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Moderna’s Phase I Data

Well, it’s finally here – eight weeks to the day after press-releasing some top line results, the full paper is out on the Moderna mRNA vaccine candidate’s Phase I trial. I’m very glad to see it – it’s going to be very important for the full data sets on all the vaccine candidates to be made public.

So how’s it look? As we found out back in May, we’re looking at three groups of 15 volunteers each, 18 to 55 years old, getting 25 µg, 100 µg, or 250 µg of mRBA-1273 in two doses 28 days apart. The vaccine itself is an RNA sequence for a trimer form of the S (Spike) protein of the coronavirus (similar to the Pfizer/BioNTech mRNA vaccine in that way). It comes with a transmembrane anchor and the S1-S2 cleavage site between the subunits still intact, stabilized in the “prefusion” conformation that it will present in the wild-type virus before it infects cells. That stabilization is through the substitution of two residues at the top of the S2 subunit with proline residues, the “S 2P” form, and the same trick has been used to stabilize other surface proteins of other viruses entirely. (For those who aren’t into protein engineering, proline is unique among amino acid residues in forcing a much more limited conformation in the protein chain, particularly when you have two of them back-to-back). It’s in a lipid nanoparticle (LNP) formulation

As mentioned before, all patients seroconverted within 15 days of the first dose. The antibody titers generated were dose-dependent and were much higher (several-fold) after the second round of injections. Adverse events (fever, chills, pain at the injection site) were definitely more common after the second injection, too, which is just what you’d expect. With that in mind, it’s worth noting the design of the trial, a standard one that’s quite sensible when you’re stepping in to tweak the immune system. The dosing started off with four “sentinel” patients at the lowest dose, followed by four in the middle dose. After those showed nothing serious, both of those groups were then fully enrolled. After Day 8 of the full dosing, four sentinel patients were injected in the highest-dose group, and after them, the rest of that group were enrolled. For the wrong way to try out a new immunology approach, see here.

The patients were assayed for antibody levels (in a standard ELISA format), for neutralizing antibodies (by looking for inhibition in various cell-infection assays), and for T-cell levels. As you’d expect, none of the patients’ plasma showed the ability to neutralize the coronavirus before the trial dosing began. And neutralization was still low after the first injection, although the antibody titers had gone up. By Day 43, though (post-second injection), all participants were able to neutralize the effects of the virus in the cell-infection assays by at least 80%, with those responses also being dose-dependent. A comparison showed that this activity was the same or higher than that found with the plasma of convalescent patients (samples from 38 people, collected 23 to 60 days after onset of symptoms). But one thing that you do notice as you look over the data was that day 43 was the best – there was a further evaluation at day 57, and all three groups had gone down a bit in just those two weeks. You can see this happening in the pseudovirus neutralization assays in the paper’s Table 2 and in Figure S8. These patients are no doubt continuing to be monitored, and it is of great interest to see how their neutralizing antibody titers hold up.

That said, antibody levels are not the only thing that determines immunity. T cells are a big part of this story, although we don’t know all the details – you’ll generally hear a lot more about antibody titers because they’re a lot easier to measure, and to be fair they are often a good proxy for overall immunity. But not always. As for the T-cell data here, CD4+ cell responses were noted, but there was much weaker CD8+ activity (and that only after the second dose in the 100 µg group). Those CD4+ cells can be further differentiated into Th1 and Th2 cells, which each produce a different suite of cytokines. In this case, the vaccine seemed to mostly elicit Th1. The balance between those two types is a complex subject indeed (they have different modes of action and can influence each other’s activity as well), and that also goes for the balance between the CD4+ and CD8+ T cells in general.

I’m not enough of an immunology geek to be able to tell you what profile we would be looking for, and I don’t think we even quite know yet. My impression is that CD8+ cells are more well-established as being important in clearing viral infections (especially respiratory viruses), but the CD4+ ones (and the ratio of the two) are real players as well. As for the Th1 and Th2 subsets of those CD4+ cells, there’s evidence that the Th1 type are more powerful against viral pathogens, at least for some viruses. The general belief, in fact, has been that Th1 cells are more important in fighting intracellular pathogens in general, with Th2 cells going after extracellular parasites and the like, but (like everything else in immunology) that framework has only become more complicated as we learn more about it.

