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Clinical Trials

The Vaccine Protocols

We now have the official clinical trial designs for the three biggest and most advanced coronavirus vaccine trials: Moderna, Pfizer/BioNTech and Oxford/AstraZeneca. Now, as for you, J&J, Novavax, Merck, and all the others that are pushing into efficacy trials as fast as possible – don’t think for a moment that you won’t be expected to do the same. But this is a good start. So how do these trials differ?

Let’s start off with some background, starting with “vaccine efficacy” (VE), which is pretty much what it sounds like: the percentage difference of infection by the virus between the vaccinated group and the unvaccinated control group. The FDA has already said that they want to see 50% at least (i.e., the vaccine cuts the rate of coronavirus infection at least in half). All of these trials have different subgroups, especially broken out by age and/or pre-existing conditions, and there will be not only an overall VE for the trial but separate VEs determined for all of the predefined subgroups. As is standard, the trials will be using what’s called a Cox proportional hazard regression model to assess the differences between the various groups – I won’t go into the details here, but that’s how you get the eventual figures of “Group A is 2.1x less likely to get infected than Group B” and so on. The Cox model actually gives you the “hazard ratio” (HR) which is just the opposite of the VE, so a 60% HR would mean a 40% VE. Update: this is one way to do it – the various trials have different statistical approachs.

The trials will be doing a similar analysis for different endpoints as well. For example, rather than calculate what effect the vaccine had on just sheer infection by the coronavirus, they will also be checking how many of the infected cases were severe (as opposed to those cases in the placebo group), how many asymptomatic cases there were, how these categories might look under alternate diagnostic criteria, the comparisons between these figures and different immunological readings (neutralizing antibody titers, for example), how many deaths took place, and so on. The same sorts of calculations will be going on for adverse events, looking for differences between the vaccinated and placebo groups and how these differences might change across the various subgroups. We’re talking a lot of data for any given trial, and with the number of trials going on, it’s going to be an absolute downpour of information.

The next thing to go into is statistical power. I will again avoid breaking out any equations, but the idea is that given a certain rate of infection in a population that you need enough patients in such a trial to demonstrate a given level of VE within given statistical bounds. The key to a controlled clinical trial is to lay out your statistical landscape in detail before you start, defining what success and failure will look like, and making sure that you have enough patients (and will see enough events) to distinguish them to an acceptable amount of rigor after a given amount of data gets collected.

All three trials have basically the same definition of failure, which would be a VE of 30% or worse. And they are all designed to have greater than 90% chance of demonstrating that the VE is better than that (if in fact it really is, and it had better be!) That’s the first thing you have to make sure of: to be able to say if the vaccine has succeeded or failed, and it should go without saying that if such a trial just enrolled (say) 100 people that it would be impossible to make such a call. And it would be even more impossible to say anything about safety in such a small study – adverse events are expected to be rare (but by no means impossible!) and you’ll thus need a sample size that can at least let you set some lower bounds on their frequency.

So all these trials are enrolling at least 30,000 people. Moderna is dividing their enrollees into 15,000 treatment patients and 15,000 controls. Pfizer is also 1:1, but AstraZeneca is going 2:1 treatment/placebo (more on that in a moment). That sample size is also related to how quickly you’ll be able to determine success, as you would figure. Remember, in a trial like this you’re waiting for people to get infected with the coronavirus – the number of people infected in the treatment group versus the control group is the most important data point in the entire trial. That’s why you want not only to have a lot of people, but to run the trial in areas where the virus is actively spreading.

Another important thing is the how you specify the interim analyses. Clinical trials often aren’t run “straight through” to the final data collection while flying blind the whole way. There are independent groups that keep an eye on the data (and on the adverse events), variously known as Data Monitoring Committees or Data and Safety Monitoring Boards, etc. These people are kept separate from the investigators, obviously. You need to lay out your plans for such interim looks at the data in advance, to avoid the temptation to move the goalposts once you’ve seen what’s going on. Note that none of these trials going to stop the study if they see good results early on – they’ll continue to collect data, but in the knowledge that they’re on to something effective. That’s both to get better statistics on the efficacy and to keep an eye out for safety: all these trials have prespecified alerts and stopping criteria if the DSMB sees a given number of adverse events as well.

So for Moderna’s trial, they have estimated that they are likely to see about 150 infection events during the whole trial. They have specified an interim analysis at 53 events (35% of the way through) and another at 106 events (70% of the way). At that first IA, the study will be considered to be already declared a success (rejecting the null hypothesis that the VE is only 30% or below) if the p-value for such a rejection is less than 0.0002. That would mean that the vaccine itself would be at least 74% effective. If the efficacy doesn’t meet the cutoff at the first IA, success will be declared at the second one if the p-value for rejecting the null hypothesis is less than 0.0073, which would mean a VE of at least 56.5%. If they have to go all the way to the end, then they’ll need a p-value of less than 0.0227 to reject the null, and that would mean a VE of 50% (the FDA’s floor, and it is no accident whatsoever that these two coincide).

As for Pfizer/BioNTech, they have a somewhat more aggressive approach. They calculate that they’ll hit 164 cases by the end of the study, and they have four IAs planned, at 32, 62, 92, and 120 cases. If they can reject the null hypothesis at that first one, that will be considered “overwhelming efficacy”, with a VE of at least 77%. The VEs if they clear the bar at the later analyses instead are 68%, 63%, and 59%, and if they make it only at the end of the study that would be a VE of 52%.

And the Oxford/AstraZeneca trial also estimates that they’ll see 150 cases by end of the study, and they have one interim analysis set at the 75-case mark. They estimate that will give them > 70% power to detect a VE of 70% and > 90% power to detect a VE of 75%. By the end of the trial, they believe that they’ll have a 90% chance of being able to say if the VE is 60% or greater.

So how quickly will these trials hit these readouts? That depends completely on the attack rate of the virus in the study population, as mentioned above. The more you are testing in viral hotspots, the faster you will collect data. If you decide to test in New Zealand, on the other hand, you will probably never hit the cutoffs at all. Pfizer has said several times that they expect to get a first readout by the end of October, and Moderna has said that they expect to get a look by the end of November. AstraZeneca, with only one interim analysis, will probably have to wait a bit longer from the start of their trial, although they did start on the early side. I would expect the companies involved to announce a positive result if they do make any of these interim analysis hurdles, though (wouldn’t you?)

So that’s roughly where things stand, and I hope this gives people a clearer picture of what’s going on. Now, as with all trials, we just have to wait for the data to come in. . .

145 comments on “The Vaccine Protocols”

  1. EpiGal says:

    Many thanks for the summary of the protocols- and in particular, very helpful to understand the way-points for IAs for the various vaccines. Is there anything in these protocols that will shed light on whether vaccinated individuals are less (or more) likely to be asymptomatically infected (e.g., intermediate PCR sampling)? One worry I have is that vaccinating individuals may just increase the pool of potential asymptomatic shedders spreading the infection… protected from sickness but not necessarily from being infected.

  2. Ben Shannon says:

    Ordinarily, when clinical trials do an interim analysis and don’t find evidence of overwhelming efficacy, the companies don’t release that information. Do you expect it will be different this time? Will Pfizer be releasing the results from the first look regardless of what they say?

    1. Derek Lowe says:

      Yeah, good point. I think that with the spotlight on everyone the way it is that they’ll have to. Pfizer, for example, has put that “by the end of October” timeframe out there so many times that they’re not going to be able to just whistle past it. Not if they don’t want everyone assuming the absolute worst, that is.

      1. Duncan says:

        Perhaps a note of caution? I do fully appreciate that the unprecedented sums of public money on these trials do mean that there is a clear interest in these documents. I don’t think anyone serious would dispute that. But do we want pharma to disclose things like this as standard – and if not why not? I don’t think anyone has ever routinely demanded to study the protocols before taking a drug or vaccine before now have they? Why not ask (say) those testing antiviral treatments for their protocols and start poring over those online? Indeed why should all this be restricted to publicly financed Covid vaccines and drugs?

