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Pfizer and BioNTech’s First Vaccine Candidate

We now have a preprint with a great deal of data on the first mRNA coronavirus vaccine candidate from the Pfizer/BioNTech effort. This is actually the first real data set on any of the genetic vaccines, since Moderna’s paper on their Phase I trial has not yet appeared (all we had was a brief press release) and a brief press release is all we got from Inovio’s DNA vaccine work as well.

I’m very glad to see this – some of the other vaccine programs (Oxford/AZ and CanSino, for example) also have been very forthcoming with information, and it’s extremely important that all of the human trial data be made public. I realize that doing so opens the door for a lot of people who don’t understand human trial data at all to wander through it misinterpreting things – no doubt about it – but the dangers of that are far, far outweighed by the need for full disclosure. There are lots of qualified eyes out there, too, and for the public to have confidence in the vaccines that get approved we have to have everything out on the table with no room for suspicion. No one gets a pass: everyone publishes everything if they want to be taken seriously.

So what do we have today? It looks like good news. Recall that this effort actually has four different mRNA vaccine programs: two with modified RNA bases, one with extra uridine bases, and one in the “self-amplifying” category. This preprint covers the initial data on BNT162b1, which is one of the modified-base candidates (incorporating 1-methyl pseudouridine, which should cut down on the innate immune response attacking the mRNA vaccine itself and also increase protein production once it gets into the cell. And it encodes a trimer of the coronavirus Spike protein’s receptor-binding domain (RBD), the most common antigen that is being studied in all the vaccine programs worldwide. The trimerized variant uses a “foldon” protein scaffold that displays three of the RBDs simultaneously in a three-dimensional array – it’s a motif borrowed from a bacteriophage that has been used in vaccine production before.

In this study, 12 patients got 10 microgram doses at Day 1 and Day 21, 12 patients got two 30 microgram doses in the same way, and 12 got a single 100 microgram dose at the start. There were nine placebo-injection patients as a control, and a convalescent serum panel as a comparison group for antibody response.  Male/female almost 50/50, ages from 19 to 54, mean 35 years old. No serious adverse reactions: one patient in the 100 microgram group reported severe pain at the injection site, and several others reported moderate pain or soreness after the first shot (by comparison, 2 of the 9 placebo patients reported the same). Pretty much everyone reported it after the second, which is to be expected. There were reports of headache, fatigue, and fever, which were dose-dependent and also more severe after the second dose, and in fact these are what limited the 100 microgram group to only one initial injection. This is also exactly what you expect from a vigorous immune response.

And that appears to be what the team got. The patients were profiled at Day 7, Day 21, Day 28, and Day 35 (with dosing, as mentioned, at Day 1 and Day 21). RBD-binding antibodies (IgG) were detected at Day 21 after the first dose, and were much stronger 7 days after the second dose (Day 28). In terms of just geometric-mean concentration of antibodies, the levels achieved after the first dose were 1.8x and 2.8x (in the 10µg and 30µg patients, respectively) the levels seen in the convalescent serum panel. After the second dose, these went up to 8x to 50x the convalescent levels (!) The antibody response was further profiled for titers of real neutralizing antibodies – at day 28 (seven days after the second dose) neutralizing antibodies were 1.8x and 2.8x (in the 10µg and 30µg patients, respectively) those seen in the convalescent patients.

That definitely sounds good, since the convalescent patients, remember, had already beaten the coronavirus infection with the levels they’re showing. One variable in this, which we’ll have to address, are the reports that antibody levels in such recovered patients may drop off faster than expected. You might want to try to standardize when you draw plasma from such a comparator group (compared to when they stop showing viral RNA, perhaps). As Matthew Herper noted, the antibody titers in the convalescent patients show a much wider spread than the treated patients from this study. Everyone will of course be monitoring the persistence of vaccine-induced antibodies as these trials go on as well, and we’ll get more data on the topic. Another thing that I hope we see plenty of data collection on in the trials is T-cell response – this recent preprint suggests that this might be an even more sensitive indicator than antibody titer, and that there are indeed people who develop such a response without ever really seroconverting (developing antibodies).

The FDA has published guidelines for such clinical trials, and they look reasonable. The gold standard will of course be protection against coronavirus infection versus a placebo control, and right behind that is the severity of disease in people who do get infected. Blood chemistry/immunology is not addressed in detail because we just don’t have enough predictive detail yet about antibody and T-cell responses (as this latest Pfizer/BioNTech manuscript also notes), but the guidance leaves open the possibility of approval on such markers if we get a clear enough picture later on. Any such surrogate endpoints will have to be tied directly to those clinical endpoints, of course.

