we went back and checked … and we found out that they had underpredicted the dose of the vaccine by half,”

      Anyone able to explain what “underpredicted” means in this context?

      1. Barry says:

        A factor of two sounds like they read kilograms for pounds in calculating the dose.

        1. Roy Badami says:

          (a) I don’t believe anyone in the UK would ever use pounds as a unit in a scientific or medical context (would they really, in the US?) so I doubt it.

          (b) Still curious about what the word “underpredicted” means in this context. (The word is apparently from a quote by a senior AZ person.)

          1. En Passant says:

            Roy Badami wrote “I don’t believe anyone in the UK would ever use pounds as a unit in a scientific or medical context (would they really, in the US?) so I doubt it.”

            The NASA Mars Climate Orbiter was destroyed 11 December 1998 due to erroneous control software which incorrectly used English instead of SI units.

            A major error mistaking pounds for kilograms in a technical context (but not strictly speaking “scientific”) occurred in Canada, 1983, during Canada’s changeover from imperial to metric units.

            Air Canada Flight 143, a new Boeing 767, ran out of fuel due to the error.

            Luckily, chief pilot Bob Pearson was highly experienced in gliders. He landed the 767 safely, with no injuries, at the long abandoned Gimli, Manitoba RCAF base. Very exciting flight for passengers who experienced their very first sideslip on the final approach, in a 767 no less.

            You can find the incident under “Gimli Glider” on wikipedia or youtube.

      2. Duncan says:

        If you look here:

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

        at 20:50 on there is a more detailed account than I’ve seen so far reported in the media. What you make of it I suppose is another matter.

        1. Chris Phillips says:

          What I make of it is that I’m starting to think that if I have a choice it may be better to defer having this vaccine until they have sorted themselves out.

          We now have a suggestion that the interval between the doses may be the reason for the difference in efficacy. I can’t even see that mentioned in the AZ press release.

          1. Duncan says:

            ‘I can’t even see that mentioned in the AZ press release.’

            For all this (muddle-headed in my mind) talk about ‘science by press release,’ we don’t do ‘drug approval by internet commentary.’ Regulators, not journal editors, peer reviewers or the internet commentariat make approval decisions based on whatever evidence they see fit and what is put in front of them. For any and all of these vaccines we are all going to have to trust, or not, the system at some stage.

            For what it’s worth I agree with you – I think that something rather fuller than the press release will be needed and I hope that AZ, and many others, present just that to the regulators. My reading of the AZ data is that the vaccine is approx 70% effective, including asymptomatic cases and likely higher in terms of preventing severe infection. I’m more concerned about the age profile than anything else here.

            Beyond that it is over to regulators – that is all any of us, however well-qualified, can say. In any case surely we were all prepared for a scenario where those in the higher risk groups received a vaccine that performed better in a time of low supply?

          2. Chris Phillips says:

            Of course, I agree that the decisions have to be made by the regulators on the basis of the full data, which we don’t have.

            It’s just that the press release presented the difference in efficacies unambiguously as the result of the initial half-dose, and in that interview the speculation seemed to be that the interval between doses was also important. Presumably that implies there was also a difference between the two arms in that regard? The more we hear, the less I get the impression that they’re likely to be able to make a sound decision about the best way of administering the vaccine any time soon.

  22. Candido Ferraz says:

    I wonder whether in the future, what happens if individuals get shots of different vaccines (which depending on availability and not choice, is a situation that can take place in some countries). Ex: AZ vaccine (70% efficacy) + Pfizer (95%).

  23. Gray says:

    Thanks Derek. How much of an oversight is it, in your opinion, that the 3 top contenders aren’t measuring, focusing, or releasing information on asymptomatic transmission? Vaccines will be rolled out to different groups within countries on different timelines, making many populations extremely vulnerable to the disease even from vaccinated individuals if the transmission rate doesn’t change. Thanks!

    1. AVS-600 says:

      Measuring asymptomatic *disease* in trial participants might be doable, although with low disease prevalence you have to be very careful about figuring out your real false positive rate with whatever test you are using.

      I’m not an expert but I don’t think there is any real way to measure asymptomatic *transmission*. That would involve testing and tracing a massive number of people who didn’t actually participate in the trial. It’s absolutely a worthwhile question, but I don’t think it is answerable in the context of a clinical trial; as with many things in medicine, we’ll just have to wait and see.

      1. Marko says:

        With their weekly PCR swab data , AstraZeneca might be able to get some idea about transmissibility without extensive contact tracing. Viral load differences between placebo and vaccine groups would seem to be a reasonable proxy. False positives shouldn’t be a problem if they do follow-up antibody confirmation of positives , or simply do a second PCR or antigen test on asymptomatic positives in a timely fashion.

      2. Michael says:

        It doesn’t seem plausible that highly effective vaccines like Pfizer and Moderna wouldn’t reduce transmission. Because it doesn’t seem plausible that they won’t reduce asymptomatic infection.

        One reason pointed out by an immunologist on Twitter, which turned on a light bulb for me, was that the math doesn’t work out. If your theory is that asymptomatic transmission will occur post-vaccine, then you are assuming that the lower respiratory tract is protected but the upper respiratory tract is infected. But there *are* some upper respiratory symptoms, such as taste/smell being temporarily affected (~20% of cases for that symptom alone). The combined score so far with Pfizer and Moderna in symptomatic infections is 252 placebo, 13 vaccine. It’s not plausible that the upper respiratory tract is not meaningfully protected when so few symptomatic cases are reported among the vaccinated group.

        1. Dark Day says:

          Interesting point about the loss of taste — I haven’t seen that mentioned in any other discussions of whether or not any of the current vaccines might confer sterilizing immunity, or at least help reduce transmission. Are we sure that was monitored as a “symptom”? I’m assuming it must have been, but it does seem a little strange that no one has mentioned this before as a possible indication that upper respiratory infection might, in fact, be at least somewhat ameliorated by the vaccines currently up for EUA.

          1. Michael says:

            “New loss of taste or smell” is indeed a symptom per the protocols.

            Here’s the immunology thread making the point:

            https://mobile.twitter.com/deeptabhattacha/status/1330979378692460545

          2. Michael says:

            Dark Day, in the all-out rush to attach as many caveats as possible to the Phase III results of Pfizer and Moderna, not all of these caveats are being carefully thought through. (Many commenters on this blog have pointed out the fallacy of saying “small sample size.”)

            Don’t know if it’s an abundance of caution, preparing the public against overconfidence, or just media being media.

          3. David G Whiteis says:

            Interesting, though, that some caveats which might very well be appropriate aren’t being heard, concerning the Oxford/AZ vaccine. (E.g., I hadn’t been aware that the half/whole-dose regimen was only administered to people under 55 — and, as several people here have pointed out, Oxford/AZ seem to have been somewhat disingenuous, at best, in the way they’ve collapsed the results of their two different trials into their one press release, without really emphasizing the difference in same sizes and demographics.)

          4. Michael says:

            Agreed, David. Pfizer and Moderna results (and, indeed, the trials themselves) inspire much more confidence. Plenty of important caveats around the AZ release.

  24. Marko says:

    One important difference that may exist between the various vaccine candidates is the duration of protection , which we have no clue about so far. If efficacy declines by 50% after 3 months for vaccine “A” but only by 25% for vaccine “B” , initial apparent efficacy differences could be reversed rather quickly. Considering that it will take from many months to a year or more before everyone can be vaccinated once , much less receive a booster dose(s) , these differences could have important effects on the protection afforded to the overall population.

    This study shows that neutralizing titers decline by 4-fold (i.e. by 75%) from month one to month four following symptom onset from natural infection , illustrating the potential for vaccine efficacy to wane relatively rapidly if neutralization is the primary correlate of protection :

    https://pubmed.ncbi.nlm.nih.gov/33000143/

    1. Michael says:

      Others are more confident about longer-lasting immunity:

      https://www.microbe.tv/twiv/twiv-684/

      1. Marko says:

        Actually , I’m fairly confident about long-term protection against severe disease , but based on what we know about the seasonal common-cold coronaviruses , I wouldn’t be surprised if sterilizing immunity wanes rather quickly. To the extent that even mild cases may contribute to community spread , this waning of immunity could impact on the success of the vaccines in halting the pandemic , and thus protecting the not-yet vaccinated.

        My only real point was that these early readouts on efficacy of the different vaccines, determined so soon after vaccination , may be much ado about nothing. Real-world and longer-term efficacy results could look very different.

        1. Michael says:

          Perhaps, but common-cold coronaviruses have evolved much more than this one over time. One of them is estimated to be ~1000 years old!

          This was a useful thread:

          https://twitter.com/deeptabhattacha/status/1298376137639260165

          1. Michael says:

            The key quote being in the last tweet:

            “Given the recent and *rare* reports on heterologous infection by SARS-CoV-2, perhaps we should pay more attention to virus diversification and immune escape than to duration of Ab production, which looks good so far. Prob more of an issue post-vaccines, but best to be prepared.”

          2. Marko says:

            “….perhaps we should pay more attention to virus diversification and immune escape than to duration of Ab production..”

            I agree that immune escape is something else we have to watch for , but I’m hoping that the dominant escape mutants will be those that have such profound alterations in spike/RBD that they no longer bind ACE2. Some viral entry would likely occur by other routes , but probably less efficiently and with less severe disease outcomes. Thus immune escape could be the mechanism that turns circulating COV2 into the fifth common cold coronavirus , a mere nuisance , relatively speaking. If we’re lucky…..

  25. The vaccine hunt is shaking down as the greatest scientific achievement of the 21st Century thus far. And maybe just the greatest achievement……..

    1. Aweson Walles says:

      And, as ever, what back stories going on behind the scenes? Let’s not get too carried away yet, Prof Skogan. Four score years of the 21st century still to come – who knows what lies in store. You ain’t seen nothin’ yet, ponders the Cosmic Scriptwriter…

      Meantime, good to hear Three Princes of Serendip saddled up again. “The reason we had the half-dose is serendipity,” Mene Pangalos, the head of AstraZeneca’s non-oncology research and development, told Reuters. “Clinical leads noticed expected side effects such as fatigue, headaches or arm aches were milder than expected,” he said. “So we went back and checked… and we found out that they had underpredicted the dose of the vaccine by half,” said Pangalos.

      Might just be more to it than that, Sir Mene? Chris Phillips: 25 November, 2020 at 1:56 am herein points out the Head of The President de-Elect’s Warp Speed programme advised in a phone call with reporters that “…the regime was administered to participants in a group whose age was capped at 55,” and that…

      “The initial half-dose was used in some people because of an error in the quantity of vaccine put into some vials,” before concluding, “There are a number of variables that we need to understand, and what has been the role of each one of them in achieving the difference in efficacy.”

