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Coronavirus Challenges in Primates, Compared

We have a sudden influx over the last few days of preclinical rhesus challenge studies with various coronavirus vaccines, and it’s only natural to try to compare them. I have worked up a table with all four of the current results and the previously reported SinoVac inactivated virus vaccine, whose rhesus challenge numbers were officially published earlier this month. This is the closest to Phase II human data that we’re going to have until later in the summer, so let’s see what we can make of it!

Here is the Oxford/AstraZeneca vaccine, ChAdOx1, which is (as many have had the chance to memorize by now) a chimpanzee adenovirus repurposed with genetic material from the coronavirus Spike protein. This is the final published version of a preprint that came out earlier this year, whose results attracted wide comment and some criticism at the time. Since this one has already been discussed here, I’ll defer it to the comparison table I’m putting together.

And here we have Moderna’s mRNA-1273 results. The short readout is that the vaccine induced an antibody response in the monkeys similar to that seen in convalescent human serum, and a T-cell response that was heavily biased towards CD4+ Th1, with no detectable CD8+. That’s quite similar to what the company has reported in the human Phase I trials, which may add to one’s confidence in trying to learn something from the primate viral challenge studies. We’ll go into the actual numbers in the comparison table, but although the challenge in this case showed strong effects, it was not quite “sterilizing immunity” where the possibility of viral infection is completely shut down.

Then comes J&J, and I believe that these are the first numbers from their vaccine, which is another adenovirus vector, but an obscure human strain (Ad26) rather than a chimpanzee one. It’s been a bigger effort than we knew: the paper shows that they investigated seven different forms of an Ad26 vaccine, coding in various amino acid mutations for stability, different “leader sequences” to try to get the genetic material expressed more robustly once into cells, and different antigen sequences entirely. All of the latter are variations on the Spike protein, but some are full-length, while some had the cytoplasmic “tail” region or the transmembrane region deleted. They also tried mutations in the furin protease cleavage site and (like the first now-dropped Pfizer mRNA candidate), tried a foldon trimerization domain to present the antigen in multiple ways.

The one that stood out in antibody response was the “S.PP” candidate: wild-type leader sequence, full-length Spike protein, furin cleavage site mutated, and proline stabilizing mutations, so that’s what will be in the comparison below. Interestingly, this candidate had the lowest T-cell response of all seven that they tried (their paper’s Figure 3). After looking over the challenge data, the paper has some conclusions (their Extended Figure 6) on immune correlates (what markers are most indicative of efficacy): “these findings suggest that serum antibody titers may prove a useful immune correlate of protection for SARS-CoV vaccines. By contrast, vaccine-elicited ELISPOT responses, CD4+ ICS responses, and CD8+ ICS responses did not correlate with protection“. Which is interesting!

And finally, we have the Inovio DNA vaccine (INO-4800), which I’m glad to finally be seeing more data on. This is a DNA construct for the Spike protein, delivered intradermally. We need various technologies and routes of delivery to be running simultaneously, so the publication of this preprint is very timely. INO-4800 also produced antibody and T-cell responses, which will be summarized below.

 

There are a number of take-aways from this. I particular want to draw attention to the “Virus Challenge” row, since not all of these studies have been performed with an equivalent amount of virus. I have taken the various measurements as given in the papers and converted them all to Plaque Forming Units, using the conversion factor between that and the TDIC50 measurement given in the Moderna paper. (Update: the J&J paper uses a different conversion factor, and after hearing from Inovio, I’ve changed the J&J number to the PFU count that shows in their Methods section, which is the same as Inovio’s). So Inovio’s  and J&J’s challenges are the weakest of all those in the table, but at the same time Inovio’s response is also the weakest (albeit also measured at the longest time since the vaccination as well: when their animals do get back down to zero when measuring subgenomic RNA (which is more indicative of replicating virus), it doesn’t seem to be any faster than the unvaccinated controls. I am not optimistic, based on these numbers, about how their candidate will perform in Phase II/III human studies, both on the absolute scale and relative to their competition, but it would be good to see how the other candidates perform at the same time interval as well. (Update: as noted, edited this from the original version)

The second lowest is J&J. Their efficacy number are very good indeed, but one has to wonder if Moderna (whose viral challenge dose appears to have been tenfold higher) and the other competitors might have shown similar numbers at that same dose. On the other hand, that was only one dose of the J&J vaccine, which is impressive – they are the only company so far to report such a dosing protocol, and that’s a very big deal, from a logistics standpoint. But on the third hand, that single dose was tenfold more viral particles than the other adenovirus vector in the table (Oxford), so is J&J prepared to manufacture five times more active viral vector? They will, on the other hand, be using up only half as much fill-and-finish capacity after that. And so on – isn’t drug development a blast? Don’t you just wish that you could have decisions like this hanging over your head for a living?

