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Clinical Trials

What Might Go Wrong

With all of my posts here about vaccines and antibodies, it’s only fair that I spend some time talking about the potential toxicology problems with both of those. I remain optimistic about both categories, but it’s for sure that not all the candidates being advanced are going to make it through. So what sorts of things go wrong?

Well, efficacy, for one: some of them just don’t work so well against their targets. Efficacy is straightforward – well, relatively straightforward. Some of these antibodies and vaccines are just not going to work well enough, either on the absolute scale of not providing enough protection, or on the relative scale of not doing as much as other candidates. This is what Phase II and Phase III trials are for. We’re going to need to know how well these therapies protect people against coronavirus infection, and in the case of the monoclonal antibodies, we’ll also need to know how useful they are when given to people who are already infected.

You know all the arguing that has been going on about the various antiviral ideas, the repurposed drugs and so on? Most of those are arguments about efficacy. And as we’ve seen, even though this is an answerable question, it’s not answerable without a lot of work. We’re going to need to know a new treatment’s effects in various age groups, across male and female patients, people with pre-existing conditions (and those taking various other forms of treatment for them), and so on. What happens if you’re over 70? Or if you have hypertension or asthma? Or are taking one of the therapies for rheumatoid arthritis, for example, that alters immune function? There’s a long list of such questions, and here’s hoping that the upcoming trials will be able to provide real answers to as many of them as possible.

I would not expect all the candidates being tested to be equally efficacious (see below). There’s no way that’s happening. But I don’t expect all of us handicappers to even be able pick the ones a priori that will work the best. Have you ever seen an NCAA basketball tournament play out exactly according to the seeding? Exactly. No, the only way we’re going to sort out efficacy is by clinical results, lots of them, obtained in as well-controlled a way as we can possibly manage. Predictions aren’t worth much at this point. I only hope the picture is reasonably clear once we’ve gotten to the end of the trials, although there is of course no guarantee of that, either.

What about safety? With the repurposed drugs that we’ve been seeing, safety has been overall less of a concern, since they already have a history in human patients. Now, whether that’s always enough, when you’re giving such drugs to people are are ill with a virus that we’re never encountered before, that’s a real question (and is part of the argument about hydroxychloroquine). But some of the things that are coming have never been into people at all. As with any investigational drug, we will have to cross our fingers, taking our best shots based on all the antibody work and vaccine development that has come before.

What does that history tell us to look out for? First, let’s talk about the monoclonal antibodies, where there’s one thing that we have going for us right at the start, in that we are not targeting a human protein. You may have noticed the advertisements for monoclonal antibody drugs tend to list a lot of side effects, but that’s because of their targets. The highest-profile mAb drugs are things modulating immune response and the cell cycle, which are never going to be touched without risk. Targeting any human cell proteins comes with risks, honestly – you can occasionally set off a cytokine-storm response (cytokine release syndrome, CRS) when this process goes awry. (This and some other problems are associated not with the variable target-binding region of the antibody, but with the more constant Fc part of the molecule). But when you’re trying to shut down a pathogen’s protein, well, it’s more full speed ahead.

That said, one thing you want to make sure of is that the antibodies you are administering attack the coronavirus protein and only the coronavirus protein – you don’t want to find yourself hitting a human cell-surface protein without realizing it. There are plenty of autoimmune examples where an inappropriate response is raised to a bystander protein (more on this later in the vaccine section), and you don’t want to jump-start such a thing with a nonselective antibody. There are  other immune responses, lower than outright CRS, that you want to look out for, such as hypersensitivity (which can be immediate or delayed, site-of-injection or more general). The good news here is that the mAbs that are being tested are based on antibodies raised by recovered human patients, so that tells you that these were able to clear the coronavirus without apparently setting off anything else. That’s the biggest factor in the speed with which these new agents are moving into human trials – in many important ways, these antibodies have already been in people. Overall, you would expect some sort hypersensitivity, not a threatening level, is going to probably be the most common adverse event.

But the bad news is that human immune systems vary so widely that you still need to be alert for trouble – that, as you’ll see, is a general theme in all this. Such events are probably going to be low-frequency, but potentially severe, which is just what you don’t want in a clinical development program. Human dosing of the mAbs and the vaccines is going to be wide, fast, and jumpy – accelerated clinical trials with a huge number of patients, but dosed with great attention to any potential adverse events. We’re going to sort these things out by efficacy, of course, but it’s quite possible that we end up with more than one similarly-efficacious therapy and end up ranking them by the incidence of rare side effects.