      Cue spooler dooler. FYI Dear Reader, The Great Vire has brought all sorts of life forms popping left, right and centre out of Castle Pharma’s ancient woodwork. Hot on heels of Moderna CEO the other day, now comes The President De-Elect’s Head Vire Honcho, incidentally old chum of GOV.UK’s Chief Scientific Adviser (another Knight of the Realm, no less…

      …He, Chief Scientific Adviser, of the throwaway remark that 20K UK deaths would be a good result, being also he who swallowed hook, line and sinker the 500K UK and 40M worldwide deaths predicted by the notorious Prof Flummoxingham, he of the equally notorious Imperial College Gang that’s been up to epidemiological mischief for decades…), being he GOV.UK’s Chief Scientific Adviser and Knight of the Realm who, along with Head Honcho, once upon a time last featured distinctively in the old Corante blog, in that long lost reworked Conan Doyle masterpiece, The Strange Case of the Disappearing Drug:

      https://blogs.sciencemag.org/pipeline/archives/2010/01/12/the_sirtris_compounds_worthless_really

      …Where by way of example, inter alia, alig says: 12 January, 2010 at 10:22 am; Anonymous says: 12 January, 2010 at 10:53 am #14 Alig is absolutely correct; and anonymous2 says: 12 January, 2010 at 11:48 am, and at 12.00 pm; just before LongGoneButStillWatchingInHorror says: 12 January, 2010 at 12:15 pm…

      I digress. GSK’s long lost 720 million bucks best left long lost. Although the 720 million must have ended up somewhere, for economics abhors differentially coloured holes and missing ackers. Anyway, bad luck chaps. Stuff happens. Looking on the bright side, maybe Knight of the Realm and Head Honcho learnt from past experience? Scroll down below LongGoneButStillWatchingInHorror at the preceding link and draw own conclusions. Total of 125 comments. Plenty to go at from former good burghers of the principality of GlaxoSmithKlinea.

      Moving on… Three Princes of Serendip longstanding academic and corporate partners at Oxford (as per The Enchanted Ring by J C Sheehan, etc, etc, etc) and of AstraZeneca forebears (delve into Losec, Arimidex et al, et al, et al). Cosmic Scriptwriter always was fan of giving Princes strong ride on parts.

      But hold on, not off the hook yet, Sir Mene, for Jim Ancona 25 November, 2020 at 1:25 pm herein directs to Wired…

      https://www.wired.com/story/the-astrazeneca-covid-vaccine-data-isnt-up-to-snuff/

      …Where Hilda Bastian, who “…has a PhD in Health Science, and expertise in assessing the validity of evidence for health claims,” duly claims, “The AstraZeneca Covid Vaccine Data Isn’t Up to Snuff… a closer look reveals some very shaky science.”

      Steady on Hilda, give Sir Mene a break please. Facts seem to be Oxford-AZ vaccine did seem to do the business – 62%, 70%, 90% all > 50%. And fact is, just like in real warfare, in heat of R&D battle (and tittle tattle) all sorts of stuff goes on.

      Who knows, in early 2Q this year maybe Oxford-AZ study protocol put to bed at 2.30 am, ahead of drop dead noon deadline, by Study Director Working From Home in bijou 3 bed as per GOV.UK edict, in bosom of family made up of Key Worker Hero mummy, Study Director daddy, 18 month old toddler and temperamental three year old, as per ditto both Playing At Home with daddy in charge, regular childcare being closed by GOV.UK edict and no other option now being available within 10 mile range that undertakes to change nappies.

      Changing nappies, muddy wellies, drying dungarees, sleep suits and dish cloths sprawling over radiators, domestic bliss all consumed by domestic logistics. Serendipity’s quantum level…

      …Bijou 3 bed being best family can afford in UK’s most up and coming expensive area, being in orbit of country’s highest prestige scientific ecosphere and biohub, whence company chose to move from more pastoral and less pricey set up in darkest scientific backwater, where quite by chance 14 drugs in 57 years discovered through serendipity, seizing the day and science as happened upon in the real world. Sometimes that’s the way the cookie crumbles.

      So please arise, Sir Mene, and press on with AZD1222, although by way of tangent once upon a time R&D scientist still to this day can’t help but wonder how 2000s exec reward package typically >100x “shop floor” (and climbing), when biography of R. J. Mitchell, written by son G. Mitchell, tells 1930s Chief Designer and Technical Director at Supermarine Spitfire, Southampton, took home mere 12x shop floor.

      Over to you, Mr Alexander Boris de Pfeffel and/or Sir Keir Rodney, to review that old chestnut, which from some time soon now on in might just start to matter more than at least one of you thinks. You’re first up, de Pfeff. More mere college blagging won’t do, old chap. Need some substance, some end product. Would make a nice change.

      (Real time: Beyond the back field the wild sheep are up in the badlands again, taking down the last of summer’s dock leaves, ragwort and thistles. Only a matter of time before they’re down the side trail again looking for lunch. Jeeves – send for the hounds, before the flower beds get trashed, immediately!).

      Whoops, another digression, Big Time and little time. Back to the here and now. Interesting times. Three Western vaccines hit jackpot straight off, making for hat trick barely minutes from kick off. Goals bulging back of Chinese and Russian nets too. Looks like we could almost be spoilt for choice.

      Yet back of mind there’s that 10 minute interview on talkRadio the other week, between Julia H-B and Dr Mike Yeadon, formerly Head of Pfizer respiratory R&D, back in the days before the Pfizer Mizer shut down the old Sandwich UK R&D site, where if memory serves right 8 drugs or thereabouts brought about in about 40 years R&D…

      https://www.youtube.com/watch?v=4FQUmw5QljM

      Now I’ve never met Dr Mike, never having worked in respiratory, unless you count those two years at the old warehouse four and a half decades ago, kicked off by making those triazolo[3,4-f]triazininones oozing heteroaromaticity gram at a time first off for the weekly mouse Passive Cutaneous Anaphylaxis test, that led into a secondary test never heard much about, rarely being anything much that got that far, apart perhaps from those derivatives of that imidazo[1,2-a]pyridine AH10499 that’d dampened down the allergic reaction in the PCA test and were a doddle to make.

      If I’m hearing Dr Mike right, sees SARS 2 as a seasonal epidemic that, in some areas of the country, has now pretty much run its course, thanks to the immunity headstart around 30 percent of us had from past exposure to cold coronaviruses, community immunity since being plasuibly reached, and any above-5-year-average excess deaths being primarily due to other causes, such as deaths at home that’re getting conveniently swept under the carpet in the national death stats fest.

      Meanwhile, increases in “tested positives” an artefact of mass testing of healthy people, reflecting false positives GOV.UK doesn’t release any stats on, while increases in SARS 2 hospital admissions mainly reflect way admission stats gathered, collated and presented. As ever, meaning behind numbers that matters, not numbers per se.

      Seem to recall Dr Mike went on to say that only the 1 in 500 head of population that are elderly and/or clinically vulnerable would really essentially need a vaccine when one comes out, given that the wider population may well have got to community immunity already.

      That of course assumes the 1 in 500 can be reliably identified. Need to look into this for myself. Meanwhile, this very morning our old friend the Chancellor of the Duchy of Lancaster, the one and only Mr Rovergover, is up to tricks again…

      https://www.bbc.co.uk/news/uk-55112078

      …Pulling the old flanker about the NHS being overwhelmed again, as blackmail fodder for rebel Tory MPs opposed to GOV.UK’s replacement of Lockdown 2.0 with Tier 3.1 that’s more stringent and widespread than Tier 3.0 that preceded Lockdown 2.0 that came along later, instead of the earlier Circuit Breaker that never was but Labour thought should have been, what with Cymru’s Nanny Drakefford going for the Firebreak to keep the poxy English out, Scotland’s Nanny MacFish going for Tier 4.0 and the haste ye back from Blackpool but don’t go there in the first place policy, and Northern Ireland’s Nanny O’Foster no doubt privately having second thoughts about a hard border.

      So that’s politics for you, same politics that now makes the vaccination juggernaut pretty much unstoppable. So, well done to all involved in SARS 2 vaccine R&D, not only for the science but ahead of bailing the politicians out. Sure thing the politicos will be immediately grateful to you for, but then put you out of mind, ahead of taking credit for how the One Year Action Plan in place all along Vanquished the Vire.

      Never before in virology history will single virus have been hit for six by sixteen to sixty new vaccines. All being well, The Great Vire could be all over bar the shouting by next Easter. At least that’s what GOV.UK’s Health Minister says (so don’t book next year’s foreign travel just yet…).

      Really though, The Vire can’t stand a chance, can it? Am somehow reminded of the old chestnut about a bit of Abraham Lincoln being in all of us. All down to the power of Avagadro’s number, that awesomely wholesome to-one-significant-figure 6 x 10 to the power of 23 that underlies the extant form of living and material things.

      Abe Lincoln’s body may lie a mouldering, but the maths tells us, thanks to Avagadro and conservation of atoms, a minimum handful of old Abe’s presidential atoms must seven score and fifteen years later have duly arrived within all of us. And by analogy, plausibly within all of us are a minimum handful of dead SARS 2 units too, viral waste floating around in the physiology until phenomenon of clearance tidies up nicely thank you very much.

      Somehow too reminded of H G Wells’ War of the Worlds, published in 1897. Pioneering science fiction about invasion of Earth by Martians. Begins by telling of, “Minds that are to our minds as ours are to those of the beasts that perish, intellects vast and cool and unsympathetic…”

      First reduced to media by Orson Welles, that 1938 Halloween eve radio spoof that had Martians landing in New Jersey and crossing the George Washington Bridge, and Americans across the nation jamming the switchboards, as recalled 50 years later by AT&T operators who took the calls…

      https://www.youtube.com/watch?v=R29BTsoIHpQ

      …Mass panic, for which Welles apologised at a press conference the following morning, while also pointing out @ 1:12 into modern day YouTube clip, “You don’t play down the melodramatic effects of… a melodrama…”

      https://www.youtube.com/watch?v=8vbYyDh-BRI

      World War came along for real year after, and not until 1953 did Hollywood get in on the act with Invaders from Mars, benign dark fantasy in which a young boy helps save Earth from Martian insurgency, “He saw them land from outer space, he saw them capture only to destroy… A general of the Army becomes a saboteur… Trusted police turn into arsonists… The boys parents’ turned into killers…”

      https://www.youtube.com/watch?v=EJMgz6ZG-2w

      Quite a few more War of the Worlds since, most recently Beeb dramatisation aired late last autumn, plausibly pretty much coincident in time with primitive life form of sorts emerging from the bat cave and heading off on its wicked way to the wildlife markets to launch the latest phase of a viral insurgency humanity’s immune system’s been fighting off since time immemorial…

      https://www.youtube.com/watch?v=r-yas0yPbLU

      …Take a close look @1 second – “Ladies and Gentlemen, it seems that something has arrived in England,” @ 13 seconds, when the 1890s Martian insurgency begins in woods outside Guildford, @21 seconds when the PM stands on the steps of Whitehall and proclaims, “This is nothing to be concerned about…” and @33 seconds when the heroine screams in despair, “Is this the wages of our sin?” Plot sound at all vaguely familiar..?

      Fast forward to the here and now, and The Great Vire about to be zapped away by a global mass vaccination programme of 16 to 60 vaccines, or thereabouts. Can anything conceivably go wrong, or are we on the home run at last? But the Cosmic Scriptwriter doesn’t just do happy endings, you know. Bear witness to this account of how after successful deployment of the Dengue vaccine in 16 countries, release in the Philippines went wrong due to conflation of cirumstance not seen before and not envisaged this country round…

      https://www.scmp.com/magazines/post-magazine/long-reads/article/3006712/philippines-suspicion-dengue-vaccine-linked

      Thank you again to “Biochemist” for pointing this one out in “Vaccine Possibilities” 28 November, 2020 at 1:04 am. So whoever the Virefirer is, wherever the Virefirer is, let’s hope the Virefirer doesn’t up the game too. ‘Cos then we’d be into conflict escalation and an arms race, just like we are with antibacteral resistance…

      …For who knows, maybe through unforeseen and unprecedented virology, the Great Vire will evolve through natural selection in face of apparent overwhelming human firepower into something respiratorily akin to the HIV retrovirus that all the B cells, T cells and antibodies in the universe can’t see off. By werretin’ away to see off with a vaccine a SARS 2 virus that Dr Mike says already on its way out, with best intentions humanity goes and puts its foot in it and makes things worse.