So from my bozo-immunology perspective, I think at first glance that I would rather see a more robust CD8+ response than what Moderna has shown here. Others seem to feel similarly. But that said, I don’t know what the convalescent patient T-cell situation is, either: what kind of response did these people have when they cleared the virus on their own? We don’t have the figures from the set of patients in this paper (they just took plasma to evaluate antibodies). But we know from a study of 10 infected patients with respiratory distress that those patients had a higher CD4+/CD8+ ratio, and that they had a higher Th1 response among the CD4+ cells. But you’d want to hear about the people who recovered smoothly as well as about the ones who ended up on respirators, wouldn’t you? The main thing I’ve been able to find on that is this paper, which also showed a shift towards CD4+ cells in pooled plasma from convalescent patients, and among those cells a very pronounced Th1-driven response (note: more on this one here, and in a separate blog post, coming shortly). So the Moderna data might well resemble the profile of recovered patients, which doesn’t sound so bad, although keep in mind that there might still be better ways to clear the virus than the response that we tend to get. We’re just going to have to see how things play out in Phase II/III, aren’t we? One also would like to see such profiles for the other vaccines in the race, and I assume that we will.

The comparisons are going to be pretty darn interesting. As you can see, Moderna’s candidate is absolutely going to need two injections (as did the Pfizer/BioNTech vaccine candidate), and the reaction to the second dose is pretty vigorous. Will that cause trouble in moving into a larger and more diverse patient cohort? The Moderna neutralizing antibody response seems broadly similar to the Pfizer study, but we don’t have any T-cell profiling from Pfizer yet, so it’s impossible to make any comparisons in that department. The Pfizer/BioNTech adverse event profiling looked a bit better – is that going to be a distinguishing characteristic as the various vaccines go on? Will there be (can there be?) a single-dose vaccine from someone, which would make life and logistics much easier? What will the differences be in the strength of  real-world protection against infection, and in its duration? I have no earthly idea, and neither does anyone else: that’s why everyone is charging into the later clinical trial phases.

 

39 comments on “Moderna’s Phase I Data”

  1. Louis T Freeh says:

    Which specific tissues, organs take up and express these nucleic acid based vaccines?

  2. Matt Gruner says:

    Comparing neutralizing antibodies (prevent damage to host cells by binding to virus before cell entry) induced by the different vaccines I think it will be important to evaluate the evolutionary conservation of the particular residues in the viral protein’s that are targeted and changes in glycosylation on the vector. Viruses have multiple documented ways of evading neutralizing Ab’s, exhibit A HIV-I uses two mechanisms 1) low density of surface proteins makes Ab binding sparse and 2) heavy glycosylation that can change depending on the cell type infected. As many will undoubtably be aware the search for a vaccine that generates broadly and durably neutralizing Ab’s against influenza has become something of a ‘grail quest’ for viral immunologists (ie many people have worked over many years on this and yet no vaccine). Another big concern the majority of the vaccines are targeting Spike, what if there is a fatal flaw with this target we don’t find out until phase 3? In important comparison here will be to the inactivated virus based vaccines which contain all the SarsCov2 proteins. Keep up the great reporting!

  3. Dmitry says:

    What’s obout GMT (55, 166 and 575) of RBD specific IgG at 1 Day of injection (Table 2)? How it possible?

    1. cole says:

      This is pretty curious. In vitro one can see evidence (eg protein expression) of successful mRNA transfection with LNPs after 24h. Recent literature indicates that some anti-spike/RBD nAbs have sequences that are germline or very close to germline. I would imagine that these dose-dependent titers at such an early time point could reflect stimulation of these B cells, although the timing is still faster than I would expect.

  4. Dixon says:

    All our eggs in the Spike protein basket with only “very low” CD8 response.

    1. Dr. Manhattan says:

      “All our eggs in the Spike protein basket with only “very low” CD8 response.” With these two approaches, yes. But there are a number of broader vaccine approaches and candidates underway. An excellent and updated summary of the vaccines, including a brief description of the vaccine target strategy, can be downloaded here: https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines

  5. A Nonny Mouse says:

    Apparently, the Oxford group will have a Lancet paper out this week where they have also done the T-cell work which supposedly looks good (TV interview this morning).

  6. Steve Scott says:

    Here is an important quote from the published Moderna paper:

    “In this interim report of follow-up of participants through day 57, we were not able to assess the durability of the immune responses; however, participants will be followed for 1 year after the second vaccination with scheduled blood collections throughout that period to characterize the humoral and cellular immunologic responses. This longitudinal assessment is relevant given that natural history studies suggest that SARS-CoV and MERS-CoV (Middle East respiratory syndrome coronavirus) infections, particularly mild illnesses, may not generate long-lived antibody responses.20-22”

  7. bacillus says:

    Of course, we still have to show that one or other of the immune responses elicited correlates with protection. In this regard, it will be interesting to see what happens to convalescent patients who have cleared the virus. Are they susceptible to re-exposure, and is colonization shortened or symptoms ameliorated upon re-exposure. Doubtless, this data is already being collected and will show whether the relatively weak neutralizing antibody titres generated by natural infection correlate with a beneficial outcome following re-infection.

    1. Wondering about so many things says:

      Immunology is not my field so please excuse my question if it was all answered above and I missed it.