So let’s talk about the vaccines, then. In this case, we don’t have the already-in-humans advantage that the mAbs have, or at least not to the same degree. What we do know – and it’s no small thing – is that it is possible to raise a useful immune response to the coronavirus, antibodies and T cells, which means that we just have to recapitulate that without the disease itself. That’s as opposed, say, to viral diseases like hepatitis C (or rabies!) where disease-clearing immune responses basically just don’t happen, so that’s good.

Note that we’re going to be trying to raise this through several rather different mechanisms, although they all get to the same place in the end: an immune response which translates to protection against the real viral infection. I’ve done more detailed vaccine posts, but for reference, we have in one group administration of individual viral proteins, or of inactivated (“killed”) virus, or of viral-like particles. You give those direcly and let them set off the immune system. In the other group, you’re looking at co-opting the body’s protein production machinery to (in effect) dose yourself with such proteins. That includes weakened forms of the coronavirus, engineered versions of totally different infectious viruses carrying genetic material for coronavirus proteins rather than their original make-more-virus payloads, or administration of DNA or RNA for those to be taken up by cells and set off such protein production from that direction.

As mentioned, there will be efficacy differences between the different vaccine candidates, and these are just the sorts of things you look out for in a more “normal” development pathway.  Some of them may require larger doses than others (potential manufacturing issues there), and some may require more shots and at different intervals, if so (logistic and manufacturing problems both). Some will have different immunological kinetics (the time it takes to develop a protective response after dosing), and some of them will produce longer-lasting response than others. (It should almost go without saying that that last one is something we’re just not going to know; there are no good ways to predict it). They may behave differently in different populations – different antibody and/or T-cell profiles with younger or older patients, among other things. There are plenty of things to sort out! A big advance that might come out of the Phase II trials (and associated studies) is a marker that can be used going forward, an immune correlate of protection. You would want to be able to say “OK, you have raised a titer of at least X of this particular type of antibody, so that means that yeah, you’re protected”. We don’t have that now (not enough data), but the hope is that we can get closer to that for the Phase III studies.

Past efficacy and on to adverse effects, one thing that has been extensively talked about is antibody-dependent enhancement (ADE), because this has been seen in other vaccine candidates (such as for dengue, where the reasons don’t really apply here) but also in attempts to develop vaccines against the closely-related SARS coronavirus. To be honest, I am getting less and less worried about that as time goes on. The various mAb and vaccine teams have been alert for signs of ADE all along the way, and so far we appear to be in the clear. This doesn’t mean that we can forget about the issue, but it’s not at the top of the worry list, either.

Those earlier worries about hypersensitivity and inappropriate immune responses do apply, though. The classic example intersecting with infectious disease therapy is Guillain-Barré syndrome (GBS). This can be set off after a (sometimes unnoticed) bacterial or viral infection, and involves an immune attack on the myelin sheaths of the nervous system. That’s obviously very bad indeed – although most patients recover, not all of them do, and some of them need intensive care while the myelin damage gets reversed. The exact mechanism of GBS has eluded discovery, despite intensive research – there’s obviously something about the myelin sheaths that are vulnerable to immunologic misidentification, but the details aren’t clear, and the vulnerability varies according to a person’s individual immune system in ways that we cannot yet screen for. So such things will be watched for very carefully indeed.

Even with that, we will not know the real risks of such rare events, because they’re rare. GBS, for example, might occur on the order of one or two people out of a million with the seasonal flu vaccine. You’re only going to see things like that after you’re out in a very large patient population. It’s just not possible to assess something like that in even a rather large clinical trial involving tens of thousands of people. That’s not just the situation with these new coronavirus vaccine candidates; that’s how it is in general. But in this case we’re talking about vaccines that may well be going into hundreds of millions of people as quickly as we can roll them out. If one vaccine candidate gives GBS to 100 people out of a hundred million dosed and another one affects only ten, there is absolutely no way that we will be able to be sure of that before dosing the hundred million people.