      Doomsday stuff. Fancifully pessimistic, I know. But then, the Cosmic Scriptwriter didn’t write all those divine tragi-comedies and get where he is today without being fanciful. Might need to invoke bit of latest Reed Theory those clever physicist chaps come up with – pull both protruding ends of waxy reeds sticking out of pond on surmise might somehow be joined together in fundament at bottom of pond, where all those tadpole leptons, gluons and mesons and other chums lark about telling each other stories.

      For all that tadpole larking about has to mean something, doesn’t it, and has to manifest somewhere in the extant world up above the pond, hasn’t it? Next thing you know you’re onto that everything a metaphor for everything else stuff that went out of scientific fashion centuries ago, just before Newtonian Mechanics and The Electromagnetic Spectrum came in, although maybe still there waiting in wings after Sudden Light of All Relative, Nowt Certain gave metaphysics nudge back in earlier direction…

      I HAVE been here before,
      But when or how I cannot tell:
      I know the grass beyond the door,
      The sweet keen smell,
      The sighing sound, the lights around the shore.

      Written circa 1853. Nobody writes ‘em like that any more. Anyone else, Dear Reader, can’t resist looking for parallels all the time? Surely. Maybe there’s theoretical physicists out there at the edge of existence doing the maths of the unfolding space-time-event continuum to express a new aspect of old madly sane Ludwig Wittgenstein’s Things Which Can Be Shown But Which Cannot Be Said…

      Where can we live but days?
      Ah, solving that question
      Brings the priest and the doctor
      In their long coats
      Running over the fields.

      On that one, over to you, Phillips, Dawn Melissa (2002) What can be shown, cannot be said: Wittgenstein’s conception of philosophy in the tractatus and the investigations, Durham theses, Durham University. Available at Durham E-Theses Online: http://etheses.dur.ac.uk/4614/

      Digression (again). No worries, Prof Skogan, all will no doubt be fine, as in the long run it usually is. Vaccine(s) to do the business, SARS 2 all pretty much done and dusted by next Easter.

      And thank you, Prof Skogan, for the tee up. Replier got a bit carried away. Not the first time theoretical physics touched upon In the Pipeline:

      https://blogs.sciencemag.org/pipeline/archives/2019/09/18/and-now-for-a-bit-of-quantum-mechanics

      Enough of amateur physics sleuthing. Last word to Holmes, as once upon a time said to Watson, “Life is infinitely stranger than anything which the mind of man could invent. We would not dare to conceive the things which are really mere commonplaces of existence. If we could fly out of that window hand in hand, hover over this great city, gently remove the roofs, and and peep in at the queer things which are going on, the strange coincidences, the plannings, the cross-purposes, the wonderful chains of events, working through generations, and leading to the most outre results, it would make all fiction with its conventionalities and foreseen conclusions most stale and unprofitable.”

      Doubting word count will pass muster with Pipeline spam filter, unless words rescued by Moderator. Over to you, o captain! my captain! Your call. Our fearful trip is not yet done. It never is. No matter if Moderator bins, word count can always be recycled into another forum.

      Enjoy the last of the Thanksgiving pecan pie. Off in to the badlands now to check what the sheep are up to…

  26. Thoryke says:

    Shouldn’t there have been a protocol amendment posted that would let us all see why one group was getting a lower dose? And why was dosing left to the discretion of people at testing sites?

    I like ‘better’ results, but they aren’t worth a damn if they aren’t also based on “better science”.

  27. Barry says:

    As long as they’re delivering DNA or RNA code for the same antigen(s), the vaccine and booster don’t need to use the same viral vector at all.

  28. Ole says:

    Two questions based on this
    – Is it possible the other vaccines would work as well (better) with half +full? Is it something that should be investigated? It would mean 1/3 more people protected.
    – Could it be that a first shot of one vaccine followed by a second shot of another one would be better? Or as good, while getting more doses?

    1. Roy Badami says:

      If it’s due to the larger first dose creating a stronger immune response to the vector, as Derek posits, then presumably at best only for other viral vector vaccines.

      Interestingly, the Oxford team don’t seem to be thinking along those lines (at least, not publicly). A couple of suggestions from them in interviews that it’s down to the optimal dose to prime the immune system….

  29. CC says:

    “AstraZeneca vaccine ‘will never be licensed in the U.S.,’ says SVB Leerink SVB

    Leerink analyst George Porges notes that AstraZeneca (AZN) announced that after two doses, its modified chimpanzee adenovirus COVID vaccine ChAdOx1 had achieved an average 70% efficacy after 132 infection events in its ongoing pivotal trial. The company is likely to be roundly criticized for its disclosure, since the safety disclosure simply state that “no serious safety events related to the vaccine have been confirmed,” which is hardly reassuring, Porges adds. The analyst points out that the company “tried to embellish” its results by highlighting a reported 90% efficacy in a relatively small sub-set of subjects in the study who received a modified initial vaccination, followed by a “full dose” four weeks later. Porges believes that this product will never be licensed in the U.S., given the design of the company’s pivotal trials and the occurrence of severe safety events that resulted in the extended clinical hold on enrollment into the trials in the U.S. Lastly, he believes this result rather confounds his thesis that “all spike protein vaccines are created equal.” This manifestly is not the case now, and the result puts into question the outlook for Johnson & Johnson’s (JNJ) adenovirus based COVID vaccine as well.”

    I will also add to the above that I remember hearing of one death in the AZN trial in Brazil, and it is not 100% clear if that was perfectly explained.

    1. A Nonny Mouse says:

      The death was a 29 year old medic who was in the “dummy” arm of the trial (meningitis vaccine given).

  30. Tom Maguire says:

    As to why the half dose/ full dose protocol was more effective, a posible reason might be in the company’s study design.

    Surely they had a reason for testing this alternative. Might have been simply to economize on dosing, but they might have offered other reasons.

    1. debinski says:

      As noted above, the half dose was given by accident, it wasn’t part of the protocol. Then they discovered the error, and decided to continue using the half dose. Doesn’t make a lot of sense. I have my doubts they’ll be granted an EUA on the current data.
      https://www.reuters.com/article/health-coronavirus-astrazeneca-dosing-in/dosing-error-turns-into-lucky-punch-for-astrazeneca-and-oxford-idUSKBN28329M

      1. Juan E says:

        They will be granted an EUA in the UK even if not elsewhere.
        There maybe some fine tuning to be done -indeed 62 to 90% efficacy may not be precise, but it’s positive enough. Safety data is the other important issue and Oxford/AZ have had participants enrolled the longest and so it should be no issue.

        1. debinski says:

          I meant an EUA in the US, didn’t know it was called the same thing in the UK. And they don’t have the most safety data in terms of total numbers – not to mention they had a questionable SAE.

      2. Pablo E Garibotti says:

        The Reuters report indicates the “error” ocurred in April, so probably during the phase I / II.
        It makes total sense they decided to include a half / full dose branch to their phase 3 protocol.

        To my knowledge, deciding the right dosage is part of the phase 3 trials

        1. Chris Phillips says:

          There are some details of the study here (dated 26 May, last updated 18 November):
          https://www.clinicaltrials.gov/ct2/show/NCT04400838?cond=Covid19&intr=Vaccine&phase=2&draw=3

          Perhaps someone more knowledgeable can comment, but where the two doses differ, this seems to specify a higher dose followed by a lower one.

  31. James Daily says:

    “The next vaccine effort to report efficacy will be J&J, another adenovirus vector, and this time with a one-shot dose. ”

    Note that J&J just started a Phase 3 trial with a two dose regimen (ENSEMBLE 2), which will run in parallel with the existing single dose ENSEMBLE study.

  32. “Why might there be such a significant split in efficacy?” Elementary immunological theory states that an antigen can produce one of two fundamental responses. 1. It may switch on an immune response, which may be amplified by a subsequent injection (“secondary response”). 2. It may switch off immune responsiveness (“tolerance”), so the secondary response is decreased (or absent). The difference is dose-dependent. Too high an initial dose results in tolerance, which may sometimes result from actual deletion of the very cells that are needed for an efficient immune response. For more, please see my “two signal hypothesis” (Lancet 1968) that, with subsequent work, has recently been updated (see Scandinavian Journal of Immunology 89, e12746. “Two signal half century”).

  33. Robert Rose says:

    A hard truth: 90-95% efficacy will get us to herd immunity much more quickly than 60-70% efficacy.

    1. Mariner says:

      Not if the vaccines with 90-95% efficacy are only available widely enough 6 months after those with 60-70% efficacy.

      Perfect is the enemy of good, as the saying goes.

      As I live in the UK, I’m expecting the AZ to be the one mostly widely used as we’ve apparently got 100 million doses ordered. 4 million doses ready now with tens of millions due to be available relatively quickly. With a roll-out potentially beginning around Christmas, this could well be enough to shut down the pandemic a great degree by next summer. If we’re waiting some months for the Pfizer/Moderna vaccines to be available outside of the US in quantity, it could be a different matter.

      1. Roy says:

        That really depends.

        The UK government deal for the Oxford/AstraZeneca vaccine was originally reported to be 100m doses, with the first 30m doses to be delivered in September 2020. Now, we’re told, production difficulties mean we’re expecting 4m by the end of 2020 with 40m by the end of March 2021 (not clear if the 40m includes the 4m or not – not that it makes a huge difference).

        The UK government deal for the BioNTech/Pfizer vaccine was originally reported to be for 30m doses (subsequently reported as for 40m doses) with the first 10m delivered in 2020.

        If Pfizer manage to deliver on the 10m in 2020 promise, we might actually see the bulk of the early roll out being Pfizer. It’s also possible that the logistics of the dry ice cold chain will mean that the Pfizer vaccine is limited to the mass vaccination centres, with GP practices and pharmacies using the AZ vaccine.

        (There’s also Moderna, of course. We have 5m doses on order, but we’re not at the front of the queue and not expecting delivery until the Spring.)

    2. Bill says:

      Not if the 60% is significantly more broadly available for both supply and cost reasons.

      Something early is likely better than something better but later.

  34. Dark Day says:

    It’s being claimed that the Oxford/AZ vaccine protects significantly against potential asymptomatic spreading, whether or not it offers true sterilizing immunity.

    https://www.youtube.com/watch?v=ndYtzD1LmQw ( Adrian Hill, director of Oxford University’s Jenner Institute, discusses this at 4:40 in this clip)

  35. Bill says:

    All these candidates are doing well at suppressing symptoms. Do we know what benefits have been seen in avoiding infection altogether?

    1. Roy Badami says:

      AZ trials cautiously saying that it does (based on PCR tests) but also saying more work is needed. Sounds like the statistical signifcance of the result may be marginal until more trial data comes in.

