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Monoclonal Antibodies and Vaccines: Q and A

I’ve had a lot of questions from people about the prospects for monoclonal antibodies and vaccines against the coronavirus, and I thought that it might be helpful to answer them in this format. Let’s start the press conference!

We’ll start with monoclonal antibodies. Why are you so optimistic that this technology will work?

Two big reasons: one is that mAbs are already extremely successful drugs. If you look at the best-selling drugs from last year, 11 of the top 25 are monoclonal antibodies (and one other is a fusion protein with an antibody side chain). We know a lot about producing these things on scale (through several different routes) and a lot about evaluating their effects in human patients. The second reason is even more salient: the great majority of people who have recovered during the COVID-19 pandemic did so because they raised their own neutralizing antibodies to the virus. We know, then, that neutralizing antibodies to the virus really exist and that they are effective. In fact, many of the mAb candidates that are being developed have been isolated via the immune cells of just such human patients (the others are generally raised from the same sorts of cells from humanized mouse models). And remember, it takes some time before an infected person’s immune system can mount a full antibody response, so giving the neutralizing ones in quantity, right at the start, should have a strong effect.

Those things on that linked chart are all for arthritis, cancer, and other diseases. Are there any against infectious diseases like the virus?

There are, but that’s been more of a specialty area. Antibodies have to be given by injection, so it’s not as easy as making (and taking) a pill, but for serious infections it’s a real option. Here’s a recent review on what’s out there now, but it’s important to realize that in recent years we’ve gotten a lot better at discovering and developing mAbs. It’s become more feasible to think about mAbs for other indications, and people have actually been gearing up for their use in the case of an emerging epidemic. Here, in fact, is a 2018 article by an obscure physician named Tony Fauci on just that topic. Monoclonals have turned out to be very useful in the treatment of Ebola (a totally different kind of virus, but one that’s even more infectious and more fatal than SARS-CoV-2). Interestingly, one good source of antibodies for that one could be people who have participated in vaccine trials against it.

OK, fine. But that chart of yours is for best-selling drugs, and the reason the mAbs are so high on it is because they’re so damn expensive, right? What are they going to cost in this case?

Yeah, that’s a big one. That lands us right into the drug-pricing debate, and it’s important to realize that the existing mAbs, like pretty much every other drug, are priced at what payers are willing to pay. And that is tied to the value of the drug, of course. But all these calculations are pushed aside in the current situation: the value of a drug that will keep health care workers and other front-line people from coming down with coronavirus is clearly huge, but at the same time you’re not going to see companies scooping up billions of dollars, either. They’re very aware of how that would look, and frankly, the industry has been hoping that this whole pandemic might lead to some more goodwill. But that will go right out the window if someone looks like they’re profiteering. You’ll note that J&J has explicitly stated that they’re doing their vaccine work on a not-for-profit basis. I’m sure that there will be arguing about recovering costs, but I would expect that being the company that helps knock down the pandemic is a pretty big gain all by itself. We shall see.

And as for those internal costs themselves, it’s going to be hard to estimate, because we’ve never tried to do a mAb under these time constraints. I would be very interested in estimates from people who know better than I do.

On to vaccines, then. What do you say to people who say that there’s no such thing as a coronavirus vaccine?

Well, that’s not quite the case. There is, for example, a canine coronavirus vaccine available, although one has to note immediately that it’s for an enteric virus, not a respiratory one, and that it itself is of no use whatsoever (in dogs or in people) against the COVID-19 epidemic. But one big reason that there’s no human coronavirus vaccine is that we haven’t needed one. SARS was the first time there was a major coronavirus problem in humans (otherwise there are some that cause a portion of the common colds every year). And it disappeared before a full-scale vaccine effort could come to fruition.

How about the claim that developing one may be impossible, then?

