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Pfizer and BioNTech Pick a Vaccine Candidate

In a bit of a surprise move, Pfizer and their partner BioNTech announced yesterday that they were moving their BNT162b2 mRNA vaccine candidate forward into Phase II/III trials. The surprise was because all the publications from this effort so far had been on another one of their four candidates, BNT162b1.

Fans keeping score at home will know that there were originally four candidates: two with modified RNA bases, one with extra uridines, and one self-amplifying RNA. From that press release linked above, it appears that the latter two fell behind during the preclinical and early clinical studies – we haven’t seen that data, but apparently BNT162b1 and BNT162b2 have been the front-runners for some time as far as the two companies were concerned. (In retrospect, maybe it’s a good thing that I never got around to doing a detailed post on the self-amplifying RNA mechanism! Update: OK, with the Imperial College vaccine doing human trials, I’ll go ahead and do that post anyway. . .) So what’s the difference between the two remaining ones?

It comes down to the antigen(s) being coded for. The b1 candidate, the one we’ve been hearing about, codes for the coronavirus Spike protein’s receptor-binding domain (RBD), and this was constructed as a trimer, three RBDs attached to a “foldon” protein core. Meanwhile, the b2 candidate codes for what they say is an “optimized full-length Spike” protein instead, not just the receptor-binding domain. Pfizer’s press release says that both the b1 and b2 candidates “induced favorable viral antigen specific CD4+ and CD8+T cell responses, high levels of neutralizing antibody in various animal species, and beneficial protective effects in a primate SARS-CoV-2 challenge model“. But they made the choice for the b2 variety partly because it seemed to be better tolerated on injection, and also because it led to a wider variety of T-cell responses. These include both CD4+ and CD8+ T-cells, and these were raised not only to recognize the RBD region, but also other regions of the Spike protein that weren’t contained at all in the b1 candidate. And they’re quite right – that could well be beneficial, and the better tolerability is a bonus. The release says that the neutralizing antibody response was similar between the two candidates.

I look forward to seeing the numbers on that – in fact, I look forward to seeing the numbers on everything. That’s going to be really important as we move forward, because any hint or appearance of secrecy will be toxic here. We already have enough people who are (1) suspicious of vaccines, (2) suspicious of what various authorities say about coronavirus treatments, and (3) suspicious of the motives of the pharmaceutical industry. I might add a fourth group, who are suspicious of the motives of the Trump administration, particular as regards getting a vaccine announcement out in a timely manner before the November election. It’s a mess, an awful mess, and we do not need to make it any worse by giving one or more of these groups more ammunition.

The only solution (as far as I can see) is full disclosure. Let’s have all the clinical data for every candidate and have the decision-making process be as open as it can be. We have a lot of decisions to make (it’s going to take a whole other post to get into that), and it’s going to be way too easy to screw that process up and make things worse than they are already. That actually seems to have been the hot happenin’ trend here in the US for 2020; I’d be very happy if we could manage not to do it for the vaccine selection and rollout. . .

67 comments on “Pfizer and BioNTech Pick a Vaccine Candidate”

  1. A Nonny Mouse says:

    Go one, tell us about the self amplifying! My daughter has had the Imperial vaccine and has a follow up tomorrow, though there appears to have been no reactions at all (don’t know which of the 3 doses it was, though).

    At least Pfizer weren’t in the government programme to slow them down………

    1. James E says:

      I’m also part of the Imperial Phase II trial so would be curious to hear more about the mechanism…

        1. A Nonny Mouse says:

          Many thanks.

          Looking into it myself, I noted that the Prof leading the team has a patent on the self replication, though I couldn’t find it after a hunt.

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        1. Paul says:

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  2. Marcus Theory says:

    “That actually seems to have been the hot happenin’ trend here in the US for 2020”

    Pessimists get only pleasant surprises. Here’s hoping….

  3. Old says:

    Maybe I missed it somewhere in the avalanche of Covid vaccine papers but has Pfizer published (either in pre-print form or otherwise) the NHP challenge studies with BNT162b1 and BNT162b2 that are mentioned in the press release yesterday? Thanks in advance.