I wish that we had similar primate challenge data for the Pfizer/BioNTech candidate, but I honestly don’t even know if they ran that experiment, or when we’ll see it. I still like that one from what we’ve seen of what we now know was its inferior competitor in Phase I, and I like the J&J vaccine as well. Those would be my personal front-runners, with Moderna and Oxford right behind them. Unknown factors in the human efficacy trials could rearrange that list in any direction, though, so my handicapping isn’t worth that much. That said, I don’t have similar hopes for the Inovio candidate based on what we’re seeing, and I don’t really know what to make of three-dose SinoVac inactivated-virus vaccine. Two boosters would be a major pain, and the data package on this one is, in retrospect, the thinnest of the bunch (although it does indeed appear to have worked). I’m not sure if anyone knows what they’re doing in their clinical trials.

On to Phase II!

104 comments on “Coronavirus Challenges in Primates, Compared”

  1. Phil says:

    How predictive are primate challenge studies to showing efficacy in humans? Have there been cases where challenge studies were successful in primates but then the vaccine showed little efficacy in humans?

      1. Another Guy says:

        A significant problem: it may not be possible to infect the animal model with the human variety of the virus and instead the researchers have to rely on using the animal version of the virus. Example: HIV (human immunodeficiency virus) and SIV (simian immunodeficiency virus). It may not be as bad as comparing apples and oranges, but maybe sort of like comparing apples and pears. The human immune system may or may not respond to the same degree as the animal immune system when exposed to the vaccine, but it is a starting point. If it doesn’t work, try to think of why, then modify vaccine, test again. Etc etc. This is why vaccine development can take 5 – 10 years (or much more in the case of developing a vaccine against HIV-1).

        1. Another Guy says:

          Also, after reading the comment section attacks on Derek for making the comparison chart, I think it is safe to assume that Derek made it just to illuminate the differences between the various vaccine candidate studies, and without an agenda. Just look at the chart, every box shows the experiments are being set up and measured in totally different ways. Maybe a disclaimer should be included stating the chart is for “illustrative comparison purposes and is not to be construed as a head-to-head study” and maybe “your mileage may vary”?

          1. dme306 says:

            A comparison chart that he uses to make inferences while excluding some very important details. If your going to infer one product is demonstrating a more superior response over another, or that one is inferior…be honest and make an inference using apples to apples.

          2. johnnyboy says:

            I really hate the way Derek’s blog has been infected by day-trading morons and stock fanboys.

          3. Derek Lowe says:

            Tell me about it. This too shall pass!

      2. Mojay says:

        What’s th alternative?

        Data is better than no data. I don’t understand this placement of critique. There is more nuance to the topic than any single paper has to say about it unless your plan is to give ammo to antivaxxers.

  2. jimbo says:

    agree Pfizer and JNJ vaccines look the best, and of course they have infrastructure to deliver them.

  3. Hayden says:

    Nice comparison table. Your summary doesn’t mention Time until Challenge data. A primary difference between RNA and DNA vaccines is how long they last in vivo (RNA is readily degraded unlike DNA), so duration of response would be an important assessment. Also, doesn’t assess the importance of T-cell response in the summary. Would be interested in your assessment of these data.

  4. Bobby says:

    Pfizer and JNJ vaccine operations and manufacturing were not traditional their strength. I may be wrongh, I thought both company use the contract manufacturing

    1. Mammalian scale-up person says:

      Pfizer has announced they will cook their own at Andover MA, previously a Wyeth / Genetics Institute site.

      JnJ is using Catalent, as I believe they are within reasonable driving distance of the Janssen facility where they do their development.

      1. ajn says:

        `I thought JJ was using EBS as was AZN

        1. Mammalian scale-up person says:

          https://www.catalent.com/catalent-news/catalent-signs-agreement-with-johnson-johnson-for-lead-covid-19-vaccine-candidate/
          https://www.bizjournals.com/washington/news/2020/07/06/emergent-lands-480m-manufacturing-deal-with-johns.html

          Looks like both? Wonder if they are using one to fill finish and the other for the actual manufacturing? or did one not have enough capacity?

        2. simpl says:

          in May, JnJ were reported in Europe to have signed a long-term agreement with Lonza – could be that both Catalent and Lonza are to be suppliers. There also appears to be a deal with the spanish firm Rovi. These things are not as well documented as clinical trials, however.