But back to these latest results: I agree with the paper’s conclusion, which says that its findings “are encouraging and strongly support accelerated clinical development and at-risk manufacturing“. So far, so good, and remember, these folks have three more mRNA vaccines coming along simultaneously. I very much await Moderna’s paper on their Phase I mRNA results for comparison – it’s been six weeks since the press release, guys, an eternity in Covid-time. Bring on the data, everyone!

82 comments on “Pfizer and BioNTech’s First Vaccine Candidate”

  1. Barry says:

    is there no adjuvant?

    1. Derek Lowe says:

      mRNA vaccines are thought to sort of have their own adjuvant effect by themselves, partly by virtue of being foreign nucleic acids. I don’t think any of these candidates (from any company) have an adjuvant dosed with them

      1. Barry says:

        I’m no immunologist! But it was my understanding that the choice of adjuvant (and of route of immunization) can shift the balance between IgG and IgA response.

        1. Dr. Manhattan says:

          Usually an adjuvent is combined with a protein or polysaccharide antigen in a vaccine. In contrast, the mRNA based vaccine versions (coated with a lipid (liposome) to protect and deliver them to cells) enter the body cells (muscle, etc.) and encode the viral antigen which is then made by the host cells and presented to the immune system. As Derek pointed out, the mRNA itself has a tendency to activate the innate immune system, and the mRNA in this series has been modified to tamp this response down.

      2. MrXYZ says:

        Although the lipid vehicles used to deliver the RNA probably have some adjuvant effect (as well as being a source of other toxicities).

        1. Derek Lowe says:

          Good point! Those vehicles aren’t invisible, either. It’s a real balancing act between protecting the RNA oligo, allowing it to enter cells, and not setting off too many alarm bells at the same time.

  2. Hunt says:

    One thing that caught my eye in this post was the comment about measuring neutralizing antibodies from patient samples. Does anyone have a sense for how well this in vitro vero cell assay (as described in the methods) translates to actual human responses? Is this giving reliable data to suggest that these antibodies would also be neutralizing in the clinic? Have these assays been clinically validated in another viral disease setting? For example do they translate well in the context of an influenza vaccine?

    I think the convalescent serum is good idea to try and get a positive control but of course has issues with timing, identity and concentration of antibodies in these samples (as noted in the post above).

    1. Derek Lowe says:

      My guess is that these data are being collected to compare them to the forthcoming clinical responses – I don’t think there’s enough orderly data from the infected patient population yet to say.

      But in general, yes, development of neutralizing antibodies is seen as a strong correlate in other vaccination programs – see: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3821995/

  3. anon says:

    Looks promising.

    Any idea why Moderna hasn’t published their data yet? Is it really that difficult to follow up on patients and analyze their antibodies?

    1. Dr. Manhattan says:

      This preprint will probably put pressure on Moderna to come forth with their results as well. It will be interesting to see how their patient responses compare to these data. One hopes that several of these efforts succeed and the strategy for the most optimal vaccines emerge from the data.

      Of course for Moderna, why publish data when a press release can boost your stock price?

      1. Steve Scott says:

        According to Time Magazine on June 11: “The full details of that study aren’t available yet; that will soon be published by Moderna’s collaborators, a team of scientists at the National Institute of Allergy and Infectious Diseases.”
        Moderna apparently does not have the right to publish on its own. I wonder if other companies partnering with, or getting funding from the US Govt. have restrictions as well.

        Note that Pfizer has declined government funding, and maybe that allows them to publish what they want, when they want.

    2. Derek Lowe says:

      Moderna surely has *all* that data; it’s exactly what they would have been collecting. As to why it’s not published yet, well, ya gotta wonder.

  4. RA says:

    Thanks for the post! Agree with hoping that we will see more data on t cell responses.

    Why aren’t all these studies collecting and distributing data on T-cell responses? They are small studies so I would think it would be very feasible to collect such data. Or are they collecting it, but not reporting it?

  5. Kevin says:

    How confident can we be be that generating a seroconversion by vaccination will lead to protection? You indicated a T-cell response may be a correlate of protection, without the need for seroconversion.

    1. Derek Lowe says:

      Big question, but no big answer yet. I think that the controlled conditions of the Phase II and III vaccine trials will be our best chance to answer it. Which is a bit like building a plane while you’re flying it, but such is the situation we’re in.

      1. Kevin says:

        Do you think challenge trials should be utilized for these purposes, alongside the Phase 2/3 trials?

        1. Derek Lowe says:

          Honestly, it doesn’t look like we’re going to need them. The challenge trials could only take place ethically in a younger cohort, and given the situation in various US states, we should have plenty of people to enroll. FWIW, the FDA guidance on clinical trials (linked in the post) leaves open the idea of challenge trials, but only if insufficient data could be obtained otherwise.