    1. Derek Lowe says:

      Not that I can see!

      1. Old says:

        Thanks, I didn’t think so.

  4. Oudeis says:

    I agree that full transparency is the right way to go on everything–don’t just publish the data, but get cameras into the vaccine factories, etc., so people can learn as much as possible about how all this works and realize just how *cool* it all is.

    It won’t satisfy the serious anti-vaxxers; in fact, it will give them ammunition. They’ll take the information they’re given and misrepresent it, misinterpret it, pull it out of context, etc. The more they know, the firmer they’ll become in their position. That’s just how conspiracy mindsets work.

    The transparency isn’t for them–it’s for the people who haven’t picked a side yet, who are larger in number than you might guess.

    1. Neon says:

      Agreed. Just like letting a kid play with the stethoscope at the doctor’s office

    2. Mammalian scale-up person says:

      For Pfizer, you can see some of their plant tours on YouTube. Here’s a nice video of a prefabricated facility going up in Groton: https://youtu.be/tPmcwyfuqhE

      CMOs like to put virtual tours of their facilities online for marketing to clients, here you go:

      Samsung; https://samsungbiologics.com/front/en/aboutUs/milestones/virtualTour.do

      Fujifilm Diosynth has theirs password protected, presumably to force you to talk to a salescritter. Guys, make it public!! https://fujifilmdiosynth.com/360-tours/

      LSNE YouTube: https://youtu.be/h2MKA7S2rwQ

      Lonza: https://lonzavirtualtours.com/

      Catalent, who is making the JnJ vax, another YouTube: https://youtu.be/uJoOCeKvxI0

      When they’re in operation there isn’t actually a lot to look at. Everything is in steel tanks or pipes, we don’t look at stuff very often. Someone might peek in a sight glass to see if it’s foaming, but for the most part we don’t eyeball what’s going on inside a tank. And it’s nearly all run by automation these days, you’ll only see a handful of guys in bunny suits wandering around the manufacturing floor – for the most part I catch them messing around on Facebook in the controls room… In the olden days there were a lot more manual valves, but in the new facilities we have automated valves and less deviations because someone forgot to turn valve #476.

      The liquid handling robots in the QC lab and fill-finish suites can be very soothing to watch, I think. Here’s a Tecan: https://youtu.be/6z4lc_26duk
      Hamilton liquid handler: https://youtu.be/fz41pJvcfQc

      Here’s a vial fill-finish system: https://youtu.be/5a_J1kRiD3w The first few minutes are all about the washing and sterilization system, but after that it starts filling and shows the optical sensors and checkweights.

      People love to look at anything with a Staubli arm, for some reason, even if what it’s doing is very boring pipetting or unscrewing caps on flasks. I used to have a SelecT cell culture maintenance system which has since been bought by Sartorius and they don’t seem to have a video of the thing in action, but people loooooved to watch it.

      1. Josh says:

        As I understand it these RNA vaccines are synthesized chemically and do not need 1000 liter fermenters. They get run on a couple of columns, go to a mixer to get lipid encapsulated and then get packaged and frozen to -80.

        1. Mammalian scale-up person says:

          There is an initial fermentation step to generate the DNA that’s used as a template – but this is typically E coli and smallish scale fermenters in the hundreds of liters range. Synthesis is carried out in the same type of tanks we use in mammalian for process intermediate holds, and the columns are identical to what we use in mammalian purification operations. The TFF systems are single use scale, about 10m2.

          Many of my Drug Discovery colleagues have never seen operations at clinical / commercial scale, they always seem sort of awed by them. I remember one of the Drug Discovery PIs asking me where one of the technicians did his PhD to learn to run such complex machines (this was when a lot of our systems still had manual valves) and he was shocked that the guy had barely graduated from high school. In Europe they tend to have a certification process that’s a bit like community college, but in the US experience is a perfectly acceptable substitute. If you ever saw the old Genentech Vacaville site, it looked pretty complicated from all the manual valves and everything packed together.

