What Makes the Pfizer and Moderna Vaccines So Promising

Using messenger RNA alleviates some of the problems with traditional vaccines.

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Amid all the grim news about the pandemic, Americans finally have some cause for optimism. Over the past 10 days, Pfizer and Moderna have announced that analyses of the Phase III trials for their respective vaccine candidates show they are remarkably effective in preventing the infection. Pfizer announced last Monday that early analysis showed an efficacy rate of 90 percent for its vaccine, and the company has since announced the rate is closer to 95 percent. In the interim, Moderna announced that its vaccine demonstrated 94.5 percent efficacy in its trial.

Moderna’s results were based on a 30,000 patient study. There were 95 cases of infection among patients who received a placebo, compared to only five cases in those who received the vaccine. Pfizer’s final review was conducted after 170 COVID cases had been confirmed, with 162 in the placebo, and eight in the treatment arm. Pfizer is preparing to file for FDA approval, and in the best-case scenario, the first doses of the vaccine could be ready for distribution as early as this December. 

Given that vaccine development generally takes several years, these accomplishments are impressive. And the success can be attributed to a number of factors: The government preordered a large number of doses through Operation Warp Speed, and the Gates Foundation funded the efforts of both Pfizer and Moderna. 

But another major reason for the rapid progress was a new approach to vaccine design. It’s not a coincidence that Pfizer and Moderna saw similar results in their trials: Both vaccines are based on messenger RNA (mRNA for short). While mRNA vaccines have many advantages compared with standard vaccines, there are some drawbacks that may limit how quickly and efficiently the vaccine gets distributed to the public. 

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  1. Avatar photo
    Frank Colburn

    How long does it take after receipt of both shots to confer immunity? I have not seen this information anywhere.

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    Connie

    I am a participant in Moderna’s Phase III trial. We were contacted this week about the data, and it is still being discussed how to move forward with the participants. We were told they want to provide us the opportunity to get vaccinated, in case we received the placebo, but there is much to consider and resolve, given all the regulatory agencies involved. So, I wait to hear whether I received the vaccine or the placebo, and if I got the placebo, I want Moderna’s vaccine. I participated in their trial because I found their mRNA delivery so intriguing, and it made good scientific sense to me. Here’s hoping I already received it!

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  3. CatoTheElder

    Nice article, well done.

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    William Miller

    Thanks for this helpful article. Let me first start by disclaiming that I am not an expert in this field, so please understand that I'm trying to get feedback on my questions from someone who is.

    I agree that I think there is a lot of potential in mRNA treatments both for this and for other maladies. However, I do understand the concern of an earlier commenter that wishes there were time for a longer safety-vetting process for these first-of-their-mechanism vaccines. While these would be the first two mRNA vaccine based treatments to potentially be approved, maybe it would help people better understand and be comfortable if someone were to put out more information about the history of other mRNA vector treatments that have been in development/testing. It is my understanding that there have been numerous therapies in the research stage and that the main hurdle that had not been previously overcome had to do with efficacy rather than with safety. If I'm wrong about that, please correct me; but if that is correct, perhaps it would help people to have more knowledge regarding how extensively using introduced mRNA to send protein-manufacturing instructions to cells has safely been tested in humans (even if the treatments haven't been ultimately successful in their desired outcomes).

    I also want to follow-up on an item at the end of this article. It references: "Candidates by Johnson & Johnson and AstraZeneca, are also expected to allow for storage at -20 Celsius or warmer. Those vaccines are based on a similar strategy but use DNA instead of RNA." It is my understanding that both the AstraZeneca/University of Oxford and the J&J candidate are using a viral vector approach where they are utilizing an attenuated Cold virus (adenovirus) to create the spike proteins (in a similar mechanism to J&J's Ebola vaccine). While the adenovirus does have DNA itself, I think a lot of lay-people may read that sentence and think that the "similar strategy" references using or modifying the human cell's own DNA (because the mRNA candidates use human cells as the protein-factories). I wanted to follow-up and hope this may even prompt a clarification because I would not want people to be unduly wary of the J&J/AstraZeneca candidates, when that approach has had some success in other applications

    The only vaccine candidate that I'm aware of that actually does have a mechanism of introducing DNA plasmids into human cells themselves is the Inovio one, which based on their site is only currently gearing up for Phase II trials.

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    1. Avatar photo
      Justin Perry-Naw Dawg Doctrine

      Well-stated. I'm sorry to say this, but this article is extremely unhelpful and is riddled with technical inaccuracies and misinterpretations or misrepresentations of the current state. It would take me an entire article to update or fact check what was written. For instance, "other vaccine candidates using DNA" is woefully misleading, given several of them are viral vector-based, and not to mention there are two seemingly successful inactivated virus vaccines also in the pipeline.

      In some regards, these sorts of articles are helpful in the lay sense as a first introduction to Covid vaccinology. But these sorts of articles, often more technically accurate, have been around for a long time. It's time for some better articles to be written addressing exactly these sorts of questions.

      Again, for what it's worth, if you are able I'd recommend popping onto the Discord channel where we have been discussing these very sorts of things. It's a place where I (and others who know more about the science) can address these questions in a conversational atmosphere.

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    2. CatoTheElder

      It's a bit on the techie side, but here's a good review, from 2018, of the state of affairs at that time [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906799/]; it's relatively easy to see why there'd have been great interest in pursuing an mRNA vaccine based on this reading.