        Bluntly I am rather doubtful that the release of these documents will actually change anyone’s mind, and will rather be pored over by academics and investors and then discussed on various social media and talkboards in threads of very varying quality.

        I know that it’s a can of worms, but this seems to me to be another example of science needing to dramatically rethink its relationship with the media (mainstream and social). Not all that long ago all of these debates would have taken place in seminar rooms and on the pages of journals. Now we see scientists joining the online bunfight – and it’s not pretty and it’s not done science any favours. We’ve generated a lot of heat, but not a commensurate amount of light.

        So yes, welcome the transparency. But has anyone actually thought what we’re going to do with it?

        1. Robert says:

          Because this pandemic has been politicized in ways that recent previous ones have not, and so having data rather than rhetoric is important. People may not use it (because you can’t make people think if they don’t want to) but they can only use it if it’s available at all. Arguments over data are better than arguments over opinion because there is a common object to which everyone can refer to judge the arguments (if someone doesn’t believe the data provided, then they’d either provide better data or be ignored).

          If we’re going to find some way out of the messes we’re in as a society, having better data on issues like this and focusing on it is a start.

          1. Pontificus says:

            We’re talking about reaching the general public here, right? (Forgive me if I’m misunderstanding.)

            Any good rhetorician knows that all four components of the classic rhetorical model — “Logos” (logic, facts, data, well-ordered and rational delivrey), “pathos” (appeal to values and mores [not just “emotions,” as is commonly misunderstood]), “ethos” (perceived reliability of the one delivering the message) and “kairos” (timeliness) –are essential components of persuave argumentation.

            In this case, the “kairos” is a given — we’re in the middle of an international public health catastrophe. “Ethos” will depend on the audience we’re trying to reach, and in the highly politicized atmosphere we’re in right now, this one will be dicey. Some folks trust Dr. Fauci, others don’t; some folks will trust someone associated with Trump, others will trust someone associated with Biden. Some will only trust someone with whom they share “identity” (race, culture, gender, etc.) — some trust “experts,” others don’t. If the “experts” (e.g., the FDA, the CDC) have found their trustworthiness compromised, that adds additional layers of complexity to the issue — either way, though, the messenger, as well as the message, needs to be considered very carefully.

            The “Logos,” of course, is in the data, although whether the listener is inclined to trust the reliability of the data will also have to do with whether s/he trusts the one delivering it, which bleeds back into “ethos” again. The “pathos” will include whether or not the audience has preconceived biases — in this case, either for or against a vaccine — but it will also include how risk-averse they are, and how they balance the perceived risks of getting vaccinated vs. the perceived risks of contracting COVID and/or the financial/social/emotional toll taken by living under COVID conditions for an extended period of time.

            So far, I think, the messaging has been pretty muddled and confused. I hope that will change as we get closer to an actual vaccine rollout.

  3. Steve Scott says:

    New York Times: “Moderna’s chief executive, Stéphane Bancel, said the company would report publicly on the results of the first so-called interim analysis, and the next one, when they are conducted. Pfizer has said that it will share information about the analyses only if a decision is made that the trial should be stopped, either because it is very effective or because it does not appear to be working.”
    _______________________________________________________
    So, there is not total transparency here. Also, I do not understand why these detailed testing protocols needed to remain secret at all. I don’t see that they give any company a competitive advantage. And after all, early on in a White House meeting, the big pharmas pledged to cooperate with each other.

    1. Chris Phillips says:

      Given that the Pfizer trial had reportedly enrolled 23,000 participants by early September, and given that there are currently about 80 cases a week per 100,000 in the USA, isn’t it safe to assume they have already done at least the first interim analysis?

      1. rvhees says:

        No, unfortunately not. The incidence rate in the study population is significantly lower than the incidence rate in general population. People that display risky behavior to catch COVID tend to not join these kind of studies. The people that do join the study tend to be more cautious and are therefore less likely to get infected.

        1. Chris Phillips says:

          Thanks. I can see that might well be the case.

          I wonder if you (or anyone) has any thoughts on which of the four interim analyses Pfizer may have had in mind when they have talked about mid-October.

          1. Marko says:

            I can imagine a scenario where they file for an EUA approval based on the first or second interim look in early-mid Oct. , then reveal the next ( i.e. second or third ) interim look data just before the Oct. 22 public FDA Advisory Committee meeting. Assuming all the data looks good , this would make for a pretty dramatic and convincing presentation.

            I think your numbers for case rates/week may not be too far off the mark when you consider that they’ve probably tried to choose trial sites that would be expected to have higher infection rates than the overall US average.

  4. chris says:

    Important to note that Oxford aren’t running the US trials – only the UK, South Africa and Brazil trials so the protocols in those trials are likely to differ slightly. And I presume Oxford will most likely get data from Brazil quicker than the US trial.

  5. Paul Rydell says:

    Do the trials test every participant for covid on a regular interval so they can catch the asymptomatic cases? Do their trial designs explain how often the tests occur?

    1. daksya says:

      For the Oxford trial in the US, a predose PCR test. Then weekly tele-checkups. If a patient reports symptoms as per certain criteria, then an “illness visit’ at which a swab sample is taken and tested.

    2. Just another chemist says:

      Skimming Moderna’s protocol it sounds like they have to have symptoms

      >To be considered as a case of COVID-19 for the evaluation of the Primary Efficacy Endpoint, the following case definition must be met:
      -The participant must have experienced at least TWO of the following systemic symptoms: Fever (≥ 38ºC), chills, myalgia, headache, sore throat, new olfactory and taste disorder(s), OR
      -The participant must have experienced at least ONE of the following respiratory signs/symptoms: cough, shortness of breath or difficulty breathing, OR clinical or radiographical evidence of pneumonia; AND
      -The participant must have at least one NP swab, nasal swab, or saliva sample (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by RT-PCR.

      1. Joey says:

        Hi, mRNA-1273 participant here. The primary endpoint is based on confirmed infections. Almost zero of asymptomatic infections will be detected. Repeat PCR-testing is not part of the trial protocol, it’s entirely symptom-based.

        1. Alec Kynes says:

          The Moderna mRNA-1273 trial does use repeat PCR testing. They always take one sample for the test on day 1, and another on day 29 (see page 7 of Moderna’s protocol). In addition, if you do show symptoms of COVID for more than 48 hours, they will take another sample for PCR testing (see page 8 of Moderna’s protocol).

          Finally, page 10 of of Moderna’s protocol says that they will only consider you infected if, among other things, you test positive for SARS-CoV-2.

          And this makes sense: you can’t really determine infection based off of symptoms alone. You will need some method to detect the virus, and PCR is a very good method to do this.

    3. eub says:

      This is going to be an issue. People who’ve had a vaccine are going to be out there reinstating their social lives, and I can’t honestly blame them, but the consequence is that virus prevalence may go way up, and anybody who’s “wait and see” on a vaccine, or who has a limited immune response to it, had best be bubbled up for that. Fingers crossed that a vaccine reduces disease severity and saves lives among harder-hit groups.

      People talk about CoV-2 vaccines and herd immunity in the same sentence and we have no data to indicate they belong in the same sentence at all. Sterilizing immunity seems beyond anyone’s hope, and I don’t see anyone’s trial gathering data to show reduction in R.

    4. rvhees says:

      As indicated in the response below, they make use of electronic diary devices (smart phones etc). These devices trigger a couple of times a week a question to ask the participant if he/she experiences respiratory tract infection symptoms. Upon selecting “yes”, a procedure is triggered and the participant will be asked to record a number of symptoms for the following days and to go to the study site for a nasal swab. It’s considered a case when the swab is positive AND the subject has symptoms meeting the case definition.

  6. Andy says:

    Is it a concern if we only end up with 3-4 months of safety data by the time a trial “succeeds”, at which point (presumably) the placebo arm will all end up being offered vaccination? That means that long-term safety data will be collected – but with no placebo arm to compare it to.

    I can’t quite decide if that’s a problem. Really rare events (<1/10,000) would only be seen in post-marketing surveillance anyway so maybe it's not an issue. Does it compromise the data though? Does it erode trust in the process?

