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Coronavirus Vaccine Update, May 26

We have a lot more vaccine news to catch up on, and I’ll use this as a new “frontrunning vaccine candidates” post, replacing this one (and updates therein) from about a month back. That one will give you some more general information on most of the projects below; if you haven’t read it, it’ll be a good intro. A general vaccine background post is here, and here’s a recent one one covering some other candidates. The ones below are in no particular order; no oddsmaking is implied, because you’d have to be a lunatic to try to guess which ones will work and which won’t at this point. We can be pretty sure, though, that many of them will fail for one reason or another, just because most drugs and most vaccines fail. We can also be sure that as we go along there will be likely be many hard tradeoffs to consider in efficacy, manufacturing, safety, and other issues – I’ll frankly be amazed if that doesn’t happen. So with those points out in the open, here we go – note that the J&J entry also has some general vaccine news that might be of interest:

CanSino’s Ad5-nCoV

Just in the last few days, there has been a very detailed report in The Lancet from the CanSino team on Phase I studies of their vaccine candidate. As you can see from the name, it’s a viral vector using adenovirus-5, a choice that on the one hand speeds up development, but on the other hand raises worries about efficacy and tolerability. The adenovirus in this case is engineered to express the coronavirus Spike glycoprotein, a common target to many of the vaccine efforts. Many people already have antibodies to this sort of adenovirus. Past vaccine development efforts by this route have run into problems because of an immune attack on the vector, which (as you’d figure) can then interrupt the plans of developing immunity to its payload.

This one was an open-label dose-escalation study, with the primary endpoint being adverse events at day 7 post-dosing (intramuscular injection), with follow-up for 28 days. They also determined neutralizing antibody and T-cell responses – valuable data, although it has to be said up front (as the paper does) that until we get into Phase II we won’t know what responses are really needed for protection. There were three dosages, with 36 patients in each group, median age 36 years, almost exactly 50/50 male/female.

75 to 83% of each group reported at least one adverse reaction by day 7, generally pain at the injection site and sometimes general fever, muscle pain, etc. There was more of this at the highest dose, which is no surprise. Keep in mind, with any viral vector you’re looking at giving someone an entirely new viral infection, albeit one that produces your antigens of choice rather than producing more virus. So you can expect it to come on with flu-like symptoms. Importantly, there were no serious events within the 28 day study period in any group – “serious” is a term with regulatory implications, meaning anything leading to hospitalization or the possibility of permanent damage.

How about the immune response? All patients developed neutralizing antibodies, and all of them showed T-cell responses as well (both CD4+ and CD8+). So that’s good – as mentioned, we don’t know what sort of  response is needed, but these look significant and dose-responsive, which is all you can ask at this stage. As we get more hard data from the other vaccine efforts, we can compare. But there are some wrinkles in the data. It turns out that 44 to 56% (depending on the patient group) of the people in the study already had high levels of neutralizing antibodies to the Ad5 virus, and the CanSino team found that this definitely hurt the immune response to the spike protein payload. There was also a generally lower antibody response in the older patients (45-60, which prompts me to say “that ain’t so old”). This is something that they’re going to specifically look for as they move into Phase II, especially given how the severity of the disease increases with age.

So this is honestly just about what one would have expected: a real immune response to the Spike protein, but with headwinds from Ad5 antibodies. On to Phase II, where vast amounts of stuff are going to get sorted out.

Oxford-AstraZeneca’s ChAdOx1-nCov19

For this one, I’m going to refer folks to this recent post on the rhesus animal model data. Short version: there are arguments about the way the vaccine did not induce “sterilizing immunity” (i.e. complete protection from infection) in that study. It’s impossible to directly compare these numbers with the SinoVac monkey studies, unfortunately.

The other news on this one has been the statement from Oxford’s Adrian Hill in an interview in the Sunday Telegraph that he thought the vaccine had about a 50% chance of working. This made a lot of headlines, but you know, in a more informed world it wouldn’t have. The vaccine trial failure rate is around 90% overall. That’s not a completely fair comparison, since it goes across all sorts of different pathogens and in this situation we’re only looking at one. But on the downside, if there’s some kind of systemic problem with developing protective immunity to this virus, it’ll be common to all of the vaccine efforts (I should note that I don’t think that’s the case, but until we get to Phase II results we can’t rule it out, either).

Hill’s other point was what should be an obvious one, too: you want to do those Phase II trials in a population where the virus is actively spreading, in order to get the best data about whether your therapy actually protects people. In countries where public health measures (lockdowns, masks, social distancing and all the rest of it) have cut down on viral transmission, this gets harder. We may well have to chase the virus from area to area, country to country, to do the best vaccine trials. Then again, if we have opened back up too quickly, as some fear, we might have plenty of places to test in – we’ll just have to wait and see. The problem is that setting up these trials takes some real time and organization, and it will be hard to guess where the best places to run them will be, so far in advance.

