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Clinical Trials

First Results from Moderna’s Coronavirus Vaccine

This morning brought news from Moderna of the very first human results from trials of their closely-watched mRNA vaccine candidate (mRNA-1273) against the coronavirus. Here’s Stat on the news, and here’s Endpts – the results can be summed up pretty quickly, because it’s all just at the press-release level to start with.

The trial was dosing volunteers in Phase I at three levels 25 micrograms, 100 micrograms, and 250 micrograms of the mRNA species. First off, immunogenicity (whether or not these doses caused people to produce antibodies). The good news there is that every participant at every dose level began producing antibodies (in other words, they “seroconverted) by day 15 after the first injection. The actual amount of antibodies produced went up in the higher-dosage group, and for the 25 and 100 µg folks, it went up after the second “booster” shot of mRNA as well. (The high-dose 250 µg voluteers seem to have maxed out after the first shot, actually).

That’s promising on the relative amounts of antibodies: everyone responded, and the response was dose-dependent (both in amount and across time, with the booster shot). As for a comparison to the outside world, the company says that the lowest-dose (25 µg) cohort (15 people), two weeks after the second dose, showed levels of binding antibodies that are the same as seen in the blood of people who have recovered from the coronavirus on their own, as tested in the same assay. And the medium-dose group (ten people), tested at the same time, showed antibody levels that “significantly exceeded” the levels seen in recovered patients. The company says that it doesn’t have the numbers yet for the rest of the trial participants; presumably we’ll be seeing those soon.

Now that’s good, but it only measures binding antibodies. What you want are neutralizing antibodies, ones that not only bind but do so in a way that shuts down the virus entirely (background here). Moderna says that they only have data to this level on the first four participants in the 25 µg and 100 µg groups, but the good news is that those results are consistent with the overall binding antibody numbers: all of these people developed true neutralizing antibodies, and the company says that these were “at or above” the levels generally seen in the blood of recovered coronavirus patients.

What about safety and tolerability? There were no adverse reactions in the lowest dose group, and one in the middle 100 microgram group – a so-called grade 3 erythema (redness) at the site of injection. In the high-dose group, there were three participants with systemic reactions, and the company doesn’t go into the details, but those would generally be fever, flu-like symptoms, perhaps body rash. All of these resolved themselves, the release says, and it mentions that there were no serious reactions. That’s important – as you might guess, the language here is pretty precise. “Serious” is a regulatory term, meaning hospitalization, perhaps permanent damage, etc., as opposed to “severe” which is a broader term (and which Moderna doesn’t use in their press release at all, either).

So these results have led to some clarity on the Phase II trials, as they should. The 250 microgram dose is being dropped – it seems to be more than is needed, with a greater chance of adverse reactions. The company is now going with 50 and 100 microgram dosing, and the 50 microgram dose is going to be tried out under these Phase I protocols right now. The Phase II trials should be starting soon, and the plan is to use that data to narrow down on a single dose for going into Phase III, which is now set to start in July. That will be somewhere below 100 µg; we’ll see how the Phase II pans out.

Now if you read the post here earlier this morning, you’ll wonder about how the Moderna vaccine compares to the Oxford and SinoVac ones. We don’t know: Moderna hasn’t run a rhesus monkey challenge test, and as you can see from that post, even when two different organizations have done that there’s still plenty of arguing room. What Moderna has done is a mouse challenge, also mentioned for the first time in today’s press release. All we have is that “vaccination with mRNA-1273 prevented viral replication in the lungs of animals challenged with SARS-CoV-2“. No further data on the dosage, challenge method and amounts of virus, etc., but they say that the amounts of neutralizing antibodies seen in the mice is consistent with the human results.

I’d characterize today’s results overall as “limited but promising”, and in other words, so far, so good. This is what you’d expect to see from a vaccine that works, and although it looks that way we don’t have enough information yet to quite say that it works, or how well. That is what Phase II and Phase III trials are for, and waiting for those results, from Moderna and from everyone else, will make the latter part of the summer and the fall interesting indeed. Won’t it, now?