    1. Matthew says:

      How long after vaccinations would we typically see ADE or a Th1 pathology?

  7. Barry says:

    If the FDA is holding out for efficacy greater than or equal to 50%, would it grant approval for a particular vaccine in some age-groups but not in others, if e.g. older subjects didn’t respond as well?

    1. Derek Lowe says:

      Good question! You can see that the trials are stratified to pick up on those differences, but how the different companies act on them (should such differences be truly significant) will be up to them (as is the FDA’s own response!)

      1. Barry says:

        If the Phase III trials are run in separate cohorts for separate age-groups, would there be independent applications to the FDA for each age-group?

      2. Dav says:

        One risk of interim analysis is that, if a trial is stopped early because of efficacy at the primary endpoint, there is an overall smaller sample size and less power to detect efficacy differences among subgroups.

    2. rvhees says:

      Yes, a risk/benefit assessment will be made for all age group. If the benefits of vaccination for certain group outweigh the risk of vaccination, then an indication can be granted.

  8. Anders says:

    If AstraZeneca is doing the 2:1 ratio, aren’t they setting themselves up for an even longer wait to reach those endpoints (if the vaccine works) compared to the other trials? While also increasing the chance for finding adverse events.

  9. JoBlo says:

    One thing that I’d like to confirm, which would seem confusing for most laymen, is what efficacy means for those vaccinated. Epidemiologically, it would seem that in order to protect the elderly and immunocompromised with “herd immunity” requires that the VE of 50% mean that at least half the inoculated individuals cannot transmit the virus (e.g. become infected and transmissible). However, many in the broader community would simply assume that a 50% effective vaccine reduces their risk of death by 50%. This seems very pessimistic (even assuming autoimmune risks) since any improvement in initial immune response is likely to dramatically slow/reduce peak viral load to the point where many (even transmissible) infections are asymptomatic. Of course in the fully immunocompromised a vaccine has no effect, but even in the elderly/pre-existing one might see better than order of magnitude reduction in mortality by vaccination.

    Making that point could be the difference between having an effective herd immunity vaccination effort and one where only 20% of the population bothers (including young and old).

    1. Derek Lowe says:

      That’s a tricky one, and will require a lot of attention to asymptomatic cases and knowledge of whether such people can spread the virus (and how likely that is). I agree that you’d expect to see viral load going down to the point that you’d expect more asymptomatics and for those to be less infectious as well.

      1. Hopeful Layman says:

        This relates to what has been one of my questions all along (I hope I’m asking it clearly). We know (or at least it’s estimated) that upwards of 40% of all infections are transmitted by asymptomatic carriers. However, do we know, or do we even have an idea, whether these infections are as serious as those transmitted by symptomtic carriers?

        Given this — in a post-vaccine world where most of the cases were the result of transmission from asymptomatic (or, possibly, even mildly symptomatic) carriers, would most of those infections be relatively minor? In other words, would we be more or less in the situation predicted by some here, where COVID would be reduced to something akin to what the flu is now — a health risk requiring attention and vigilance, especially for the high-risk and the elderly, but not a crisis that would noticeably affect the everyday financial and personal behavior of most people?

        1. Adrian says:

          Young healthy people tend to be asymptomatic carriers, people who are old or have pre-existing conditions tend to get seriously ill.

          If you are 70 year old and obese, it will likely not make much difference whether you are getting COVID-19 from your asymptomatic teenage grandchildren or your dying wife.

        2. Hopeful Layman says:

          Will this still be true if you’ve been vaccinated? If, as JoBlo suggests, “any improvement in initial immune response is likely to dramatically slow/reduce peak viral load to the point where many (even transmissible) infections are asymptomatic. Of course in the fully immunocompromised a vaccine has no effect, but even in the elderly/pre-existing one might see better than order of magnitude reduction in mortality by vaccination . . .” it seems to me that this might not be the case. Of course, we can’t know this yet, but I would not discount the possibility.

        3. PV=nRT says:

          I suspect the coagulaopathies covid causes will scotch this. Even young people can suffer permanent damage from clots — covid toes, heart attacks in 20 year olds, etc.

          1. Dark Day says:

            . . . which should, of course, heighten the urgency even more for younger people to get vaccinated. Until all populations realize they’re at risk for contracting and spreading the disease, as well as for suffering serious, debilitating symptoms, we won’t have sufficient uptake to develop sufficient immunity. That’s really the bottom line. A massive, culturally aware vaccine education / adovacy campaign will be absolutely essential.

            In my opinion, the toughest nuts to crack, at least in the U.S., won’t be those with legitimate doubts about the safety of vaccines developed and approved at “Warp Speed;” they’ll be people who are convinced — because of a false sense of security (esp. among the young), or maybe even because, like some folks I’ve spoken to, they feel perfectly content to live most of their lives online while masking and “distancing” themselves whenever they go out in public, and so they’ll feel no dire personal need to get vaccinated — that the beneifts, for them, simply aren’t enough to bother.

        4. J N says:

          Severity of disease, all other things being equal (which they aren’t) seems to be related to viral inoculum. So however much virus your carrier is shedding, times how long you are exposed to it, is probably all that matters. How much virus someone sheds is not strongly related to severity or symptoms afaik, and presymptomatic patients shed a lot of virus.

          1. Hopeful Layman says:

            Would vaccinated people who then contracted a “mild” (or asymptomatic) case then be carrying a lower viral load, due to having been vaccinated and thus havng acquired at least “some” immunity? Or is this another wrong-headed “Layman’s” question?

          2. Adrian says:

            Many things regarding what is actually relevant for virus transmission, including whether viral load influences the severity of COVID-19, are not really known for sure.

            But it is generally accepted that grandparents can die from COVID-19 transmitted from their asymptomatic grandchildren. It is the same virus in any case. Viral load may influence the probability of transmission and the probability of serious COVID-19 if infected.

            Right now symptomatic carriers should only be involved in a small fraction of transmissions, since the easiest effective action to reduce the spread of COVID-19 was to tell symptomatic people to stay at home. But there are still people dying.

      2. David E. Young, MD says:

        I am on the Moderna trial and have had my first shot about 5 weeks ago and the second a week ago. Curious, there are several trial sites in California; Redding, Sacramento, UCLA, two in SanDiego and….. Banning. Banning is a tiny town but it serves the Inland Empire to the west and the Coachella Valley to the east. It is like having a trial site in Boston, Province, Hartford and Pittsfield. The UCLA site has not opened (IRB problems) but the Banning site is recruiting well. Very professional people in my experience. I give my demographics and medical history. List of medications. I get a brief physical exam. 8 tubes of blood drawn (less blood than what you think) and you get one of those tiny nasal swabs way in the back of the nose. (It gives you the same feeling that you get if you are swimming in a chlorinated pool and some water goes up your nose…. very weird feeling that lasts for about 5 minutes). Then you get your shot.

        Got the shot. Got the booster. No pain, no swelling, no redness, no headache, no fever, not aches, no nausea. Nada, zilch, nothing. Can I make a guess which shot I got?

        Had an app put on my cell phone. For 7 days after shot I complete an online form. Take my temperature and answer 10 questions about how I feel. Takes 90 seconds of my time.

        Get phone calls periodically. “did you see a doctor for any reason in the past week?”

        If I get “sick” I have to report and they check me for Covid19. (That hasn’t happen yet, I’m glad to say.) So, the clinic checks out “sick” visits. Those may or may not be Covid19, but that is how they find cases.

        I don’t think that they can catch asymptomatic cases. That would require regular nasal swabs. Well, I am not sure that I would agree to those monthly. Maybe I would but a lot of people would not.

        I do have additional visits, every so many months for up to a total of 6 visits over 25 months. Probably more blood draws and I am sure that they check for antibodies in those draws. (The are all special “red topped” tubes, so the blood draw is not for blood counts nor is for regular chemistres.)

        1. J N says:

          Yeah, why not give a flu vaccine as the placebo …?