Moderna’s mRNA1273

I’ll refer people to this recent post for more details as well. Moderna has taken some criticism for the way that they released these data, and especially for the way that they did so just before a planned sale of more Moderna stock. I also wonder (as do people in that article) about who’s buying the stock at these valuations, considering that uncertainties in vaccine development, in the whole COVID-19 epidemic, and in the mRNA vaccine mechanism in particular. It would be good if we had as comprehensive a look at Moderna’s results as we do at CanSino’s

But I’m still glad that Moderna is in the hunt. We need a number of different mechanisms going to spread around the considerable risk. It’s certainly true that we don’t know how well mRNA vaccines will work in humans – we’re finding out a bit ahead of schedule thanks to the coronavirus. I would not be taking a flyer on Moderna stock, but I’m glad that they’re taking one on the virus.

BioNTech and Pfizer

No recent news here; human dosing has been ongoing but there’s no word on results. Here’s a good background article on the effort, though, from Forbes. Keep in mind that Pfizer and BioNTech are going in with four vaccines rather than just one; they’re taking a massive risk on a massive scale. There will eventually be a lot of data to sort though, and the expectation is that only one of those four (if that!) will be able to move on.

Sinovac’s PiCoVacc

Nothing new here, either, from what I can see. The company did provide one of the earliest looks into animal model data for their inactivated-virus vaccine candidate, but we’re just going to have to wait for some human data (I’ll update here on this post when they do). There was an odd bit of news a few days ago, a press release about how they’d received more funding for the vaccine’s development. But this was only $15 million, a laughably small amount compared to what’s going to be spent in this area by anyone in human trials. Put an asterisk next to anyone you saw rebroadcasting that one as some sort of useful news item; odds are they that don’t know much about the field,

The Wuhan Institute For Biological Products / Sinopharm

Another inactivated-virus candidate here. Latest word is that 96 patients (three age cohorts) have completed a Phase I trial and that the vaccine has moved into Phase II, but that news is about a month old. This one is probably the quietest of all the major vaccine efforts, from what I can see. Will that change?

Inovio’s INO-4800

The company recently published a paper on the results with this DNA vaccine candidate in mice and guinea pigs. The results look good, as far as I can see, but they’re just on immunogenicity. There appears to be a robust antibody response, but we have no data yet on viral challenge in the animal models, and no human data yet on immunogenicity or tolerability. The company has said that it expects a readout in June, and their head of R&D rather informally told Reuters last week that so far they are seeing no safety signals in the human dosing.

Johnson & Johnson (Janssen)

No news in the last couple of weeks on the Ad26 adenovirus vector candidate from J&J. This (like the Oxford vaccine) aims to use an adenovirus type that humans have not really been exposed to, to avoid the problems noted with the CanSino Ad5 candidate (see above). This will all have to be proven in the clinic, of course, and that’s just where all of these candidates are piling up.

In the meantime, the Barouch lab at Harvard (developers of the Ad26 platform) have published a paper with a long list of coauthors, including some at J&J. This takes a look at several DNA-based coronavirus vaccines in rhesus monkeys, and to my knowledge is the first detailed look we’ve had at these in such a model. It’s a lot of work: they tried six variations, namely (1) DNA coding for the full-length spike protein, (2) a variation without the cytoplasmic “tail” region, (3) one that deleted this and the transmembrane domain (leaving only the exposed part of the Spike), (4) one with just the S1 domain of the Spike (and a trimerization tag), (5) one with just the RBD (receptor-binding domain) region of the Spike (and a trimerization tag), and (6) a rather heavily engineered one with deletion of the furin protease cleavage site and two introduced proline mutations (along with the trimerization tag), intended to make the resulting protein more stable overall.

These each gave a somewhat different antibody response, when the team looked at the titer and type of antibodies raised (3 and 6 looked the most similar to each other, and 5 was probably the most distinctive outlier – see the paper’s Figure 2E). They also saw T-cell responses, with the shorter constructs showing weaker activity. After these vaccinations and three weeks after a booster at the 3 week mark, the animals were challenged with live coronavirus. The paper’s Figure 4 has the results (nasal swab and aveolar fluid checks for viral RNA), and the differences between the six candidates are overall not gigantic – all six had efficacy. But it does look like the plain spike protein one (1) and the RBD one (5) perhaps looked strongest overall, with the unstabilized shorter Spike one (3) looking the weakest. That’s good news, most likely, since the vaccine candidates in the clinic are mostly Spike and RBD, from what I can see. There were definite variations among the individual monkeys in each treatment group as well.