      Does it even make sense to compare the immune response (“neutralizing antibodies”) produced by convalescent patients with those who produced “neutralizing” antibodies with an RNA vaccine? To me it looks like those would be comparing Granny Smith apples with a basket of berries. With the vaccine derived antibodies being very target/narrow towards that specific piece of spike protein, vs the patient derived Abs likely being a very broad spectrum, responding to all kinds of protein fragments and who knows what. Or – in other words – does the word “neutralizing” here in the publication refer towards that specific piece of spike protein or does it relate to the whole virus?

      1. Athaic says:

        “Neutralizing” relates to the whole virus.
        Well, technically in this case it’s about catching the spike protein and stopping it for doing its job.
        But in vaccine parlance, neutralizing is always about getting an immune response which will block the pathogen from circulating freely (or, like in case of the tetanus vaccine, targeting and blocking the delivery of its main toxin).
        A natural immune response, or one obtained with a whole-cell vaccine, will indeed have a lot of antibodies/T-cell types targeting different parts of the bug. But not all of them will be equally efficient at blocking the pathogen.
        By example, an antibody targeting a protein hidden in the inside of the virus will not be much useful.

  8. electrochemist says:

    When publications reference “the plasma of convalescent patients,” are those patients people who exhibited symptoms and then recovered? To my unsophisticated way of thinking, it seems like that cohort of recovered patients might not be best from which to recover and clone antibodies. Might they actually be people with “mediocre” neutralizing antibodies who were chosen just because they were easier to identify?

    Out of curiosity, are there companies working on treatments developed from antibodies from “asymptomatic” patients? Say, someone whose spouse was clearly symptomatic and infected, but who displayed no outward signs of infection?

    1. aairfccha says:

      That only works if asymptomatic patients actually defeat the virus with antibodies rather than for example having the luck of an innate immune system which targets the virus more effective than in other people.

  9. TallDave says:

    thanks, interesting details, though as you note this is all a bit too “terra incognita” to infer much about protection from data in Phase I

    just have to throw the vaccines into the immunological black box and see what comes out

    hopefully with 30K participants we’ll get useful data

  10. johnnyboy says:

    As another bozo-immunologist, I would advise not getting too far into the weeds comparing results of CD4/CD8/Th1-2 assays as a measure of viral immunity – especially not trying to predict efficacy of one vaccine vs another based on these complex and variable assays, for which predictivity is really not well known. The real test is whether they are protective or not in the patient population.

  11. Andy says:

    You talked about antibodies and T cells but didn’t mention memory B cells. Is it known whether vaccines can provide adequate protection via memory B cells even if serum antibodies fall far below neutralizing levels?

  12. mp says:

    Surprised how little people are talking about the safety signals in this paper.

    If you read the paper (rather than just what’s reported in table1), you’ll see that a patient in the 25ug group had to drop out after the first dose due to urticaria on both legs.

    In other words, 1out of the 15 people who got the lowest dose of the vaccine could not handle getting a booster shot…. this doesn’t seem very encouraging for a therapy that theoretically will be administered to billions of people.

    1. ezra abrams says:

      +100
      As Derek himself pointed out a while ago, the prev record is 4 years, and ~90% of vaccines that enter clinical fail

      I honestly don’t get how a new technology (nucleic acid as immunogen) is the answer when we are rushing timelines; it just seems like a hi risk that we don’t need to take
      Can anyone actually point to an advantage of NA vs protein ?
      not in manufacture; at that scale you need a factory and we know how to make proteins, where as we only know how to make antisense or oligos or RNAi at scale

      iirc, the error rate in synthetic oligos is ~ 1/10,000 due to carry over of phosphoramidites in the lines in the synthesizers; this sort of thing has been worked out, ad nauseum for proteins, but not for NAs

      If we, the PhD/MD/Regulatory community screw this up and the 1st vaccine has safety issues, it is gonna be a catastrophic sh*t storm

      1. gcc says:

        A commenter called “Mammalian scale-up person” has posted some detailed notes on previous posts suggesting that scale-up of mRNA vaccine production may actually be relatively low risk. Obviously unforseen problems could come up since it has never been done on the scale needed, but this person seems to know a lot about the field. See comment from 14 July, 2020 at 2:43 pm in the post below:

        https://blogs.sciencemag.org/pipeline/archives/2020/07/14/pfizers-progress

        Of course, whether an mRNA-based vaccine will be safe and effective is another question…

    2. Marko says:

      This guy , who seems to have been on the high dose , had some nasty side effects , including a fainting episode :

      https://www.statnews.com/2020/05/26/moderna-vaccine-candidate-trial-participant-severe-reaction/

      1. Mister B. says:

        Following that. Which dose has been selected to go through phase II trials ?

        I’ve been briefly through the paper itself and I spotted that one too. But I don’t fully understand the consequences.

  13. woodsong says:

    A question occurs to me.