  5. steve says:

    So the argument has been that it doesn’t matter if neutralizing antibody titers wane over a few months (as they do with natural COVID vaccinations as well as with Moderna’s vaccine) since T cells will maintain immunity. If that’s not true then you have to wonder about the durability of the response. There are 4 naturally occurring coronaviruses that cause about 20-30% of seasonal colds. We never develop “herd immunity” to these and they infect on a yearly basis. There is no a priori reason to assume that SARS-CoV-2 is any different. Possibly epitope focusing with vaccines could matter but it’s not clear from the above data that they do.

    1. Jatsu says:

      Hey Steve,

      I think you should look at SARS and MERS data before throwing in the towel so easily.

  6. alx says:

    If I’m understanding correctly, J&J downplays the role of T-cells in immunity responses (among their vaccine candidates, existence of T-cells in animals didn’t necessarily correlate with protection/immunity).

    However: is J&J talking about short-term immunity only here? Could it be that in their experiment only short-term immunity didn’t correlate with T-cell response, but they have no idea what happens long-term?

    1. Roland says:

      Yup. I don’t think they’ve even said anything useful about T cell response. The one stand out vaccine induced such a strong antibody response that the challenge was almost undetectable, and also – maybe not coincidentally – was the stand out for low cellular response. Correlations reflect that single result, unless I’m drastically misunderstanding what they’ve done in their ‘data not shown’ work. The numbers seem too small to see T cell importance after controlling for antibody differences.

      So the conclusion is that antibodies are very helpful at 6 weeks, not that T cells aren’t helpful.

      1. alx says:

        Roland- thanks for answering a non-expert! I’m basically trying to reconcile these facts in animal data:

        – The J&J vaccine T-cell response: low (according to Derek’s table and the paper)
        – The J&J vaccine antibody response: strong and clears out the virus very effectively
        – However: antibodies may wane over time, as research has shown
        – T-Cell activity may be the culprit for longer term protection, as pointed out by research

        Now it’s reasonable to assume J&J researchers have an explanation or thoughts here, just as a layman I don’t see what the explanation is. When they say the T-cell response didn’t correlate to immunity in animals and yet human response to the actual virus definitely generates T-cell response, I guess it must mean that either animal models are somehow different OR their vaccine is going “a different track” than the actual infection immunization.

        Derek wrote that this is interesting (lack of T-cell response) and I’m looking forward to an explanation of this – what are J&J researchers’ (or other experts) thoughts on this.

  7. Calvin says:

    I might be missing something, but for example, the Oxford paper does not report the actual viral load in their untreated controls (which is not the same as the challenge amount), or at least I can’t make sense of it. Whilst all of these challenges report different challenge amounts, what really counts if what the stable viral load on the lungs is. Some groups are better at running these than others and so don’r need to give such a high challenge to get the same or very similar viral loads.

    Respiratory virus animal models are notoriously…..crap. So are the viruses actually replicating or are we getting a couple of turnovers before they disappear.

    I really can’t tell. I might need to spend quite a bit more time going through the charts.

    But the differences in challenge title are, in my view, misleading.

    As ever the real story will emerge in patients.

  8. Damien Leung says:

    You have not accounted for the different time points between the competing vaccine candidates since vaccination when the subject was challenged and then readings were measured. For example Inovio challenged the subject monkeys more than 3 months later since vaccination – way way after the peak response time for the vaccine – than Moderna, which challenged the monkeys at about a month since vaccination when response to the vaccine was known to be at peak levels. Despite the drastic difference in the time points, both vaccine responses were still very close. This should suggest that INO-4800 is more durable in defending the subject against the virus.

    1. Tade Williams says:

      Bingo.

  9. Bruce says:

    Wow, is this supposed to be a “scientific” comparison between vaccines? Lol! The Inovio primates were challenges well after “peak immune responses” had waned (17 weeks after first vaccination). Are you just another big pharma shill, who rally expects the public (at least educated) to let you get away with such unscientific drivel? You should be embarrassed by this unscientific comparison written in a “Science” magazine!

    1. Derek Lowe says:

      I hope that your investment in INO works out for you.

      1. Bruce says:

        No comment in the merits of the “scientific” integrity of your comparative analysis?! Lol!

        1. Rick Mabolz says:

          Hey Bruce,
          You Laugh by yourself a lot, don’t you?
          Did your mom make meatloaf tonight? i hope so! See you tomorrow morning for her pancakes.

      2. SK says:

        I hope your loyalty to BP pays off.

      3. DK says:

        This reply of yours suggests that you have no business of writing any objective scientific evaluation of anything because you are do unprofessional!

        1. loupgarous says:

          “This reply of yours suggests that you have no business of writing any objective scientific evaluation of anything because you are do unprofessional!”