The group looked at what markers and assays might correlate best with actual protection against viral challenge. Interestingly, neither the CD4+ nor the CD8+ data were good predictors. The aveolar fluid viral load was a better readout than the nasal swab one, probably due to more variability in the latter. The best reading overall was the titer of neutralizing antibodies. Most animals in this study (as with the Oxford vaccine, see above) did not achieve sterilizing immunity – they still got infected, but in a much milder fashion than unvaccinated animals. But the ones that were completely protected showed significantly higher titers of neutralizing antibodies than the others; that measurement seems to be the way to go. We’ll have to keep all this in mind as the human data pile up.

Sanofi/GSK

No recent news on this collaboration, either, from what I can see. That will change!

Novavax

I just highlighted these folks in a post the other day – they have a recombinant protein vaccine candidate in the works. Word is today that they’ve enrolled their first patients in a Phase I/II trial. Good luck to them! That has sent the company’s stock up, naturally, along with everyone else in the space. Just to emphasize this again, trying to come up with a coronavirus vaccine play in your stock portfolio is a very bad idea, in my opinion: this is going to be a wild, volatile ride and most of the candidates are going to lose out. We are going to need a lot more human data before we have the faintest idea which ones might win, and every fresh wave of news over the summer and fall is going to stir the valuations around chaotically. If that appeals to your investment style, well hey, have at it. But you’ve been warned.

Merck

Finally, Merck has come out of stealth mode with some vaccine news of their own. They’re buying Themis, a Vienna-based company that’s been working on a weakened form of the human measles virus as a vector for vaccine delivery (this is already in use as a measles vaccine itself). A coronavirus vaccine candidate using this technology is planned to go into human trials “in a few weeks”, likely in France. And in that same post last week where I mentioned Novavax, I brought up the VSV vector idea, which reached fruition in the Ebola vaccine. Merck has also announced that they’re working with IAVI, a nonprofit that has been focusing on on HIV vaccine using this technique, to try a coronavirus vaccine as well. Merck seems to have made a deliberate decision to focus on viral vectors rather than mRNA, recombinant proteins, etc., in the belief that these have a better shot at potent immunlogic responses. That will get sorted out in the clinic as well!

So that’s the current roundup. I’ll use this post as a platform for updates until there’s enough news to start a new one. And there will be – of that I’m sure. . .

66 comments on “Coronavirus Vaccine Update, May 26”

  1. Paul Brookes says:

    Screw Covid19, what real scientists want to know is what the hell did NCBI do to PubMed, and why?

    1. Christophe L Verlinde says:

      I agree. I guess their hand was forced by the competition with Google Scholar. I recommend that you use the ADVANCED search mode and have a good look at the new manual: https://pubmed.ncbi.nlm.nih.gov/help/

      1. In Vivo Veritas says:

        Lit search had been ripe for a “better” solution for a while. Some my employer have looked at have been pretty good – Qinsight/Quertle comes to mind, but many are bad. I’m a pretty competent user of the old PubMed interface, and Google Scholar sucks……. would be good to have a new free, powerful, intuitive option. Sadly, the new skin on PubMed ain’t it.

    2. sgcox says:

      You can still access old site !
      https://pmlegacy.ncbi.nlm.nih.gov/
      Not sure how long will it last. 🙁

      1. Erebus says:

        That’s precisely what I was looking for, but wasn’t able to find. Thank you!

    3. Publius says:

      Why? The same thing happened to Apple when Steve Jobs was forced out of the company. Except David Lipman will probably never return.

  2. Oudeis says:

    “Themis, a Vienna-based company that’s been working on a weakened form of the human measles virus as a vector for vaccine delivery . . . .”

    Won’t this run into the same problem as the CanSino adenovirus, only worse? I.e., people already have neutralizing antibodies to the vector, so the vector doesn’t stick around long enough to give you neutralizing antibodies to the Spike.

    1. gcc says:

      I was wondering about this too.

    2. Klagenfurt says:

      They looked at this in a previous clinical trial with their measles/chikungunya hybrid vector. Preexisting neutralizing antibodies to the measles backbone didn’t diminish immunogenicity. Looks like they excluded individuals with recent (last 5 years) measles vaccination though.

      1. Oudeis says:

        Cool. And interesting. Thanks!

      2. Glenn says:

        Actually, Themis did a Priorix-controlled Phase II study to definitively rule out any issues with pre-existing immunity to the measles vector, and the results were excellent.

        https://pubmed.ncbi.nlm.nih.gov/30409443/

  3. Robert T. says:

    Derek, as always a wonderful review provided for the various potential COVID-19 therapeutics in clinical trials. I was just wondering, if you hadn’t done already in a past post and I had missed it, if you could provide your insight and/or any update regarding EIDD-2801? Last I had heard, it was supposed to start clinical trials in US in May and UK in June, despite some potential mutagenic safety issues.