53 comments on “First Results from Moderna’s Coronavirus Vaccine”

  1. jz78817 says:

    the question I have as an outside observer (chemistry and medicine is not my field) is how/when do they test whether vaccinated patients are actually immune to a real exposure to the virus?

    1. DoctorPizza says:

      They would check the same way we check for all vaccines. Levels of neutralizing antibodies in the blood.

    2. Patrick says:

      I think there’s a misunderstanding in the first response…

      They test that in phase 2 and phase 3 by vaccinating enough people in at risk areas (ie, where the virus is spreading) that some significant of them being exposed in a way that would normally generate infection is guaranteed. IE, say NYC is still having issues, vaccinate 3K people there and see how it does, working from control group data to see what % of those folks should be infected in absence of the vaccine..

      This is one reason we never got a SARS vaccine; it stopped spreading before we were able to do trials.

    3. Elisa says:

      And safety of trial participant to wild type virus.

  2. Rhodium says:

    I am sorry for being too busy to look it up, but 1. How do you make kilogram quantities of mRNA and 2. Is it chemically modified in any way?

    1. GM says:

      It is chemically modified as far as I know (they use uridine analogs). It is also packaged in some sort of liposomes for delivery

      But the bigger problem is that this will require refrigeration. As in actual freezers.

      And that means you can forget about going around the world in places that don’t even have electricity and vaccinating people. It may be a challenge even in the US.

      1. tlp says:

        Can you freeze liposomes and expect them to be stable after thawing?

        1. GM says:

          I’ve never had to deal with these things so I don’t have answert.

          But every RNA reagent I have ever used has required deep freezing.

        2. Mammalian scale-up person says:

          Depends on liposome. Some are more stable than others; it’s predicated on the lipid cocktail and the characteristics of what it is packaging.

          We freeze to -80C for mammalian expression routinely (glass transition of many proteins tends to be -50C to -20C), but yes, you are correct that stability in overseas shipping is not trivial and we tend to make things in locations where they will be easier to distribute to their point of use for this reason.

          In any case will have to pass stability testing prior to distribution. Preformulation studies typically occur during Phase 1 for both bulk and final packaging storage methods; final formulation studies with real time confirmation of accelerated studies must be complete by end of Ph 3a.

      2. Jim Hartley says:

        For a Moderna paper on lipids for mRNA delivery, see PubMed Central PMCID: PMC5986714.

    2. Jim Hartley says:

      As far as I know, long RNAs like that of the spike protein would be made by transcribing a DNA template with T7 RNA polymerase. Moderna has had years and plenty of money to optimize their reactions, but the unit definition and specific activities of the wild type enzyme show (if my arithmetic is correct) that making 1 kg of mRNA (10,000,000 doses of 100 µg) would take 2 grams of enzyme. And 250 grams of each of the ribonucleotides and a gram of the DNA template. It’s a pretty long mRNA, 5 kb, and the modified uracils would probably decrease yield.

      1. Mammalian scale-up person says:

        Is it the whole protein or only a short antigenic region? Can you concatenate antigenic regions together? I’m just thinking why make a whole entire sequence if you only need a small piece or a few pieces – when we’re doing Fc-fusions, we normally only use a small piece of catalytic domain, chop off all the other structural bits we can get away with chopping off. Save some reagent and reaction time.

        1. Jim Hartley says:

          The spike protein we are making for serology is full length, I think, with the substitution of a phage trimerization domain to make the homotrimer more efficiently. And since Moderna injected a human only a couple of months after the sequence was published, I speculate there was not time to test smaller versions. But only speculation.

          1. Mammalian scale-up person says:

            Well…I’m thinking with a longer piece of nucleic acid, in addition to the issue of having to make a lot of sequence which is not relevant to the immune system’s interests (waste of reagent and time if nothing else), you risk having a stability issue with solvent becoming entrapped in the tertiary architecture of the thing as it folds off the T7 pol, no? And won’t a long stringy thing be sensitive to shear stress and unfolding during processing? Even when I make big complex proteins with a lot of fancy multimeric architecture, unless they have some *really well defined* disulfides, the loopy unstructured ones (clotting factors…) tend to denature all by themselves even after affinity purification that should get out the majority of protease. The only thing holding together a long RNA piece is a bunch of salt bridges – unless there’s a refolding step in the process to get the lowest energy conformation of those salt bridges, and depending on sequence there may be no great way to tie it up neatly in a bow, it may just be inherently chaotic. Seems like it would be better to use the smallest piece you can get away with, and optimize the sequence for stability characteristics, as we do for proteins.