I do not want to provide ammunition for the anti-vaccine camp by going into these details, but we can’t ignore medical (and mathematical) reality. All drugs have side effects, and every therapy is a tradeoff. The levels that I’m talking about for something like Guillain-Barré (which is generally not fatal) are, in fact, completely acceptable for preventing a disease like this one. As you see from that link in the paragraph above, they’re acceptable for something like seasonal influenza, which is definitely not as big a problem as the COVID-19 epidemic. State and national governments have already been talking overtly about how many coronavirus deaths are acceptable to avoid shutdowns that harm their economies, and if you’re willing to make that tradeoff, you should jump at the chance to make this one. It’s a much better deal.

This is one of those times when it’s instructive to do the math, as they say. There are (for example) outright fatal immune responses to some drugs (not just vaccines), which are generally very difficult to predict. Think penicillin as the famous example, although there are others. But as shown here, the death rates for these across the population are in the same range as death by lightning bolts (one out of a few million). Now, one should reduce one’s risk of being hit by lightning by not being out in the open during severe thunderstorms, and one should reduce the risk of harming people with a vaccine through careful clinical testing. But (to put it gently) many populations are not showing themselves to be very good at risk reduction these days. I cannot help but picture a bunch of unmasked people in a crowded bar yelling at each other over the music about how they’re not going to let themselves be poisoned by any damned vaccine.

All the issues mentioned are about to become very real as the various antibodies and vaccines move into larger patient populations. Keeping track of everything will not be easy, but, well, here we go!

53 comments on “What Might Go Wrong”

  1. Barry says:

    wrt Efficacy, I’ll highlight again the experience of BCG. The vaccine does elicit neutralizing antibodies in the serum and does protect against tuberculosis in plasma-exposed tissues (“miliary TB”) where it fails is in protecting against the (far more common) TB infection of the lung surface. That “mucosal” compartment is beyond the jurisdiction of IgG. BCG fails to elicit the IgA that is needed for airborne TB. We need to develop a Coronavirus vaccine that does better. And we may learn in that process how to do better against TB.

    1. aairfccha says:

      BCG has another issue, its efficiacy varies with location – it tends to become less effective closer to the equator – and the reason isn’t really known.

      1. Kenneth Crook says:

        And even the non-lay!

  2. Michael D says:

    Thank you very much for this, Derek. Tremendously informative for the lay folks among us.

  3. Garrett Wollman says:

    It seems likely that we’re going to get a multitude of potential vaccines that show *some* efficacy and a reasonable safety profile before there’s enough evidence to say that one is clearly better than another. In an ordinary situation, policymakers would just let the market work and wait for more evidence, but this is no ordinary situation, and there’s substantial political pressure for something solution-shaped even if it isn’t the best possible intervention. How should people be thinking about this? How can scientists better communicate that any recommendation is provisional and subject to revision when better evidence comes in? How many of these vaccines, if many of them prove marketable, can the market ultimately sustain?

    1. Carl says:

      From what Mr Lowe has said in that past it depends entirely how the trial/s are structured. ideally the efficiency phase of the trial would be structured such that it will give a clear reading at readout time which completely bypasses this issue because you go fro no vaccine straight to high efficiency.

      You have to remember a lot of the stuff we’ve been hearing on repurposed drugs has been a mixture of deliberately bad science in a small number of cases and in the majority of cases summaries of after that fact studies on doctors trying things out based on what limited past data suggests might help.The “rials” in these cases simply haven’t been setup so that they will provide a clear reading. But you can bet with these programs everyone is going to be going hard for a clear reading.

    2. eub says:

      If two vaccines look similar in clinical trials — both look viable to roll out more broadly — could we roll out both of them, in a randomized enough way to learn whether one has a lower rate of rare side effects?

      Ideally a straight-up randomized trial, but I doubt you could ever sell that to people. Deliberate distribution to one or the other of matched pairs of locations? But no matter the mechanism, you do need to be watching both and tracking whether and when to make a decision that one vaccine should go 100%, and enough people hate being experimented on that I dunno.

      1. aairfccha says:

        This sounds like the situation of the competing polio vaccines, it took a while until the quirks were worked out and a general agreement formed what vaccine to use under which circumstances.

      2. Charles H. says:

        Well, with various countries backing different vaccines, often for political or economic reasons, that test is going to happen. It’s just going to take awhile to sort things out, and (due to the political component) the best contender may not even be in the running.