There certainly are diseases for which vaccine development has (so far) been impossible. Some of these are nonviral (tuberculosis, malaria) and in those cases the organisms themselves are very hard to get an immunological handle on. But there are also viral diseases that we can’t yet vaccinate for, the biggest example being HIV. But remember, that one is specifically targeting the human immune response, which makes it a bigger challenge right from the start. Among the more common types of viral attack, hepatitis C comes to mind as one where a vaccine approach has never succeeded. That’s largely because there are a lot of different strains, and it has a high mutation rate. That’s similar to the problem with influenza viruses, which notoriously mix-and-match components to produce a different blend every time around. This coronavirus, though, is in a different family than any of these – fortunately – and while we’ve seen mutations, they are not occurring at a particularly rapid rate and do not look (so far) like they would limit the usefulness of any of the vaccines under development. In short, there’s no reason to think that the SARS-CoV-2 virus is going to be “unvaccinateable”. The opposite, in fact: it has an excellent target (the Spike protein), and many effective antibodies from recovered patients turn out to be hitting it.

So if we can probably get a vaccine that raises immunity to the virus, what’s the biggest worry?

Safety, as usual. We’re stipulating for now that one way or another we can make enough of the vaccine, but that is of course another problem entirely, albeit one that responds fairly well to having enormous amounts of money thrown at it. But any time you’re messing with the immune system you have to be concerned about safety. There can be bad reactions in small numbers of patients that are difficult to catch in clinical trials, and we’re going to be doing a lot fewer of those this time around than we have been for the marketed vaccines. I’m sure that we’re going to be doing as much as possible given the timelines, but there’s really no way to work something out as thoroughly as usual if we don’t want to wait for a few more years.

What happened with the SARS vaccines, anyway?

That’s very much worth studying. Here’s a look from during the original epidemic, and you’ll note that the landscape is pretty similar to what we’re seeing now (attenuated viruses, inactivated ones, virus-like particles, recombinant protein antigens). One thing that didn’t feature the first time around was the mRNA vaccines, which have been getting a lot of attention now, of course, but we don’t know yet if those are going to work. As you’ll see from this WHO list, though, DNA vaccines were indeed in the mix. Several of these went into clinical trials, but the problem was that the disease itself disappeared during this process, so none of these got the full investigation. There are, though, some of these that are being looked at now for cross-reactivity to the current coronavirus, which is quite similar.

So the SARS story is incomplete, but the good news is that the the lessons learned from it are generally applicable to the current epidemic – things like zeroing in on the spike protein and its receptor-binding domain, being alert to antibody-dependent enhancement, etc. We actually have much more of a head start on SARS-CoV-2 thanks to version 1.

How long is it going to take?

And that’s the big question that none of us can answer. We’ve got a lot of different mechanisms heading into humans, with no good way to be sure which will be more effective. And safety is, as always, a hold-your-breath-and-find-out process, as it is for every investigational therapy, vaccine or not. Then there’s the manufacturing and scaleup – these different technologies can call for very different sorts of manufacturing processes, so we’re probably going to spend bushels of money to push more than one at the same time (as we should). There will be problems there, too, most likely (aren’t there always?) So after you’ve run your time estimates through three fan blades like this, what’s left? The timelines you see about having one early next year, it’s safe to say, are for a candidate for which everything works perfectly the first time. If we take enough simultaneous shots, we could have one of those. Or not.

64 comments on “Monoclonal Antibodies and Vaccines: Q and A”

  1. KM says:

    Given all the stories of people doing poorly long after recovery, plus the inflammatory conditions in children with antibodies, what’s the level of certainty that this is an acute rather than chronic long-term virus? I’m a novice so apologies if this is a dumb question it’s just increasingly weighed on my mind.

    1. johnnyboy says:

      Coronaviruses in general don’t stay dormant/persistent in the body (like say herpes or retroviruses). They cause their damage, the body raises an immune response, and that’s generally it.
      The people that are showing signs after recovering from the disease have had lung damage, which has likely led to lung ‘scarring’ (interstitial fibrosis), which unfortunately is a permanent sequelae. But it doesn’t have to do with the virus remaining in the body and continuing its injury. The syndrome in kids is not very well understood, but it’s probably due to an abnormal immune response of the body to the virus, not a direct injury of the virus itself.

      1. Mark says:

        With due respect, you are incorrect, many coronaviruses can last months even trivial colds, but not chronic forever, doctors like to refer to coronavirus that lasts months as sinusitus – that is a load of nonsense it is definitely low level virus taking a long time to clear, but no one ever dies of a cold so no real research on the possible length of low level coronavirus in the body has ever been done.