          1. Kevin says:

            Can’t it be said concretely that, in general, challenge trials allow for the collection of information on early stages of infection/immune defense responses that no other method can? It may be especially important for COVID-19, as the wide-ranging physiological impacts are just being elucidated. It seems the pathogenesis of coronavirus is unique and requires in-depth analysis for complete understanding, which maybe inform vaccine development.

          2. Adrian says:

            No. There is a huge number of people where you know they have just been exposed accidentally, in countries that failed to get the pandemic under control like Brazil or the US you could easily get this kind of data if needed.

            COVID-19 vaccine development is ongoing since January, most relevant data was collected back in the days when there was COVID-19 in Wuhan.

  6. Calvin says:

    The simple fact is that we have absolutely no idea if the levels of antibodies in survivor convalescent plasma mean anything or can be correlated with anything. Especially as you note that these may fall away quite quickly, more quickly than we expected. What we really need is viral load and antibody response in a wide variety of patients, those that are asymptomatic, symptomatic, mild, severe and with all the outcomes. I’m still surprised we’ve not see more of this basic virology even though I know it’s hard. I’d just sample an entire care home as soon as it has a case and collect as many samples and data as you can.

    Of course, we’d expect that decent antibody levels should be good, but we’re still guessing. I’m actually beginning to think (against my better judgement) that a half-life extended mab might be much better than any vaccine. We shall see.

    One thing I’d note on the Pfizer vaccine is that at the high does the tolerability profile looks…..weak. Most subjects with significant fever etc. Given the low number of subjects this makes me veeeeeery nervous.

    1. Derek Lowe says:

      That will be worth watching in a larger population. Wonder what dose they’ll pick for Phase II?

    2. mz_chem says:

      Do the more involved virology assays require BSL3 containment? That may be a bottleneck for testing. Many research labs and large hospitals may have them, but they are not plentiful.

      1. x says:

        I’m not aware of any nCoV assays that mandate BSL3 handling. BSL2 and normal PPE is considered sufficient. Patients are being handled with airborne precautions, though (N95 or respirator, eye protection, gown, gloves).

  7. Zambo says:

    How great would the logistical challenge of a multi-dose vaccine be?

    1. Adrian says:

      Depends on the quality of the healthcare system.
      With a good healthcare system you just book two appointments at your nurse instead of one.

      1. Zambo says:

        That’s true, I was just thinking more in terms of just how many people we could dose as we ramp up production (double the amount of doses needed=half the people dosed).

        1. Zambo says:

          Maybe logistical wasn’t the right word

          1. Adrian says:

            The number of doses is not the only variable for that.
            The trial in question compared one dose of 100µg, 2 doses of 30µg, and 2 doses of 10µg.
            30µg is triple the amount of 10µg, and 100µg is even more.

    2. PV=nRT says:

      Anyone else remember the multi-patient polio gun?

  8. loupgarous says:

    Thanks for a clear and understandable report on Pfizer/BioNTech’s first human trials… and fuel for legitimate (if cautious) optimism. If the other studies are like this… I think some of us can remember the Salk and Sabin vaccines, which left huge vaccination scars and weren’t fun experiences – but who gets polio in the US, nowadays?

    If this shows what the necessary immune response is for actual protective immunization (even if it just moderates the level of illness to what we deal with with each year’s crop of influenza) then it’ll have been worth the effort.

    1. loupgarous says:

      My wife, who is as Robert Louis Stevenson says, “the domestication of the Recording Angel”, corrected me – the huge scab/scar on the upper arm was probably owing to some other vaccination than the polio vaccines.

      1. Some of those of us who have those vaccination scars recall that they are from the smallpox vaccine. I’ve never gotten a scar from any other vaccination, not even from a smallpox booster I received at the age of 11 for a trip to Europe, when there was still a possibility of encountering the disease.

        1. Barry says:

          The smallpox vaccine was delivered intradermal, often with a bifurcated needle.I’m not aware of any other vaccine that has used that. Yes, it leaves a scar.

          1. Mammalian scale-up person says:

            If you are as old as I am, depending on where you lived as a child, you may also have a TB vaccination scar, or, heaven forfend, a scar from the old multi-tined TB challenge tests the school nurse used to give, if you had a bad reaction.

          2. Carl says:

            I knew somon back in high school, (2001), who had a really nasty reaction to the triple jab and for years afterwards i’d have mine intermittently swell up, (i know plenty of others with the same issue).

          3. fajensen says:

            We got lined up in long rows in school with our shoulders bared, and then one nurse per row would go “jab, jab, jab” as the kids moved through her station.

            The bigger kids in front would pretend it hurt a lot to wind up the smaller kids at the back of the lines. It wasn’t that bad, as far as I recall.

      2. RedFiona says:

        When we got our jabs, it was TB that caused the big round scars, if that’s the sort of scar you meant.