  36. winston says:

    So we have 24,000 subjects; 8895 in the full-full treatment; 2,741 in the half-full treatment; 131 cases; 101 in the placebo; full-full at 62% effective and half-full at 90%. That means 28 cases in the full-full (out of 101/12364 * 8895 = 73 expected) and 2 cases in the half-full (out of 101/12364 * 2741 = 22 expected). (Which I now see matches what Oz Amram got above!)

    So we have 28 out of 8895 in the full-full treatment and 2 out of 2741 in the half-full treatment. A chi-squared test on that (28,2\\8895,2741) yields a p value of 0.0496. I’m not sure if that’s the right test, but if so, it suggests there’s a fairly decent chance this 62/90 business is all just a statistical artifact.

    1. Marko says:

      Yes , it seems that the confidence intervals overlap to a significant degree , and that an analysis using a larger sample size might reduce , if not eliminate , the difference :

      https://twitter.com/EricTopol/status/1330979579867983873

      1. winston says:

        Ah, thanks. And this reply has a full calculation, including the distribution on the difference. He gets 94.5% above 0 on the difference, surprisingly close to my clumsy chi-squared approach.

        https://twitter.com/cheianov/status/1331006287627382784

      2. Chris Phillips says:

        That’s interesting to me, because those confidence intervals (41 to 75 and 66-97), apparently credited to Stephen Evans, are quite similar to the ones I got yesterday from my simple-minded Bayesian calculation (41-76 and 69-97). Though on that basis, I’d have thought there was a pretty strong but not conclusive likelihood that the difference was genuine.

        However, to get those intervals I had to try to back-calculate some of the numbers, and given that the apparently more efficacious regimen was all in the UK and the less efficacious one was mostly in Brazil, I should like to see the numbers broken down into the separate groups. Each efficacy needs to be calculated against placebo given in the same country and at the same time. It’s certainly to be hoped they did that correctly, but given the amazing dosing error, it would be nice to see the working. (Obviously if the placebo results were pooled before the efficacies were calculated, and if infection rates in general were lower in the UK than in Brazil, then the efficacy of the half-full regimen would be overestimated, and that of the full-full underestimated.)

        1. Andrew Kewley says:

          It is not sufficient to conclude that “the difference” is genuine, because that difference might be small. That statistical comparison simply suggest that the efficacy in the subset is higher than 62%, it does not provide much confidence that the true efficacy is 90%.
          Secondly, this difference may be influenced by other factors (Brazil vs UK) for example.

  37. Pawel Czekanski says:

    Should immunity only last 12 months or so, will there more likely be any safety concerns with repeated vaccinations with the same vaccine type with the Pfizer/Moderna or the Oxford AZ vaccine? That means, if you would take the same vaccine, for instance every year (or every two years), for which vaccine type there might be higher safety risks with such regular repeated long term dosing?

    1. Andrew Kewley says:

      Immunity is highly likely to last substantially longer than 12 months. The rate of mutation of the epitope region is low.

      However, hypothetically if boosters were required every 1-3 years due to significant change of the epitope regions (of similar magnitude to seasonal influenza), then the AztraZeneca vaccine is out of the question due to immunity against the vector limiting the efficacy.

      1. Marko says:

        “…hypothetically if boosters were required every 1-3 years due to significant change of the epitope regions (of similar magnitude to seasonal influenza), then the AztraZeneca vaccine is out of the question due to immunity against the vector limiting the efficacy.”

        I don’t think that’s necessarily the case. Anti-vector antibody will likely wane over that period of time. A memory response will take some time to develop , by which time the booster shot may have delivered its payload and served its purpose.

        Still , trials will be needed to establish the effect of boosters on immune markers , regardless of the vaccine type.

        1. Brian B says:

          I’d also like to add the vector was further modified to minimise anti-vector immunity with removal of both E1 and E3 regions (normally just E1)

  38. cynical1 says:

    The trial was paused twice because of adverse events. It was reported (perhaps incorrectly) that the first SAE was initially diagnosed as transverse myelitis and then later believed to be a case of previously undiagnosed multiple sclerosis which would not be altogether unreasonable with those two diseases. To my knowledge, the company did not release the diagnosis for the second clinical hold but it was obviously serious and rumored also to be transverse myelitis as well. I am also assuming they were not in the control arm or they would not have paused the trail. I am definitely NOT an anti-vaxer but if there were two demyelinating events in this many people in that short a period of time, I would be worried. Astra and Oxford should release what those two diagnoses were. If it was demyelination, I would really like to know if those two patients had a spinal tap and if either had oligoclonal bands in their CSF. You don’t usually see those IgG bands in TM but you usually do with MS. We can look at TMEV and know that viruses can definitely induce demyelination and we don’t understand it all that well either. And transverse myelitis has an incidence of around 1-10 per million per year (in the US). Statements like “No serious safety events related to the vaccine have been confirmed” smacks of plausible deniability. ‘Confirmed’ is not ‘observed’. 2 in 10,000 is still a smaller number than ~2% death rate in COVID but I’d still prefer one of the other ones please.

  39. exGlaxoid says:

    I’ll take any vaccine that is > 50% and reasonably safe, if it will stop the madness of 1000’s of people dying daily. A vaccine in the hand is worth 2 in trials… If we vaccinate as many people worldwide with whatever vaccine we can produce as quickly as possible, we can always revaccinate people in the future with a better one. The nRNA and protein vaccines can always be given again, as they won;t have issues with viral vector antibodies, so they are fine for a first dose, not as good for multiple doses. But I will take a 50+% reduction in illness any day, especially if it leads to meaningful reductions in hospitalizations and deaths. Once we get everyone vaccinated with anything, then we can evaluate all of the choices and retreat people with the best ones.

    1. anjampie says:

      So this bit: “we can always revaccinate people in the future with a better one”
      Yes, but does the effectiveness of the attempted revaccination get affected by initial exposure to a not-very-effective vaccine? I’m not sure I’m signing up for the first thing that comes along if the promise of better is just around the corner.

  40. TallDave says:

    still curious to see peptide vaccine results… might end up being the longer-term solution due to their cost/distribution advantages

    of course COVID will probably die out forever in Q2/Q3, as our best guess right now seems to be that there is no animal reservoir outside the Mojiang mines

    long forgotten are all the caveats about reported case/death rates… reported US excess deaths have not even reached August levels, let alone April, and while the August milestone seems likely to have already been exceeded (just not recorded yet) whether we will reach April numbers (or worse) remains an open question even as transmission rates soar

    at any rate CFR certainly appears to be falling due to various factors such as not stuffing COVID into nursing homes and increased D supplementation

    and now the parade of EUAs begins

    the beginning of the end? the end of the beginning?

    next month we’ll revise all our priors again

    1. sort_of_knowledgeable says:

      “of course COVID will probably die out forever in Q2/Q3, as our best guess right now seems to be that there is no animal reservoir outside the Mojiang mines”

      Minks
      https://www.who.int/csr/don/06-november-2020-mink-associated-sars-cov2-denmark/en/

      There are also transmission from humans to dogs and cats although it hasn’t gone the other way yet as is currently known, over a time span of years rather than months I wouldn’t bet against it.

      1. TallDave says:

        not impossible, but there’s little evidence minks (or cats or dogs) would function as a true reservoir species that could carry on the infection indefinitely once it dies out in the humans they are currently getting it from

        1. sort_of_knowledgeable says:

          There’s not a lot of evidence because we haven’t had a chance to check feral cat colonies or other possible animal reservoir. Although I suspect the most likely reservoir are humans in remote areas of the Congo, and other places of that ilk.

    1. A Nonny Mouse says:

      Not a good comparison when the given AZ price is 10x more than it actually is.

  41. Chris Phillips says:

    I’m a bit puzzled by some of the comments that imply the USA will easily be able to do without the AstraZeneca vaccine. Maybe it’s incorrect, but I’m seeing that the USA has ordered 100 million doses of Moderna and 100 million doses of Pfizer. Also 100 million doses of Johnson and Johnson, but of course the timescale for that is unclear. Is it being assumed Moderna and Pfizer will be able to supply an extra 400 million or so doses to the USA in the next few months? If not, doesn’t that leave quite a large hole in the country’s immediate requirements?

    1. Sc says:

      The order was for 100m with an option for 500m more.

      1. TallDave says:

        as with ventilator production, the ultimate question may be how much we throw away

  42. KTY says:

    I have seen antivaccine concerns that the vaccine will affect fertility and I am trying to figure out where that comes from. Once sentence you wrote “slipping messenger RNA directly into the cells.” makes me think that idea is behind the concern. I am pretty sure that this would not have any affect on fertility, but I can sort of see why some people might be concerned. Are there any experts who can speak with confidence about this issue, so that the anti-vaxxer concerns can be allayed?

    1. steve says:

      KTY – The unfortunate fact is that anti-vaxxers worries CANNOT be allayed. They are not rational, much like the conspiracy theorists on the right promulgating dead Venuzuelan politicians as engineering our election. Pointing out that Hugo Chavez died in 2013 or that Trumps 34 cases were all laughed out of every court in every state he tried does nothing to change some people’s conspiratorial minds. Similarly, pointing out that mRNA vaccines only end up in the draining lymph nodes and mediated a specific immune response will do nothing to rid anti-vaxxers of their misconceptions. Crazy is just crazy and no rational thought will change it.

      1. sgcox says:

        Or as Spitting Image put it succinctly – “there ain’t no cure for stupid”
        https://www.youtube.com/watch?v=CTqwQPe1z7U

      2. Dark Day says:

        The hard-core conspiracy-minded anti-vaxxers (e.g., the “Bill Gates is injecting microchips into our bloodstreams” crowd) are probably unreachable. But there are a lot of people with honest doubts about what they see as a “rushed” vaccine, and there are a lot of other people, such as African-Americans, with legitimate reasons to distrust the U.S. medical care system. These folks will need to be reached with informative, culturally aware information/advocacy campaigns in order for us to have sufficient uptake. I haven’t seen any evidence that Biden’s COVID Task Force has taken on a project like this, but it will be essential.

  43. An Old Chemist says:

    Here’s a look at how the different coronavirus vaccines work (CNN)

    https://www.cnn.com/2020/11/24/health/covid-vaccines-design-explained/index.html

  44. Marko says:

    A great study by Crotty et al. on immune memory after natural infection , covering IgG and IgA antibodies vs. several antigens , neutralizing titers , CD4 and CD8 memory , etc. Well worth reading the intro and conclusion sections for a good review of the current knowledge regarding sterilizing immunity vs. protection against severe disease as well as their results on immune memory :

    https://www.biorxiv.org/content/10.1101/2020.11.15.383323v1.full.pdf

    The only thing missing is an analysis of local URT / mucosal immunity , perhaps because of lack of sample availability.

  45. Chris Phillips says:

    It’s being pointed out that the half-full dose regimen was given only to people under 55:
    https://www.bloomberg.com/news/articles/2020-11-24/astra-vaccine-s-90-efficacy-in-covid-came-in-younger-population

    If that were the reason for the big difference in efficacy between the two regimens, surely it would be pretty obvious to those with access to the full results, including those for the UK full-full dose participants. If they failed to notice a gross difference between the UK and Brazilian results, and are speculating instead about more subtle mechanisms, they must be pretty dim!

    Still, the way the results from the two different trials have been combined in the press release is far from satisfactory.