        1. Konstantinos Spingos says:

          This is so intriguing, can you please provide any referances?

      2. Toni says:

        To complete Mark’s answer with 2 links:
        Within host RNA virus persistence: mechanisms and consequences:
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474179/

        Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding :
        https://www.nature.com/articles/s41591-020-0817-4

    2. Charles H. says:

      Another answer:
      Some of the reports indicate that blood clots in various parts of the body may be causing problems after you recover from COVID. How long that takes to recover from is highly variable. Clots in the brain sometimes take decades. I’ve heard that clots killing part of the kidney are never recovered from. OTOH, clots that cause your toes to swell are relatively quickly recovered from.

      1. KM says:

        So the idea would be that the virus is truly cleared and the blood clots – initially a COVID symptom – have become the underlying cause of lingering bad effects? That makes sense and is scary though I suppose slightly less concerning than actual persistent virus that could continue to cause new clots.

    3. Buzz says:

      No Worries.

      As an RNA virus it basically has to replicate to survive. Once it is suppressed by the immune system it is essentially gone.

      Other Viruses: HIV, HBV, herpes viruses have DNA forms that can hang around and go latent for a long time

  2. Philip says:

    The difficulty in developing a vaccine for feline FIP concerns me for the development of a SARS COV-2 vaccine. Am I reading too much into this?

    https://www.sheltermedicine.com/library/resources/?r=feline-infectious-peritonitis-feline-coronavirus-fip-fcov

    Is there a vaccine for camels for MERS?

    1. Aleksei Besogonov says:

      MERS in camels is very mild, so there’s not much incentive to develop a vaccine for them.

      1. Stewart says:

        I would have though that the incentive for developing a vaccine for MERS in camels is to eliminate the virus before it mutates into a form with human to human transmission.

    2. Scott Stewart DVM says:

      FIP in cats as a model coronavirus scares me. My understanding (which I am in general practice) is that FIP is a mutation of the enteric coronavirus where the virus loses it’s specificity to infect GI cells. Then it becomes a race between the virus and whether the immune system makes neutralizing vs non neutralizing antibodies. There was a vaccine on the market for a while but it appeared to cause antibody-dependent enhancement.

      There is a lot more incentive to come up with a vaccine for the human virus than there is the feline one but the fact that FIP is still a thing especially in cat breeding operations with no good vaccine is worrisome.

      1. johnnyboy says:

        The pathogenesis of FIP is more complex than just being due to viral mutation. Whether cats develop FIP appears to depend a lot more on host factors, particularly a deficient (or not persistent enough) T-cell response. I have also been concerned about appearance of a FIP-like syndrome in this pandemic, but I’m guessing if that was the case we would have seen it by now.

  3. Barry says:

    The barrier to a TB vaccine is not the lack of an antigen. The BCG vaccine does work against miliary TB (infection in tissues outside the lung that are accessible to IgG). It fails however to protect against the usual form of TB on the lung surface where IgA is needed. Only more recently have we learned that choice of adjuvant and route of immunization can shape the distribution of immunoglobulin classes
    J Immunol. 2017 Jul 1; 199(1): 9–16.
    doi: 10.4049/jimmunol.1601775

    1. Giannis says:

      Yes. The route of vaccination is always important. This is why I support attenuated vaccines since they can be applied to e.g. nasal mucosa and elicit strong immune response and antibody response.

    2. Toni says:

      Yes, although a few antigens are known in Mtb, the problem is that adequate antigen presentation to mount an efficient and balanced T cell response is hampered. This is due to the way Mtb survives intracellularly. The current vaccines based on recombinant BCG strains are designed to induce a better response by altering the antigen processing. In the light of COVID19 it is very interesting that these vaccines could induce a “trained innate immunity” via certain invariant T-cells and NK-T-cells eventally leading to mucosal IgA responses, too.
      https://www.nature.com/articles/s41577-020-0337-y

  4. Paul Zhang says:

    With regards to “So if we can probably get a vaccine that raises immunity to the virus, what’s the biggest worry?”, anti-vaccine sentiment might turn out to be an important consideration (although safety very much runs parallel to that). See https://www.nytimes.com/2020/05/13/technology/coronavirus-vaccine-disinformation.html.