    1. exGlaxoid says:

      Merck has agreed to partner on the EIDD-2801 compound. That should allow it to move forward faster. The initial data for it looks good, but works best as an early treatment as expected. That was the smartest thing Merck has done in a while, as the compound appears to be active against many viral infections.

      1. David Young MD says:

        Yes, I was glad to hear this too.

  4. Neil Readwin says:

    The Oxford did not say that the vaccine only has a 50% chance of being effective, they said there is only a 50% chance of their clinical trial saying anything either way on efficacy because there may be too few people exposed to the virus as they enroll patients. It is a very different statement.

    1. David Young MD says:

      Correct, but every news agency misinterpreted that.

    2. PAndriola says:

      I also came here to say this. It’s a subtle but important point given that every % matters

    3. Michael Hawkins says:

      I find the lack of a serious push for a human challenge study astounding. It’s the most ethical no brainier in my lifetime, and nobody seriously pushing for it. It would dramatically increase the odds of determining efficacy. (Disclosure I have volunteered to participate in such a trial if it happens).

  5. fh says:

    What about Vir and their nature article? Modification of its antibody should be vaccine equivalent no?

    1. M says:

      No, it’s actually a completely different approach. Vaccines are basically trying to goose humans to invent their own effective antibody production system, which the immune system will then deploy if it finds the virus is present. When it works it’s great and takes advantage of all sorts of things we’ve evolved to protect ourselves.

      You can’t vaccinate someone and get them to make a specific antibody, and dosing someone directly with antibodies wears off after a couple weeks. So it might be an (expensive) prophylactic or more plausibly a treatment but it’s not vaccine-like.

      Getting someone to actually make a desired antibody with a known sequence would involve something like T-cell gene editing.

  6. LG says:

    I asked Derek for an opinion on timing of things but didn’t make the comment field. Not a cool enough kid in nerdville I guess …

    1. Moses says:

      The man has a full-time day job as well as writing this. Give him credit.

  7. nobody says:

    Governments need to step up and start doing challenge trials instead of waiting for fresh outbreaks for phase II testing.

    Even if a challenge trial goes ***catastrophically*** wrong and kills a few thousand people, as long as the resulting data shaves even one day off vaccine availability we’re still far ahead in the net balance of lives lost/lives saved.

    Allowing hundreds of thousands to die just to avoid putting a few hundred test subjects at risk is not ethically justifiable.

    1. intercostal says:

      I agree that we should do challenge trials – but I wouldn’t agree if I thought there was any chance of thousands of deaths from them*.

      I think that a competently done challenge trial would have a death rate well under 0.1%, hopefully more like 0.01% – so unless you are going to enroll millions or tens of millions of participants…

      The US Navy data seems to show a death rate under 0.1% for young people. These are reasonably healthy people, but for a study, you could do far better selection for health (exclude pre-diabetes, hypertension, obesity, etc.), and pick only from say age 18-35 (the one death on Theodore Roosevelt was age 41). Doing this should give significantly lower risk (men seem to have higher risk, so a 50/50 male-female population would probably also show a lower risk than a Navy population).

      *That being because I fear that vaccine deployment will be unavoidably slow in less-developed countries, and I think that the part of the pandemic in North America and Europe (which were hit earlier than South America, Africa, and India) may be over before even an accelerated vaccine can be available for mass distribution.

      So saving thousands of lives per day cut off the schedule is probably unlikely – even a fall wave may have dipped well below those numbers unless distribution is incredibly fast.

    2. RA says:

      A question I have about potential challenge trials is when in the process of vaccine development should they be considered and with what scale? Do you wait to do them later in the process with a lot of participants or early on with just a few participants (i.e. like the small rhesus monkey studies)? I wonder if some small challenge trials early in the process might help “weed out” the less effective approaches so more resources can be devoted to the approaches that work better and involve risk to fewer individuals overall.

      It’s interesting that fighting COVID is often likened to a war and some people are designated as being on the “frontlines,” yet there is tremendous hand-wringing over challenge trials….we think nothing of sending young people into fight shooting wars of dubious benefit, but wring our hands about challenge trials in those who give informed consent?

    3. Chris Phoenix says:

      A well-done challenge trial could also answer questions about viral load vs. severity of disease. How much of the variability of outcome depends on whether you were near a spreader or a super-spreader? Can variolation possibly work well enough to be worth doing? A decent answer to those questions could save lots of lives.

      1. Chris Phoenix says:

        To clarify: An answer of either “Disease severity is random once you catch it” or “It’s a lot worse if you get a massive dose” would be extremely useful. Fine-tuning our recommendations for behaviors that minimize our chance of dying would save a lot of lives (in sane countries where people actually wear masks instead of violently politicizing them).

        An answer of “No, variolation doesn’t work” would not save a lot of lives. An answer of “Yes, it does work” might save a significant number of lives, depending on a lot of details.

      2. RA says:

        In normal times, I would think variolation is a totally crazy idea…but these are not normal times.