  4. myst_05 says:

    Another interesting question is what governments would do if, say, 30% of the population refuses to get injected with the first batch of the vaccine and the vaccine does not provide a neutralizing response, meaning that vaccinated people can still spread the virus to others. Would you still mandate social distancing? Or would all responsibility shift onto the unvaccinated to keep themselves safe?

    Lots of moral questions are about to be unraveled.

    1. Michael D says:

      That scenario – a safe and effective but non-sterilizing vaccine that is not mandatory – is the first, and probably only, persuasive case for an “immunity passport” that I have seen.

      Didn’t get vaccinated? Don’t have your passport? Fine, but then you can’t enter the school assembly/stadium/concert hall for your own safety.

    2. x says:

      If there’s one thing that modern America seems to be utterly inept at, it’s moral reasoning – which is one good explanation for why our public policy and institutions are completely and utterly inadequate to protect the country against this virus. (No universal healthcare, no mandated sick time combined with widespread financial insufficiency, no money for PPE but plenty for police to brutalize protesters exercising 1st Amendment rights, big unaccountable bailouts for corporations but crumbs for ordinary people, science funding cuts, etc etc.)

      In any case, it’s too late to fix all those things now. People will die who could have been saved, and all we can do is hold on tight and wait for the ride to end.

    3. confused says:

      Assuming that everyone had the *chance* to get vaccinated, I really don’t see any moral argument for retaining social distancing measures in that situation. By refusing the vaccine, they’re accepting the risk. If vaccinated people could still spread the virus, then there wouldn’t be a moral need to get it to protect *others* – you would just be accepting more risk for yourself.

      (Usually, the big moral worry in this sort of thing is children with anti-vaccine parents. But COVID is so low-risk to children – seems to be significantly less than seasonal flu *in that population* – that it’s not much of a concern here.)

  5. Steve Scott says:

    Another consideration: Suppose the most effective vaccine can only be manufactured in tens of millions of doses over a given time period, while a less effective- but still acceptable- vaccine can be turned out in hundreds of millions of doses. You know which one is going to get to the public first.

  6. Victor says:

    Something that could go very wrong: To put forward a vaccine lacking crucial data for political reasons, before November. That could backfire big time

    1. Hap says:

      Yes, but I’m not sure how much Trump would care if he’s in office. The rest of his party is chained to him and so it would be difficult for them to remove him without admitting their own culpabilities at the same time. Caring about what happens to anyone else does not seem to be a problem for him as President (or considering his business records, in business, either).

  7. Zee Bendelstein says:

    I wonder given the limitations in establishing, a priori, probability of success, what criteria our government uses to select a relatively limited number of programs to back. Perhaps they are simply forced to choose a limited number of programs given limited resources. But given the printing power of the Federal Reserve, would it not be prudent to support all (plausible and reputed) programs given the constraints you laid out?

  8. loupgarous says:

    Thanks, Derek – you constantly leave us better-informed than when we started reading.

    In related news, some of the daily tabloid-type newspapers in Britain are saying Oxford’s vaccine group say they’ll have Britain vaccinated with their vaccine by Christmas..

    “A coronavirus vaccine could possibly be available by Autumn, according to Oxford University trial leader, Sir John Bell. When asked by what time he thought the entire British population would be vaccinated, Sir John said Christmas. LBC host Matt Frei was stunned and reminded the professor that many experts originally predicted the process of starting vaccinations wouldn’t begin until spring 2021.”

    That got my attention, because I’m used to seeing hard limits on how quickly regulatory studies can be run on new KINDS of any therapeutic class of drug, and how quickly the regulators are prepared to approve radically new vaccines.

    “The professor said: “There are a lot of wise people in the vaccine business who turned the problem across to the standard development programme for vaccines, which gave them a read-out in mid-2021. “What I don’t think they acknowledged is that you can speed lots of the bits of the process up. “You could manufacture in anticipation of regulatory result. That saves you three months at least, and maybe more. “You can do your clinical trials in the way that the Jenner Institute scientists have done, which are much faster and much more efficient than the usual approaches to vaccine development.”

    So, Derek, would FDA CBER agree to “speed lots of the bits of the process up” for these new vaccines? I was an early adopter of the mid-1970s swine flu vaccine, along with a couple hundred other LSU students that summer, and I felt like crap for much longer than the shots I took before going to college.