    1. Daniel Welsh says:

      Thankfully, the R0 of this coronavirus is low enough that we probably only need to get to about 70% vaccination for herd immunity.

  5. Oudeis says:

    Ebola is more infectious than SARS-CoV-2? That’s a surprise to me. I assumed infectiousness meant transmissibility–is there a different meaning?

    Thanks.

    1. Derek Lowe says:

      My mistake – if Ebola had the R0 of the coronavirus and its known fatality rate, it would be the second coming of the Black Plague. Which we do not need.

      1. Hap says:

        Wouldn’t that just be The Stand with more blood?

  6. Zee Bendelstein says:

    Thanks for the public service as always.
    Couple of Qs:
    1) how do we know that the Spike-hitting antibodies from recovered patients were actually sufficient and necessary in their recovery?
    2) what about all the various safety challenges on the vaccine front and identifying/finding a remedy to those in a timely manner?

  7. Adrian Bunk says:

    You didn’t mention what I would consider the biggest reason why a SARS-CoV-2 vaccine should be less impossible than a vaccine against HIV or hepatitis C:
    Our immune system is able to defeat the live virus, and from what is known so far it is likely that most people have immunity for some time afterwards.

    Most hype is around the exciting novel approaches in vaccine development, but the boring old option of using inactivated virus is also available (and being tried) for SARS-CoV-2.

  8. Mammalian scale-up person says:

    We aren’t going to have one early next year. I promise. Even if we had real estate, permits lined up, utilities available and an empty shell building ready to be stuffed full of bioreactors, the equipment purchasing, installation, commissioning + validation runs at least 2 years. There’s not enough welders or steel to go around to do anything quickly. The majority of spare capacity I know of, is in smallish single-use type systems which cannot possibly produce enough doses to go round – and those will get bottlenecked by plastics manufacturing capacity. Even if we used up the existing capacity in 2kL single use, it would be longer than a year to get a cell line nailed down and PPQ batches run and then ramp-up and batch release done. Everyone and their brother is working on some sort of COVID biologic, they’re not going to let someone jump the queue, so even if the mAb that works is right around the corner – still have to wait in line for the other manufacturing slots to be completed, and those get scheduled out years in advance: realistically even a facility with spare capacity, won’t have it available until at least halfway through next year, and that’s before you do engineering runs and qualification.

    1. mymagoogle says:

      Generally speaking, I agree with you. I mean, sterility testing takes a month, and there is no accelerating that.
      However, it should be noted that some of the RNA vaccines need a very low dose compared to conventional vaccines. And then because it is synthesis, the yield and timing could be on the order of half a million doses from a 5L wave bag with upstream bulk completed in under a week.

      1. Mammalian scale-up person says:

        Still need to do real time stability verification of the accelerated stability studies, which – please, for the love of god, I’m begging every process developer on earth on this one, do your stability testing in different types of parallel storage containers, because we might not be able to get your favorite weird bottle, and large bottles are the absolute WORST things to fill and store at scale.

        I don’t have a ton of confidence in RNA-based vaccines on account of there have been many many clinical trials that failed even when things looked good in animal models. Other RNA applications and mechanisms seem to work pretty well (hi, Alnylam!) but for vaccines not so much, and not for lack of trying. At least they fail quickly.

  9. navarro says:

    You didn’t really get into the difficulty I perceive as the largest potential stumbling block which is an uptick in anti-vax sentiment among the public at large. I recognize that doesn’t interfere with vaccine development but it could damage the overall utility of any potential vaccine.

    I am from Texas which is not exactly a hotbed of calm, reasoned, analysis of scientific information. Among those folks to whom I am connected on social media, there were already about 10% who were anti-vaxxers on the basis of any number of absurd rationales. To those you can add another 30-40% who are already talking about “deep state” conspiracies or Fauci conspiracies and saying they wouldn’t take anything he recommended. There’s also a small cluster of folks who are describing the current situation as “the will of God” and saying that a coronavirus vaccine would be defying God’s will.