        The reason I think it is worth thinking about in the US specifically is that there are a lot of Americans who are saying in polls they will not take a COVID vaccine…unfortunately, many fear the vaccine more than the disease itself and the fast, disjointed, sometimes financially sketchy development process is unlikely to assuage their fears. Sadly, this sentiment will probably extend well beyond the rabid anti-vaxxers who think bill gates is injecting a microchip into them. So, with sub-optimal public trust, there is no guarantee that even a rapidly-developed, safe, effective vaccine (of which there is no guarantee) will get us to herd immunity anytime soon.

        So, the question is whether there is a variolation strategy that could be beneficial from a population health perspective? It seems like we would need to be certain that variolation leads not only to individual protection with re-exposure but also that those individuals can’t spread the disease to susceptible hosts after recovery/re-exposure. Without those certainties, probably not worth considering. I wonder if you used a small dose of the virus, perhaps a somewhat attenuated strain in low-risk individuals in a controlled environment whether it could achieve what we want with an acceptable risk/benefit ratio.

        If it were sound biologically (a big if), then one crazy idea (that will never happen) would be “Camp COVID.” Young, healthy adults who provide informed consent may voluntarily spend the summer in residential camps, where they can get variolated, party with each other away from (and thus protecting) their older higher risk relatives and contacts, and then return home only after they are certified immune and non-infectious…then they can more safely get into the workforce or college in the fall and society benefits from a step towards herd immunity that will give an incompletely protective and adopted vaccine a lower bar to clear to get us to herd immunity.

        Maybe it would be better to have the Ozarks partiers et al in “Camp COVID” instead of returning home to their older relatives or unrealistically thinking we will ever get enough of these clowns to social distance and wear masks. Maybe, given our population’s unique social dynamics and dysfunctions, we need variolation and vaccination options to develop in parallel to get the best result for the proverbial herd.

        The ethics are challenging of such an approach, yes. However, the ethics of the status quo are perhaps even more more troubling. By “opening up,” we are essentially pursuing slow-motion, passive-aggressive variolation that is uncontrolled and unmonitored and disproportionately affecting those who are the most vulnerable in our society…even researchers are kinda hoping the epidemic rages a bit to make it easier to study interventions. I think we are in “choosing the least of many evils” territory here. Ugh.

        1. intercostal says:

          People being nervous about a COVID vaccine isn’t just anti-vaccination sentiment, though. The concern (justified or not) is that development is being pushed too fast for safety.

          I think anti-vaccinationism is one of the craziest things out there and I’d still be a bit skeptical of a vaccine that became available, say, this winter or early spring.

          I’d still get it* (unless there were specific reasons for concern), but I wouldn’t feel nearly as comfortable as I do with an annual flu shot (where I never even think about side effects).

          *Even though I’m in a low-risk age group. My risk of dying if I got the disease would probably be somewhere between 1 in 1,000 and 1 in 10,000. I don’t think even an accelerated development process would let something that dangerous through.

          1. eub says:

            Yeah, the headlines about “only half would get vaccinated” leave out a large (~30%) “not sure”, which I might well answer myself, waiting to see just how Slaouied up this whole thing looks by that time.

    4. nobrand says:

      Institutional hubris of science driven by military interests is what got us into this mess. I think the world has had enough miscalculated risk by experts, or experts pressured by industry. The 1000’s you coldly speak of will be relatively young and healthy, and would likely not die from covid.

  8. Is TIMOMODULIN not effective in the production of CD4 and CD8? Could it be a path?

    TIMO deficiency, with age, also has effects for the elderly as in the study, where there is no response in the production of new antibodies to CD4 and CD8 being produced by the body

  9. Walter Sobchak says:

    The PBS “American Experience” series is running a documentary released March 31 titled “The Polio Crusade” about the organization of the March of Dimes and the Salk and Saban vaccines. You can watch it at:

    https://www.pbs.org/wgbh/americanexperience/films/polio/

    “During World War II, Jonas Salk was part of a government effort to develop an influenza vaccine. He believed he could apply the same killed virus approach to polio. But established researchers scoffed at Salk’s theory and dismissed his methods. A bitter feud arose between Salk and his leading rival, Albert Sabin, an established polio researcher at the University of Cincinnati who was working on his own live virus vaccine.

    “The two men were unrelenting in their pursuit of a vaccine, but it was Salk who would introduce his formula first. … On April 12, 1955, almost a year since the end of the field trials, the Salk vaccine was ruled “safe, effective, and potent.” Within just a few years of being licensed, the Salk vaccine decreased the number of polio cases in the United States by fifty percent. By the early 1960s, the number of Americans contracting polio fell to a few thousand annually.”

    I was a boy in the 1950s. Polio was very scary. In 1955 when the Salk Vaccine was released our parents ran to get us vaccinated. Everyone was much relieved.