          Your rejoinder to Derek suggests you’d benefit from additional study of English, while Derek and other posters here manage to communicate well in that language.

          1. KC says:

            Are you kidding?! There was one typo of the word “do” rather than “so” – the “s” and “d” are right next to each other, in case you haven’t noticed. Great way to attempt to invalidate a solid point by being a spelling Nazi (and a bad one at that).

          2. loupgarous says:

            KC says Are you kidding?! There was one typo of the word “do” rather than “so” – the “s” and “d” are right next to each other, in case you haven’t noticed. Great way to attempt to invalidate a solid point by being a spelling Nazi (and a bad one at that).

            Let’s revisit the Serbo-English original:

            “This reply of yours suggests that you have no business of writing any objective scientific evaluation of anything because you are do unprofessional!”

            The initial clanger wasn’t the puzzling word choice of “you are do unprofessional”, but earlier in the sentence

            “you have no business of writing any objective… “

            . Nothing in that sentence rises to the dignity of a typographic error. It would have to be written entirely in English, first. If a solid point was made there, I missed it.

      4. bonobo says:

        its up 598% the past year, how is your portfolio doing bro..don’t hate congratulate..lol

      5. TallDave says:

        lol

        well I for one enjoyed the chart quite a bit

        at any rate we’re all just twiddling our thumbs till we get human trial data

        full disclosure: long VFINX since ’97 🙂

    2. Cmon says:

      The table presented is a summary of aspects of several ‘scientific’ studies, not a study unto itself. Surely our humble blogger would design a more rigorous head-to-head trial were it his to do. NO company is positioned to run such a trial however, especially absent any sort of pre-determined criteria for demonstrating pre-clinical efficacy.

    3. Rick Mabolz says:

      Hey Bruce,
      Sell you’re Invovio stock asap

  10. MTK says:

    What are the controls in the various experiments?

    No vaccine, no challenge, both?

  11. Bruce says:

    Ah, yes, Novartis employee writing this “scientific” review—there’s the big pharma connection! Did you read this in the Inovio paper today? And, remember, Mr. “Scientist,” this challenge study was 17 WEEKS post first dose!

    “Seven days post-challenge, robust geometric mean endpoint titers for the ECD ranging from 409,600 – 1,638,400 were observed in immunized animals, compared with the naïve group which displayed seroconversion of only 1/5 animals (GMT 100).”

    Pretty significant findings if you are looking for longer-term protection following vaccination! But, of course, you cherry-picked your comparison data using a comparison of challenge studies performed at markedly different time points…Shameful!

    1. mymagoogle says:

      Are you doing OK there, mate?
      We saw your first comment, no need to add any more.

    2. dme306 says:

      Bruce,
      Thank you for pointing out the flaws in this extremely and hastily written piece of unscientific journalism.

      Derek,
      Your efforts to manipulate the results with your own misguided sense of stats are obvious and no longer work in a world filled with scientists, researchers, statisticians and doctors who are closely watching these results around the world. Please, for the sake of mankind, have some sense of decency and for once in your life, do the right thing instead of succumbing to greed when you put yourself out like this. Your life’s work mean anything to you or are you just another puppet?

      1. matt says:

        Was this mentioned on some investor forum for Inovio? Would you care to disclose any possible conflicts of interest? Are you the same person as Notyouraveragedoctor, Bruce, Alex Srajer, etc, or do you all happen to know each other (from the Inovio watercooler or investor forums, for example)?

        It’s not the specific criticism–the time between vaccine dosage and viral challenge is an interesting variable to follow, and DNA vaccines–if they are working–may have some advantage in longer term protection, although the body’s own long-lasting immune cells may provide that for all comers. Those are valid criticisms. It’s not possible to get a perfect comparison table at this point, even if we knew exactly what to look for.

        It’s the foaming saliva at the corners of the mouth as you attack the blog author as a shill (do you realize that’s projection?) that marks you as not really interested in scientific conversation. The scientific conversation understands that we’ll have to wait and see, and that any handicapping at this point is, well, like picking race horses. I.e., unscientific guesses. The investor conversation, on the other hand, is about shouting down any opinion that might be construed as negative in order to boost your short term holdings. If you REALLY believed in Inovio, you would be holding them for the next 5-10 years, and negative publicity would give you the ability to grab more value-priced stock.

        You guys need to up the entertainment value of your shill game. Have you sold all your earthly possessions and liquidated all your retirement investments, put them in long call options on Inovio, and then prepared to blast Dr. Lowe for being solely responsible–through a lukewarm blog post–for ruining your financial future if it doesn’t pan out? If not, don’t bother, somebody’s already done that.