    I’ve been reading a number of things lately, including the post on challenge studies with the risks & rewards. I’ve also seen anecdotal commentary from people saying that they know someone who was hospitalized with Covid-19, who was given convalescent plasma in an effort to help, with good results. Reading this page, comparing vaccine patient plasma to convalescent plasma, gives me an idea:

    Would it be worthwhile to test the immunity that the vaccine gives by giving vaccine patient plasma to Covid patients, and comparing the response to Covid patients who have been given convalescent plasma? If not, why not?

    There are certainly enough Covid cases out there that I’d be wildly surprised if participants couldn’t be found! I’d also be surprised if there’s enough convalescent plasma (assuming it’s as effective as the anecdotes suggest) available to treat all (or even most) hospitalized patients.

    Has there been a study done along these lines?

    1. EJ says:

      What would the comparison show though? What would the results tell us?

      1. Tony says:

        I think he is arguing for convalescent plasma vs vaccine volunteer plasma. See how well they compare at eliminating the virus from hospitalized covid patients.

      1. woodsong says:

        Thanks for the link! It’s interesting.

        It looks like there’s an investigation currently underway regarding the efficacy of convalescent plasma as a treatment for hospitalized patients. I presume they’re comparing convalescent plasma to standard care, and testing for whether the plasma provides any significant benefits.

        My suggestion is to make that a many-armed study: standard of care; convalescent plasma; and vaccine volunteer plasma, with a separate study arm for each different vaccine for which volunteers have seroconverted. If a given vaccine produces seroconverted plasma that can be demonstrated to be effective at reducing disease severity in active Covid cases, that would be evidence that the vaccine works at conferring some degree of resistance in a way similar to that of a challenge study, without the need to infect anyone.

        That could be helpful to know.

  14. Hi y’all

    Overall it’s very exciting that vaccine data are beginning to come out through peer-review. I am always wary of the stuff that appears on the pre-review servers. I’m also glad that these data come pretty hard on the heels of the Pfizer information, because now there’s a clear and in-real-time comparitor.

    Anyway – I’d like to pick up the point about lack of CD8 response and perhaps reassure on that point a little. While it is certainly true that CD8s do kill virally-infected cells pretty well, I do wonder whether long-term T-cell memory is deeply invested in CD8s unless there’s a viral capability to .. how to put this .. maintain itself within cells. In other words, viruses such as EBV, HSV, HPV and CMV that cause the body to maintain active CD8 cells may be the ones that require a general CD8-mediated long term memory while others rely on CD4s to drive teh regeneration of B-cell responses upon re-infection.

    Can someone help me out / straighten me out on this, please?

    best
    GOP

  15. Walter Sobchak says:

    I would like to be a crash test dummy in the next phase. How do I go about doing that?

    1. Kim PA-C says:

      I’m in the phase 3 trial. Dose is the 100. It’s double blinded. I received my injection four days ago in left deltoid. Still have pain at the site, but gradually better each day. No lymphadenopathy yet, baseline temp has increased slightly from 97.5 to 99.5, but otherwise I feel fine.

      1. Kim PA-C says:

        The injection site pain is very similar to the shingrix injection pain.

  16. Daren Austin says:

    Nice dose response for the Moderna data, but I’m going to stick my neck out and say that the compound has a low therapeutic index. the relationship between dose and ELISA response mimics that of severe adverse events. I think they need the top dose but clearly can’t deliver it. Myagia on second dose is impressive, even at mid-dose. i guess we shall see, but seldom do matters improve in larger trials

    1. TabeaK says:

      Would myalgia really be such a big deal? Every tetanus shot I get, I hurt like hell for a few days. Doesn’t stop me – or anyone else that I know. Of course, that one is only once every 10 years.

  17. Ian says:

    Would Inovio’s vaccine be viable if it had no antibody response but robust t-cell response?

  18. James Cross says:

    For what it’s worth, there is a second part to the Moderna Phase I trials that includes ages 56-70. I don’t know when those results will be reported but it would be hugely disappointing if the older group fails to produce antibodies at reasonable levels since older people are the most susceptible to the complications.

    1. Barry says:

      We mustn’t focus only on antibodies (if by “antibodies” we mean exclusively IgG, which is the easiest thing to measure). It may be that the elderly will rely more on herd immunity than on their own immune responses. But we’ve seen already that circulating IgG levels correlate only roughly with disease outcome for Covid19

      1. James Cross says:

        That assumes that herd immunity is possible and that there aren’t too many anti-vaxxers and other “not trust the government” people to prevent reaching the necessary thresholds.

        I have a personal interest in this because I was a part of the trial and received the high 250 µg dose with relatively few side effects.

  19. Roger Callaway says:

    Phase 3 starting up in Charlotte now. Search news. I hesitate to name names.

  20. Marko says:

    Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates

    https://www.nejm.org/doi/full/10.1056/NEJMoa2024671

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