          1. PV=nRT says:

            How do the artificial bases get installed? Can’t be via normal fermentation. I assumed that ASOs and mRNA therapeutics were made on an oligo synthesizer.

          2. Mammalian scale-up person says:

            @ PV=nRT: in vitro transcription at scale (gram quantities, not do-able on the liquid handlers used by most synthesizers) is a not-too-terrible mixing problem, but a very terrible polymerase source problem. T7 isn’t typically made as GMP quality material, there’s not a ton of sources capable of providing the controls for this level of material purity and activity.

      2. Oudeis says:

        This is very cool. Thank you.

        I hope the PR people are thinking hard about how to get the word out.

      3. eub says:

        This is really cool and I’ll look at all your Staubli arms thx.

    3. Mammalian scale-up person says:

      FYI, there’s a post stuck in moderation due to many links, but there are plenty of YouTube videos and virtual tours of pharmaceutical plants available online. CMOs in particular love to make such things for marketing purposes.

      I don’t know how much it helps to see these things – there’s a lot of piping and support systems that you don’t see in real life without climbing into grayspace, and we mostly only “see” and interact with the automation drawings. Even if there’s a really cool reaction going on inside a vessel with something interesting to look at, we mostly never look at it directly except to check if it’s going to foam out the vent. But, you can admire how clean and shiny it is.

      1. Derek Lowe says:

        Just approved it – thanks!

        1. Mammalian scale-up person says:

          Great, thanks!

          Also forgot to mention, there is an International Society of Pharmaceutical Engineers channel on YouTube that has posted some videos about manufacturing and how these things are designed. It’s intensely boring unless you are REALLY fascinated by water purification and persnickety little validation details, but unfortunately the best-paying and most stable jobs in pharma are the ones nobody else wants to do.

          It doesn’t really answer any of the complaints the anti-vaxxers make, because there’s…nothing to see, really. We work very hard to keep it boring, if my job is suddenly exciting then I’m doing it wrong.

          1. Aspiring boredom says:

            Do you have the link to that channel handy?

          2. Mammalian scale-up person says:

            @ Aspiring boredom: Here you go
            https://www.youtube.com/user/ISPE3109

  5. M says:

    Derek, I couldn’t tell from the Pfizer press release (and maybe I missed it), but is the b2 candidate also the one they are manufacturing at risk, or is it both b1 and b2? I would assume b2.

  6. ProVAX Prophet says:

    Maybe we could get wristbands with unique QR codes when we get our vaccine, and have our photos put in an on-line database that is linked to those QR codes. So the bouncer outside the bar can scan your wristband, see if the photo matches, and then let you in to the ProVAX Lounge? Okay not realistic, but better than Bill Gates shooting me up with nanotags, or invisible tattoos, right?

    1. Zambo says:

      You just no the anti-government types would have a field day with this one.

      1. Zambo says:

        *know

  7. Izzy says:

    I don’t understand why both this and Moderna’s mRNA have been picked for Warp speed. Seems redundant?

    1. pjp says:

      One, or both, may yet prove to be useless, and even if they are both effective, one may very well be much better than the other for reasons unknown.

    2. Orange_Pills says:

      They don’t use the same formulation. Even if both used the same exact RNA sequence they would be different drugs. And then you can consider trace impurities from different manufacturing processes. That may or may not have known and unknown effects. Or one goes bust due to management errors, toxicity or a plant that burns down.

    3. sPh says:

      Having more than one effective vaccine with different manufacturing pathways would help avoid bottlenecks in implementation as well.

      1. sophia compton says:

        But I wonder what it would mean to mix them, if you got the booster in a different vaccine?

    1. theg9 says:

      Memory T cells may end up being more important than antibodies in the case of coronaviruses. There is evidence that infection from prior coronaviruses like SARS-1 or a common cold coronavirus results in milder symptoms of Covid, possibly due to memory T cell response.