        1. Miles says:

          Its easy to trace people like eberhart, yes they have financial interests, not scientific ones.
          Derek you really got the trolls wound up … those who use “lol” in comments just look like tossers.

    3. Signal to Noise says:

      Recommended website improvement – the comment captcha is replaced with an elementary retrosynthetic or PK question

      1. Some idiot says:

        🙂
        Brilliant!
        Retrosynthetic for me, thanks!
        🙂

        1. Mister B. says:

          I’ll second this Idiot who is not an idiot.

          Retrosynthetic or reaction mechanism to me please

    4. Zambo says:

      What date do your Inovio calls expire?

    5. Biteme says:

      Your blatant attempt at mischaracterizing this blog post in order to cash in on your near-term option expiration is shameful.

  12. L.F. says:

    Any post or comment on the DIY efforts. Reading about Georgey Church snorting some lipid formulated corona peptides; wonder if full-length proteins are commercially available. Maybe safer than cocaine or demon matter.

    1. LF says:

      It is via the more seemingly pathophysiological mucosal membrane IgA-mediated-defended route, so there is that.

  13. Alex Srajer says:

    Another consideration overlooked by the author is that Inovio’s vaccine is DNA based and stable at room temperature for a year. Rna vaccines like Moderna’s require intensely cold refrigeration. Tough to do in most of the world.

    1. loupgarous says:

      No need for us to gratuitously comment on Inovio promotional messages. A dram of Glenmorangie each time their vaccine’s praises are sung makes for a nice drinking game.

      1. Some idiot says:

        Cheers! 🙂

      2. Alex Srajer says:

        Send over a couple bottles. I’ll join you.

  14. CG says:

    This is a poor comparison of the vaccines because of significant differences in the timing of measurements taken and because of massive differences in the viral loads noted in the controls. It is like comparing apples to oranges. There needs to be more standardization in these studies so the vaccines can be compared side by side in an appropriate way. It is nearly impossible to draw any meaningful conclusions from this comparison.

    1. eyesoars says:

      Dood… You should be aware that the poor blogger is not in charge of these studies, and has had to make do with what is available, rather than what he, or you, or me, would like to have.
      As for similar dosing, trials, challenges, &c, vaccine development, so far as I am aware, is still as much art as science. This is biology, not physics.

    2. Just another chemist says:

      The only real way to compare these vaccine candidates is large scale phase 3 clinical trials. As long as they work and are safe several should be approved. In order to be able to distribute enough vaccine to enough people we will need more than one approach. And collecting data on the vaccines in post approval studies will inform us which method was “the best”.

      Don’t let the perfect be the enemy of the good.

  15. James says:

    This comparison is biased. If all these vaccines were compared with a virus challenge at 17 weeks or 30 weeks out, I highly speculate that some of them might fail miserably due to the lack of T cell memory.

  16. chris says:

    So if the monkey study for the Oxford vaccine is replicated in humans, then people would test positive but not get ill. So how would they test for this in Phase III trials as surely the number of people who test positive in the control group will be the same/similar as the vaccine group.

    Or will they just test people who develop symptoms in the trial?

  17. AB says:

    I will echo the concern that the timing of the challenge is probably a confounding factor that makes side-by-side comparison very difficult here since some groups appear to be challenging the memory response while others are targeting various levels of acute protection.

    If you’re going to spend two paragraphs comparing challenge doses, why not at least address the timing of the challenge (relative to first and last dose)? I appreciate that it’s included as a row in the spreadsheet, but the fact that this major factor is not even discussed in the article, is a glaring omission at best and comes across as biased at worst.

  18. Notyouraveragedoctor says:

    Inovio Viral RNA BAL on Day 7 showed significant statistical difference from naive group (10^1.6 vs 10^3.7). Cherry picked data at day X isn’t the best way to compare.

  19. Notyouraveragedoctor says:

    Quote: “You will note that Inovio’s challenge is the weakest of all those in the table, but at the same time their response is also the weakest: when their animals do get back down to zero when measuring subgenomic RNA (which is more indicative of replicating virus)”

    INO-4800 reaches baseline at day 4 in subgenomic RNA BAL versus naive group at 7 days. Moderna reaches baseline at day 4 online on their 100 ug dosing (their dosage with horrific side effects). NOT STATISTICALLY DIFFERENT FROM MODERNA QUIT TRYING TO BRING DOWN INOVIO.