    There is a lot more backstory than the show laid out, but it did a very good job with the atmosphere of fear in that era. https://en.wikipedia.org/wiki/Polio_vaccine

    It is hard to understand how much detailed our knowledge of biology is now than it was then. Remember that the Watson and Crick paper about DNA was published in 1953, well after both Sabin and Salk had started their respective efforts.

  10. Brian says:

    Does anyone have any thoughts about how many organizations have the manufacturing capabilities to make doses of vaccine by the billion and whether additional vaccine plants need to be built? If so, is this something that we should be starting now for a designated vaccine to be named/ licensed later?

    1. steve says:

      Already being done. All the leaders – AZ, Novartis, Moderna, etc are planning for success and building capacity in parallel with clinical trials.

  11. anon says:

    What Moderna did last week did not smell right…I don’t know if we should have more faith in their vaccine than their leadership does.

  12. steve says:

    Moderna built a $30B cap table with no product. They originally were built on the promise of mRNA therapeutics but they turned out to be immunogenic so – AHA! – vaccines. Came to that conclusion after raising 10’s of billions of investor dollars on a false premise. STILL has no product on the market so I would take any hype that comes out of there with an ocean of salt.

  13. anon200 says:

    With a world population of about a 30th of its size today in the “cradle of civilization” era around 3000BC, a 6 month shutdown today would equate to about a 15 year shutdown in terms of human life-years then. What technological advance could have this stopped? Its a hard thing to estimate, since it took tens of thousands of years to crawl out of the darkness of human beginnings around 100K BC, but its safe to say any time matters. Certainly, a promising natural product like hydroxychloroquine would have been considered a medicine candidate by our ancestors even if the clinical trial data was not there.

    1. Chris Phoenix says:

      We could regain that loss many times over simply by educating our entire population well, rather than a small lucky fraction.

    2. loupgarous says:

      The pharmacopeia around around 3000BC wasn’t tested as rigorously as our current one mostly is.

      Our understanding of risk and benefit has evolved since then, as has our body of law and corpus of medical care.

    3. zero says:

      People in 3000 BC didn’t have the internet. Our civilization is still productive. Granted, at the moment it’s grinding through a rather gory reallocation of labor with the potential for significant social change. This isn’t the first time and it won’t be the last.

      As for HCQ, sure. So was datura, foxglove and calf’s piss. Thing is, we have quite a bit of clinical data now. HCQ kills people. More than it helps. It should not be prescribed for COVID. We certainly shouldn’t ignore what we know now and use HCQ because our ancestors would have; these were the same people sweetening their wine with sugar of lead (not to mention the lead pipes, lead shingles, lead bullets, lead paint and lead patch amalgam), whitening their faces (or improving vigor) with arsenic, lining their eyes with antimony-based kohl, filling their teeth (and thermometers) with mercury, and irradiating themselves (and smoking tobacco) because marketing said it was healthy.

  14. Erik Dienemann says:

    Great info, as always, thanks! As a former Merck employee for over 30 years, retiring this past December (and current one, as I’m doing some consulting for them, part-time), it was great to see us finally broke radio silence today. I’ve been wondering when we would, as I knew we had a few irons in the fire.

    I had also been more optimistic about having a vaccine by the end of the year, especially if we take advantage of the “human challenge” approach to shave months off timelines. However, I now have to say I’m a bit less optimistic based on what Merck’s R&D head, Roger Perlmutter, was saying in the Stat article, that a truly effective vaccine might take longer than 18 months. He’s concerned that the early vaccines will not be “sterilizing” vaccines (with no viral infection), which makes for longer studies to prove safety and efficacy.

    As an aside, he is the most brilliant scientist I’ve ever had the pleasure of meeting and talking to (back in the 90s on his first tour at Merck on a project I was on), plus, since he came back to Merck, he’s also been a fantastic leader and an incredible speaker – the man can get up, without notes or visual aids and speak coherently on the most advanced scientific topics for 30+ minutes. Have never seen anyone else do that that well. I hope for all our sakes that he’s wrong, but he knows a helluva lot more about this than I do.

    1. Valdis Andersons says:

      I know and understand that from a scientific and medical point of view a sterilising vaccine is the ideal goal for any disease that a vaccine is possible for.

      In this case, I think, given our global predicament, the practicality would favour a faster to deployment non-sterilising vaccine if it prevents people from severe and critical disease. Having a potentially deadly disease be turned into something that resembles nothing more than the average Common Cold would be of enormous benefit. It would help get people out of lock-downs and would buy us time to get a fully sterilising vaccine developed and tested.

      1. Adrian says:

        Even the most optimistic estimates are that we are at least half a year away from any vaccine being approved and produced in sufficient numbers.