    So there’s half of the people I know who claim right now that they aren’t going to take it. Most of these are mature, college educated people. I don’t doubt that the proportion of people in other deep red states break down in a similar fashion.

    1. Derek Lowe says:

      As I’m fond of saying, you can’t use reason to argue a person out of a position that they didn’t get into by reason. . .I also see a lot of people saying that they “won’t take the Gates vaccine” or that they think that the vaccine will have “nanochips” so that the government can track them. What can you do with such people?

      1. Olandese Volante says:

        > What can you do with such people?
        Nothing.
        It ain’t worth the time and effort.
        As a local proverb goes, washing a donkey’s head is a waste of water, soap, and effort. And I guess applying this to the QAnon crowd is offensive to donkeys, too.

        1. Matthew Burk says:

          There is Supreme Court precedent for forcible smallpox vaccination. Given the impact of this pandemic, that should be an option.

      2. Adrian says:

        It would be good to look at the data, instead of focusing on whatever is currently being discussed on social media.

        In the end the one thing that will matter for acceptance is the safety of the COVID-19 vaccines.

        It is not helpful that half the population in the US thinks that the other half are stupid/deplorable/such people, and that they are 100% immune to reason.

        Let’s look at data for the Texas discussed:
        https://www.dshs.texas.gov/immunize/coverage/schools/

        In 7th Grade > 96% of students in schools have all the listed vaccines.
        Home schooled children were included, but it shouldn’t make a huge difference in the overall numbers.

        You will never get the < 5% of hardcore vaccination opponents, but they are not the ones that matter.

        I (not in the US) would try to avoid being one of the first people to get whatever first COVID-19 vaccine gets approved, I do not 100% trust that whatever gets rushed through the process is actually safe. The situation is different for healthcare workers with more exposure.

        If the vaccine is proving to be safe and effective in practice I would trust it more.
        And many other people will.

        If any COVID-19 vaccine that gets rushed through approval ends up having safety issues, you will lose the trust of many people that COVID-19 vaccines are safe.
        And the problem would not be "such people", the problem would be that an unsafe vaccine was approved.
        Other COVID-19 vaccines might not have the same problem, but it would be a fact that you cannot trust that all approved vaccines are safe.

        It is really scary when companies announce the start of production of a vaccine before it has entered phase 3 trials. It creates an immense pressure to approve a vaccine with 100 million doses already produced, nearly impossible to err on the safe side when there are doubts.

        1. A Nonny Mouse says:

          The idea here in the UK is for “ring” vaccination- those who have been in contact with an infected person- rather than the whole of the general population. Hopefully, this will bring the rate of infection down rapidly.

          Latest results from the monkey studies of the Oxford vaccine show that antibodies are being produced and that the monkeys are able to fight off the infection.

      3. Philip says:

        “What can you do with such people?” Be patient and show them the error of their ways. When that fails dismiss yourself from their presence with the excuse that you are late for your pig’s singing lesson.

    2. ezra abrams says:

      gonna push back a bit
      my general view is that in American politics, nothing is more powerful then Moms worried about the health and safety of their kids

      If anyone gets crosswise with moms, they will be crushed

      I think the Kawasaki thing might be the thing that gets moms upset

      go ahead, call me sexist; not the 1st time

      1. Marcus Theory says:

        Not arguing with your core thesis, but a great deal of the anti-vaxx movement precisely *is* moms worried about their kids’ health. Namely, the misinformation that vaccines cause autism spurs a lot of fears about getting one’s kids vaccinated.

    3. Christophe Verlinde says:

      There is an excellent remedy to deal with people who will refuse to get vaccinated against COVId-19: denial of coverage for hospital care when they get the disease.

      1. APAJ says:

        That sounds like a very European point of view, considering the peculiar American Dream of not having health care cost covered as a Human Right of Freedom. How many anti-vax would be covered in the first place?

    4. Jane says:

      I’m actually seeing the opposite. I’m observing the anti-vax sentiment from the left – the same individuals who are extremely into organic foods, alternative medicine, anti-plastic, etc etc. Those who have a simply have a preference for these things are reasonable but the true believers cannot be reasoned with.

      1. intercostal says:

        Anti-vaccination beliefs are found on both the far-left and the far-right (oddly), for somewhat different reasons … idealization of the “natural” vs. fear of government conspiracy – to massively oversimplify.