  20. ghyu says:

    All of the vaccines seem to work to some degree. Wouldn’t the ethical choice be to just take the cheapest one and offer it on a right to try basis to those most at risk? Even if there is no strong or long lasting immunity, there’s at least a good chance of reduced severity. There haven’t been any reports of antibody dependent enhancement yet, so what would be the harm of just giving everyone who wants it an investigational vaccine? Waiting for perfect data and a perfect vaccine will cause tremendous damage to human civilisation.

  21. John Neumann says:

    Not sure how much money Derek Lowe got for this poor comparison, but making predictions based on a 2D Table reflects how much time he spent with the research.
    Not to mention the unprofessional reasoning which just shows how amateur he is. Well, this is a blog, with good reason..

  22. Lane Simonian says:

    If T cells are critical for fending off this novel coronavirus what level of T cell activation in primates would correlate to the T cell activation that you would want to see in human beings? I don’t know if that is either an appropriate or answerable question, but I am unable to make heads or tails out of any of the vaccine data with so much left outstanding at this point.

  23. steve says:

    Wow. Is it anywhere within the realm of possibility that Derek missed the timing issue without it being some malicious plot? Any way to possibly make your point without baseless ad hominem accusations? Could you actually pretend to be scientists?

    1. eub says:

      Stock pumpers may not have a lot of practice pretending to be scientists.

  24. Monkey Business says:

    I question the Author’s motivation in comparing only primate challenges. Are we falling prey to a shill for Big Monkey?

  25. Niduterpenoid A says:

    Thanks Derek for the good summary. This many companies trying to scrabble for a vaccine… it’s going to end in tears for at least a few of them!

  26. Some Dude says:

    Wow, this post brought in a different kind of crazy from the usual science deniers and esoteric types. Hope you have a thick skin, Derek!

    1. loupgarous says:

      These new guys seem focused on attacking Derek in much the same way as the HCQ refrain. Instead of the “Why don’t you want us to have a cheap and safe pill for COVID-19 that’s been used to treat malaria for decades?” mantra, they’re accusing Derek of having one particular dog in the vaccine fight at the expense of (insert name of new vaccine candidate).

      The “poor, maligned new guy” seemed to be Inovio’s vaccine at first, but a fresh look at the ad hominem accusations show unnecessarily vicious attacks on Derek’s methodology in this post’s presentation of data surrounding available data on experimental viral challenges.

      It’s unclear which vaccine Derek’s supposed to be attacking, but some common threads among the attackers include poor English syntax of the sort we’re used to from many of the pro-HCQ keyboard warriors here. It almost looks like an spoofed attack on Derek and some or all of the US COVID vaccine programs, sowing fear, doubt and uncertainty.

  27. anonymous says:

    I thought a big part of the push for Operation Warp Speed was to be able to run head-to-head comparisons of the vaccine candidates?

    “By July, Warp Speed hopes to have its eight lead candidates in human trials. At the same time, it will fund a large-scale comparison of their safety and efficacy in hamsters and monkeys to help winnow down that group. “If something’s really bad, we’ll get rid of it,” he says.”

    https://www.sciencemag.org/news/2020/05/unveiling-warp-speed-white-house-s-america-first-push-coronavirus-vaccine

    So far, I see no coordination. Let’s hope that the human phase 3 trial designs allow useful comparisons–I haven’t tried to check this.

  28. Luis says:

    I could not care less about stock markets and shares! I am just happy that at the moment we have very promising candidates coming through with vaccines. I hope they are all successful so more doses will be available quicker to the wider population.

  29. drsnowboard says:

    Did someone open a door to a particularly shrill part of the internet…? I thought the HCQ crowd were loud but at least you could argue they wanted better health outcomes, the guys above sound desperate.

  30. Mathijs van den Bergh says:

    Very interesting, thanks Derek.

    This table does bring home how useful it would have been to have standardised tests, possibly coordinated by NIAD or others from a very early date. Of course we don’t have a good model for either disease or transmission so it would be challenging to pick something but it would have been very valuable if all vaccine developers had been told back in March or early April that they were expected to use certain dosing or timings for their viral challenges. As it is, we can look at the data available which you have kindly gathered and use our own judgement as to which ones are most likely to succeed but imagine how much easier this would be if everyone challenged on the same day post vaccination, with the same dose, and via the same route before measuring the same outcomes.

    As it is, all we can really say is that they all seem to “sort of” work without evidence of ADE.

  31. VB says:

    If bashing Inovio was Derek’s ultimate goal here, he would not have included the “Time to challenge” row in his table. Those who are in the field know that there’s hardly a situation where we have all the data that makes apples to apples comparisons possible. You make decisions based on what you have.

  32. aleks says:

    Hi Derek, thank you for writing this blog post, it is very informative not only for experts but for general public.