      1. Riah says:

        Intriguing…..I wonder if the findings of this following paper was a factor in their decision to switch to the vaccine that elicits a wider variety of T-cells???
        16 June pre-print :SARS-CoV-2 T-cell epitopes define heterologous and COVID-19-induced T-cell recognition: https://dx.doi.org/10.21203/rs.3.rs-35331/v1
        This found that of people that had been confirmed as COVID-postive, those that had mild symptoms or were asymptomatic had greater number and variety of T-cells but either fewer antibodies or even no antibodies. In contrast, the people that had been severely ill had more antibodies but fewer numbers and less variety of T-cells.

  8. theg9 says:

    I’m a chemist, not really an expert on vaccines, but I’m very suspicious of why challenge trials are not being widely going to be used to test the performance of these vaccines. To me, it just seems like the pharmaceutical industry’s worst nightmare if they did challenge trials and found low efficacy, perhaps because simply forcing your body’s ribosomes to make viral spike proteins turned out to not be an ideal way of generating permanent immunity against a highly mutable coronavirus. The FDA says they will approve a vaccine which prevents Covid in 50% of the people who take the vaccine trial. What’s to stop all the trial participants from deliberately sheltering at home, avoiding crowds, and making it seem as if it was the vaccine that kept them healthy? On top of all this, we still have no clue if these mRNA based vaccines are going to trigger long term autoimmune reactions due to the insane time pressure. The easiest method would have been to isolate and reproduce viruses from asymptomatic patients, assume that these variants caused milder forms of the disease, and inoculate young, healthy, volunteers with these live viruses. We could have hit herd immunity months ago. I would feel safer with getting and recovering from the actual coronavirus than I would with taking an mRNA vaccine, unless there had been years worth of safety data supporting it.

    1. Mark says:

      “….I would feel safer with getting and recovering from the actual coronavirus than I would with taking an mRNA vaccine, unless there had been years worth of safety data supporting it.”

      If you want to go that route , hang around in crowded , rowdy bars , or go to lots of choir practices , but still wear a mask. There’s evidence that asymptomatic or mild disease is associated with smaller inocula , and the mask would probably help you hit that sweet spot.

      I think I’ll take my chances with the vaccine , but I won’t be happy if it looks like they’re doing a rush job re: safety. Nothing but bad options to choose from , it seems.

    2. Ken says:

      “What’s to stop all the trial participants from deliberately sheltering at home, avoiding crowds, and making it seem as if it was the vaccine that kept them healthy? ”

      The point of a blinded study is that the participants don’t know if they received the vaccine or a placebo; thus behaviors of both the treatment and control groups would be similar. Without reading the trial design, hopefully they are using an already-studied vaccine as the control such that symptoms on dosing are similar (itching, irritation, immune response at the site of injection, etc)

      1. theg9 says:

        That’s a good point, but still, the concern is that both vaccine and placebo participants will be living in places where things are *not* normalized (many businesses closed down, working from home, avoiding large crowds, etc.) This is simply what the current baseline trend is right now in most places. Using results obtained from this baseline trend, and assuming that the obtained trial results will stay consistent even in a normal setting (where large crowds are commonplace and interactions with people are very high), might be a problem.

        1. Derek Freyberg says:

          Yes, but I think they are going to try to pick areas where there is high community spread already, so that people in the trial are at some risk of contracting COVID-19 if not immunized. California sites, for example, include at least one location in the LA area, one in the Sacramento area, and I forget the location of the third, though they should all be on clincaltrials.gov. And some vaccine trials are reportedly to be conducted in places like South Africa and Brazil, where the spread/risk seems to be, if anything, even worse than the US.

    3. Alps says:

      Totally agree with your comments. I can’t believe there aren’t challenge trials for fit & young volunteers. Heck, if you took a fishery or forestry worker and paid them not to work for a year, their chance of death & injury would be lower, even if the vaccine failed.