        On the West Coast you probably find more of the former, in interior US states more of the latter.

        I doubt it will be a problem for COVID; this isn’t as contagious as measles, so we probably wouldn’t need over 90% vaccinated. And (somewhat unfortunately) before we have a vaccine a lot of people will probably have developed immunity naturally…

    5. egl says:

      I’m not an anti-vaxer. I’m professionally and philosophically a STEM guy, and I have all the recommended vaccinations. BUT I was also slow to get the shingles vaccines because I wanted to see the safety profile in larger populations. The same would be true for a rushed COVID-19 vaccine, and I’m in an elevated risk category.

  10. Walter Sobchak says:

    Dereck: I am not a scientist or a physician, and I thank you very much for a clear and readable presentation.

    As for MAB pricing. The cost of a medicine must be compared to the cost of alternatives. Gilead the company that is working on remdesivir, brought out a Hepatitis C treatment a few years ago. IIRC, they charged more than $80,000 for a treatment. But, compared to the cost of treating a patient who had chronic Hep C for several years and perhaps needed a liver transplant, the drug was a huge saving of money.

    Similarly, and MAB drug that is effective against COVID-19 might be best compared to two weeks in an ICU on a ventilator. Avoiding that cost, would justify a very high price for the MAB.

  11. ezra abrams says:

    I don’t know how much mAb we need, but guess on the order of Kgs
    Do we have spare fermentors, enough fetal bovine serum ?
    Even columns for purification of the mAb from the culture supernatant ?

    you don’t build plants to produce Kgs of injection grade mAb overnight; alot of the specialty items are custom, iirc

    Given the urgency, and the trillions (literally) of dollars this is costing, does it make sense as a backup to put 100 million or so into phage display, aptamers ?

    Can we make a antisense RNA that you can spray in the nose and have it enter the virus particle ? (ok, that is a little out their, but alnylam does have an optic, product, right ?)

    1. Anon says:

      In a normal world you don’t need, or want, to use a 20K liter reactor for Phase 1 mAb CTM, or need at that point fully optimized cell line and purification process.

      Some time could be saved by starting transfer of that pilot scale cell line and process into commercial plant following a well designed Phase 2a study giving a hint of efficacy, but with likely having to accept lousy yields and higher cost of goods.

    2. Mammalian scale-up person says:

      We don’t use serum in commercial lines. We wean the cells off serum fairly early in the cell line development process. It’s too big a contamination risk, as Genzyme found out to their sorrow. There are many defined media formulations that work perfectly fine.

      Based off the dosing in this convalescent plasma study (https://jamanetwork.com/journals/jama/fullarticle/2763983) you’re looking at a dose of 3-5 g / patient. Phase 1 scale would be produced in single use 2kL scale; Phase 2 would be in either many 2kL scale or 5-6kL. We wouldn’t go to 20kL until Phase 3.

      Back of the envelope: 5g / patient, but let’s say that as with convalescent plasma we will only dose the sicker patients: 10% of cases at 30,000 new cases / day in the US x 5 g / patient = 150 kg / day requirement. Most modern mammalian platforms have titers of 3-5 g/L but ~50% is lost in purification, so one 20kL can produce 50kg per batch. Each batch takes on average 15 days to ferment + 2 days to clean and resterilize, and even the most streamlined purification processes take about 4 days to run, clean and re-sterilize. You’d need 16 (assume incomplete efficiency, occasional contamination, downtime for maintenance) 20kL bioreactors, minimum of three complete downstream purification trains, minimum of two fill-finish suites operating continuously.

      There’s not 16 spare 20kLs in the whole world sitting around doing nothing – manufacturing idle time costs $500,000 – 750,000 / day, depending on location; in terms of capacity they might have a spare three months here, a spare two months there that isn’t completely booked up, but that’s all there is. Some aren’t working 100% efficiently and can have modifications made to squeeze a few more batches out per year. Lead time on equipment is 2 years minimum, assuming you even have somewhere to put it, and making heavy equipment at that scale needs a lot of steel and has to come from multiple suppliers, as the bioreactor fabrication people usually do only a few at a time. Frankly that’s where the federal government could help: find somewhere to put a new site or three, help with the logistics and coordination of specifications and standards, lift steel and equipment tariffs.