    Also- where could one find data on animal’s baseline response to the virus (without any vaccination)? This would be a nice addendum to the table, to be able to compare with vaccine-elicited responses.

    1. aleks says:

      Actually I see that it is already partly in the table (a few bottom top left table fields).

  33. somniture says:

    It’s downright shameful to see attacks on an expert who is educating the public about science and providing insight and context on the flood of COVID research. If you have legitimate issues with his methodology, by all means express them. But there’s no call for questioning his motives or being insulting. His content is valuable and we get it for free.

  34. Charles H. says:

    I find it worrying that all the TCell numbers are low or absent. IIUC COVID antibodies are transient, and disappear over a couple of months, while TCell responses are durable. And, IIRC, it was said a few days ago that CD8 type TCells were believed more important that CD4.

    I *hope* that I’m wrong about something here, being a programmer and not a medic or chemist, but if so, what?

    1. steve says:

      Charles – Immunologist here. It doesn’t really matter if circulating antibodies decline, they do with all vaccinations. What you want is to induce memory B cells. These are the cells that decades after you’ve had your childhood vaccines still protect you; if you encounter those viruses again the Bmem spring into action. The role of T cells in protection from this and other infections is less clear; better to have it but humoral immunity may be sufficient.

      1. Steve Scott says:

        A complicated topic, but many (but not all) memory B-cells require “Helper” T-cells to go into action when the antigen is encountered, and then the B-cells can generate new antibodies.
        I wonder if the Phase III trials will be able to measure this mechanism in their short announced time frames before general release.

        1. steve says:

          In general, Th is needed for generation of Bmem, not so much for secondary responses and differentiation into plasma cells.

  35. Aaron says:

    Hi Derek,

    Can you clarify the 2 points below?

    1. Can you explain how Inovio has the weakest Viral Challenge (inoculum) when Inovio claims that “The initial viral loads detected in control unvaccinated animals in this study were approximately 2 logs higher (109 PFU/swab in 4/5 NHPs on day 1 post-challenge) than in similar published studies performed under identical conditions”?

    Inovio also stated that: “High-dose challenge inoculums are frequently employed to ensure take of infection, however such high dose challenge may artificially reduce the impact of potentially protective vaccines and interventions”

    2. For nasal PCR (sg mRNA), you have 10^4.5 for Inovio. I am looking at their preliminary data, isn’t the subgenomic RNA demonstrated in 2nd graph of Diagram D which shows under 10^2? The 10^4.5 is for “Viral RNA Nasal”

    Thank you.
    Aaron

    1. Somerset says:

      Supplement to Q1 above from Aaron:
      Includes findings from 2011 and 2019 to support this statement:
      High-dose challenge inoculums are frequently employed to ensure take of infection, however such high dose challenge may artificially reduce the impact of potentially protective vaccines and interventions (Durudas et al., 2011; Innis et al., 2019).

      I’ll add:
      “Despite these limitations, this study demonstrated significant reduction in peak BAL sgmRNA and overall viral mRNA. These titers are significantly lower than our NHP challenge dose and support the potential for the vaccine to exhibit great impact in the field against natural SARS-CoV-2 challenge.”

  36. TallDave says:

    interesting, wish we could see similar study results for synthetic antibodies, the Lilly and Regeneron mAb cocktails particularly… believe it has been reported in interviews that animal results exist but don’t know if they have ever been made public

    on Aug 12 the human Lilly Phase 2 results are allegedly due, if one or more of these pans out that could make vaccination much less urgent

    https://clinicaltrials.gov/ct2/show/NCT04427501

    https://clinicaltrials.gov/ct2/show/NCT04425629?id=NCT04425629

    1. TallDave says:

      looks like September instead? also a Phase 3 underway

      https://investor.lilly.com/news-releases/news-release-details/lilly-initiates-phase-3-trial-ly-cov555-prevention-covid-19-long

      “…BLAZE-1, a Phase 2 study in people recently diagnosed with COVID-19 in the ambulatory setting (NCT04427501), is ongoing. Based on current trends, enrollment is estimated to be completed in September, with initial data readout soon thereafter followed by full data in Q4. LY-CoV555 has been well tolerated at all doses tested and no drug-related severe adverse events (SAEs) have been observed to date. Efficacy data are not yet available.”

    2. TallDave says:

      and just like that, some primate data for REGN-COV2

      have not tried to dig deep into this yet

      https://www.barrons.com/articles/regenerons-covid-19-antibody-looks-promising-in-animal-test-51596554640

  37. Robert Lingerston says:

    Sort of unrelated but this made me question how will they test efficacy for these vaccines? What if John Doe was part of a vaccine trial and exposed to the virus and didn’t come down with COVID — that would be credited to the vaccine. However, what if John Doe wouldn’t have come down with the virus regardless because he had immunity already that wasn’t due to the vaccine?