          🤔

          1. David Eugene Young says:

            Even those who get the actual vaccine might still want to get the actual flu vaccine…

          2. ST says:

            The Oxford/AstraZeneca trial actually uses a meningitis vaccine as the placebo, which seems far more effective (in terms of arm soreness and mild fever) to keep participants blinded about which trial cohort they’re in. Disappointing that Moderna and Pfizer did not do something similar.

        2. Marko says:

          They can probably pick up many asymptomatic cases in the antibody tests done during the periodic visits. An antibody test for nucleoprotein should distinguish between vaccine-induced and infection-induced seroconversion.

          1. debinski says:

            I have a question related to this. If I walked down to my local Labcorp and got an “antibody” test (only $42), and it came out positive, would I know if I had been infected with SARS-COV-2 (asymptomatically) vs. had antibodies produced by an active vaccine (I’m in a trial) vs. had previous exposure to a different coronavirus that is cross-reactive? If it came out negative could I be sure I did not get an active vaccine (if I got the test within a couple months of the vaccine)?

          2. Marko says:

            You would need to know what protein the antibody test detects. If the test is for anti-spike (S) antibodies , you probably couldn’t tell whether a positive result was due to vaccination or infection. If it tests for anti-nucleoprotein ( or “N” , nucleocapsid , etc. ) , a positive test would indicate past infection.

            You generally don’t have to worry about cross-reactivity to other coronaviruses in tests used by commercial labs today. Lots of early tests were junk and non-specificity may have been a real concern in many of them , but I don’t think it’s much of an issue today. You’ll find lots of people on twitter who will disagree , but without the evidence to back it up.

          3. Marko says:

            ” If it came out negative could I be sure I did not get an active vaccine (if I got the test within a couple months of the vaccine)? ”

            If you get the anti-spike antibody test , I think it’s very likely you’d get a positive result if you got the vaccine. I suppose there’s some possibility that the immune response to the particular spike-based vaccine is limited to epitopes that are not captured well in the common assays used today , but I think it’s very unlikely. Look into the research on the vaccine in question. You might find results using a commercial assay used by LabCorp and others , which would answer the question definitively.

            You could get the vaccine and fail to seroconvert , of course , but I suspect that’s also an unlikely outcome.

        3. Doug says:

          I assume you’re still required to wear a facial covering and maintain social distancing? Seems like this will minimize some exposure to the virus overall in both the control and treated groups, and hence extend the duration to achieve the number of events required to hit statistical significance.

    2. Alan Goldhammer says:

      I just saw the first paper that comes up with what ‘might’ be a reasonable value for herd immunity. It comes from data gathered in the Amazonian city of Manaus. This are was extremely hard hit by SARS-CoV-2 and while they are careful to say this might not extrapolate to other areas, they estimate that the herd immunity value was 60%. Paper is here: https://www.medrxiv.org/content/10.1101/2020.09.16.20194787v1.full.pdf
      It is a worthwhile paper to read.

      1. Chris Phillips says:

        This seems to be just an estimate of the percentage who were infected. That can’t simply be equated with the percentage needed for herd immunity. Indeed, in the paper itself the authors refer to a model (evidently a simple homogenous one) with R0=2.5 which would predict a “herd immunity threshold” of 60% but a “final size of the epidemic” of 89%. Potentially if there is a rapid wave of infection it can overshoot the herd immunity percentage by quite a long way.

  10. Giannis says:

    Based on animal data, none of these vaccines will provide sterilizing immunity. So RT-PCR testing of Upper Respiratory Tract fluids is unlikely to show differences. What might happen is that we will see far less pneumonias and hospitalizations and ICU admissions. Unfortunately this means that the data analysis will be far from straightforward.

    1. Calvin says:

      This is what is concerning me most of all. So there is a difference between being infected and getting disease. None of these vaccines appear to prevent transmission, nor prevent you catching the virus. There are thus, 2 massive questions. Do they vaccines prevent disease? I do worry that the trial design and end points might make differentiating the groups rather tricky. Worst case scenario is that we have a vaccine that doesn’t show sufficient efficacy without it being clear why. And then the bigger, long term question is if the vaccine does not provide sterilizing immunity, do you have a lower viral load and is there evidence that they are less likely to spread the virus to others? PCR testing regularly is going to be critical and good to hear below that the Oxford group are doing jus that. But, if the vaccine does not prevent infection or spread, then in time, every person in the world will be infected and everyone will need the vaccine to prevent disease. . So this could very much become a global annual question……That’s a lot of vaccine!

      1. Giannis says:

        This is why I was a big supporter of an attenuated vaccine and used in healthy < 60 year olds.

        1) Data from SARS and MERS suggest that an NSP1, EXO double mutants would be severely attenuated. SARS-CoV-2 is already not very lethal to young individuals, these attenuating mutations would bring lethality to something like 1:1,000,000 , which is on par to the chance of getting polio from the Sabin vaccine.

        2) It would be extremely cheap and extremely easy to produce tens of billions of doses in days…

        3) It could be administered in your house intranasally. So multiple immunisations would be very easy.

        4) It would in all likelihood provide sterilizing immunity.

        Why did it not happen? We live in an extremely risk averse society. For example we consider more ethical to let people die by the millions, than start an attenuated vaccine trial in ~100 people healthy and young volunteers…

        Extreme risk aversion does have negative consequences…

      2. JoeBlo says:

        I share your concern, but I don’t see how they can claim 50% VE, if the herd immunity is 0%, because the vaccinated are still infecting carriers. If the immunocompromised aren’t protected, then the vaccine isn’t working. Now, perhaps the viral load is reduced and super-spreader events are less likely and you can get Re below 1 with a 70%+ vaccination rate, but I don’t see that happening with so many people “concerned”. Really, if it only cuts fatalities in the vaccinated by 50% it sounds like a complete failure for the susceptable counting on herd immunity.

        1. Marko says:

          “I share your concern, but I don’t see how they can claim 50% VE, if the herd immunity is 0%, because the vaccinated are still infecting carriers.”

          The FDA stated early on that a 50% reduction in the incidence of moderate-to-severe disease was sufficient for approval. That’s the standard of “effectiveness” in these trials , and is similar to the way effectiveness is measured for flu vaccines.

          People in high-risk groups won’t readily dismiss the idea of reducing the risk of a severe outcome by 50% or more. Sterilizing immunity , if it does happen , will be a bonus.

    2. Michael says:

      Giannis, I wouldn’t give up on J&J or Novavax inducing sterilizing immunity. Those two candidates, unlike Pfizer/Moderna/AZ/CanSino, use the specific antigen that completely protected mice in this study:

      https://www.biorxiv.org/content/10.1101/2020.09.16.300970v1

      1. Dark Day says:

        And Novavax also incldues an adjunvant in its vaccine.

        I haven’t heard anything from them recently, but I know they’re a little behind the others in the so-called “race” to approval — and now that Trump is “promising” a vaccine in October, which will certainly annihilate any possibility of its being trusted and used by most Americans (instant financial catastrophe for whichever pharma company is “lucky” enough to be selected), having a vaccine that passes Phase III strongly and wins approval sometime in December or January (assumng a new administration is in place by then) could be the best thing possible.

        1. Michael says:

          Dark Day, while I personally believe that J&J and Novavax will be the best vaccines to emerge over the next several months, it is certainly possible that Pfizer/BioNTech will be safe and effective (they just bought a Novartis plant based on their confidence)…and it behooves me to point out that it is entirely possible to both be glad with good news if and when it comes *and* to vote Biden/Harris.

          Pfizer/BioNTech aren’t even “Warp Speed” participants.