  46. hamid says:

    Well, the content and the article were interesting
    The world of news is always fascinating to me
    I also liked the opinions of people about this article

  47. Bill says:

    https://mbio.asm.org/content/11/6/e02628-20

    So is an MMR II booster a bridge to the eventual Covid vaccine?

  48. Jim Ancona says:

    A negative take on the Oxford/AZ vaccine in Wired:
    https://www.wired.com/story/the-astrazeneca-covid-vaccine-data-isnt-up-to-snuff/

    Complaints include pooling data from multiple studies, lack of pre-registration, only including certain sub-groups from the study populations. I didn’t realize that none of the participants in the 90% efficacy group was over 55.

    1. Chris Phillips says:

      Some of what’s said there would be very worrying if true – for example “The two subgroups chosen leave out perhaps half the people in the Brazilian trial”.

      But is it true? If the n numbers in the press release included both those vaccinated and those receiving a placebo, then it would look that way. But I’ve been assuming they were just the numbers vaccinated.

      Obviously the one thing there is no doubt about is that the way these results have been reported is very poor indeed.

      Could they really have completely omitted half the participants from their report, or has the writer of that article misunderstood what they meant by n?

  49. Nigel Johnson says:

    As a DNA vaccine works by making our cells produce viral proteins what is this the risk of induced autoimmunity, something that could take years to show up?
    How many and what type of cells is the AZ vaccine affecting, and how long does the DNA inserted into those cells stay active? As the vector doesn’t replicate I guess the number of cells “treated” is low, possibly even limited to the injection site???
    Other than the fact that the virus doesn’t replicate is this differing in any other way from the way viruses naturally add DNA to our cells? But are any such viral infections also associated with causing autoimmunity?

    1. debinski says:

      This makes a lot more sense that the dosing error was caused by a manufacturing error. It could also explain why the error only occurred in the 18-55 age group. The randomization was stratified by age group and perhaps the young group got a different batch of vaccine (in the Cov002 UK trial).
      On another front, if you look across their preliminary trial results it appears that they were having a hard time picking the dose. In the phase 1/2 trial (Cov001) they start with a single dose (for most groups) of the higher/full dose vaccine. But there’s a protocol amendment after 2 weeks where they allow prophylactic tylenol at 2 sites (won’t this affect immune response?). Then the phase 2/3 study (Cov002) starts a month later using the half dose (both 1 and 2 doses) (to reduce AEs?). But a week after starting that trial, there is an amendment that adds another dosing tier using the full dose. Maybe they got immunogenicity data from the phase 1/2 trial indicating the low dose wasn’t enough? The study flow chart from COv002 is mind blowing and of course it doesn’t even include the dosing arm that got half dose/full dose. Check out figure 1: https://www.thelancet.com/action/showPdf?pii=S0140-6736%2820%2932466-1

  50. Nick Schaefer says:

    Very interesting comment section!

    As it looks today, the Astra Zeneca (AZ) vaccine might be somewhat less effective than Moderna and Pfizer, but is 10-20x cheaper per treatment, and a million time cheaper in distribution, as it does not require a -70°C cold chain.

    So at this point the AZ vaccine is the only choice available for less developed nations.

    Globally, the main objective is not the most effective vaccine.

    Much more important is a safe AND available AND somewhat effective vaccine AND fast.

    If a vaccine today pushes R0 from 1.2 down to 0.5, that is all we need.

    Much better than a vaccine two years later which might then give R0 at 0.3 – but only after another dozen million deaths.

    1. Dark Day says:

      Nick — Point well taken, although I’m not sure whether the data on the Oxford/AZ vaccine show that it will necessarily push the R0 down to 0.5, at least not without something close to universal (or at least 90% – plus) uptake.

      The problem, of course, is that now we’re again poised on the edge of yet another “two-tiered” situation, where the wealthy countries (and/or wealthy individuals and regions within countries) get the “Cadillac” of care, and the “others” get whatever’s left. Given that a lot of poor and underserved areas in the U.S. are unlikely to have easy access to the Pfizer and Moderna vaccines (given how the difficult and expensive they are to store and distribute), I could see those communities being “stuck” with the less efficacious (and possibly less thoroughly vetted) Oxford/AZ product, meaning that at best, our most at-risk populations will lag behind more privileged ones in terms of establishing some semblance of community safety.

  51. exGlaxoid says:

    Given that the nMRA vaccines need special storage, it makes sense to use them in urban areas with good access to power, airports, and highways, If other vaccines are cheaper, easier to ship and store, and available in large quanties, then it makes sense that they will be used more in developing countries. I don’t see a lot of people saying that they will skip the best vaccine and pay to ship it specially to someone in Africa. Sometimes you just have to be real and accept that the world has limited resources and try to work the best you can with what you have.

    But I just enrolled in the AZ vaccine study, as it helps us get another answer, and may well help get SOME vaccine to many countries and people as soon as possible. I don’t know of any reason that people who use the AZ or J&J vaccine cannot get another different vaccine in the future, as I have gotten various vaccines over my life, and never had a problem, and am not aware of any issue with taking two different vaccines, other than not repeating a virus vector one being a weakness in that type. But I am willing to stake my health on the ability to do that.

    I did not specifically enroll in that study, just registered and this is the first one that wanted me. I would have been happy to do the other ones, as I have pretty good faith in the companies involved, and again, getting a vaccine quickly is critical to saving thousands or more lives in the near future, so I encourage all scientists to consider it. It’s only the second time I have been in a study, but it is an easy way to help the world.

    1. Dark Day says:

      @exGlaxoid —

      From a practical perspective, I agree with you. I just think it’s unfortunate. Health inequality, like the overall social inequalities from which it largely derives, is a national and international tragedy. That being said, of course, access to a decent but less-than-optimal vaccine is hardly “tragic” for poorer populations that might otherwise have no recourse at all, but it does yet again reflect the larger systemic iniquities.

  52. Chris Phillips says:

    The Guardian reports:
    “Sir Mene Pangalos, AstraZeneca’s head of biopharmaceuticals R&D, has confirmed that the low-dose trial included nobody over the age of 55.”

    Also, Professor Sir John Bell of Oxford commented “We weren’t cooking this up as we went along”. I’m tempted to say you’d have an accurate description if you changed just one letter of one word.

    But the good news is that “he hoped the full, peer-reviewed data would be published in the Lancet medical journal at the weekend.”

    https://www.theguardian.com/world/2020/nov/26/scrutiny-grows-over-oxford-universityastrazeneca-vaccine

  53. debinski says:

    The cause of the dosing error becomes even more clear! I found this in the Lancet publication of their preliminary phase 2/3 COV002 (UK) trial data: ” The 18–55 years standard dose cohort received vaccine manufactured by COBRA
    Biologics for both first (ie, prime) and second (ie, boost)
    doses and all other cohorts received prime and boost
    doses, as randomized, manufactured by Advent.” COBRA screwed up.

  54. theasdgamer says:

    in the news…

    More gaslighting from the New York times in an opinion piece by Ashish Jha.

    https://www.nytimes.com/2020/11/24/opinion/hydroxychloroquine-covid.html

    Jha uses LATE treatment studies to attack treatment with antivirals and calls experts who advocate EARLY treatment with antivirals “snake oil peddlers.”

    Either Jha is an incompetent fraud or he is corrupt.

    What say ye?

    1. WST says:

      Prof Jha uses a very bad study to support his case, the “veteran” one, here is critique of it by prof Raoult team:
      https://www.mediterranee-infection.com/response-to-magagnoli-medrxiv-2020/

      The “veteran study” was also analysed in depth by prof Professor Roger Seheult at MedCram.

      Anyway, all RCT trials like Recover have proven that HCQ in late covid phase does not work but is safe.

      Prof Jha could be right but using a study with an obvious selection bias does not help his argument.

      1. theasdgamer says:

        Does Jha even test the antiviral hypothesis? Isn’t it implied that antivirals must be given early for an acute viral disease? So do late treatment studies test the antiviral hypothesis? I think that the answer is obvious.

        So Jha is supposed to be an expert on infectious disease. As a non-expert, it took me a while to understand that antivirals must be given early and that is possibly forgiveable. But I don’t see how an expert can be forgiven his failure to understand what is implied in testing the antiviral hypothesis. I don’t see an alternative to either incompetence or corruption.

  55. Bill says:

    So I’m reading that the AZ debacle includes age mismatch between the two dosing groups and they intend to start new trials. Does this development mean AZ is no longer a 1st wave vaccine? IE, new trials will take several months by which time current contenders will be in high gear, distribution-wise.

    1. Chris Phillips says:

      They seem to be pressing ahead with seeking approval in the UK. The suggestion I’ve seen is that approval would be granted for the full-full dose initially, and that the dosage could be amended later in the light of further results. (Of course there is a large US trial in progress, though recruitment seems to have been pretty slow, even allowing for the fact that it was suspended for more than a month. And they’re now talking about trying to amend the protocol for that trial too.)

      I think it poses quite a difficult practical dilemma. If it wasn’t for the age issue (and maybe other issues we don’t know about), it would have seemed that despite the low numbers the half-full dose was no worse and perhaps quite a bit better than the full-full dose. But if that conclusion is unsafe, you don’t want to approve the half-full dose, particularly for the elderly. And in fact, do you want to give the AstraZeneca vaccine to the elderly at all, if it could be significantly less efficacious than the mRNA vaccines? They would have been first in line for it – but now?

      Perhaps the regulator can dig into the data and resolve the age issue.

      1. Bill says:

        I don’t remember the details but I do recall announcement that AZ was having good results in elderly sometime back. That would have had to be with the full/full combination since apparently no elderly were enrolled in the half/full trial.

      2. Tony M says:

        If the data supported it, the regulator could always just approve the half/full dose vaccine to those in the age group it has successfully been tested on ie. those under 55 Years. Extending that approval to other age groups could be dependent on the conclusion of further studies.

        Regards

  56. Dark Day says:

    Informative journalism? Or “clickbait” that could discourage vaccine uptake (and encourage doom-and-gloom fatalism) among readers who don’t read carefully or get past the headline and the first few paragraphs?

    https://www.msn.com/en-us/health/medical/the-coronavirus-won-t-stop-evolving-when-the-vaccine-arrives/ar-BB1bqbf0?ocid=msedgdhp

    1. Todd Knarr says:

      Clickbait, I think. Any medical professional or pharmaceutical researcher knows that viruses mutate constantly, the question isn’t whether but how quickly. That’s been taken into account in all the vaccines currently in trials, they target portions of the viral protein that don’t appear to mutate very much and where mutations seem to hinder the virus’s effectiveness rather than help it.

      The article comes off kind of like warning car owners that their cars will eventually run out of gas and stop running: well duh, that’s why they come with gas gauges to tell us when we need to fill up again.

      1. Dark Day says:

        Yes, that’s my take on it as well.

        Maybe I over-react a little bit right now, knowing how much vaccine skepticism there is out there (and being worried that too many people will see the Oxford/AZ problem as evidence to confirm their fears) — Far be it from me to want to tell journalists what they “should” do, or how to write their stories, but if ever they had a public responsibility to encourage rational thinking and behavior (incl. vaccine uptake!) among their readers, this is the time.