        1. eyesoars says:

          Nope, as above, the big round scars are from the smallpox vaccinations. Usually on the outside of the upper arm. I had the TB test several times (small tines, usually on the inside of the forearm), and have no scars from them.
          Unlike most of my generation, I’ve got two smallpox scars, both on my left arm. One from the usual childhood vaccination, and a second, slightly less obvious one obtained prior to moving to the middle East as a teenager. In both cases, fluid was squeezed out of a capillary onto my arm, and then I was repeatedly jabbed with a needle.

          1. Derek Lowe says:

            I got the “Med-E-Ject” injector gun treatment in about 1968 (I remembered what the thing looked like and looked it up years later). That was just a few years before they started phasing out smallpox vaccinations in the US, I believe. And yes, I still have the scar.

          2. Lambchops says:

            Depends on age, I’m too young to have had a smallpox vaccine but just old enough for the BCG vaccine for TB (before routine use in the UK was stopped) and the distinctive upper arm scar. Though when it came to the actual injections the tester was the scary one, I don’t think any kid enjoys something that has 6 needles!

          3. Harvey 6"3.5" says:

            I had the “good” fortune of not only getting the med-e-jet injector, but also using vaccinia virus as an expression vector during my doctoral research a long time ago with a mentor who remembered Asilomar. My titers (and those of a few of my labmates) were too low for him, so we had the joy of getting revaccinated against smallpox in the 80s, by doctors and nurses who’d never given this vaccination and ended up pricking us many, many times. Our titers did go up, at least.

      3. Brent Heimuller says:

        the smallpox vaccine involved a dozen or so pokes with the bifurcated needle in a small circular area to deliver the drop of vaccine inbetween the tines with each poke right under the skin, as I recall. most born before 1980 would bear such a mark

  9. Marko says:

    A nice , old-fashioned attenuated live vaccine makes the most sense to me. Get the full spectrum immunity of natural infection in all its glory. Consign COV2 to the common-cold coronavirus dustbin and be done with it.

    1. loupgarous says:

      Any kind of live COV vaccine gives me the willies. What if it’s “live, attenuated and MUTATING?”. A friend active in local work with SARS2_CoV at one of the university labs in New Orleans says two mutant strains have grown from at least in the space of a month from one well-characterized parent strain in high-level biocontainment.

      It’s hard not to think in terms of Andromeda Strain right now:

      “When the bomb goes off there’ll be a thousand mutations! Andromeda will spread everywhere! They’ll never be rid of it!”

      The charitable assessment of the origin of COVID-19 is zoonotic spread from an open-air market in China. But we fatten pigs and cattle and other livestock here in pens which are also open-air. Some outbreaks of, say, swine flu are attributed to zoonotic spread from birds to pigs, and then from pigs to us.

      Can humanity afford more zoonoses from our food chain? Burger King has shown a reasonably good-tasting hamburger can be made without meat (I’ve tried their “Impossible Burger” and found it to taste like overly-seasoned beef). If we just happen to need meat in our diet, we can now culture it from strains of animal muscle without having to fatten and slaughter animals who, by the way, are intermediate zoonotic hosts from birds to man.

      Look around you at the costs of meat in China to the entire world (if SARS_CoV2 is indeed a zoonosis and not a bioweapon). We may want to re-prioritize government and industrial action from lowering carbon footprints to on a global scale securing our species’ food chain from zoonotic spread of pathogens like SARS_CoV2 – or worse.

  10. myst_05 says:

    Shame that vaccine companies are not willing to use the 18k volunteers on 1DaySooner to just go ahead and run a live challenge trial. If they did, we’d already have real data on how well the vaccine protects people from an actual infection, completely forgoing the need for Phase III trials. Unfortunately each day of delay costs us 5k deaths – and that’s just the officially reported figure – orders of magnitude more than the number of people who would potentially be harmed by a human challenge trial. So if vaccine deployment is delayed by a month because of this stubbornness, we would effectively lost another 150k people to COVID, all for the sake of following some ancient rules of bioethics.

    A real shame that unfortunately doesn’t get enough press attention.

    1. Pat says:

      Challenge trials might not save much time, if any, and there are other issues that go beyond the obvious risk of infection for the subjects. Michael Rosenblatt wrote a recent editorial in Stat arguing against using challenge trials for COVID-19 vaccines.

      https://www.statnews.com/2020/06/23/challenge-trials-live-coronavirus-speedy-covid-19-vaccine/