        2-3 months of proper lock-down are enough to get rid of COVID-19 without a vaccine.
        Nearly all countries in East Asia and Southeast Asia and Oceania have succeeded with that, or are close to success.

        If you want people to get out of lock-downs soon, look up to countries like China or New Zealand or Thailand and learn from their success.

        1. Gyre says:

          . . . and for another truly remarkable COVID-19 response see:

          https://medium.com/@indica/covid-underdogs-mongolia-3b0c162427c2

          1. Adrian says:

            441 infections and 7 deaths in Taiwan are pretty impressive for a population of 23 million in a country that had 3 different airlines offering direct flights to Wuhan.

            Vietnam is also impressive: A population of 95 million, a border with China, and 0 COVID-19 deaths.

            None of these success stories are getting the attention they deserve.

          2. eub says:

            Big agreement, the successes of many countries deserve attention. Actually having a peak instead of an altiplano! Even just looking at your household-name Western European countries, Italy — early hotbed — is down something like 10x from the horrible peak; Spain and Switzerland also, and France and Germany with similar reductions.

      2. Erik Dienemann says:

        Agree to some extent, but if a vaccine isn’t a sterilizing one and is essentially more of a “cure” in some respects, then if – and this is a big if – but if, say, engineered antibodies kind of do the same thing, i.e., not stopping infections, but making the impacts minimal (and perhaps working as a short term – months? – prophylactic for folks in riskier positions), then I could see many people wanting to wait for a safer, more effective sterilizing vaccine.

        1. Valdis Andersons says:

          I agree on that point, if we can get mAB cocktails deployed before the first vaccines, then it’s an option. With mABs the usual caveat has been cost and scale of production and the need for repeated administration. Maybe with the current money influx that can be solved? The other side is cost, but at this point I think that particular problem is of secondary or even tertiary nature.

    2. RA says:

      The sterilizing vs non-sterilizing issue is really interesting. Say the first vaccines are non-sterilizing but reduce the risk of severe respiratory disease…that’s still a great thing for high-risk groups…health care/public-facing workers, elderly, nursing home residents, etc..especially in the midst of a bad Wave 2. But, if a non-sterilizing vaccine doesn’t stop infection and infectiousness, then it puts people who can’t/don’t want to get vaccinated in a pickle. They won’t be able to rely on the herd immunity of those who are vaccinated, at least at first.

      I also wonder if you get a non-sterilizing vaccine and then you get (mildly) infected after….would you then be completely immune after recovery, at least for a while? If so, could we deploy a non-sterilizing vaccine and then somewhat safely let unrestricted viral spread do the rest to get to herd immunity?

      Or if you get a non-sterilizing vaccine, could you get to full sterilizing immunity with a different type of vaccine? For example, what would we expect to happen immunologically if you got an adenoviral vaccine and then after some period of time, an mRNA one?!!?

      1. Valdis Andersons says:

        Either exposure to the real virus or a second vaccine of a different type would act as a booster shot. Even the same type of vaccine can be used if it’s not a viral vector type that the body develops antibodies against.
        There is some evidence that T cells play a role in fending off the infection, so the things to look out for in vaccine induced immune respones would be IgG titres and T cell populations specific to SARS-cov-2.
        The ChAdOx NHP challenge paper didn’t mention anything about T cells. Either they didn’y look for them or they did not have the equipment to look for them. Some other papers have mentioned T cell responses in other vaccine candidates in mice and NHPs.

  15. bacillus says:

    So Oxford immunized 6 monkeys, and J&J between 4-5 per vaccine candidate, and looked at immune responses a few weeks later. These barely qualify as pilot studies, and I for one, and hopefully too most of my vaccinology brethren, am completely unimpressed. Firstly, who has determined that this NHP model is the most appropriate for developing a vaccine against COV2 versus ferrets, guinea pigs, hamsters, and mice that are also being assessed in this space? Secondly, you can get any result you want by manipulating the vaccine and challenge dose and route, the time between these events, the time post these events at which you look for immune responses etc. Thirdly, are all of the challenge viruses of equal virulence, given reported mutations as well as the attenuation that can follow in vitro passage. The hype from the media and the companies involved is borderline unethical. It’s basically a free-for-all as all parties vie for publicity, CNS papers and the oodles of cash being thrown willy nilly at this problem. I’ve seen used car salesmen with more integrity.

  16. myst_05 says:

    Are there any news on companies attempting “human challenge” trials? This seems to be crucial to accelerating Phase II/III trials, as you won’t have to wait for people to get infected “naturally”.

  17. steve says:

    Yes, there’s a movement to do challenge studies but they are ethically questionable given that this is a potentially lethal virus and we have no clue why some are more susceptible than others or what the long-term sequelae of infection are. Vaccine trials are 10,000 people or more so the idea of intentionally giving that many otherwise healthy people the virus is horrific.