  57. 이웅견 says:

    So now the BBC caught up with what we could learn here first.
    https://www.bbc.com/news/health-55086927
    IIRC this is my first comment here, although I have been lurking here for a few months.
    High praise to Derek Lowe for providing this public service, and for seemingly endless patience even with some fools.
    Bonus: https://youtu.be/hnhs–EG55Q Busan city government PSA re:wearing masks

  58. theasdgamer says:

    Update on early-treatment HCQ studies…

    Should we hold our theories tentatively or stubbornly?

    1 small study of low-risk patients was negative/inconclusive

    5 inconclusive small studies of low-risk patients

    21 studies showed benefit median 64% reduction of hospitalization

    https://c19study.com/#early

    Which are weightier–RCTs of small numbers of low risk patients or retrospectives of small numbers of high risk patients?

    1. Bill says:

      That’s an interesting website…thanks.
      The apparent conclusion is that HCQ has some value used early. Otherwise it’s a crapshoot.
      Best argument against the use of HCQ is to compare that chart to the similar one of Ivermectin.

      IE, HCQ might be of some value under some conditions, but there are much better choices.

        1. theasdgamer says:

          The newsguardtech website is not credible. It uses ad hominems instead of focusing on the arguments.

          By contrast, the c19study website is VERY useful and asks for readers to submit studies for inclusion. Not cherry picking, despite the smear by newguardtech.

      1. theasdgamer says:

        Actually, since HC and Ivermectin have different modes of action, including both in a cocktail is better than either alone.’

        Additionally, HC has a far better safety profile than Ivermectin.

        It’s up to physicians to make the treatment decision and both should be in a physician’s toolbox.

    2. rondi says:

      I’ve learned much from this forum–thanks Derek. The problem with these HCQ studies is–they do not, nor can they start when the patient has the very first symptoms. Most require positive test results–which in normal times–results take 3-4 days–maybe more depending where you live. We know–the virus has now replicated and done it’s job. Waiting 5 days after symptoms start is almost too late is too start. You’d have to have the scripts already in possession (means you gotta pay full retail–no insurance) so you could start the protocol when you loose taste/smell, fever + other symptoms–IOW not wait for a Dr to ok a PCR test and wait for the results. It has also been shown daily–Vit D3 5k iu, Zinc 50mg, Vit C—etc. are almost required to fight it. NIH/FDA has not addressed any of this ( in fact discourage it) while we watch all the unnecessary deaths add up! Kudos to the Drs out there who have had great success with these protocols and are willing to help folks like me.

      1. rondi says:

        I forgot to mention–almost all the studies do not include Zinc—which is the bullet. HCQ is the gun 🙂

  59. Rudolf says:

    Astra/Oxford have handled the release appallingly to everyone’s disadvantage. The 70% number was pure garbage.
    However….the US establishment have been bad mouthing this since the summer when it became apparent AZ were going into P3 trials a month before Pfizer and Moderna. Initial trials were originally planned wholly for UK with readouts in Sept. Then virus disappeared in UK during summer requiring rapid switch to Brazil. UK and Brazil now reported together but late November.
    It is untrue to claim protocols and rates were a surprise to UK regulators who were in close contact throughout.
    The UK trials were the ones to use the lower rate and were run to a higher standard than US trials. Firstly a proper placebo was used. Reading blogs it appears most US subjects were well aware when they received the saline shot. Secondly most of the subjects were followed up with swab tests identifying asymptomatic cases.
    The weakness is the sample size is smaller than ideal and older subjects were not included. Both these must be rectified but the P2 data suggests age response is unlikely to be a problem.
    Of course it is critical for Pfizer to knock AZ as if in practice the outcomes are similar Pfizer’s cost and handling disadvantages will restrict its use to early adopters in rich countries.
    It reminds me of the old professional boxing adage. If you are fighting in the States you need to knock the guy out to get a draw.

    1. debinski says:

      I agree that the AZ vaccine trial was more “blinded” to participants than Pfizer (or Moderna) but that is actually a disadvantage when it come to proving efficacy. Those who suspected they got placebo would be less likely to risk Covid exposure than those who suspected they got the real thing. The result is more exposures in the active vaccine group than in the placebo group.

      Also – the primary endpoint in the AZ trial was not just a positive PCR test. Symptoms were required. From the UK trial (COV002): “The primary efficacy endpoint is PCR* positive symptomatic COVID-19.
      This is defined as a participant with a PCR+* swab and at least one of the following symptoms: cough, fever ≥ 37.8, shortness of breath, anosmia, or ageusia. “

      1. debinski says:

        *That is, the trials that use a true placebo as a control are at a disadvantage for proving efficacy.

      2. theasdgamer says:

        That very same endpoint could have been produced by a flu patient with minimal systemic viral RNA. Too much uncertainty in all this. Culture the dam virus or stfu.

      3. Rudolf says:

        Yes I understand that, but a frequent US criticism seems to be a lack of professionalism and irresponsibility both from AZ and from the UK regulator.
        How trials outside the UK, including Brazil, were conducted, may be another matter.
        Actually given what we have seen elsewhere, I am more surprised the result in Brazil appears relatively poor especially given the broad similarly across P2 trials between different candidates.
        There are of course smaller scale P2/3 trials underway in half a dozen different countries which have yet to report.
        I would be surprised if ultimately far more AZ wasn’t used worldwide than Pfizer. But Sinovac and Sputnik probably more still.

        1. Dark Day says:

          . . . and we still have the one-dose J&J coming soon, and the highly-promising-in-early-trials Novavax in the bullpen. It’s very possible that within a few months we’ll have an unprecedented array of vaccines available, all of which will be at least acceptable, most of which will probably be significantly more than that.

  60. Shehla says:

    Can I please ask in the Oxford ( AZ ) trial what is the lowest definite efficacy in the 2700 sample size ? I know it has been reported as 90% but if we consider the margin of error due to sample size what would still be the lowest definite efficacy in this small group ?

    1. Chris Phillips says:

      Assuming it’s based on a split between vaccine and placebo of 3 to 30, I reckon the expected value of efficacy would be about 87% and the 95% confidence interval would be about 69-97%.

      1. Shehla says:

        Thanks Chris Phillips. So it means that in the low dose-high dose group 18-55year olds we can be certain that vaccine efficacy is no less than 69%. I think even 62 % efficacy in high dose -high dose group is not bad considering it is easy to store the vaccine at fridge temp.

        1. Chris Phillips says:

          Those figures are probably best viewed as a “guesstimate”. The lower end of the confidence interval is fairly close to the one reportedly calculated by Stephen Evans of the London School of Hygiene and Tropical Medicine, which was 66%:
          https://www.nature.com/articles/d41586-020-03326-w
          Evans’s assumptions about the figures, reported elsewhere, are a bit different from mine:
          https://www.sciencemediacentre.org/expert-reaction-to-phase-3-interim-analysis-of-the-oxford-astrazeneca-covid-19-vaccine/
          With his assumptions I get within 1% of his figure, though not exactly the same. With the paucity of data released, I needed to assume the number given the placebo was exactly the same as the number given the vaccine, but maybe that’s not precisely the case. (The figures in the press release don’t quite seem consistent with that assumption.)

          Of course, the 62% observed figure in the full-full group would imply a much lower confidence interval, with the lower end perhaps at 41%.

          But I don’t think that there can be any real doubt that both regimens and the trials in both countries meet the target that was stated for the US trials – significantly more than 30% efficacy, and observed efficacy more than 50%. However, I think the practical dilemma arises if the Oxford vaccine is not known to be so efficacious for older people, while the Pfizer vaccine is reportedly highly efficacious – a 94% headline figure for over-65s, though as far as I’ve seen no numbers that would allow a confidence interval to be estimated. (I really don’t think anyone should be reporting a headline figure without a confidence interval estimate!)

      2. Shehla says:

        Thanks Chris Phillips. So it means that in the low dose-high dose group 18-55year olds we can be certain that vaccine efficacy is no less than 69%. I think even 62 % efficacy in high dose -high dose group is not bad.

        1. Bill says:

          I wonder. For those with the math tools, what would be the difference in achieving herd immunity in some hypothetical population given the vaccine is 95% vs 60% effective? Assume the effectiveness describes the reduction in infectionous as well as outcome.

          1. Chris Phillips says:

            In a simple model of herd immunity I think you would just need to mutliply the percentage vaccinated by the percentage efficacy of the vaccine and then compared with the percentage required for herd immunity.

            I don’t think there can be much doubt that the estimates of the percentage required for herd immunity – if they are based on simple homogeneous models – will be substantial overestimates, because estimates of R from numbers of cases will reflect the parts of the population most liable to contract and transmit the infection.

  61. Paul says:

    Derek, is the Oxford/AZ vaccine the only one where the placebo in CT is another vaccine? Might there be some immune “bystander” effect from that immunisation in the control groups that could impact end points and/or severity and make the efficacy seem poorer in comparison to those trials where the placebo is saline?

  62. theasdgamer says:

    Just in case Derek is posting about this news already, I’ll post it here so that his posting will supercede mine.

    Review report Corman-Drosten et al. Eurosurveillance 2020: External peer review of the RTPCR test to detect SARS-CoV-2 reveals 10 major scientific flaws at the molecular and methodological level: consequences for false positive results.

    https://cormandrostenreview.com/report/

    The authors have requested that Corman-Drosten be withdrawn.

    Corman, et. al., “Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR”

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988269/

    1. Chris Phillips says:

      Does this explain the assertion a couple of days ago by one of the authors of that “report” that “the pandemic is fundamentally over in the UK”? He should go to a hospital in the North of England and take a look.

      Talking nonsense is one thing, but talking nonsense that can cost people their lives is quite another.

      1. theasdgamer says:

        Yeadon was likely slightly premature, but the disease is probably peaking soon if it hasn’t already. I have a relative in the hospital now from covid and I have had the disease and so has my household and other people I know. For months, I didn’t know anyone who had had covid. Now, I know several people with covid or who have had it.

        1. Chris Phillips says:

          “Yeadon was likely slightly premature, but the disease is probably peaking soon if it hasn’t already.”

          You really should think about what you’re saying.

          It peaked back in April. Would it have been “slightly premature” to say the pandemic was over then?

          On this subject, stupidity costs lives.

          1. Barry says:

            “peaked back in April”?! Deaths/day from Covid (in the U.S.) have never been higher than they are at present, even though we’ve learned a lot (dexamethasone!) about reducing lethality in the interim.

          2. theasdgamer says:

            “Peaking” is highly geographical. I would think that this would be obvious. And it is certainly possible for reinfection to occur–especially as it gets colder and vitamin D deficiency increases among populations.

            In the US (this is my context), New York and New Jersey experienced peaks in April and non-therapeutic interventions slowed the spread to most of the rest of the US. New Orleans was hit hard because of Mardi Gras. Now most of the rest of the US is nearing its peak. For months I didn’t know anyone who had had covid, and now my family has experienced it and my family hundreds of miles away and people in town and more people hundreds of miles away. So covid appears ubiquitous and that implies that soon almost everyone will have been exposed.

            You can see lots of news reports about increased hospitalizations. (My own county is strange, however. Lots of new cases and disproportional deaths, but hospitalizations in my county aren’t proportional to either cases or deaths.). So this is confirmation that covid appears ubuiquitous in the US.

            What will the result be? Probably lots of chronic conditions from covid. I have a relative who has been in the hospital for a week and was admitted because of symptoms and a positive covid test. We are worried.