        2. Dale Yuzuki says:

          I am one of the lucky 1636 participants in the Novavax Phase IIb trial, got the day 21 second immunization last week. Very interesting five arm study design – where only 1/5 of the group gets placebo (normal saline), two of the arms with 21 day spacing and two different doses of nanoparticle / full-length spike protein (same amount of adjuvant), two of the arms only differ with 189 instead of day 21.
          I know I was one of the 4/5 group that got vaccine – pain and tenderness at the site of injection for about 4 days (all recorded by smartphone app for 1 week after injection).
          For the second shot, I knew I had a 50/50 chance of getting placebo; I ended up getting vaccine for sure. Redness, soreness, the next day I had a headache, fatigue and muscle pain, along with 100.7F temperature (they issued thermometers to self-check with the smartphone app daily for 7 days).
          It lasted about three days, a follow-up call the second day was right on top of it, no need for any doctor visit or anything.
          From the Phase I data on Novavax it had some pretty remarkable results, so I am not complaining at all and look forward to seeing the results months down the road.
          https://www.medrxiv.org/content/10.1101/2020.08.05.20168435v1

  11. Richard Lawson says:

    In answer to the question about intermediate PCR testing: I can’t speak for the other trials but Oxford phase 2/3 in UK is giving participants a weekly swab (home self administered test kit that you post off for analysis). So far I’ve tested negative each week since June and am getting bored of making myself gag and sneeze every Monday morning.

    1. Dr. Manhattan says:

      I just saw an article on Covid response which interviewed Bill Gates. He mentions in it that “ Gates is also perplexed as to why testing is still being conducted using nasopharyngeal swabs — an unpleasant procedure that people liken to having your brain stabbed. The Gates Foundation led research that showed swabs circled in the nostril were as accurate and far easier to administer. They also don’t trigger bouts of coughing that can spread the virus.

      “But even today in this country, that’s not 100% [of the tests],” Gates said. “So, you have health care workers getting coughed on and people are reluctant to take the test because of that obsolete approach is still quite prevalent.”

      If you want to read the Gates article further, it is here: https://www.statnews.com/2020/09/14/bill-gates-slams-mismanaged-u-s-response-to-covid-19-pandemic/.

      The nasal swab article is here: https://www.statnews.com/2020/04/16/fda-changes-coronavirus-testing-swabs/

  12. ishan says:

    Are the trials accounting for the fact that the individuals who are getting vaccinated may vary in their day-to-day behavior? In other words, the average number of human interactions could vary between the placebo and treatment. This wouldn’t be an issue in something like a flu vaccine where the disease itself and the administration of the vaccine presumably isn’t altering human behavior.

    1. Adrian says:

      That’s why the control group is getting a placebo vaccine – all this only works because the participants do not know whether or not they are getting the vaccine candidate.

      1. ishan says:

        That’s besides the point. Ideally, the control and treatment group will have the same baseline risk for getting the virus. The risk is dependent on your specific biology and how you behave in the real world. I’m assuming the former was accounted for (i.e age, comorbidities, etc.), but how do you account for the latter? An obvious first pass would be to ensure similar geographic demographics between the two groups as that serves as a rough surrogate for human behavior.

    2. Joey says:

      An easy to forsee issue is when the placebo is saline, there are no local injection site reactions, which occur overwhelmingly in the vaccinated arm. This gives a clue to vaccinated trial participants that they didn’t receive placebo, and visa-versa, if the participants are sufficiently knowledgeable (read the phase 1 data). This leads to the vaccinated participants increasing their environmental exposure to an unknown and unstudied degree, which means the reported efficacy for confirmed case reductions from the trial is a lower bound.

  13. Chris Phillips says:

    “Note that none of these trials going to stop the study if they see good results early on – they’ll continue to collect data, but in the knowledge that they’re on to something effective.”

    The Moderna protocol seems to be saying that if the success criteria for efficacy are met in an interim analysis, they will then prepare a “final” report. But they will continue to collect data which will go into a later report, after the “final” one.

  14. debinski says:

    So it seems that AstraZeneca is way behind both Moderna and Pfizer as far as getting any results from their interim analysis. Not only do they require the most cases (75) but their trial remains on hold in the US. This must be screwing up everything. What will happen to the subjects who got the first vaccine but now can’t get the second because of the hold? If they have more than 28 days between vaccines, what will happen to those subject’s data? They could lose a lot of their evaluable subjects that way, correct?

    1. eyesoars says:

      I haven’t re-checked, but they stopped the Trial about two hours after my spouse was offered a chance to join (she turned it down). And then I heard somewhere it’d been restarted the next day.

      1. debinski says:

        It was restarted in the UK a few days later but is still on hold in the US as of today.

  15. Mike says:

    *AstraZeneca is going 2:1 treatment/placebo (more on that in a moment)*

    Derek, did you not comment on the 2:1 ratio or did I miss it. I was actually looking forward to learning more about that design choice!

    1. Marko says:

      Yeah, I was wondering this as well. What is the reason for having a 2:1 experimental/placebo ratio?

      1. Chris Phillips says:

        Is it not statistically beneficial to raise the expected numbers of cases in the vaccine group, at a cost of lowering the expected numbers in the control group?

        1. Thomas says:

          Having more members in the vaccine group allows for more certainty on the (low) numbers in that group.

    2. Marko says:

      One legitimate reason for doing so is that this ratio provides a better opportunity to observe vaccine-related adverse events.

      A less legitimate reason is that it might provide a competitive advantage in recruitment over trials running a 1:1 ratio.

    3. DataWatcher says:

      My understanding is that it’s usually done the opposite way — a 1:2 (or higher) ratio between cases and controls incresaes statistical power. .

  16. Dark Day says:

    Meanwhile, the “October Surprise” scenario is getting very, very scary and scarier by the minute . . .

    https://www.nbcnews.com/health/health-news/signs-october-vaccine-surprise-alarm-scientists-n1240617

    1. Dark Day says:

      Maybe the best be is to hope against hope that Trump gets defeated in November, write off his “October Surprise” vaccine as a lost cause, and focus on a vaccine that completes Phase III and garners legitimate approval sometime later. The problem, of course, will be that by that time, NOTHING that gets approved by the FDA will be trusted by the majority of the American population, so — once again — we’re back to the nightmare scenario of being unable to emerge from COVID Purgatory, possibly for years, while millions of doses of unused vaccines go bad on the shelves.

      1. Dude says:

        You are vastly, and borderline comically, overstating the negative possibilities of vaccine outcomes.

        Get off Twitter, get off the web, go talk to your neighbors and friends about gardening (6+ feet apart), interact with people. It’s a better world out there in real life. Seriously.

          1. blogreader09 says:

            Mr/Ms “Dark Days” is no doubt also concerned (very, very) that Trump has plans to stay in office and seize power if he loses the election.

            The Attorney General’s apt (very, very) response to said power-seize notion could also apply to the October-Surprise scenario called to our attention by Mr/Ms Dark Days.

            https://www.realclearpolitics.com/video/2020/09/15/bill_barr_democrats_projecting_with_idea_trump_will_stay_in_office_and_seize_power_and_all_this_shit.html

          2. Dude says:

            Yes. Really. You are wildly overreacting.

          3. SteveM says:

            It’s a shame that rank politics sometimes pollutes what is an excellent science site.

            But because of that, I hope the Gamaleya vaccine from Russia turns out to objectively be the best candidate. Just so I could visualize some heads exploding.

        1. JoeBlo says:

          Well, maybe he’s a 55yo with pre-existing conditions?
          COVID could be a 10% mortality risk… and in terms of worst cases, the long tail can actually happen 20% of the time. It’s worth trying to maintain trust in vaccines and medical approval and clinical trials, because keeping the length of the tail down prevents terrible eventualities. Relax, Dude and play roulette on your own time.

          1. Dude says:

            His/her complaints have nothing to do with epidemiology, and are completely evidenceless, fear-mongering theories about an unsafe approval in this administration. This is in spite of assurances from thousands of career scientists at the CDC, FDA, and major drug companies undertaking literally the most public and scrutinized vaccine development campaign in history. If one cannot “trust” that environment, then they are no better than the anti-vaxxers.

            Believe it or not, virtually all of society (myself included) have vulnerable family members and a massive incentive for a safe, effective vaccine, ASAP.

            The difference is, when I say that I trust scientists, I actually mean it.