      1. RA says:

        Interesting article. Seems like the Pharma establishment is against challenge trials. The question is why? Ostensibly, it is concerned about ethics, safety, generalizability, etc. But I don’t know…way more people are dying and suffering every day as a result of delays…that is an ethical issue. They say it takes a while to create a protocol for a challenge trial, but why not do a naturalistic one? Measure their tcells, Abs, etc before, give them the vaccine and a MAGA hat and send them to church services with choirs. Controls can be plandemic supporters in the same church. Ok, I jest…but theoretically, one could find a way to expose challenge volunteers by mimicking the ways that we know people get infected in the real world instead of some time-consuming, precise rhesus-monkey like experiment. The perfect isn’t the enemy of the good. We are in a freaking pandemic…have some flexibility…think outside the box…change a few regulations! And heck, maybe a naturalistic intervention is more generalizable to the real world than some controlled lab challenge trial. If you think about it, a phase 3 trial is just a passive-aggressive challenge trial…hope transmission stays high where you are testing …wink, wink…hope participants are sloppy about masking and social distancing…wink wink…then hope you get enough exposure in the pool to be able to show a response…wink wink. The oxford people said themselves this could fail. If your participants happen to be careful about their social distancing or transmission goes down in the area, the trial is screwed. Yet, research approaches with a high risk of failure (not of the vaccine, but the study itself) are considered the “prudent, ethical course” while the pandemic rages. Fiddling while lungs burn in my opinion.

        So I don’t know, I have a hard time with the arguments against thoughtful challenge trails in those who give informed consent. Are we are being duped by Big Pharma to give them money and PR credit for going down mRNA and adenoviral rabbit holes while effectively outsourcing the unprofitable work of actually producing an effective COVID vaccine to the Chinese (are they doing secret challenge trials?!?!?) while Pharma gets support for accelerating technologies they will be able to a patent for more profitable uses down the road. In this scenario, challenge trials are bad because they risk showing quickly that some of their approaches don’t work very well and they need to string us along until the Chinese save the world and they can go back to doing the stuff that is actually in their financial interest. No challenge trials, moderna data…any…day…now…no t cell data from anyone…wait till phase 3!….in the meantime, we’ll get taxpayer money, manage our PR, pump and dump some stock and/or raise our h scores…woo hoo!

        Hope this is is wrong, because it would majorly suck if this is what is going on.

        1. loupgarous says:

          “So I don’t know, I have a hard time with the arguments against thoughtful challenge trails in those who give informed consent.”

          Part of the problem is that nobody’s well-informed enough to assess the risk to participants in a challenge study. The research community can’t wrote an informed content form which honestly lists all the risks involved to exposure to live CoV2 virus – which mutates in the lab at a rate that might make the term “informed consent” oxymoronic.

    2. Adrian says:

      What actually costs these deaths are people believing there will be a vaccine very soon, and not trying to get rid of COVID-19 without a vaccine immediately instead. Worked in Wuhan and worked in New Zealand and works in Thailand.

      My biggest worry are safety issues in a vaccine discovered only after emergency approval and administering it to 100 million people. It would rightfully destroy the trust in the safety of approved vaccines.

      The track record of emergency approvals for COVID-19 treatments is not good, with marginally helpful (Remdesivir) and even harmful (hydroxychloroquine) medication gotten approval.

      Let’s be grateful if we are lucky and a safe sterilizing vaccine is available at some point during 2021, it is possible that there might be none.

      1. confused says:

        >>What actually costs these deaths are people believing there will be a vaccine very soon, and not trying to get rid of COVID-19 without a vaccine immediately instead.

        Actually, I think most of the people who think trying to eradicate COVID isn’t worth it are very *pessimistic* about a vaccine’s availability and/or effectiveness.

        New Zealand probably can’t sustain its economy with indefinite quarantine from the rest of the world, but if a vaccine comes along early next year, their plan will have worked great.

        But this probably couldn’t be done in the US anyway.

        1. Adrian says:

          You are very mistaken in your assumption all the world would be like the US.

          In Oceania and East Asia and Southeast Asia most countries are pretty far at eradicating COVID-19.

          Check the COVID-19 numbers for countries like Thailand (a month since the last day with more than 10 new infections in a country of 66 million people) or Vietnam (still at 0 deaths with a population of 96 million people) – amazing success by poor countries that does not get the appreciation it really deserves.

          Economically, for countries like New Zealand or Australia or Thailand or Vietnam the relationship with China is far more important than the relationship with the US.
          Trade, tourism, foreign students – in all areas China is more important than the US for these countries.

          1. confused says:

            >>You are very mistaken in your assumption all the world would be like the US.

            I’m not assuming that.

            But Europe seems to have it mostly under control. Africa (so far at least) is fairly mildly affected. So most of the deaths going forward will likely be coming from the Americas.

            So if we’re talking about deaths likely to be prevented by a vaccine, that’s largely US + Brazil + Mexico etc.

            Just because eradication or very good control is possible in East Asia doesn’t mean it’s possible in the US, Mexico, or Brazil (not just because of current leadership, it’s a radically different culture, history, and governmental structure).