            Could this have been avoided? Probably, if antiviral therapy had been studied aggressively and accurately. Instead, a pretense of study with late treatment was done. (Or maybe it was just incompetence. Maybe Fauci was thinking he was studying AIDS and the timing of antiviral therapy wasn’t so urgent.)

            I studied covid intensely, as I also studied treatments for it, PCR testing, and masking. I didn’t merely read abstracts, but dove deep into the weeds. I came up with a plan for my immediate household and implemented it and we came thru covid swimmingly. Twice, even. No physician intervention was required, as per my plan. Treatments were administered promptly upon symptom onset and cleared within 24 hours. And two of us are 65+ with multiple comorbidities.

            There are any people supplementing now to eliminate vitamin D and zinc deficiency, which tends to promote a healthy immune system and these people should not experience chronic problems. People with dementia are severely at risk as are nursing home residents generally.

            Looks like there will be a lot more deaths and chronic conditions of which many were very preventable had there not been such a major screwup by health authorities in testing antivirals and spreading unreasonable fear of treatment with them.

          3. RHB also says:

            Qualifier: “Cases” refers to hospitalisations/deaths, but judgement now reserved on SARS 2 attribution in light of:

            https://cormandrostenreview.com/report/

            Geographical peaking fits with experience over here in England – peak of cases in London and South East in March/April, cases declined through summer, then local peaks September onward (e.g. Northern cities, e.g. Liverpool, Manchester).

            Cases declining again now – politicos attributing to Lockdowns, Tiers and fit and healthy teenagers by GOV.UK decree cooped up playing FIFA20 on the Xbox in teenage bedrooms, but NOT PLAYING competitive junior football 4 weekends in a row on the astro at space-time averaged 1 participant per 100 square metres. As ever, correlation not causation.

            Simple-minded physical science view, all other things being equal, case severity dependent on viral exposure. Bigger the exposure, the more likely a virus to get down the windpipe and deep into the lungs where the serious damage gets done.

            So at risk of hubris – airy supermarkets, watching football on the astro, and even being intermittently in the same household at 1 person per 50 square metres with two fit and healthy young men at worst likely to shed minimal viral load, deemed lowish risk for late 60something and wife a few years younger, both thankfully in reasonably good health. As for vitamin D, let’s get out in the fresh air come hail rain or shine and do stuff!

            Real time – within right earshot, BBC Panorama Special covering the children’s adventure centre closed 4 months by GOV.UK edict, then only allowed to re-open with socially distanced numbers. Debt piling up and counting. Staff about to be laid off. Ditto for for the town centre gift shop and the business that hires out tents and marquees. Kerching! Closed down again for Lockdown 2.0.

            State Sponsored Madness. Same Madness that keeps a fit and healthy 6th former out of school for 38% of the term for being pinged within 2 metres of a tested positiver when not a sniffle, cough or sneeze to be heard. Same Madness that has student scientists doing two terms of an experimental sciences degree minus the experiments. Government by Theatre of the Absurd.

            Panorama Special Ends. “Crunch time for British businesses,” says the voiceover. Marquee business bust. 40 Jobs lost. Adventure centre and gift shop teetering on. Clown government led by a Clown Prince. Anyone else starting to suspect asymptomatic spread a pernicious little myth worthy of the Brothers Grimm?

      2. RHB says:

        I’d welcome the opportunity to go inside a North of England hospital and take a look. Except they wouldn’t let me near a hospital anywhere in England for fear of taking virus in or bringing virus out. Ditto for the local GP surgery – thankfully not really needed over the last 9 months, although for a couple of weeks I did wonder if it would be. As for the NHS dentist, don’t get me started…

        Task for this eve is to print off and take highlighter pen to the Yeadon et al report and the original paper it analyses, and to teach myself what it all means, in as much as a chemist with little formal molecular biology training can. Impression the Yeadon paper doesn’t really go into all the implications or the extent of the problem.

        At cursory glance, interim view is whole SARS 2 testing worldwide past and present could be seriously undermined. Doesn’t get much bigger than this in peace time:

        CONCISE REVIEW REPORT

        This paper will show numerous serious flaws in the Corman-Drosten paper, the significance of which has led to worldwide misdiagnosis of infections attributed to SARS-CoV-2 and associated with the disease COVID-19. We are confronted with stringent lockdowns which have destroyed many people’s lives and livelihoods, limited access to education and these imposed restrictions by governments around the world are a direct attack on people’s basic rights and their personal freedoms, resulting in collateral damage for entire economies on a global scale.

        There are ten fatal problems with the Corman-Drosten paper which we will outline and explain in greater detail in the following sections.

        …For a start, would assume all those patients in North of England hospitals that Chris Phillips refers to have “tested positive” and are being treated accordingly. Yet if test questionable, then so would become diagnosis and etiology (and indeed all the death stats paraded before us and used to justify public heath policies around the world for the last 9 months, let alone all those contacts banged up at home, children taken out of school, etc, etc…).

        Piece duly said. Off outside to cut hedges, then sit back, draw breath and reflect awhile.

        1. Marko says:

          “At cursory glance, interim view is whole SARS 2 testing worldwide past and present could be seriously undermined. Doesn’t get much bigger than this in peace time ”

          More rubbish , from a seemingly endless supply.

          Hospitalizations aren’t determined by PCR , but they reliably follow case counts with a lag. Similarly , deaths aren’t determined by PCR , and they also reliably follow case counts and hospitalizations with a longer and shorter lag , respectively. No other explanation besides COVID-19 can explain these data streams since the outbreak began.

          Who are the multiple authors who contributed to this ground-breaking denialist claptrap ? Why are they in hiding? Probably because they don’t want to experience the same fate as the other denialist gurus , who’ve been proven wrong at every turn , on everything from”dark matter” herd immunity that was supposed to end the outbreak months ago , up to the current nonsense about “false positives”.

          Commenter “Riah” unveiled a new denialist guru a month ago , Dr Clare Craig , claiming that the pandemic was “all but over ” in the UK. Since then , the 7-day moving average of daily deaths have climbed from ~200 to over 450 today. That would correspond to over 2000 deaths per day in the US , adjusted for population. Does that sound anything remotely like “all but over” ?

          https://blogs.sciencemag.org/pipeline/archives/2020/10/27/more-antibody-data#comment-331459

          1. RHB says:

            You seeee what you seeee, Marko… I seeee what I seeee.

            In the last resort, all we can do is tell each other what we’ve seeeen.

            And for the record, I’m not saying what you see is rubbish, so please do me the same courtesee in return.

            Thank you, much appreciated.

          2. theasdgamer says:

            “Hospitalizations aren’t determined by PCR , but they reliably follow case counts with a lag.”

            Nonsense. If the county health dept. is pushing testing, you’ll get all kinds of false positives show up and hospitalizations won’t be proportional, even with a lag.

            Pro tip: Many times false positives aren’t associated with symptoms.

          3. theasdgamer says:

            Also surprising, by some sleight of hand, in my wealthy suburban county covid deaths are increasing and anticipating an increase in hospitalizations.

            That’s right, “Covid” cases and deaths are up (deaths more than cases, proportionally), while hospitalizations are level. Something is rotten in Denmark,

          4. Marko says:

            ” Thank you, much appreciated”

            RHB , you’re counting chickens your before they hatch. If you continue to promote rubbish , you should expect to be called out for it , by myself or others , without apology.

          5. RHB says:

            Apology neither sought nor expected, Marko. Nowt to apologise for.

            Real time: Off to opticians today for annual eye test. Think I can still see.

            Meanwhile, chips still on table, sheep still out in badlands, and chickens in eggs smashed against brick walls for sure won’t hatch. Time to stake spiritual alms house all way back to weekend of going back of the British clocks 26-28 October 1990, the symbolic equinox:

            The Scientist

            As a kid I had Bako,
            then Lego came in.
            Who knows what they’ve got today,
            i’ve no young kin.

            At Meek High we had substances,
            then compounds came in.
            Who knows what they’ve got today,
            the lab’s in the bin.

            *****cricket

            At Beans we had Dr Heatley,
            Then young who? came in.
            Who knows what they’ve got today,
            but electrons must still spin.

            In the lab, I had my rotavap
            and flasks to collect things in.
            They’re still there, I know,
            they’ll never go in the bin.

            *****hills

            Today I don’t know what I have,
            yet I know I wear.
            For Who is right and who is wrong?
            You, maybe, but will I dare?

            …There’s a hush in the close tonight. Have put up, will shut up.

        2. Chris Phillips says:

          This really is witless nonsense, and frankly it strikes me as malicious too, because if it’s believed it’s capable of costing lives.

          The fact is that the hospitals in parts of the UK are close to capacity because of large numbers of people with COVID-19 symptoms, regardless of any doubts about the accuracy of testing.

          Unless you have an alternative explanation for these large numbers of sick people, perhaps you should reflect further before propagating more nonsense. People who are advocating a relaxation of anti-COVID-19 measures should reflect on what would happen if the capacity of the hospitals – and of the health workers who are putting their own lives at risk in caring for patients – was exceeding.

          You need to get real.

          1. theasdgamer says:

            Chris Phillips, quit pushing nonsense.

            Hospitals are full of people with “flu-like” symptoms, not “covid-19 symptoms”.

            Your logical fallacy is called “begging the question.”

            The fact is, a viral panel with 20 targets is more likely to render a false positive for covid than for flu because the sensitivity is set high for covid and specificity is set high for flu. Such a viral panel is likely to render a false positive for more than 1 in 5 patients for one of the targets.

          2. Chris Phillips says:

            theasdgamer

            Thanks. At least it makes things clearer that you are coming out openly as an out-and-out COVID-19 virus denier.

            Of course, anyone who has been following the news at all knows that because of the anti-coronavirus measures, flu levels are currently at vanishing point. So the pretence that it’s just flu that’s causing the near-collapse of health services across the world is even more patently ludicrous than it was during the last peak in the Spring.

            As for the fact that the Phase II trials show that your supposed false-positive COVID-19 diagnoses are cut by a factor of 20 in people who have received the COVID-19 vaccines, perhaps you can turn to Rudy Giuliani or somebody similar for an explanation of that!

            Or perhaps you can reflect on the fact that large numbers of people are dying, and just stop posting misleading information.

          3. theasdgamer says:

            Chris Phillips,

            You lie and smear me. I am not a covid denier. Else I wouldn’t be concerned about hydroxychloroquine. If you fail to apologize, everyone will mark you as lacking good character. I will not be anticipating said apology and don’t care whether you offer one or not.

            As far as the news goes, this is the same news that said that hydroxychloroquine was dangerous and asserted that studies of late treatment with HC was evidence against early treatment with HC and pushed covid panic. I mark the news and test. I don’t swallow it wholesale, which you apparently do.

            You really have pushed enough of the “elite’s” codswallop and you are tentatively marked as a sheep and lacking in critical thinking ability.

          4. RHB says:

            Dear Chris Phillips,

            Been called a few things in my time, but can’t recall witless and malicious ever being among ‘em. Perhaps am growing old in an age in which wit gets taken for witless malice. Maybe better become hermit and go gently unto that good night for however long it takes (no thanks). Sticks and Stones and All That.