      The other problem is the same as the SARS vaccine: this is not a long term problem. Normally we’d have 10 year contracts to make anything this big, and expect some amortization support and the ability to repurpose the facility after the contract is over, to make it a multiproduct facility – if someone comes out with a vaccine in say, a more realistic 5 year timeline, then what are we supposed to do with facilities that are suddenly idle and costing $1,500,000/day just to keep the lights on? The cost to build those facilities is something like $2 billion just to get them to mechanical completion, and another couple hundred million to validate them and get the initial raw materials in. Unless someone is subsidizing the heck out of this project, it’s a financial no-go.

      1. Derek Lowe says:

        My hope is that your dosing calculation is off, because the convalescent plasma is a polyclonal antibody mix. . .

        1. Mammalian scale-up person says:

          Fair enough, but I would also point out that the spike cysteines and aspartic acids that would normally be cathepsin digestion sites prior to loading an MHC also don’t yield a whole lot of great 20-27mers. Here (https://science.sciencemag.org/content/early/2020/05/12/science.abc2241) they only have four that work, two of which don’t overlap. That’s not a ton of encouraging epitopes (which makes me less sanguine about the possibilities for successful vaccine development too, but…), consistent with reports that patients aren’t reliably making neutralizing antibodies and seem to be often recovering via other immunity mechanisms. Even if my dosing calculation is off by a factor of 3 or 5, we still need to build at least one new facility, and without a 10+ year commitment it’s not a good business case – though it may be one that is more palatable to subsidize than the 3-5X dosing.

        2. djaustin says:

          For a uM potent antibody, wanting 9xIC9 in the lung for 28d, it’s about 1-2g. Sorry. The sums aren’t far off. I think the real question is what are you not going to make in its place.

      2. ezra abrams says:

        awesome comment, thanks

        the average quality of replies for the entire internet went up a measurable fraction today

        just a note on money
        The US Fed gov’t alone has already spent 2,500,000,000,000.00 dollars and we may well double that

        so the cost of getting some SR71 blackbirds to deliver some blank checks, this afternoon, to anyone with a 20kl fermentor is , roughly, zero, no matter how much is drawn on the checks
        I mean, even a *billion dollars* is peanuts (when you start thinking, a billion is peanuts for one possible cure, you are thinking the right scale)

      3. ABD says:

        Am I missing something? 0.1 x 30,000 person/day x 5g/person x kg/1000 g = 15 kg/day. Right? Not 150 kg/day?

        1. Mammalian scale-up person says:

          Sorry, you’re right – for the US anyway. While I was scribbling I was looking at the JHU numbers for the whole world and then multiplying by the vague guesstimate that testing of the general population would find 2X more cases as testing becomes more available and routine (am aware some studies have found many many more) – but I should have explained that, my mistake. My kingdom for an edit button!

          1. Anon says:

            Since we are getting into the weeds (great sub-thread BTW), old school humanized IgG mAb half-life usually requires monthly dosing and the newer mAbs with Fc modifications can go 2-3X longer. Might be interesting to speculate if in the absence of a normal length Phase 3 to build the data if a single or multiple doses would ultimately be administered.

          2. intercostal says:

            Well, finding more cases by better testing doesn’t necessarily mean more doses needed – people who have only quite mild symptoms might not get the treatment (especially if it’s an injection).

            We might “top out” on finding cases by PCR testing pretty soon, anyway. Even if there are 5x or even 10x more infections per day than are being found … if you’re asymptomatic you won’t know to get tested, and if you’re symptomatic but your symptoms are mild, you might not bother.

            (In my experience, many people — especially men, at least anecdotally — have a very high threshold of what’s “worth” going to the doctor over. This is probably stronger in more rural areas and/or those with a more ‘macho’ culture, for lack of a better word.)

  12. JasonP says:

    Ok while we are on the subject of antibodies, there is this news (preprint) about Convalescent Plasma.

    https://www.medrxiv.org/content/10.1101/2020.05.12.20099879v1

    Also I see several (4+) trials on ClinicalTrials.gov

    So how are we mortals to evaluate this info in light of what we have learned so far? Does not seem positive given the study had no placebo controls and there was 14.9% Mortality rate with the ‘treatment’?