    What might go wrong if FDA chops and channels their approval requirements to get vaccinations done here late this year or first quarter 2021?

    1. simpl says:

      First production is an expensive step, and is not usually started parallel to clinical trials, but during the pause between FDA document submission and approval. If trials come out without good clear results, that is a risk which costs each producer plenty; the FDA might well be happy to see everything done in advance, not just a few batches and trials to validate the process.
      On top, biological actives are more expensive than chemical ones, as their machines are tailored to a single product, and a more complex process, with some of the methods never before tried outside a lab. Further, in this case, the amount of active substance needed will be very high – the world wants its silver bullet now. The batch size is fixed for a process, and cooking hundreds of batches in small reactors is no replacement for a batch of the size that will be needed.
      So when I recently read of a project promising 300 million doses at risk, I’m sure that already a good deal of assumptions have been made, commitments evaluated, and the calculations done.

      1. A Nonny Mouse says:

        The cost of the Imperial vaccine (very similar to the Oxford one, but with a different vector) as been out at about $4-5/dose. i don’t know if this is simpler to produce, though.

      2. Mammalian scale-up person says:

        Well….it depends on the vaccine.

        On the one hand you have recombinant vaccines such as the Sanofi / GSK recombinant spike: Those, we can make like any other mammalian recombinant protein, though getting quantities large enough for mass dosing is An Issue, basically the same issues as making a recombinant mAb. Titers are not remotely predictable for proteins that don’t look an awful lot like a mAb, I’ve seen everything from 10 g/L to 20 ug/L, there’s the problem with a recombinant spike. Do we need 500 batches to vaccinate everyone, or 5? Who knows? Not me, and not the people making the vaccine either, until it’s made and the cell line development is done, which takes a good three months. Consider that the first sequences weren’t the best (they still had 6his tags and cloning sites on them when I looked in GenBank, though presumably someone thought to clean them up), so a good quality sequence wouldn’t be available before March – then 2-3 months of cloning, sequence optimization and cell line development, and then you’re ready to make a tox / Ph 1 batch.

        On the other hand, you have the adenovirus platforms, and THOSE are a blessing to be sure. We can cook quite a lot of adenovirus in a single use 2kL, purify it through single use depth filters and orthogonal IEX (membrane chromatography is crazy fast) and call it a day. There is definitely capacity already existing for the adenovirus platforms: Samsung, WuXi, all the contract manufacturers and plenty of Big Pharma folks have single use 1kL – 2kL capacity, either spare capacity or pilot lab equipment that can be pressed into service. The cell line and vector viral platforms are fairly well developed, in any case people have their favorites. Ramp-up is perhaps a few weeks to thaw and expand some HEK293s; production takes about a week of fermentation, purification barely takes a couple of days if you’re running membrane chrom. The scale of operations is quite small and requires no massive infrastructure compared to mammalian production (about 1/10th the size). Titers are about 2E10 pfus/mL and a dose of vaccine might be 4-5E10 pfus, so 750,000 doses every week from a single reactor – and most major manufacturers of biologics have a couple they can spare – means we can crank out vaccines for the entire US in about 6 months just by liberating someone’s pilot plant for the cause. Off the top of my head I can think of at least five locations just in the Northeast that have capacity in single use 2kLs, and I’m sure there’s a few more on the West Coast and scattered hither and yon, and that’s before we get to Germany, Switzerland, South Korea, Japan etc. In addition, you can use an adenovirus-type platform to produce Merck’s VSV based material as well – it’s literally the same process, the differences are very minor. So I have a lot more hope for the adenovirus platforms and the Merck VSV plan than the other methods, they will ramp up quickly and there’s hardly any bottlenecks to production, we can manage a very short takt time easily with modern purification membrane filters and start cranking out doses.

    2. mayfin says:

      I wouldn’t pay *any* attention to the reporting in the British tabloids – in recent years they’ve proved to be more harmful than SARS-CoV-2, if thankfully less contagious on a global scale (pity there’ no chance for a vaccination …)

  9. gippgig says:

    Whether a vaccine could cause MIS-C could be a major issue requiring large & long clinical trials.

    1. Blair says:

      This is something I had not thought about. Have there been any prior examples of this or something similar? I normally work on behavioral epidemiology (e.g. IV drug use and Hep C), but have been recently pulled into building a database for MIS-C cases and would love to learn more.