          2. Dark Day says:

            For what it’s worth, that wasn’t my argument at all. I do trust the scientists, and I trust the process by which the vaccines are proceeding through the trials. My point was that, whether it’s fair or not, a significant majority of Americans have come NOT to trust this process, believing it to have been compromised by political opportunism on the Administration’s part. Virtually every polls shows this. (And, to be fair, a lot of very reputable scientists have also expressed worries about the possibiilty that Azar could cave into political pressure and approve a vaccine that hadn’t been thoroughly vetted — e.g., https://endpts.com/signs-of-an-october-vaccine-surprise-alarm-career-scientists/ — so I’m hardly alone in that regard, either.) That’s my concern, and that’s why I think that a Trump vaccine imprimatur at this point will basically be a kiss of death in terms of mass acceptance and eventual uptake.

          3. Marko says:

            Plenty of experts have serious reservations about the possibility of a premature victory celebration in the vaccine trials. The pharma companies always respond to incentives that are not necessarily aligned with the “public good”. When you combine that with the heavy-handed pressures exerted on the regulatory agencies by this administration , there is a legitimate basis for concern :

            “Are We Testing Coronavirus Vaccines the Right Way?”

            https://www.nytimes.com/2020/09/22/opinion/covid-vaccine-coronavirus.html

            “Beware of covid-19 vaccine trials designed to succeed from the start”

            https://www.washingtonpost.com/opinions/2020/09/22/beware-covid-19-vaccine-trials-designed-succeed-start/

            There is a very real possibility that the trials could reach their approval endpoints while reducing infection rates and/or severe disease outcomes by less than 50% while reducing only mild disease by greater than 50%. That’s a pretty low bar , and it’s up to the FDA to make sure it isn’t lowered to that point.

          4. Marko says:

            Aha. The FDA is feeling the heat from the scientists. That’s progress :

            “FDA to announce tougher standards for a coronavirus vaccine that make it unlikely one will be cleared by Election Day”

            https://www.washingtonpost.com/health/2020/09/22/fda-covid-vaccine-approval-standard/

            “The Food and Drug Administration is expected to spell out a tough, new standard for an emergency authorization of a coronavirus vaccine as soon as this week that will make it exceedingly difficult for any vaccine to be cleared before Election Day.

            The agency is issuing the guidance to boost transparency and public trust as it approaches the momentous decision of whether a prospective vaccine is safe and effective. Public health experts are increasingly worried that President Trump’s repeated predictions of a coronavirus vaccine by Nov. 3, coupled with the administration’s interference in federal science agencies, may prompt Americans to reject any vaccine as rushed and potentially tainted….”

        2. DataWatcher says:

          Certainly we can all agree that that having a truly effective vaccine is the only way we will ever control this pandemic. We can also agree that robust uptake will be absolutely essential for a vaccine to be truly effective.

          I’m not sure how one can argue that being concerned about thngs such as these is “overreacting.” This pandemic is an unimitigated tragedy, and it’s going to get worse before it gets better.

          On the other hand, I believe that there is hope in the response of some state governments to the current administration’s behavior:

          https://ctmirror.org/2020/09/21/lamont-promises-connecticut-will-vet-a-covid-vaccine/
          https://talkingpointsmemo.com/muckraker/exclusive-some-states-wont-distribute-a-trumpian-half-baked-covid-vaccine

          1. confused says:

            >>Certainly we can all agree that that having a truly effective vaccine is the only way we will ever control this pandemic.

            Plenty of pandemics ended before vaccines… There were no flu vaccines in 1919. And even in 2009 the second wave was already dwindling before a vaccine became generally available, IIRC.

            Social distancing will extend that timeline, but it’s still pretty limited.

            A vaccine would of course greatly reduce the number of deaths… which is the point. But the pandemic will end one way or another.

  17. Philip says:

    Please explain to me how a trial lasting under six months can demonstrate durability?

    1. Marko says:

      The vaccine companies are probably hoping that sometime in mid-to-late 2021 ( after everyone has een vaccinated ) they can demonstrate that the vaccines are NOT durable , thus requiring annual boosters. ( = Mo’ Money )

  18. Thomas Read says:

    “All three trials have basically the same definition of failure, which would be a VE of 30% or worse. And they are all designed to have greater than 90% chance of demonstrating that the VE is better than that (if in fact it really is, and it had better be!)”

    Presumably the >90% chance only applies if the true VE is greater than 50% (or some other fixed percentage higher than 30%)? If the true VE was say 30.5% then it would be very hard to demonstrate that it is greater than 30%.

  19. Thomas says:

    In 2012 they were experimenting with isolating what makes Methamphetamine stop or halt the flu? Ask a tweaker when’s the last time he or she got sick or if they’ve even caught the coronavirus yet? Not advocating using but science can pull and alnighter and figure it out.

  20. Mark Andrew says:

    Thanks so much for the rundown of these, Derek! I was trying to read though their documents themselves and my head started to hurt. So if I’m understanding this right… when the Pfizer study hits 32 cases, they will stop and do an interim analysis. If that analysis can show 77% efficacy, they can stop the study and will presumably apply for approval? If not, they will most likely not apply yet based on the low numbers?

  21. idiotraptor says:

    Two points, one of which I raised in an early COVID19 post by Derek.
    1) Why is the possibility of the vaccines eliciting sterile immunity to SARS-CoV2 even mentioned as a possibility? My understanding (if someone is aware of data to the contrary, please cite reference(s)) is the extant human CoVs in circulation prior to SARS-CoV2 do not induce durable or robust immunity and reinfection does occur.
    2) None of the ongoing PhIII RCTs will have been conducted long enough to demonstrate long lasting immunity. Unlike influenza A or RSV, which show a pronounced annual prevalence at certain times during the calendar year, SARS-Cov2 at present appears to be circulating and transmissible independent of season. Is a vaccine-induced immunity (reduced disease severity/mortality/transmission) “durable” if it last 24, 12, or 6 mos? If efficacy is concluded on the basis of the accelerated and shortened ongoing PhIII RCTs, a 3-4 month protective window is not much to get excited about.

  22. Regular Guy says:

    Thanks this is very helpful. Two things I don’t quite understand are 1. What would be the advantages of doing less interim analysis? What thinking goes into the number of IAs? And then 2. What is the advantage of setting the goalpost above the bare minimum in these IAs? Why not just set it at 50% VE for declaring a win and if you see better, then great, report better…?

    1. Marko says:

      Less interim analyses equals less alpha spending. When you take multiple looks at the data , you increase the chance that one look will show what appears to be a significant result but is instead due to chance. To correct for this , you have to adjust significance thresholds ( “spend alpha” ) when you take multiple looks.

      https://www.dummies.com/education/science/biology/how-to-incorporate-interim-analyses-of-clinical-trial-data/

  23. Interesting post, thanks. But this is wrong: “AstraZeneca, with only one interim analysis, will probably have to wait a bit longer from the start of their trial, although they did start on the early side”. The protocol they released is only for the US trial, which started at the beginning of September [1] and has been on hold since soon after that. So it is considerably later than the others.

    Their earlier phase 2/3 trial is *very* different – a 24-armed trial: no protocol available for it, or any of their other trials. BNT/Pfizer is a single trial running internationally; Moderna, a single trial in the US only. But each Oxford/AstraZeneca trial is distinct & fundamentally different from the others.

    [1] https://www.astrazeneca.com/media-centre/articles/2020/university-of-oxford-potential-covid-19-vaccine-phase-iii-clinical-trial-initiated-in-the-us.html

  24. Marko says:

    “What can we expect from first-generation COVID-19 vaccines?”

    https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31976-0/fulltext

    1. Hopeful Layman says:

      A little sobering, but interesting.

      it’s also interesting how few of the estimates/projections about vaccine efficacy, post-vaccination viral load in those who still might get infected, and potential “herd immunity” don’t take into consideration the possibility of a highly effective therapeutic being developed. It seems to me that a reasonably effective vaccine combined with a strong therapeutic (something along the lines of what the AeroNabs developers are forecasting for their product) could help us get to something approximating herd immunity, and certainly a drastic drop in serious cases, a lot faster than the vaccine by itself.