  3. Andy II says:

    Sorry, i uploaded this info onto Oxford vaccine post.

    Anyhow, my native questions: Does Moderna have data of which type of antibody (IgM or IgG) detected after 2 doses in 2 weeks?

    And, what do you think of the news of COVID-19 recovered patients get reinfected (still argument of reinfection vs recurrence)? The similar levels of antibody titer to those recovered patients.

    I, 100%, agree with your definition of the desired vaccine.

    1. Derek Lowe says:

      Not sure if they have that data – it would be good to have – but if they do, they haven’t said anything.

  4. Paul says:

    Derek, the “background here” in paragraph 4 has a missing link.

  5. Anon says:

    Quote from Moncef Slaoui: “The Department of Defense is going to be putting resources that are unheard-of in any industry setting, in any private company setting, behind the process, development, and manufacturing and distribution of the vaccine,” Dr. Slaoui said.

    What possible resources, other than distribution, could the DoD bring to bear on “process, development and manufacturing”? This sounds very Trumpy (“unheard-of”) and ridiculous, unless they intend to use offensive capabilities to commandeer big Pharma facilities and manpower, and invade China to ensure the supply chain…

    1. Mammalian scale-up person says:

      There have been many comments pre-Science takeover of this blog regarding Moncef Slaoui’s many qualities, such as they are (especially circa 2008, should you wish to go searching – it was a memorable time), but I will only point out that Honeywell, Raytheon, Lockheed, Battelle, Halliburton, Blackwater/Xe/Academi, General Dynamics, Boeing/McDonnell-Douglas, Draper Lab, and oh, wow, so many more, have been the recipients of MUCH more resources, support and development than Moderna. Indeed, they’d hardly exist otherwise.

      In terms of infectious disease and weird vaccine development, hypothetically they could leverage expertise at USAMRIID. I very much doubt they actually have done so.

      1. NMH says:

        “In 2008, Slaoui led the $720 million acquisition of Sirtris Pharmaceuticals, which folded in 2013.” (Wikipedia)

        Maybe next we will see David Sinclair take a post in the Trump admin, working closely with —who else—Jared Kushner. *spits*

    2. johnnyboy says:

      He’s going to get the Sirtris guys on board, they work miracles !

      1. eub says:

        Man-o-Manischewitz. I saw Slaoui in this news and the In the Pipeline memory banks opened right up. I hope he’s hired a better due-diligence crew this time around.

    3. aairfccha says:

      Fort Detrick?

    4. Tom Maguire says:

      I have no idea what other resources the Defense Department might have but they have an abundance of healthy young man and women who might volunteer for a challenge trial of a vaccine. Speed up the whole ‘vaccinate a few thousand and wait a few months” part of the process.

      And they can invoke American history! George Washington used the live smallpox variolation method on the Revolutionary Army. (The British Army had much less of a problem with smallpox because of its prevalence back in the UK.)

  6. JasonP says:

    Derek looks like shorting Moderna today was the right move….

    1) Once reality sets in as to how long this process takes and the bumps along the road
    2) Moderna CEO selling into the Gap Up, per @TESLAcharts
    3) Moderna jumped in with a public offering after hours.
    4) How Gilead came back down to earth after the Remdesivir excitement

  7. Craig Dauer says:

    Are there reasons the test they ran for neutralizing antibodies might not be predictive of protection in humans? Or if those results are sustained at or near 100% (8/8 so far), should that make us highly confident the vaccine will neutralize the virus in humans?

    1. eub says:

      Zooming out, of all vaccine Phase I trials with ~similar~ press releases, what percentage stall out later, and how does that break down into efficacy issues, versus safety issues, and whatever else?

      An “Estimation of clinical trial success rates and related parameters” in Biostatistics (2019) (linked from my name) is pretty encouraging for vaccines as a class: fully 32% of candidates that enter Phase I progress through to approval, and 40% of those that have passed Phase I.