  10. dearieme says:

    The people at risk of dying from this virus are overwhelmingly ill and old; among them the fat and males seem particularly at risk. Are these the people to vaccinate? Would they be particularly vulnerable to adverse side-effects? Or could you argue that even if they are, the risk/reward ratio is likely to be better for them than for young healthy people?

    Or should you vaccinate the people likeliest to infect the ancients i.e. the young?

    1. Hap says:

      If the superspreader theory is accurate, you’d want to vaccinate the people best able to rapidly spread the virus (if it’s a biological rather than situational cause for superspreading). You also might worry that the people most susceptible to bad outcomes would also be susceptible to bad outcomes from the vaccines.

    2. A Nonny Mouse says:

      Initially, it will probably medical staff plus “ring vaccination” – those to have been in contact with a known or possible case as was done with Ebola.

  11. RA says:

    Thanks for a great post!

    I certainly hope we get a good vaccine soon. I do wonder whether there are a couple of canaries in the coal mine to suggest that there may be more adverse reactions to some of the vaccines than we might hope/expect. First, the children who are getting an inflammatory syndrome long after presumed infection. Second, the fact that some infected patients have unusually prolonged periods of illness…i.e. months. It makes me wonder whether there is some subset of the population that has a genetic predisposition to reacting atypically to both COVID ….and a vaccine for COVID?

    I also wonder whether complications will be more likely in some types of vaccines vs others and whether there will be an efficacy/safety tradeoff between different options. If you are high risk for severe COVID disease, then perhaps you would want the most efficacious vaccine….but if you are lower risk for severe COVID disease, perhaps safety profile is the more important consideration.

    I also wonder how much of the population needs to be vaccinated in order to get to herd immunity? If a significant percent are COVID19 seropositive by then and some other percentage has partial protection from prior infection with other coronaviruses or some form of innate immunity, then what percent do we need to vaccinate to get to herd immunity? I wish we knew more about whether that partial protection exists and to what extent and could measure that…unfortunately, we are pretty much in the dark.

    1. daksya says:

      ” I wish we knew more about whether that partial protection exists and to what extent and could measure that”

      An interesting preprint in this regard is at

      From the paper:

      “For the management of the current pandemic and for vaccine development against SARS-CoV-2, it is important to understand if acquired immunity will be long-lasting. Therefore, we tested if individuals who recovered from SARS 17 years ago still harbor memory T cells against SARS-CoV-1. Hence, their PBMC (n=15) were stimulated directly ex vivo with peptide pools covering SARS-CoV-1 NP (NP-1 and NP-2), NSP7 and NSP13 (Figure 3A). This revealed that 17 years after infection, those individuals still possess virus-specific memory T cells, and similar to COVID-19 recovered patients, we detected T cells reacting almost exclusively to NP and not to the NSPs (Figure 3B/C). Subsequently, we tested if the NP-specific T cells detected in SARS recovered patients could cross-react with SARS-CoV-2 NP peptides (aa identity = 94%). Indeed, although at lower frequency, T cells in all 23 individuals tested reacted to SARS-CoV-2 NP (Figure 3D, 4A). In order to test whether these T cells could expand after encounter with SARS-CoV-2 NP, their PBMC were stimulated in vitro with the whole battery of NP, NSP7 and NSP-13 peptides and the quantity of T cells responding to SARS-CoV-2 NP, NSP7 and NSP13 was analyzed after 10 days of cell culture. A clear and robust expansion of NP-specific T cells was detected in 7 out of 8 individuals tested (Figure 3E). Importantly, and in sharp contrast to the T cell response to NP peptides, we could not detect any T cells reacting to the peptide pools covering NSP13 and only 1 out of 8 reacted to NSP7, despite in vitro expansion. Thus, SARS-CoV-2 NP-specific cross-reactive T cells are part of the T cell repertoire of individuals with a history of SARS-CoV-1 infection and are able to robustly expand after encounter with SARS-CoV-2 NP peptides. These findings demonstrate that virus-specific memory T cells induced by beta coronanvirus infection are long-lasting, which supports the notion that COVID-19 patients would develop long-term T cell immunity. Furthermore, our findings also raise the intriguing possibility that infection with related viruses can also protect from or modify the pathology caused by SARS-CoV-2 infection.”