      Maybe I’m just being — um — “hopeful” here, but from what I’ve seen, there are quite a few therapeutics being developed that could potentially do just that, and I’d like to believe that 2021 will be a year of very interesting, and potentially game-changing, developments along this line. I’m sure there are people here with a lot more in-depth knowledge of this than I have. Maybe the topic of treatments/therapeutics even deserves a thead of its own?

      1. DrivingBy says:

        Seconded. There seems to be a public fascination with scenarios of doom. Nature is not kind, nor is it malevolent; it is implacable in its lack of concern for us.

  25. mzchem says:

    How is “The Vaccine Protocols” not the title of a Michael Chrichton novel?

  26. In Vivo Veritas says:

    Has anyone seen a proposal for a pediatric trial from these companies? Requires additional trials, and, given the case rate in kids, will likely take longer…… but it seems like a pretty critical thing of we’re going to get schools reopened.

  27. SteveM says:

    Re: The Russian Vaccine Data

    FYI: Gamaleya responds to the Bucci et al. challenges to their Sputnik V clinical trial results published in the Lancet:

    https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31970-X/fulltext

    1. Marko says:

      Heads are now exploding across the US.

      This was probably the Russian plan all along….

  28. Thomas Smith says:

    My understanding (from TWiV, I haven’t read anything myself) is that the FDA’s target is NOT “the percentage difference of infection by the virus between the vaccinated group and the unvaccinated control group” but rather a 50% reduction in incidence of serious disease. It’s a really important distinction because the first approved vaccines might only protect the direct recipients, and fail to provide “herd immunity.”

    1. TallDave says:

      underrated point

      mitigation has value

  29. Liam says:

    I’m curious if participating in these trials would be a reliable way for someone to get a positive vaccination status early.

    1. Does anyone know *when* the companies let the participants know whether they have received a placebo or an actual vaccine?

    2. Is there a way you could make any sort of guess whether you’ve received a placebo or vaccine?

    3. For the participants that have received a placebo, are they given an actual vaccine at some point?

    4. If they aren’t given a vaccine until late (like summer 2020 or later), could someone drop out of the trial and receive a vaccine from another company?

    1. paperclip says:

      I’m participating in the Pfizer/BioNTech trial, and this is what I know:

      1) This is apparently not set in stone. (I skimmed the protocol and found no information there, either.) A nurse told me that it’s under discussion and it’s possible we will know in a matter of weeks, but that is second-hand information.

      2) You can guess, and the way most people guess is by side effects, or lack thereof. If you get chills and a fever, you may conclude that you got the vaccine, or if you have zero symptoms, you may wager that you got the placebo. However, the chills and a fever may have come from a cold, and a lack of side effects might just mean you tolerated the vaccine well, so no guess is foolproof.

      3) I was not told that that would happen.

      4) You can always drop out of a trial without penalty. But I was not asked to forgo a future COVID vaccine. I was only told I should hold off on getting the flu shot until two weeks after my last injection of the trial.

      1. Liam says:

        Extremely helpful! I’m much more likely to join a trial now. Thanks.

      2. HAJ says:

        Paperclip, I also joined the Pfizer trial (1st injection yesterday) and really hope they let us know at some point after the second injection whether we received the vaccine. All these companies need to be aware that most people who join the trials don’t plan to walk around unvaccinated if/when a vaccine becomes available. I wonder if any of the other trials have plans to inform their participants?

  30. Marko says:

    Dramatic vaccine trial results released :

    “….vaccinated patients had 80 percent fewer moderate-to-severe respiratory infections.”

    https://www.wired.com/story/could-a-century-old-tb-shot-protect-against-other-respiratory-diseases/?utm_source=dlvr.it&utm_medium=twitter

    OK , it wasn’t for COVID-19 , but still , pretty cool.

  31. RICHARD BERNSTEIN says:

    The Protocols of the Astras of Zeneca.

  32. Michael Bell says:

    There are a difficult series of questions that need to be answered:

    1. What if the vaccines being developed do not work?
    2. What if it is not possible to develop a Covid19 vaccine due to the genetics of the SARS-Cov2 virus?
    3. If a vaccine is not possible or feasible to develop, does this mean that society must shut down indefinitely?
    4. We’ve been talking about protecting those most vulnerable to the virus, however what about other people who are not as vulnerable and have been severely impacted by lockdowns, stay at home orders, social distancing, and economic hardship? Who speaks for them? Are we prepared to tell them to shelter in place for years, if not decades?

    The singular answer in my opinion is this: If it’s not possible to develop an effective vaccine or treatment, then we’re going to have to let the virus run it’s course, on it’s own, with no mitigation. Logic dictates that the needs of many outweigh the needs of the few who are severely impacted. We can not destroy society to save lives.

  33. debinski says:

    J&J has just started their phase 3 trial. Protocol is here: https://www.jnj.com/coronavirus/covid-19-phase-3-study-clinical-protocol

    Also, the preprint on an interim analysis of their phase 1/2 data will be available on medRxiv “imminently”.

  34. Luis says:

    I will look forward to the results of these trials and wish every single one of them to be successful.
    I wonder what everyone thinks on here,will you prioritise the vacination of th so called superspreaders over the elderly population of would you start vacinatating the elderly population 1st leaving the youger population which contains the higher number of superpreaders last?

    1. DataWatcher says:

      General consensus seems to be that medical care providers and other front-line workers (specific definitions of these terms still to be worked out) will be the first recipients; then, at-risk people including the elderly (again, not sure how they’ll be prioritized — oldest first? “Frail” elderly before relatively healthy senior citizens? Residents of nursing homes before people living independently?), and people with pre-existing conditions; then we’ work our way down to the general population, which will porbably include “super-spreaders” (younger people more likely to hang out in bars, etc.).

      I know this sounds rather vague, but as far as I can tell, this is as specific as it’s gotten so far. It’s even more confusing when we realize thay different agencies — WHO, NASEM, ACIP, et al. are working on their own individual versions of this.

      1. Luis says:

        Thank you. Will be really interesting to see how everyone will work it out but i am sure serious debates are raging behind the scenes,another thing that has to be spot on will coordination,this is only my humble opinion but once mass vacination is available to the wider population i would bring the army in to help out they are well trained in situations that require coordination and speed,again would be great to hear everyone else opinion

  35. Bruce Grant says:

    Meanwhile, FDA has tightened its standards for approving an EUA. If they stick (and in the current administration* that’s a big “if.”) they will make it nearly impossible for a vaccine to make it out before election day.

    Sponsors will be required to follow participants for a median of at least two months, after they receive a second dose, and to show evidence of at least five severe cases of covid-19 in the placebo group for each trial, including some cases in older people.

  36. bacillus says:

    Much as I despise Trump, his cheerleading for a COVID vaccine in the run up to the election could disabuse his many COVID deniers to go ahead and get the shot? It will be interesting to see how the need-for-speed here plays out post-election. If he wins, then he doesn’t need an imminent vaccine. If he loses, he could go back to his COVID-SCHMOVID stance which would highly discourage his supporters to get vaccinated.

    1. Dark Day says:

      Strangely, perhaps, the polls seem to show even more vaccine resistance among Republicans than Democrats. Some of them are probaly hard-core anti-vaxxers, but it seems that they’re also leery of a vaccine that’s been rushed for political purposes. Personally, I believe that Trump has hurt his own credibility so badly that if he does win four more years, any vaccine that’s rolled out under his watch will still be distrusted by a significant majority of Americans, resulting in less than optimal uptake. Whether a [hypothetical] Biden administration can undo this damage, or whether those who did not support Biden would come around ans accept a Biden-era vaccine, remains a question. Either way, though, it will be a challenge.

      1. Mariner says:

        Probably just a case that the social media filtering and advertising selection pushes those with right-wing views towards the direction of anti-vaxx propaganda. Whether or not their political beliefs which allow them to ignore Trump’s manifold failings will overcome the anti-vaxx stuff remains to be seen.