            Reading between the lines of your posts, (Dr) Phillips, infer you may well be a Doctor of Medicine working at a North of England hospital, where significant numbers of patients are being admitted with illness attributed to COVID-19 = SARS-Cov-2 (= “SARS 2”), in which case you have my utmost respect and admiration. If your hospital is overwhelmed with sick patients, I’m sorry to hear of that.

            Having re-scrolled down the Pipeline, can now see limey chemist dude armed only with book of English verse stumbled into crossfire of feud between Vitamin D Gang, HCQ Gang and Yeadon Gang all goin’ up against Doc Phillips and Doc Marko Gangs. Seems Docs deemed limey dude guilty by association, when all dude said was an online paper, authored by Pieter Borger, Bobby Malhotra, Michael Yeadon et al, might be worthy of closer examination.

            Dude bit staggered as well. That five verses dashed off at two in the morning 30 years ago could now become, “witless nonsense,” that’s “capable of costing lives.” As for getting real, seems surreal that comment buried miles underground in a pipeline could conceivably become matter of life and death…

            Molecular biology not limey chemist’s field but for the record, queries about RT-PCR assay, as disclosed in online paper, seem to be:

            • Use of in silico SARS-Cov-2 sequences, as live or infected SARS-Cov-2, or isolated genomic viral RNA, unavailable at time
            • Number of amplification cycles used – more than 35 and false positives recorded (97% probability?)
            • “Primer concentration” too high?
            • Something about two base pairs where three better?
            • “Unspecified (“wobbly”) primer and probe sequences” (No idea what these mean – gobblydegook to this chemist dude)?
            • Test can’t tell between whole virus and viral fragments?
            • DNA amplification temperature 10 degrees out?
            • No Standard Operating Procedure (SOP) made available (now this dude does get…)
            • No peer review (dude also gets, seems to be norm for much of key stuff over last 9 months, e.g. Imperial epidemiology papers loaded direct on to UK SAGE website with no review or counter from outside the immediate cabal?)

            Now maybe some or all above list sorted since RT-PCR assay first worked out starting early January this year? Later publications from same and/or other groups to this effect? If still had SciFinder, could check. Calling Lord Alfred, Sir Graeme and the Lady Rowena, if by any chance reading. Chemist dude in need of context and perspective, as ever.

            Could you, Sir Graeme and Lady Rowena, in 2-3 weeks set up, validate and write a high quality SOP for a RT-PCR molecular biology assay to be deployed at labs around the globe, including those administered by Deloitte, Sodexho et al, knowing the assay data could become social, political and economic dynamite?

            Or alternatively, how far on could you get in 2-3 weeks with a team of 25 authors across 8 centres, as named on paper submitted to journal Eurosurveillance on 21 Jan 2020, accepted 22 Jan 2020 and published 23 Jan 2020?

            FYI Eurosurveillance (established 1995) by own blurb is, “Europe’s journal on infectious disease surveillance, epidemiology, prevention and control.” And meanwhile, btw, Hygiene Police out and about over at Reddit…

            Sorry, this post has been removed by the moderators of r/Coronavirus.
            Moderators remove posts from feeds for a variety of reasons, including keeping communities safe, civil, and true to their purpose.

            Also FYI, Dr Phillips, these 9 months, starting in earnest 23 April, limey chemist immersed in aspects of epidemiology, immunology and virology that lie behind “The Science” and the “Scientific Evidence,” that the UK Government (on behalf of the UK electorate), its Chief Medical Officer (on behalf of the UK medical profession) and its Chief Scientific Adviser (on behalf of various UK scientific sub-committees, including SAGE, SPIB, SPIM and NERVTAG) keep reiterating have driven UK Government policy during those said 9 months.

            Findings distilled into early draft of private report in three sections, compiled by “an independent physical scientist”:

            1: MARKED ACUTE RESPIRATORY SYNDROME:
            – Invasion, Contagion, Colonisation, The End
            2: PUBLIC HEALTH, SOCIAL & MEDIA:
            – Historical, Governmental, Scientifical, The End
            3: THE END

            So there we have it, gracious Dr Phillips. Witless and malicious commenter at it again. Might get round to publishing report some time somewhere once dust settled.

            Inside the hospital your domain, Dr Phillips, for which I’m ever grateful. Outside hospital, surgery and wellbeing centre is everyone else’s domain too, and that includes ins and outs of RT-PCR assays.

            By all means, Dr Phillips, berate again from your moral high ground. That’s your prerogative, just as it’ll then be my prerogative to ignore (and civil Dr Marko with you).

            We here in the (dis)United Kingdom should never have been held hostage by moral imperative’s dubious mandatory altruism in the first place and need to make sure it doesn’t happen again next time.

            Meant to mention the counter intuitive. No matter, another time.

            Best regards, Rob B

    2. A C-Doyle says:

      Thank you Sir for posting. Sort of dossiers that used to send Holmes to his rooms with opium pipe and red pen, Watson to the door of Baker St to stand guard with umbrella and revolver at the ready, and in due course the plot to the Reichenbach Falls for a show down at last with Professor Moriarty…

      And for the record, my good friend A Briton reminds me he always was a bit of a virus sceptic:

      https://blogs.sciencemag.org/pipeline/archives/2020/03/12/real-information-a-public-good#comment-313468

      16 March, 2020 at 9:09 am

      Seriously, hats off to all involved for seriously meticulous scrutiny with seriously massive implications. Not my area of detailed expertise but, if I’m reading broadly right, will have leadership of country I’m posting from seriously quaking in their boots and going seriously berserk covering their own lightweight backsides. Some serious fun coming up at last!

    3. RHB says:

      Just to say thank you, theasdgamer, for posting the link to the critique by Pieter Borger, Bobby Malhotra, Michael Yeadon et al of the “Corman-Drosten paper”, which I’m taking to be the seminal paper from which RT-PCR testing derives in Europe (and N America? What about East Asia?).

      Longer comment posted and hopefully being reviewed by the Moderator. Includes summary of paper, “Post-lockdown SARS-Cov-2 nucleic acid screening in nearly 10 million residents of Wuhan, China,” published in Nature Communications a couple of weeks ago:

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

      Just thought I’d draw Nature Comms paper to your attention in case not come across already. Thank you also for your subsequent comments on this thread. Welcome reading.

  63. An Old Chemist says:

    AstraZeneca Looks to Clear Confusion Over Vaccine Results with Additional Studies (Biospace)

    https://www.biospace.com/article/astrazeneca-could-conduct-additional-studies-to-clear-confusion-of-vaccine-results/

  64. Shehla says:

    Would someone here know the answers to these questions with the Oxford covid vaccine.
    Since the vector adenovirus shuttles its genome in the nucleus of the host cell for transcription and replication, what is the risk of genomic integration?
    Once the adenovirus goes inside the host cell does its DNA stay there or is it destroyed ?
    Also are there any concerns about mutagenesis / oncogenesis with this technology ?
    What happens to human cell when it presents the spike protein antigen and spike antibodies are produced ?

    Thanks

  65. Marko says:

    Hospitalizations in US soon to break 100k. 7-day average of daily deaths to pass 2000 in the next week or so as holiday data lag catches up. It’s gonna get ugly :

    https://twitter.com/COVID19Tracking/status/1333573974404460546/photo/1

    1. theasdgamer says:

      “Hospitalizations in US soon to break 100k.”

      …so unusual for flu season

      https://www.statista.com/statistics/861153/flu-hospitalization-rate-us/

  66. Bill says:

    I see the CDC has now been called on the White House carpet to explain their foot dragging for emergency use authorization of vaccines. Their excuse is they have thousands of pages of technical documents to read and analyze. When asked why they didn’t start this process earlier when the material first became available they stated “that’s not the way we do things.”

    Right

  67. exGlaxoid says:

    I am also upset that the FDA and CDC have had months to prepare for this time, and appear to be lollygagging, when they could have been examining the Pfizer data all along, and have approved the vaccine by now, if they had been working all along. The UK has already done that, and, while there may be some delays in getting vaccine ready, the sooner, the better in my opinion. Note that I am not saying that people should be forced to get the vaccine, only that it be made available for those who want it as soon as possible.

    I hear constant media and government officials saying how difficult or impossible the vaccination task is, but it just seems overblown to me. We have had the ability to ship things on dry ice for years, and there appear to be enough -80 C freezers on hand. We have kept 3 NMRs at -270C for 10 years where I work without a problem, in the midst of a helium shortage and low budgets, so the entire US government cannot find dry ice or freezer space? Come on.

    There is certainly ample evidence that the Pfizer and Moderna vaccines are effective, and the safety data should be pretty clear, either it is safe enough compared to chances of Covid or not. Each day of delay could cost hundreds of lives or more.

    BTW, I don;t know what the AZ trial did elsewhere, but in the US trial that I am in, the placebo is saline, not another vaccine, according to my paperwork. So there should be no activity at all in the placebo group. So I either got the placebo, or the first shot has no side effects.

    1. Lambchops says:

      Pretty sure the UK authorised this so quickly because the government wanted to harp on about this being a win for Brexit (this isn’t a dig at the MHRA at all – just noting the priorities of the current government).

      Can’t speak to to the situation in the US (things may well be going slower than desirable) – but perhaps a comparison with the EMA would be more apt.

      1. A Nonny Mouse says:

        Everyone’s now at it; the German health minister saying how it’s a German company that did it (though I am sure that the bulk of work was probably done by Pfizer).

        Certainly, it’s not Brexit related, though the MHRA were probably freed from some of the EU bureaucracy.

  68. Rudolf says:

    MHRA did not authorise it on the instructions of government, although Boris is pleased they did so.
    They were first because they have been reviewing data as it came in since mid year. Neither US nor EU were doing this.
    And signed off in real time rather than as both EU and US are apparently doing waiting for their next scheduled committee meeting.

  69. An Old Chemist says:

    AstraZeneca’s Covid-19 vaccine data published in peer-reviewed journal confirms 70% efficacy (CNN): (12-08-2020)

    https://www.cnn.com/webview/world/live-news/coronavirus-pandemic-12-08-20-intl/h_f4092faa9173b5b93177c46389b8296a

    1. Chris Phillips says:

      Here is a link to the peer-reviewed paper in the Lancet:
      https://www.thelancet.com/lancet/article/s0140-6736(20)32661-1

      I thought there were two disappointing things:
      (1) It seems they don’t have enough data to estimate efficacy in the older age group, and though it seems hard to believe there were enough older participants for age differences to explain the higher efficacy in the half-dose/full-dose arm, that arm wasn’t particularly well matched with the others in terms of gender or comorbidities either.
      (2) The efficacy for asymptomatic infection seems much poorer than for symptomatic, though again it is better in the half-dose/full dose arm.

      1. Chris Phillips says:

        Here is a commentary article in Nature:
        “The first formally published results from a large clinical trial of a COVID-19 vaccine — which scientists hope could be among the cheapest and easiest to distribute around the world — suggest that the vaccine is safe and effective. But the data also highlight a number of lingering unknowns, including questions about the most effective dosing regimen and how well it works in older adults.”
        https://www.nature.com/articles/d41586-020-03504-w

        They did separate out the over-55s in the UK study, but there were only 4 cases, 1 in the vaccinated arm and 3 in the placebo arm. Far too small to give meaningful statistics, but at least the fact that there was only 1 vaccinated case makes it clear that the lower efficacy in the full-full arm wasn’t the result of a lot of infections among older participants.

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