      1. RA says:

        Thanks for the article! It’s interesting and suggestive. Unfortunately, these types of analyses are not scalable to implement in a large population…which makes me wonder whether it would be helpful to develop and scale-up serological tests, ideally quantitative, to circulating common cold coronaviruses. The research question would be whether certain antibody levels to these viruses is associated with whether an individual is likely to get asymptomatic vs mild vs severe COVID 19 disease. I wish someone would do those studies!

  12. Grasshopper says:

    I’ve been following this blog out of general interest for a few years now, and it’s always been interesting and informative- but never more so than currently, so thanks very much to Derek for writing it (and to the commenters, who make interesting points here much more frequently than is common ‘under-the-line’ so to speak). I’m also trying to follow some of the literature emerging about the vaccine effort, but since I’m not a biochemist or a medical chemist this is very much not my field. I was wondering; if several of the vaccine trials result in vaccines that are only partially successful, then can a person be vaccinated with a few different ones for greater protection, or is that likely to cause unforeseen side effects (i.e. if vaccine A and vaccine B each give an incomplete protection, do you need a whole new clinical trial to check whether it’s safe to take A+B together)? Also, is it too unethical to include pregnant women in these trials- how do you check it’s safe for them to be vaccinated, or is the mechanism by which vaccines work simply so well understood now that there’s no danger of another thalidomide disaster?

    Anyway, thanks again, it’s very refreshing to read something written from an informed viewpoint(!)

    1. Charles H. says:

      Well, FWIW, I was vaccinated with both the Salk and the Sabin vaccines against polio, without problems. This isn’t always the case with vaccines, but it often is.

      P.S.: Some people got sick with a weakened form of polio from the early Sabin vaccines, but I didn’t hear of anyone having that experience who had previously been vaccinated with the Salk vaccine. So sometimes it’s better to have multiple vaccines.

      That said, there are certainly cases where things work the other way around. Dengue is a notorious case.

    2. Derek Freyberg says:

      Like Charles H., I have also had both Salk and Sabin polio vaccines, as I think many of my generation did: we started with the (injectable) Salk vaccine when it became available – this was when I was in elementary school, as I recall – and then received the (oral) Sabin vaccine a few years later.
      Doctors are actually encouraging people to receive both pneumonia vaccines; and, while I think the new shingles vaccine is displacing the old one, many people will have received both.

    3. loupgarous says:

      Polyvalent vaccines for influenza are an old thing – the manufacturers and CDC try to estimate in advance which strains of flu will be next year’s (or this fall’s) trouble and vaccinate against a few of them. Even when they get it wrong, we’re told that partial immunity conferred when someone guessed wrong still can shorten the clinical course of influenza.

      Pneumonia vaccines are even more polyvalent than that – immunization from up to 13 different strains (Pfizer’s “Prevnar 13”). Pfizer has a 20-valent pneumonia vaccine they plan to ask FDA to approve for use in adults. Also, Diptheria, Pertussis and Tetanus are commonly vaccinated against in the same vaccine.

  13. JM says:

    Hi Derek,

    Thanks for the continuing posts. I wonder about the adenoviral platforms and non-dividing cells? These episomal genomes will be “washed out” of dividing cells in a reasonable amount of time, but I believe there is precedent for very long-lived adenoviral expression in non-dividing cells (months to years in the case of muscles and neurons). I am a little concerned around long term expression in muscle especially as some of the adenovirus serotypes in play will certainly target muscle. Any thoughts on what this may mean for the development of a chronic inflammatory state from the ongoing production of foreign antigen?

  14. An Old Chemist says:

    UK funds human trials of potential COVID-19 vaccine from Imperial

    The trials are the first human tests of a new technology which the researchers say could transform vaccine development by enabling rapid responses to emerging diseases such as the COVID-19 infection caused by the new coronavirus.

  15. C_B says:

    Bat Signal: Scott Alexander wonders what the heck is going on with vilazodone and vortioxetine:

    This seems like a question that Derek might have some good insight on!

    1. Ted says:

      Links broken.