          2. Adrian says:

            What “radically different culture, history, and governmental structure” unites New Zealand and Australia and Vietnam and China and Thailand on one side, and the US and Russia and Mexico and Brazil and India on the other side?

            If you add funny animals, a queen and a horrible accent to the US you get Australia – I am not sure the lack of a king/queen is the radically different governmental structure you had in mind.

          3. confused says:

            NZ/Australia have huge geographical advantages (NZ is an island and Australia effectively is), a vastly smaller population in NZ’s case (smaller than my metro area), and much lower density in Australia’s case. These aren’t really comparable.

            China and other East Asian countries are *much* farther over on the collectivist vs. individualist spectrum than the US. They also don’t have a federal system with 50 different states. I think the US is more individualistic and internally complex than even NZ/Australia, for that matter.

            The US has unique advantages and disadvantages that make it not really remotely comparable to any other place on Earth. All the nations with comparable income/development levels are vastly smaller (in terms of population). All the nations with comparable size and internal complexity (Brazil, India, China) are not very comparable in other ways.

          4. confused says:

            For US vs. Australia specifically – the culture and governmental structures are AFAIK more different than they seem at first glance.

            US government is designed to be limited through separation of powers. Australia uses British system with parliamentary supremacy.

            US gained independence through a revolution, early in its history. Australia gained independence through gradual peaceful means, much later in its history.

            US is much more habitable away from its coasts, thus agricultural settlement of the interior was far more extensive and successful.

            This is for example why gun control was possible in Australia but is politically impossible in the US. And why Australia has a far more extensive social welfare system. The self-reliance/individualism/independence/frontier ideal is much stronger in the US, specifically the interior-west, central, and south-central US.

          5. Adrian says:

            It is always surprising how limited it is what people in the US know about the rest of the world. The problem with your arguments is that for everything you are saying there is an obvious counterexample.

            Germany is a strongly federal country, with income/development comparable to the US and a population of 83 million people. The federal government of Angela Merkel cannot temporarily close businesses or mandate a 14 day quarantine for travelers from abroad. German has 16 states, and each state had legislation passed in its state parliament for that. Some states were strict and others were not.

            Does the US have an assembly of the state governments with veto power on most federal legislation? Germany has.

            There are no obvious criteria that would determine whether a country is handling COVID-19 good or not.

          6. rtah100 says:

            @ Adrian:

            Q: What “radically different culture, history, and governmental structure” unites New Zealand and Australia and Vietnam and China and Thailand on one side, and the US and Russia and Mexico and Brazil and India on the other side?

            A: at a glance, the first five are all culturally homogenous and historically non-expansionist; the last five are all multi-cultural societies with significant polarisation and a comparatively recent history of slavery, serfdom and caste.

            – China is remarkably homogenous, it has minorities who are local majorities in small areas but nationally they are a rounding error compared to the Han Chinese population. It has also stayed within the same borders for centuries, barring the odd border stoosh.
            – Vietnam, ditto but re Vietnamese
            – Thailand, slightly more culturally diverse but with a long history as a nation state, remaining independent when the rest of Indo-china was reduced to colonies
            – NZ and Australia, originally culturally and ethnically homogenous when settled by Europeans (at least after the reduction of the indigenous populations), now much more diverse ethnically but with very rapid assimilation of immigrants into the culture. If anything, the interesting thing is the difference between New Zealand, settled by church-going judgmental Scots, and Australia, by rakes and convicts: guess which has the better record against coronavirus?

            Whereas:

            USA – an Empire in all but name,in its own continental 48 and sadly most places overseas as well.
            India – where to begin? So diverse and so increasing sectarian with the only common ground being cricket and the railways.
            Russia – another Empire, a bit smaller officially than before but still remarkably diverse ethnically, even if Slavic culture is pre-eminent even among the minorities as the path to advancement
            Brazil – another Empire, again remarkably diverse ethnically and culturally
            Mexico – an outlier, not really an Empire, not as ethnically diverse as the others… and also doing best of the five against coronavirus as far as I can tell

            The moral of the story is live in a national that minds its own business.

          7. RA says:

            What do the US, Brazil, India, Russia, and Mexico have in common?

            Blustering leaders who trade in BS.

            The coronavirus eats this style of leadership for lunch.

      2. loupgarous says:

        @Adrian, Confused:
        One thing the Australians don’t have that we do is a Governor-General with Royal authority to prorogue the government. Translating that into American – The House of Representatives in the US has “the power of the purse” – it can, just by saying so in a spending bill, prevent or promote any governmental action. This year’s House drafted a military spending bill that gutted the 2018 Nuclear Posture Review by denying funding for any of the things (like a lithium-6 enrichment plant we don’t happen to have right now) the posture review says we need. Trump is set to veto any spending bill that has such things in it and the Senate’s not likely to pass that kind of a bill, either. So we have gridlock.