    1. intercostal says:

      >>we have no clue why some are more susceptible than others

      That seems like an extreme overstatement, given that there is a hugely obvious effect with age and a fairly apparent one with various co-morbidities.

      If you mean that we don’t know what is different about the tiny proportion of young people with no co-morbidities who die, sure. But that doesn’t mean we can’t make reasonable decisions about risk.

      If a challenge trial enrolled people in 18-30 age range with zero comorbidities (assume they all had health checks beforehand to catch unnoticed things), the risk would be far less than, say, going into the infantry in Afghanistan. Yet we don’t consider it socially unacceptable for the government to ask people to volunteer for that…

      Given that young people do much more dangerous things for no societal benefit at all, just for enjoyment, I really don’t see the ethical issue.

      And that’s assuming there is even an increased risk. If a vaccine is shown to produce useful antibodies before the challenge trial, it shouldn’t be *useless*, should it? It might be better to take a 100% chance of being infected with some protection rather than a smaller-but-still-significant chance of being infected with no protection… depends on what % of the population you expect to eventually be infected.

      Plus the psychological benefit of being *done with this* far sooner.

      If a vaccine was demonstrated to produce neutralizing antibodies in phase 1, I’d probably volunteer for a challenge trial if the option existed. (While I’m under 35, I’m probably too overweight to be chosen, though.)

      1. Lane Simonian says:

        Those with one or two copies of the ApoE4 gene should probably also be excluded.

        https://www.the-scientist.com/news-opinion/alzheimers-gene-linked-to-higher-risk-of-severe-covid-19-67570

  18. Steve Scott says:

    Check out the Reuters exclusive article that quotes a scientist helping to plan massive U.S. trials of the leading vaccine candidates. They intend to seek volunteers from groups and areas with a higher risk of contracting the virus.
    This is in contrast to the UK statement about their trial only having a 50% chance of success. Also, Moderna, in their recent conference call with investors, felt that challenge trials were of limited value because they would not establish overall safety and effectiveness across a wide age range, compared to larger studies. My own view is that you could do a limited challenge trial at the same time as the traditional trials.

    https://www.reuters.com/article/us-health-coronavirus-usa-vaccine-exclus/exclusive-u-s-plans-massive-coronavirus-vaccine-testing-effort-to-meet-year-end-deadline-idUSKBN22Y2L3

    1. eub says:

      Welp, the U.S. is contributing toward vaccine development… contributing continued exposure opportunities.

      Yes, I don’t know past practice but it seems like challenge trials are more of a rejection opportunity (“this thing doesn’t even elicit an effective response in young healthy people”) then a stamp of approval for effectiveness in broad usage, including in populations you deliberately avoided testing in. But if you can show effectiveness in the challengeable population, plus broad safety, maybe you go ahead with that under the circumstances.

      The next challenge will be to get enough people to take it.

  19. Ari T says:

    Great article and great discussions!
    Apparently to do human challenge studies , you need a well validated challenge model which could take 6-12 months to develop .
    Are any labs working on developing these challenge models? These need to be ready for the upcoming Phase iii trials .
    Also for human challenge studies , you need small numbers of trial participants. Certainly not 10 000 people .

    1. RA says:

      Yeah, I have heard one counterargument to challenge trails being that you have to have a validated protocol to do it and that takes time. I get that…but the traditional method of study being held up as the prudent course is far less standardized in terms of exposure!!!! You give a large sample of people vaccine vs placebo, release them into their normal lives, and cross your fingers that enough of them get exposed in the wild to show a difference. Even the oxford people say it is a coin flip the conditions will be right to show a difference with this method. I wonder if there is something between these 2 extremes that can be done more quickly.

  20. li zhi says:

    Anyone know if there’s a significant difference (likely) between the mutation rate of a (corona?) virus when widespread vaccination is non-neutralizing and when it’s neutralizing? If so, would that be a good reason to wait for a neutralizing vaccine prior to distribution to the general public? Another ignorance I have is is the difference between non-n and n categorical or more on a sliding scale? (I do understand that there’ll be a distribution of effectiveness either way). Or does that also depend on specifics (some are categorical, some are not)?

  21. An Old Chemist says:

    Want COVID-19 herd immunity? Get 40% of population vaccinated, says ex-FDA chief Gottlieb

    https://www.fiercepharma.com/vaccines/want-covid-19-herd-immunity-get-40-population-vaccinated-says-ex-fda-chief-gottlieb

  22. Erik Dienemann says:

    Interesting preprint on an effort mostly out of the U of Washington on single-dose replicating RNA vaccines. Their research shows the vaccine induces neutralizing antibodies against SARS-CoV-2 in 3 nonhuman primates. Long way to go, but another entrant…

    https://www.biorxiv.org/content/10.1101/2020.05.28.121640v1.full.pdf

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