  16. gippgig says:

    To partially change the subject, one thing that definitely should be done is to collect as much data as possible on those who have died from COVID-19 & turn the big data miners loose to look for ways they differ from those who haven’t. If for example those who died are less likely to have been taking a particular drug that drug might be a treatment or preventative – & vice versa. Has this been done yet?
    By the way, I just read an epidemiology textbook. It was primarily about disease studies rather than diseases themselves but it’s worth doing if you want to understand the many limitations of all the studies that are being reported.

    1. EugeneL says:

      One interesting thing to test is the portion of died people with vitamin D deficiency and compare this to the general population. There was a study somewhere that the vitamin D deficiency increases your chances to die 10-fold, which was based on blood tests of people who died.

      1. jbosch says:

        That could also be attributed to the elderly who rarely go out in the sunshine.
        And for example in Germany, 40% of the deaths were from elderly care facilities.
        Cause & effect, careful with those analysis.

      2. Riah says:

        EugeneL – sorry I’m a bit late seeing this but you might find this study of vitamin D deficiency and Covid of interest:

        1. franko says:

          Thank you for the article!

  17. colintd says:

    I’ve seen some very interesting papers recently on ACE2, syncytium formation, and methylation levels of the syncytin genes. In particular this one relates it to age and sex related trends in activation level:

    These observations seems to fit very well with the extensive lung damage that is being seen, with cell fusion clearly visible in autopsies, and with cells being observed with up to 20 nuclei.

    I’d be very interested in any more informed views on this element of the disease…

  18. Chris says:

    How do you do a trial of a vaccine that shows “some protection”? Would trial in young healthy volunteers be useful since for the majority virus infection could be asymptomatic? Would the safety and tolerability information be useful when the key target patient population would be elderly or those with other significant health issues?
    Could you even do a trial in elderly or health compromised patients?

  19. bacillus says:

    The one thing that distinguishes vaccines from all other medications is that they are given to healthy people who might not derive any benefit from it. For this reason alone, vaccine safety needs to be paramount. Therefore, I hope that neither the FDA or EME are pressurized into rapidly approving the roll out of SARs-COV2 vaccines on a massive scale. Think back to rotashield which caused relatively few cases of intussusception before being withdrawn from the market. That seems to set the baseline for the degree of risk Americans are prepared to accept for vaccines. Therefore, it would seem wise to vaccinate no more than a few million volunteers then wait and see, before forging ahead with vaccinating the planet.

    Also, call me cynical, but many of the more novel (nucleic acid, AV-vectored, etc) vaccination strategies have been around for decades and have led to no marketed vaccines. In these instances, the SARs_CoV2 crisis smacks more of certain companies exploiting the situation to get their vaccine platforms into the clinic which they have signally failed to do via the normal route to IND. We have one chance to get this right or risk large scale vaccine hesistation for the next generation of COVID-19 vaccines, which may well have a bystander effect on other vaccines. In other words, there is much at stake here, and to hear academics promising to vaccinate entire countries in time for Christmas leaves me gobsmacked to say the least.

    1. Daren Austin says:

      I want my vaccine platform technology to have been tested and prove safe in millions not thousands of humans. You aren’t the only one who has noticed how few of the technologies have produced protective products.

  20. Daren Austin says:

    The analogy with a basketball tournament is missing one glaring point. In this gameplay, the first winning mAb is tested against placebo – an outright win and new standard of care. In subsequent studies the aim will be to “not lose” (non-inferiority to new standard of care). With considerable implications for sample size estimates. Platform trials try and get over this problem by reusing the same placebo patients.

  21. Some idiot says:

    Off-topic, but RECOVERY has just reported back that dexamethasone helps seriously ill patients. Not a huge effect, but real…

  22. Steve Scott says:

    “Operation Warp Speed” answers the critics, claiming that safety will not be sacrificed. Also, talks about which groups would get a vaccine first. And it mentions that multiple vaccines might be in play (some might not work for seniors).

  23. bacillus says:

    Anyone naive enough to think that the FDA won’t capitulate to political pressure over scientific safety and efficacy standards should read “Bottle of Lies” by Katherine Eban.

  24. Dan Oster says:

    I got a case of GBS in October of last year and spend a month in two different hospitals in Minnesota.
    Was paralyzed for about three weeks, back to normal in about four months after a month of intensive therapy.
    The reason for my GBS are unknown – I’m 70 years old but without any medical problems, I did not get a flu shot nor did I notice any infection nor inflammation.
    Would taking a COVID-19 vaccine be safe for me?

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