        In most Westminster parliamentary democracies still closely enough aligned to the monarchy, failure of either house to pass spending bills in a way that prevents the government from operating would be called “a failure of supply” (anyone better informed than me, please correct me). Such failures of supply have, in Canada and Australia, resulted in the Queen’s representative proroguing Parliament, and calling for new elections for both houses of representative government. A caretaker government serve in the meantime, until new representatives could be elected and a new prime minister and cabinet elected after that.

        Some Australians have called for a change to republican government (like the US’s). There’s nothing magic about republican (lower-case “r”) government. Vetoes in spending bills or gridlock between Houses can cause horrible interruptions of governmental services here. No proroguing means the no continuity of governmental services.

        1. loupgarous says:

          corrected:
          @Adrian, Confused:
          One thing the Australians have that we don’t is a Governor-General with Royal authority to prorogue the government. Translating that into American – The House of Representatives in the US has “the power of the purse” – it can, just by saying so in a spending bill, prevent or promote any governmental action. This year’s House drafted a military spending bill that gutted the 2018 Nuclear Posture Review by denying funding for any of the things (like a lithium-6 enrichment plant we don’t happen to have right now) the posture review says we need. Trump is set to veto any spending bill that has such things in it and the Senate’s not likely to pass that kind of a bill, either. So we have gridlock.

          In most Westminster parliamentary democracies still closely enough aligned to the monarchy, failure of either house to pass spending bills in a way that prevents the government from operating would be called “a failure of supply” (anyone better informed than me, please correct me). Such failures of supply have, in Canada and Australia, resulted in the Queen’s representative proroguing Parliament, and calling for new elections for both houses of representative government. A caretaker government serve in the meantime, until new representatives could be elected and a new prime minister and cabinet elected after that.

          Some Australians have called for a change to republican government (like the US’s). There’s nothing magic about republican (lower-case “r”) government. Vetoes in spending bills or gridlock between Houses can cause horrible interruptions of governmental services here. No proroguing means the no continuity of governmental services.

    3. A Nonny Mouse says:

      Sorry, but it isn’t that simple! You can’t just jab anybody (at the moment, anyway)

      For each candidate there is a full medical screening to go through, which takes a few hours, and then medical records from the GP.

  11. Dave says:

    Any idea why the mRNA trials involve such a small sample? Novavax has 131 enrolled vs less than 50. Was it that platform being potentially riskier than protein based vaccines?

    1. Omar says:

      Indeed; a new platform with no sufficient data from animal models

  12. Angela says:

    I love all you adorable nerds. Thank you for being so smart and good at what you do.

  13. Mr T says:

    Wished they had subjects age 55 and older.

    1. Kevin O’Neill says:

      As a 55 year-old, I heartily agree!

      1. A Nonny Mouse says:

        You need to try out the Imperial one, then!

        …..Following this initial small group, the team will then recruit further healthy volunteers (aged 18-75) to trial the optimal dose of vaccine in a larger population. The combined Phase I/II studies will aim to deliver the vaccine to a total of 300 people at sites across the UK……..

  14. DiBenedetto says:

    Hey Derek I really enjoy the work you do. Its a bit over my head but learning! Anyway you could look into leronlimab ? Seeing some early promising results but not sure of the science.

  15. Toluene says:

    The data from the CDC is utterly confusing. Lower weekly deaths and skyrocketing cases??Overcounting (sputum and nasal samples from same patient counted as two cases) and combining viral and antibody tests confuses the whole analysis.

    https://www.theatlantic.com/health/archive/2020/05/cdc-and-states-are-misreporting-covid-19-test-data-pennsylvania-georgia-texas/611935/

    https://www.cdc.gov/nchs/nvss/vsrr/COVID19/

  16. Jürgen Bosch says:

    I assume to identify if someone who was vaccinated got exposed to SARS-CoV2 is to measure for other antibodies generated e.g. against Nucleocapsid protein or others not used in the vaccine. Do we know if there are specific antibody tests that are not directed towards the Spike protein or just the RBD domain?

    How do you determine if the reason why a person did not get sick and generated new non-existing antibodies agaist SARS-CoV2 is due to the protective response raised through the vaccination and not against the newly raised antibodies?

  17. DTX says:

    Thanks for all of the fascinating (and educational) comments on adjuvants. I’d love to take a course in it now that I know more of the depth (previously I knew just vaguely about aluminum based ones).

    One unfortunate thing that will promote vaccine develop is the US’s inability to control the outbreak. 2 or 3 months ago, I remember reading articles lamenting that we’d lack the ability to test the new vaccines due to insufficient incidence. Whereas this is certainly true in China, NZ, & a few other places, it looks like the pandemic will continue in the US for quite a while.