    I guess if the group studied were severe case, as per the FDA guidelines:

    https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma

    Then perhaps 14.9% mortality is a win? Seems like those that progress to ventilation have an 80%+ mortality rate. (MedCram videos)

    What am I missing? What do I need to know?

    1. Chris Phoenix says:

      One thing to know is that bureaucracy can kill people.

      My father had COVID and went on a ventilator. The hospital wanted to try convalescent plasma. They tried for a week to get the San Diego blood bank to provide them with convalescent plasma. High hospital officials spent hours on hold with that damned blood bank.

      My dad’s wife had had COVID – confirmed by test – and recovered, but the blood bank wouldn’t take her because she hadn’t had a second test. Then someone else was lined up as a donor but the blood bank was still dragging their feet.

      Finally after a week they were able to get and use plasma from a different source (Mayo Clinic?) but he died less than two days later. If he would’ve had an 85% chance of survival by getting the plasma a week earlier, then it’s likely that the hidebound ass-covering book-following idiots at the San Diego Blood Bank let him die.

  13. Walter Sobchak says:

    A little O/T but FYI, and without endorsement:

    “Gilead should ditch remdesivir and focus on its simpler and safer ancestor” By Victoria C. Yan and Florian L. Muller | May 14, 2020
    https://www.statnews.com/2020/05/14/gilead-should-ditch-remdesivir-and-focus-on-its-simpler-safer-ancestor/

  14. Kaleberg says:

    The finance sector view of the struggle for COVID-19 treatments and vaccines is kind of interesting. Matt Levine at Bloomberg explained it:

    “I will say that if I ran one of the big index-fund companies, and a pharmaceutical company in my portfolio developed a patented fully effective cure for Covid-19 that it could manufacture cheaply and planned to sell to anyone who could pay $50,000 a dose, I would call that company right up and say ‘no, you give that pill away for free, because the value to me of Covid-19 going away quickly and the economy recovering—the value to me as an owner of airlines and hotels and chain restaurants and retailers and every other company—is vastly, vastly greater than the value to me of your profits on that pill.'”

  15. Erik Dienemann says:

    Derek – any thoughts on the “human challenge” (vaccinating young healthy low risk volunteers and then exposing them to the virus) approach to cutting perhaps several months off of vaccine development timelines? I’m guessing you’ve seen the paper by Eyal et al on this. 16,000 people have already volunteered…

    https://academic.oup.com/jid/article/221/11/1752/5814216
    https://kslnewsradio.com/1925211/covid-vaccine-trials/

  16. Tyler says:

    Doesn’t the danger of antibody-dependent enhancement go up as new strains emerge? This seems like a relevant concern given the information that’s been coming out over the past month about the virus mutating faster than expected, and that there are already significant differences in contagiousness and virulence between different strains.

  17. JJM says:

    Sorrento – STI-1499 – Does anyone have experience with Sorrento? Are they legitimate or full of unwarranted hype? https://www.biospace.com/article/sorrento-ids-antibody-against-covid-19-that-appears-100-percent-effective/

    1. Derek Lowe says:

      Hype, as far as I’m concerned. This looks like in vitro only, and there are plenty of people who have reported neutralizing antibodies and are developing them now.

  18. Barry says:

    Remember that the old BCG vaccine elicits antibodies that are effective against TB–it does protect against miliary tuberculosis. But the lung surface is beyond the jurisdiction of IgG, and the BCG doesn’t elicit effective IgA/humoral immunity.

  19. Yancey Ward says:

    I will recommend every single comment made here by Mammalian Scale Up Person. Lots of good news about the mono-clonal antibodies and the vaccines understudy, but time and scale are the bad news here without any easy fixes- I don’t care that the government can throw massive amounts of money at these problems- the money can’t fix certain process issues.

  20. One mitigating factor when it comes to the cost for a MAb as a Corona treatment, is that it should be a one-dose cure. If you have RA, you will be taking Humera (or something like it) for the rest of your life.

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