        Whenever I see somebody online confidently avowing something clearly illogical and easily disproven if you just follow basic facts/scientific data, I tend to wonder just exactly what nonsense they are being pushed on social media.

        As somebody who doesn’t bother with social media, I can confidently state that I get my biases from other sources. 🙂

  37. Dark Day says:

    Isn’t Brett Giroir (HHS) a little behind in his reading of the data? Just a few days ago, he gave an interview where he said that if the first available vaccines are administered to frontline medical care workers and other “employees in contact with vulnerable demographics who are likely to suffer severe COVID-19 infections” (which he estimates as approximately “5 or 10 percent of the population”), we can “get 80 or 90 percent of the benefit.”

    My understanding is that most of the new cases of COVID now are among younger people, so — although I agree with him that the populations he mentions should receive first priority — I don’t anticipate a major drop in new cases until later, when the (mostly younger) potential “superspreaders” roll up their sleeves (if they’re willing to do so, which is a question in itself). I think he’s also missing the fact that “minorities” and others living in poverty are among the people at highest risk. To date, anyway, I don’t see any effort to prioritize low-income communities, which in my opinion is a grave mistake.

    1. confused says:

      It might make sense if by “the benefit” he means “deaths prevented” not “infections prevented”. If vaccinating those in most contact with the most vulnerable (eg LTCFs) mostly prevents infections spreading to them, and independently-living elderly mostly distance voluntarily until vaccinated, that could indeed mean a really drastic drop in deaths.

      A few million infections in e.g. college students will not really translate to a nationally-noticeable increase in deaths unless they infect the elderly.

      Poverty etc. absolutely does make a difference – but not a “three orders of magnitude” difference like age does. Otherwise we would see many more deaths in younger age groups in the “overall US by age” CDC death numbers. Despite poverty being quite widespread, we observe an enormous bias of deaths toward LTCFs (something like 40% of deaths in less than 1% of the population) and away from the younger age groups.

    1. Chris Phillips says:

      Thanks for posting the link, but I really wondered whether he had completely misunderstood the protocols, or whether it was just so badly written as to give that impression.

      And the author seemed to want to argue both that the protocols were at fault in not counting asymptomatic infections and that they were at fault in including mild infections. Conceivably each of those views can be argued, but surely not both at the same time.

  38. TallDave says:

    already wondering how many trials we would expect to meet a given guideline purely by chance

    still, we’ll eventually get some good data

    maybe

  39. sPh says:

    Am I the only person who thinks it would not be a good idea to give a brand-new vaccine to all the critical care nurses and doctors at the same time? As with the pilot and first officer of an airliner not being allowed to select the same meal from the onboard food – the risk of a correlated failure is too high.

    I would think that a better first step would be an expanded pilot program of say 500,000 across as many ages and health conditions as possible, flowers by a slow ramp up while 3 months’ pharmacovigilance data accumulates.

    1. Another Kevin says:

      > Am I the only person who thinks it would not be a good idea to give a brand-new vaccine to all the critical care nurses and doctors at the same time?

      The logistics of vaccine production and distribution will keep that from happening, at least on the time span of weeks to months.

  40. Steve Scott says:

    This from Politico on Friday Sep. 25
    “AZ CEO: PHARMA WILL BE MORE TRANSPARENT ON VACCINES — Coronavirus vaccine developers are crafting a consensus on what additional data they can disclose from their clinical trials to increase transparency, AstraZeneca CEO Pascal Soriot said Thursday.

    “We are discussing with other companies as an industry what kind of transparency we could offer without compromising patient privacy … but also without compromising the trial itself,” he said during a World Economic Forum event reported by POLITICO Europe’s Ashleigh Furlong.

    It’s a careful calculation, Soriot said. If too much information about the trial is disclosed, it could compromise its blinded nature or infringe on patient privacy.

    …His comments come after several pharmaceutical companies, including AstraZeneca, have disclosed their clinical trial protocols.

  41. debinski says:

    J&J’s phase 1/2 data was posted as a preprint today: https://www.medrxiv.org/content/10.1101/2020.09.23.20199604v1.full.pdf

    1. Hopeful Layman says:

      Very encouraging. Unless I’m mistaken, the J&J vaccine also has less-daunting storage and transportation requirements than some of the others. Is this accurate? I’m looking forward to seeing how effective it is in people over 65 (full disclosure: I’m one of them!), because I know they’ve been ambitiously recruiting as diverse a population as possible — age, ethnicity, etc. — for the Phase III trials.

    2. debinski says:

      If you look at the data, the “98% success rate” is based on the fact that 98% of subjects “had detectable neutralizing antibodies”. That seems like a low bar for success.

      1. DataWatcher says:

        That’s the problem with the way these Phase I/II trials are usually reported. I recall similar wording in most of the other instances, as well (including, if I’m not mistaken, the recently reported Novavax trials). As usual, we’ll have to wait for Phase III to see how effective it really is.

  42. How long after vaccinations would we typically see ADE or a Th1 pathology?

  43. Hopeful Layman says:

    I apologize if it looks as if I’ve been hiding under a rock somewhere, but I have never heard about this vaccine candidate — already entering Phase III trials — unti now. Does anyone have any information on it?

    https://www.nbcmiami.com/news/local/university-of-miami-enters-third-phase-of-covid-19-vaccine-trials/2299306/

    1. Michael says:

      Hopeful Layman, Janssen is the affiliate of Johnson & Johnson that’s making the J&J vaccine — and that’s the one referenced in the article.

  44. debinski says:

    NEJM published some phase 1 Moderna data in older adults yesterday. “Although the sample sizes in our study were limited, older participants (including those who were 71 years of age or older) had immunologic responses to the mRNA-1273 vaccine 1 month after the second dose and across multiple assays that were similar to the responses among younger participants.”
    https://www.nejm.org/doi/full/10.1056/NEJMoa2028436?query=RP

  45. Chris Phillips says:

    “The U.S. Food and Drug Administration has broadened its investigation of a serious illness in AstraZeneca Plc’s AZN.L COVID-19 vaccine study and will look at data from earlier trials of similar vaccines developed by the same scientists, three sources familiar with the details told Reuters.”
    https://uk.reuters.com/article/health-coronavirus-vaccine-astrazeneca/exclusive-fda-widens-us-safety-inquiry-into-astrazeneca-coronavirus-vaccine-sources-idUKL1N2GR1SK

    According to the report, the concern relates to the specific chimpanzee adenovirus being used as a vector, rather than to adenovirus vectors in general.

    But the report also says:
    “Reuters reviewed six research papers that detailed safety data of vaccines using the engineered chimpanzee adenovirus called ChAdOx1 for diseases including tuberculosis, prostate cancer and influenza. In one of those trials, one serious adverse event cited by researchers was deemed unrelated to the vaccine.”

    1. debinski says:

      Out of curiosity, I found the paper with the SAE “deemed unrelated to the vaccine.” They don’t ever specify what the SAE was or when it occurred relative to the vaccination. There are only 24 subjects in this trial and all received the active ChAdOx1 MERS vaccine. Typically authors would specify the event, especially when they are deeming it unrelated, so the reader has a sense of why it was unrelated. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172901/

  46. debinski says:

    The US press has been oddly quiet about the continuing hold on Astrazeneca’s trial. And despite the fear that the FDA will approve a vaccine prematurely, they are the only regulatory agency that has kept the trial on hold to investigate further. It’s good to see something reported on it finally.

  47. Chris Phillips says:

    I’d be interested to know whether anyone has opinions about the reported views of Kate Bingham. who is the head of the UK “Vaccine Taskforce”:
    https://www.ft.com/content/d2e00128-7889-4d5d-84a3-43e51355a751

    Apparently she thinks either that vaccinatng the whole population would be “misguided”, or perhaps that it’s misguided to think that will be possible. Given that the aim of the statement is to “clear up the public’s “misguided” perception” of the government’ policy, I find her remarks less than clear.
    .
    Ms Bingham is the holder of a bachelor’s degree in biochemistry, but it seems that her career then took a turn towards business rather than science – culminating in an MBA from Harvard Business School and a career in investment management.

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