    Challenge testing will be completely unnecessary if things don’t change. Natural prevalence of the disease will ensure that we have the needed data. To be clear, I’d much rather the US control the virus, but it doesn’t look like this will happen anytime soon. It feels like we need a cultural change to actually instill protective lifestyles in enough of the population. (until we get a vaccine)

    1. RA says:

      Possibly, but what if even in higher transmission areas, the vast majority of transmission is driven by a relatively few superspreaders.

      https://www.nytimes.com/2020/06/30/science/how-coronavirus-spreads.html

      How confident are we that randomization will ensure that both placebo and treatment arms have equal opportunity to be exposed to superspreaders? I worry that random differences in exposure risk between treatment and control arms will mess up the studies. I think a case can be made that the unique biology and transmission of this virus makes challenge trials much more imperative.

      1. Adrian says:

        As long as the number of participants and the number of people who get an infection is large enough there is no problem.

        The statistics basics behind that are taught in high school math class in many countries, if you were unlucky to not got this taught in school it would be worth for to learn more about it.

        1. confused says:

          Yeah, the question is how large the sample sizes will be. Hopefully very large for Phase III.

        2. RA says:

          High school!

          Could you point me to the high school lesson that discusses what adjustment in sample size to achieve sufficient statistical power one, if any, one must perform when exposure events that lead to your outcome of interest are relatively skewed to a small group of superspreaders?

          I think that lesson was covered on senior ditch day and I was at Six Flags!

          Will the sample sizes be enough to account for potential modest effect sizes, social distancing variations, community transmission moving targets, the skewed nature of transmission? We shall see! The devil is in the mathematical details and the quality of the assumptions used for them.

          1. loupgarous says:

            When I was writing reporting code for clinical data which did statistical testing, I worked closely with statisticians, whose understanding of which tests to choose for a given clinical dataset went far beyond mine. I was glad to have that on their shoulders and not mine. I just got to determine which of our reporting macros was liable to report those data reliably after the specified tests were applied. That just required an understanding of hierarchy of operations in Base SAS versus SAS Macro versus SAS Stat.

            That was a complex enough issue that someone else’s reporting macro for generating adverse events was reporting those events is a noticeably wrong order (the dataset was small enough to make that obvious). Soooo I compliled a top ten AEs table with calculator and mechanical pencil in a subset of the data giving us the problem, then started going through the Top Ten AEs macro… and sure enough, differences in program timing between Base SAS and SAS Macro pointed to an easily fixable issue.

            Moral: Statistical testing of clinical data is difficult and way beyond high school (or even college) math. Best left to clinical statisticians.

            Reporting the results of those tests requires something a lot more like voodoo to non-programmers. You just have to have time on the reporting language you use.

  18. Steve Scott says:

    From Derek’s summary on Pfizer: “Recall that this effort actually has four different mRNA vaccine programs: two with modified RNA bases, one with extra uridine bases, and one in the “self-amplifying” category.”

    There has been very little publicity about the “self-amplifying” category so far. According to a 2018 study involving influenza and human challenge testing: “equivalent levels of protection were achieved using 1.25 μg sa-RNA compared to 80 μg mRNA (64-fold less material).
    https://www.sciencedirect.com/science/article/pii/S1525001617305944
    It will be interesting to see whether this will become Pfizer’s final candidate. Many more doses could be produced from the same amount of material. Also, in case you need a stronger dose for seniors (similar to yearly flu vaccines) it would be easier to make. I suppose a potential drawback would be the idea that it begins multiplying after injection, which might frighten some people or lead to fears of a runaway reaction. Hopefully no serious side effects will emerge.

  19. Charles A. Pilcher MD FACEP says:

    I’m concerned that this coronavirus seems more clever than any vaccine we can make. Two questions:
    1. If a vaccine for CV were possible, would we not have outsmarted the version of CV that causes the common cold and developed that vaccine by now?
    2. If we can outsmart the CV virus and produce a vaccine that is effective against the many (apparent) versions or mutations of this novel coronavirus, could we not also develop an influenza vaccine that doesn’t have to be re-manufactured every 12 months?

    1. Derek Lowe says:

      Fortunately, there are good answers to both of those (which are questions that others have as well). #1, the incentive to go through the whole vaccine-development process for the common cold just isn’t there, for the most part. It’s an expensive enough (and risky enough) proposition, and the safety standards would be so high for a nonfatal “disease of inconvenience”, that no one really has wanted to touch it. And #2, it turns out that influenza viruses have a much more robust mix-and-match process to constantly change their surface proteins, not shared (fortunately) by the coronavirus.

  20. pfizer joe says:

    THEY ARE PUTTING RESULTS IN LAY PRESS TO BOLSTER THEIR LAGGING STOCK.

  21. David Rollins says:

    Hello. Are Pfizer/BioNTech’s vaccine entries derived in any way from fetal cells?
    Thank you.

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