      How applicable those general numbers are to this specific case I have no clue…

  8. eub says:

    This might be a good place to ask a basic RNA vaccine question: what are the advantages compared to the corresponding protein vaccine?

    Does it work better to get the antigen translated intracellularly versus being picked up as exogenous? (Is it harder because you 100% have to get the RNA intracellular or it’s useless?) You get MHC class 1 versus MHC class 2, but that’s the limit of my amateur immunology — how does their interacting with CD8+ rather than CD4+ affect the immune system downstream?

    1. Stefano says:

      This is a very good question. If you deliver the mRNA you can express the antigen on MCH 1, maybe on the cell surface. So how can you produce antibody?
      -B cells require to found the antigen in the blood, how can they if you produce it only intracellular? (And, like in Moderna, you use a viral vector that doesn’t provoke apoptosis or necrosis).
      -For the expression on MCH 2 maybe there’s some cross-presentation? I guess normally you would only have presentation on MCH 1.
      I understand the creation of cell immunity but I can’t figure out how you can provoke a humoral immunity. Maybe someone can help explaining 🙂

    2. johnnyboy says:

      I think the main reason Moderna is going for that is that they have the basic technology (mRNA + liposome), adapting it for the coronavirus is not a huge deal, and Moderna and Bancel are terminally hype-funding savvy. Even if their vaccine doesn’t live up to expectations, they’ll have gotten millions of govt funding which I’m sure they’ll have put to some use, and will have increased their profile exponentially to the level of big pharma outfits, even though they still have 0 products on the market.
      On the more scientific side, I guess a mRNA vaccine theoretically could raise a more robust adaptive immune response with a single dose and without the need for adjuvants and booster vaccinations. As the foreign epitopes are expressed by cells, it could lead to a response that is weighed more heavily towards activation of cell cytotoxicity-based immunity, which could be more relevant for protection of viral infections than the predominantly humoral response you get with a standard protein/inactivated virus vaccine. But it’s all speculative innit – as Derek has pointed out, a successful RNA vaccine has yet to be developed.

      1. Derek Lowe says:

        That’s exactly the hope – and as you say, it’s not unreasonable. But a lot of reasonable stuff flames out in the clinic, of course, and we’re going to have to find out. . .

      2. Mammalian scale-up person says:

        Yeah, this is why I don’t have a lot of hope: “even though they still have 0 products on the market.”

        It’s not for lack of trying, they’ve got a dozen vaccine candidates listed as Phase 1/2a in If it was a platform that worked, it would have worked already for something – they’ve tried it on influenza, plenty of bugs that we know are immunogenic as recombinant vaccines.

      3. Barry says:

        generating the antigen inside host cells (and therefore displaying fragments of it on MHC) holds the promise of stimulating cell-based (T-cell) response rather than “just” humoral (B-cell) response. But a clever choice of adjuvant may still be necessary to elicit IgA on the mucosa rather than just IgG in the plasma.

        1. Stefano says:

          Sure it works better inducing cellular immunity than humoral immunity; but endeed they assure the vaccine provoke antibodies generation and how this happens still remain a mistery for me XD

        2. Derek Lowe says:

          It wouldn’t surprise me if the vaccine race in general comes down to careful/lucky adjuvant choices, to be honest.

      4. J Tyson says:

        johnnyboy– Moderna had already spent a couple of years doing some work on a vaccine for MERS, so this isn’t the first coronavirus they had worked with.

        1. Mammalian scale-up person says:

          Publication is where though? I see only a 2017 paper on cytokines after natural infection with murine coronavirus. There’s a heck of a lot of Phase 1 vaccine trials with the Moderna sponsorship that don’t have published results though, and they’ve had several years to get a manuscript together, even if it’s just “look at this interesting subgroup.”

  9. Erik Dienemann says:

    Also, keep in mind that there are not any mRNA vaccines on the market that I’m aware of and that a couple of recent clinical trials with mRNA vaccines showed much less efficacy than expected and significant side effects (see the 2nd link). Doesn’t mean Moderna won’t be the first, but getting it right is not going to be easy (nor is scale up and cold chain supply).