    1. Another Guy says:

      If the study has relatively few patients, then I would test all patients for antibodies against SARS-CoV-2 and exclude anyone who tests positive. If the study has many participants, then you could allow antibody-positive patients in and observe them as a subgroup.

      The ethics of a “challenge” test (deliberately expose participants to the virus) is debatable, and a different way is to conduct the study in an area with a rising infection rate.

    2. DH says:

      That’s why trials have control groups. The intent is that the number of such people in the treatment and control groups should be approximately the same so that the effect on the calculated efficacy cancels out.

  38. Alan says:

    From JNJ NHP report: At week 6, all animals were challenged with 1.0×105 TCID50 (1.2×108 RNA copies, 1.1×104 PFU) SARS-CoV-2, which was derived from
    9USA-WA1/2020 (NR-52281; BEI Resources) .
    Isn’t JNJ use the same 1.1×104 PFU as INO?

  39. Driving, Bye says:

    Layman comment:

    Everyone here seems to be looking for a highly effective vaccine that prevents contracting the illness. Is that really the only acceptable option?

    Other view: It appears that this virus, like respiratory virus, would run a natural course and then subside into the background as did the much more lethal 1917-8 Great Flu. Along the way it would create a great deal of injury and perhaps several tenths of one percent mortality, with the morbidity hitting all ages (not evenly) and mortality mostly among people with less than 10 years left.
    Which is a long winded way of saying it’s not harmless, but it’s pretty mild by historical standards, and even without a vaccine it will naturally burn down as did the Great Flu.

    So if a vaccine only provides, say, 65% immunity, it would still sharply accelerate the natural decline of the disease, right? At some point, vaccine generated immunity plus post infection immunity would reduce R to below 1.0 and the virus would quickly fade out. It would not explode in another outbreak, because the remaining non-immune population would demand the vaccine once they believed the virus was imminent.

    Is this too simplistic?

    1. Zambo says:

      The FDA set the bar at 50% efficacy for approval as some protection is better than no protection, but people just want to know who is “leading.”

  40. Lane Simonian says:

    An open question to anyone:

    Which would you consider to be more likely: an effective vaccine or an effective treatment and why?

  41. Andrew says:

    Great article Derek! I wanted to ask your thoughts on Inovio’s vaccine having had generated neutralizing antibodies both for the earlier strain of the virus as well as the mutant variant (D614G). In the same NHP study they saw evidence of cross-reactive antibodies were also detected against SARS-CoV S1 protein and RBD. Does this not make Inovio more attractive vis-à-vis other candidates given its potential broad protection? Not to mention it’s the only vaccine to show at least fourth months of protection.

    Thanks I look forward to reading more of your work.

    Andrew

    1. Derek Lowe says:

      It looks like in every case so far when people have looked at the D614G mutant that the antibodies raised have no problem neutralizing it. This is definitely not a special property of the Inovio vaccine.

      1. Andrew says:

        Ah I see thanks!

        Also what are your thoughts the other stuff I mentioned:
        – Its vaccine also produced cross-reactive antibodies for SARS (SARS-CoV).
        – Their study was the only one to do an animal challenge, months post-vaccination.

        Are the above items also irrelevant?

        Cheers!

  42. Ed says:

    I understand the temptation of making this comparison, but are differences due to differences in vaccines, animal models, or both? From a developers’ point of view, given the competitiveness and societal urgency, is this good use of your time? In particular with so much free money sloshing around, it may be wiser to test all your candidates in Ph1. 

  43. james says:

    Where is Derek Lowe? Want to see his explanations for each comments.

    1. Derek Lowe says:

      Ars longa, vita brevis

  44. An Old Chemist says:

    Merck, via its Themis buy, to move first COVID-19 vaccine into clinical development in Q3

    https://www.fiercebiotech.com/biotech/merck-via-its-themis-buy-to-move-first-covid-19-vaccine-into-clinical-development-q3

  45. Jim Davis says:

    Derek,
    I have been reading your blog(s) now for perhaps 10 years.
    I especially enjoy the “Things I Wont Work With” entries.
    I am amazed at the vitriol with which folks have been attacking your quite reasonable chart.
    When comparable data is unavailable using what is there seems quite appropriate .
    Please keep writing. I hope to keep reading.

  46. Andrew says:

    Any chance you can update the article to include Novavax’s report today?

    1. Derek Lowe says:

      As soon as the full report comes out, I’ll be on it, definitely!

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