      Does anyone reading this know if there is a standard titre/escalation for rapid challenge trials (as opposed to long-term random community challenge)? Would it need to be set up with vaccinated people exposed to patients in order to have real-world applicability? Would it need to have a placebo arm?

      1. MagickChicken says:

        I haven’t had time to read it, but Derek did write about challenge testing a few weeks ago: https://blogs.sciencemag.org/pipeline/archives/2020/07/02/challenge-testing

        1. Alps says:

          Thank you!!

  9. debinski says:

    As someone who is about to participate in the Pfizer trial (which compares to placebo, not an active vaccine) I think the more likely scenario is those who think they got the real vaccine will go out in public more than those who got placebo. Why would I want to try to make the vaccine look efficacious if it wasn’t? But if I think I got the real thing, I’m willing to take more chances.

    I must say I’m a little shocked they are progressing the BNT162b2 vaccine. The public data on the b1 was limited enough (about 100 human subjects and no animal data) but the b2 has no data available! I sure hope they get something out there before my screening visit.

    1. MagickChicken says:

      I was supposed to be contacted last week about scheduling my appointment, but I haven’t heard anything yet. I wonder if it’s due to the candidate shuffling. . .

      1. MagickChicken says:

        *Scheduling my appointment for *this week*

      2. debinski says:

        I have not yet been contacted to set up the screening visit either, despite qualifying via the phone interview a couple weeks ago. Wondering the same thing.

        1. MagickChicken says:

          “We thank you for your patience and continued interest in our COVID-19 vaccine research study. You are currently eligible for our next phases of vaccines. You will receive a link next week to schedule your appointment. Please note there are a limited number of appointments available for the study, so we encourage you to schedule your appointment as soon as you receive the link.”

          This was on Friday, July 17th, for the trial running through Cincinnati Children’s.

    1. jimmy says:

      Kinda appropriate that its being organised by the Jenner Institute

  10. Klagenfurt says:

    The biggest risk to rushing these vaccines is the vindication of antivaxxers if something (1% is enough) goes wrong. I sure hope that BNT162b2 has been rigorously tested to exclude ADE. That risk seems lower with b1. Is the decision to go for b2 science or market driven?

    1. Question 1 says:

      How could it be market driven when both options target the same market?

      1. Klagenfurt says:

        The point is that 10 vaccines or so compete for what isn’t a free market but the desire of an incumbent government to show short term success by November 3. Whatever triggers the strongest immune response will win. All you volunteers, have a very close look at the consent form!

  11. Erik Dienemann says:

    Well, Russia has come out of the woodwork and says they’ll have an approved vaccine in 2 weeks, based on an adenovirus vector approach (like CanSino’s, which we know has possible issues with humans reacting to the human part over the spliced in COVID part). It’s Russia, so it’s sketchy, but they do have a lot of advanced science capability and they probably are taking the human challenge approach, where they’re purposely exposing healthy military “volunteers” to the virus. That will cut time off of development. Lots more twists and turns to come.

    https://www.cnn.com/2020/07/28/europe/russia-coronavirus-vaccine-approval-intl/index.html

    1. Derek Lowe says:

      Ah, this would be the Gamaleya Institute vaccine. Sketchy is the word.

      1. sgcox says:

        Here is the interview with the lead head.
        It is in Russian and lengthy, sorry. He sounds very modest, clear and down to Earth.
        No hype, no exaggerating claims.
        Yes, it is very similar to Sarnoff, based on bog standard human adenovirus.
        It uses a different strain (same as in China vaccine?) in the second dose to counter potential preexisting immune response to either strain. Laughed out British spy claims. Why would we need it ? Everybody around the world working on vector vaccine knows almost all from already published works.

        https://meduza.io/feature/2020/07/23/sozdatel-rossiyskoy-vaktsiny-ot-koronavirusa-denis-logunov-dal-meduze-pervoe-bolshoe-intervyu-on-rasskazal-stoit-li-zhdat-privivok-k-sentyabryu-2020-goda

        1. sgcox says:

          Sorry, first dose is apparently similar to J&J, based on Ad26 (not Sanofi)
          Booster is Ad5, as in CanSino.
          He does not expect roll out before New Year.
          Also says no problems with getting volunteers, “people get really sick and tired with all of this”

  12. RecoveredAmerican says:

    What I gather is Americans are bad at science. From the mask not wearing, to the Visa issue, to the lack of viable vaccines in America, to crap like hydroxychloroquine being used. I say this an American, and we basically are bulls in a china house. Let’s relearn it from the foreign countries and maybe we can do better eh??