  10. eub says:

    Some responses:
    Durbin was struck by the wording of the company’s statement, pointing to this sentence: “The levels of neutralizing antibodies at day 43 were at or above levels generally seen in convalescent sera.”

    “I thought: Generally? What does that mean?” Durbin said. Her question, for the time being, can’t be answered.

  11. Rebecca Swett says:

    Derek, any thoughts about the chance of this vaccine triggering an autoimmune response similar to the Lyme vaccine? With the new reports of children having autoimmune responses weeks or months after exposure, the implication is that the immune response may be triggered by their own antibodies. It’s a rather uncommon safety consideration and I’d like to know if you have any ideas on how this could be addressed.

  12. JP Leonard says:

    Does anyone here have qualms like those expressed elsewhere that this could be a back door to GMO modification in humans? Mrna has been used before with cancer, but that’s a life threatening condition usually in people beyond child bearing age. Widespread vaccination is another couple orders of magnitude of risk.

    1. intercostal says:

      I really don’t think an mRNA vaccine could alter human DNA. We generally do DNA -> mRNA -> protein, not the reverse.

      The post “Coronavirus Vaccine Prospects” on April 15th says that one advantage of mRNA vaccine over DNA vaccine is that “it can’t possibly be inserted into the genome”.

      Generally, doing genetic engineering – especially of eukaryotes, some bacteria are easier – is a lot harder than just injecting some DNA or RNA into the organism!

      1. JP Leonard says:

        @intercostal , What is unnerving about the Moderna vaccine is that from what I’ve gathered, it’s kind of a meta vaccine. It’s not just injecting some genetic material to get an immune response, but it’s getting the body to produce bountiful amounts of that genetic material itself, to become its own vaccine factory. To many people, this sounds like another order of meddling beyond existing vaccines.

        1. Derek Lowe says:

          Live attenuated virus does this as well, though.

  13. Anon says:

    This Kushner vetting of Moncef sets off alarm bells. Moncef clearly needs to swear himself to be loyal enough to Trump to be appointed, which was his primary modus operandi at GSK. There must have been a huge number of actually competent people who hung up on Kushner.

    Moderna has the support of NIAID, BARDA, DoD and now Moncef as a compliant leader who could run a sham competition with the other candidate vaccines and choose Moderna before the election as an October surprise before the election in November. It may never be ready thereafter, but the idea of it gets plugged into the electorate as a success. Then it will all fade away and never make it to approval.

    1. Derek Lowe says:

      That is, in fact, the nightmare. And like most such nightmares these days, it has a nonzero chance of coming true. But that means that everyone involved, and all competent observers, have a duty to watch the data closely and insist on as much transparency as possible. I’m already unhappy that we haven’t had the full NIAID trial data on Remdesivir, and I hope we’re not going down that road any further.

    2. fajensen says:

      Does Anyone still remember when conspiracy theories were just fun?

  14. Tuong Nguyen says:

    Like with the influenza virus, each year, it mutates and a new flu vaccine must be reproduced around the Summer or Fall prior to the vaccine season to cover for the additional mutational variants. I’m just curious, by the time the novelcorona vaccine comes out, if it ever gets FDA approval, it may not cover for all new Corona virus strains. Does this mean that each year, Moderna would need to update their vaccine to include the new strains?

  15. Adrian says:

    The people who know more details consider the results less promising:
    “Moderna’s chief financial officer and chief medical officer executed options and sold nearly $30 million of shares combined on Monday and Tuesday”

    1. Valerie says:

      I read that those stock sales were scheduled before all this happened and weren’t modified since then – so yes, they profited handsomely from the sale but it wasn’t in response to anything going on with the trials.

  16. Sandra G says:

    Does this particular vaccine include an adjuvant?

  17. Robin Howard says:

    For a human subject in clinical trials, is the worse case scenario that the Moderna vaccine won’t be effective? Side effects seem to be mild, but would you have questions about long-term side effects?

  18. Redna says:

    How about auto immune response over time? Will Moderna have enough time to study these? Would FDA look into these too?

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