      With regards to safety, it's important to note that the mRNA sequences in vaccines do not "insert themselves into the genome"; thus, there is no chance of disrupting existing genes or changing inheritance. Without minimizing other hurdles, I'd suggest that the biggest, most important obstacle in developing mRNA vaccines is a simple one--delivery of the mRNA into the cell. When free-floating mRNA is encountered inside the human organism, but outside a cell, it is quickly attacked and degraded by the immune system. Thus, simply injecting mRNA doesn't work--it's generally destroyed before doing what needs doing. One key to success was the development of "vehicles" or other protective strategies by which the mRNA remained intact until it was inside cells. Once in the cytoplasm of the cell, the engineered mRNA, made with all the key features native mRNA carries that tell the cell, "Use this set of instructions to make a protein," is translated by the existing cell machinery, doing exactly that--making the protein for which the mRNA encodes. It's details about the delivery mechanism that lead to the challenges with storage, shipping, and the like noted elsewhere.

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      1. Avatar photo
        Gene Godbold

        But because the mRNA doesn't replicate, you need to get a sufficiently large dose of it, in its little customized lipid vesicle, *with* the vaccine. Also, the immune system doesn't generally need to degrade mRNA outside a cell. The chemical modifications to the ribonucleotides that is the basis for most of Moderna's patents are what prevent the *intracellular* immune defenses from "seeing" the mRNA and reacting badly before it gets translated on a ribosome.

        RNA, in general, is notoriously unstable. A little bit of this is because it has an extra hydroxy group on the ribose sugar ring which can do some chemistry. DNA doesn't have this (because it is "deoxy"ribonucleic acid). But the main reason RNA gets degraded quickly is because RNases are both prevalent and horribly hard to denature. You can boil the damn things and they can still cut RNA to pieces.

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        1. CatoTheElder

          You caught me in a gross oversimplification, mea culpa.

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            Gene Godbold

            Oh, I dunno about that. I was just dilating on the topic.

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    Justin Perry-Naw Dawg Doctrine

    Also, important inclusion, is that Moderna's formulation allows for storage at 4C (refrigerator) for up to 30 days. These findings are based on industrial standards testing, so it's possible that they remain stable for longer. It turns out Moderna's LNP-encapsulated mRNA (LNP = lipid nanoparticle) is decently stable.

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    Justin Perry-Naw Dawg Doctrine

    Moderna's success with this particular vaccine has also undermined their long-term, broader portfolio for using mRNA targeting to treat genetic diseases, such as Methylmalonic Acidemia. The platform is simply too immunogenic (very much counter to their original claims) to be feasible. See, for instance, the withdrawal of a clinical trial for Methylmalonic Acidemia. https://www.clinicaltrials.gov/ct2/show/NCT03810690?cond=Methylmalonic+Acidemia

    My point? It isn't entirely clear, until someone figures out how to large scale mass-produce mRNA vaccines, how this will be a feasible approach moving forward. I suspect AAV methods, and the broader viral vector therapeutic approaches, will be the long-term future of vaccine development and anti-viral therapies (think, HIV-1 for instance)

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    Ed P

    While I am ecstatic that these results look SO promising in terms of efficacy, the new mRNA vaccine technology going through a speedy safety assessment is less than ideal. There is no good reason to believe mRNA is going to be particularly harmful, but biochemistry is mindbogglingly complicated also - there is no substitute for actual safety trials.

    I'll take and have my kids take whatever vaccine is approved by our authorities unless it is an obviously politicized process. But if its one of these mRNA ones, I'll do it with a lump in my throat.

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  8. Brain Slug

    One question: once the muscle cells start producing the viral protein, what prevents the immune system from attacking and destroying those muscle cells?

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      Gene Godbold

      The muscle cells just won't be making the cells long enough to be (much later) recognized by the effector cells. Once they run out of the injected mRNA, they're done.

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      Gene Godbold

      The protein, wherever they get made, will eventually get into, and processed by, antigen presenting cells and displayed as peptides on the major histocompatibility complex (I or II, I'm too lazy to look it up right now). So the dendritic cells then "show" this antigen on their surface to lymphocytes that then start reproducing clonal populations of effector cells that can recognize and destroy infected cells if they ever seem them again.

      Immune memory is a function of building up a reservoir of these effector cells that are now primed to act when they detect the presence of the antigen in the context of other signs of inflammation. (I'm not an immunologist, but I study microbial pathogenesis: looking at how parasite proteins mess with host processes.)

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      Justin Perry-Naw Dawg Doctrine

      I discussed this in the Dispatch Discord channel, (https://discord.com/channels/775815574650880020/775815574650880023), but how the immune system functions downstream of vaccination tells us why muscle cells would not be targeted, unlike if the muscle cell was actually infected with a virus which could cause death of that infected muscle cell or the immune system to kill it.

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    4. Tony DePiero

      I think they produce it and then release it.

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  9. Scott N.

    This is very likely going to be one of the top 5 medical developments of the 21st Century.

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    1. CatoTheElder

      It might get the play in popular press/social media as such, but from a science perspective, almost certainly not, I don’t think. There are a number of things already on the board (CRISPR-Cas, for instance) with a bigger likelihood, and several other things just over the horizon; but which will come to greatest fruition? Hmmm. If I knew that, I could make some young folks billionaires, probably.

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      Gene Godbold

      I don't think so. It's nice, but it's no PCR or (more to the point) CRISPR. And we've got 80 years of discovery left ahead of us.

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      1. Scott N.

        That's a fair point. I was more going off the potential for many more vaccines and kind of a new era of vaccine development like happened with Maurice Hilleman in the 1950s.

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  10. Patrick E

    Another excellent article Doc, all your pieces for The Dispatch so far have been great. I look forward to reading more from you in the future!

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