  13. Claudio Franco says:

    Dear Derek, since there are so many vaccine candidates going now in phase III, which is in line with urgency of having one that works, I have some questions in mind: Don’t you think there is a risk that the first safe vaccine, even if it has very mild efficacy, will be given to millions just because it is the first? What should be the threshold for efficacy? Should we wait [for how long?] to get results from the different vaccine efforts? It would be great to hear your thoughts.

    1. Derek Lowe says:

      That is indeed a real risk – and it might be given because it’s first and because there’s a short-term political advantage to declaring a victory as well. The FDA wants to see at least 50% efficacy, but I think we’re going to all be arguing over (incomplete) safety profiles. . .

      1. Duncan says:

        But essentially isn’t that a risk we take with any medication to some extent? This is just an extreme circumstance. Leave aside the more fevered parts of the internet and the media for the moment, hard as it is.

        I think that most people out there are adult enough to understand that a) any vaccine will be rationed for some time b) there will, rightly, be priority groups however those are drawn and c) science being science, future medications will be better. In this case, ‘the future,’ might well be a very short window! I would not be at all surprised if one vaccine, or at least one technology, is the clear best in class by January 2022. If that is the case managing that won’t be any fun.

        The politics… well it is what it is and there’s not much we can do about that. What I think coronavirus shows is that science and scientists perhaps need to think more extensively about their relationship with politics, the media and social media in particular.

        But, with respect, give the public more credit – they’re not dumb to these issues. The media and social media are not always a great insight into the human mind. There will be necessary and uneasy debates and debates are rarely best-conducted by megaphone in the media, social or otherwise. We as societies will just have to get on with it.

        For example one messy debate that I suspect will jump up but which no one is talking about is children. I’m very aware that children almost certainly won’t be a priority. But I really would like for my little girl to be high up the list notwithstanding priorities.

  14. Thoryke says:

    At some point, could you explain what exactly Kodak is supposed to be contributing [for a fee, of course] to the vaccine effort? Is there even enough of Kodak left to do specialty chemistry?

  15. EJ says:

    Hey Derek, what do you think of the reports on long term COVID19 cardiovascular damage coming out?

    https://newatlas.com/health-wellbeing/heart-damage-recovered-covid19-patients-coronavirus/

    Its not a pharma industry topic, strictly speaking, but it seems pretty significant. Maybe even worth a writeup?

  16. JDPatten says:

    Derek,
    Claudio hinted at an issue that’s been troubling me. Suppose one were to opt for that first available vaccine that gets the OK and then a month or so later a more effective one gets released. Does having that first vaccine preclude getting the newer? There are so many utterly new mechanisms being tried that I’m wondering which parings might interfere with each other, which might be dangerous, and which might result in syxygy. Has any thought been given to this?

    1. Jeff W says:

      Novavax’s NVX-CoV2373 vaccine, something of a dark horse among these Phase III candidates, produced neutralizing titers in the 10,000 range in nonhuman primates, a lot higher than other candidates which produce neutralizing titers in the 40–200 range (according to this article “Why Was Novavax Awarded Almost $2 Billion in Free Money?”), but is the last to start trials—in October. (Moderna’s Phase III trial is going on now, with the Oxford/Jenner vaccine Phase III trial starting in August, Johnson & Johnson’s in September, and Novavax’s in October.) So it seems like that outcome—where a more effective vaccine loses to an earlier, less effective vaccine—is not out of the realm of possibility.

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