Last updated on June 2nd, 2021 at 10:29 am
If you have been paying attention to the news, you’ve probably seen reports of the Moderna coronavirus vaccine candidate that is getting a lot of people very excited. I’ve even seen so-called pro-vaccine people, who ostensibly should be following science, breathlessly cheer them on.
Recently, Moderna had released some results in a press release, and you know what I think about press releases. Unfortunately, many vaccine researchers stated that that data was not sufficient to draw any conclusions about the safety or effectiveness of the Moderna vaccine.
However, the phase 1 clinical trial results have been published, and the hype has started again. We’ll take a brief look at those results below.
I know that people want “hope,” as opposed to possibly endless cycles of bouncing between opening up and closing down everything in response to the pandemic, especially in the USA, where the coronavirus pandemic has just gotten worse.
But hope isn’t something that interests me at all.
As anyone who reads my blog knows that the only thing that matters to me is published scientific evidence. And by published, I mean in a respected, peer-reviewed journal. Sure, I don’t need scientific evidence to support my belief that the New York Mets should be thrown out of baseball, because I hate the team – that’s just an opinion. It’s not based on evidence of any type.
On the other hand, when it comes to vaccines, we have built an amazing system of bringing the most effective and safest medical advances to humanity. Despite the misinformation and FUD of the anti-vaccine zealots, the safety and effectiveness of modern vaccines are settled science.
I’m not willing to sacrifice that for a vaccine that may not be effective or safe. That’s why I want to take a very critical look at the Moderna vaccine. And I think there are some reasons to be very concerned about their vaccine, although there might be some reasons to be somewhat optimistic.
Moderna focuses its vaccine research on mRNA, or messenger RNA, technology. mRNA are molecules in the cell that corresponds to DNA sequences and carries that information to be “read” by a ribosome to produce a protein.
When an mRNA strand exits the nucleus and enters the cytoplasm, it attaches to ribosomes, and this is where protein synthesis progresses. The ribosome reads the base sequence of the mRNA, three bases at a time. Each three-base triplet, called a codon, specifies a particular amino acid, except for a few with regulatory functions (e.g., UGA =“Stop!”).
If the first three-base codon is AUG, then a molecule of the amino acid methionine is brought into place. If the next triplet is AAA, that brings in the amino acid lysine. The methionine and lysine molecules are attached together. The next triplet is, say, GCC, and that brings in alanine, which is attached to the lysine. The ribosome has read nine bases, AUGAAAGCC, and compiled a short chain of three amino acids, abbreviated Met-Lys-Ala, or MKA (see amino acid abbreviations here ).
The ribosome continues reading all of the mRNA bases until it hits a stop signal—which is also a triplet codon such as UGA—and the now long chain of amino acids falls loose. This chain may be a functional protein immediately, or, more usually, it might undergo some additional post-translational processing by enzymes to become active.
Moderna’s vaccine technology relies on mRNA to kickstart the endogenous production of proteins similar enough to the viral antigens that trigger the body’s adaptive immune system to produce antibodies effective against the actual target. In other words, instead of injecting a live-attenuated vaccine, like the measles vaccine which contains weakened measles virus, the Moderna vaccines inject mRNA fragments that are selectively delivered to cells to produce the viral antigens (but not the whole virus, of course).
Moderna has several similar mRNA vaccines in clinical trials, but none have received FDA approval as of today.
Moderna vaccine clinical trials
Kaiser-Permanente led a phase 1 clinical trial for the Moderna coronavirus vaccine, which began in late March. The phase 1 trial included 45 healthy adults separated into three groups receiving different doses, low, medium, and high.
The results of that study were recently published in NEJM by authors affiliated with Kaiser-Permanente, NIH, and other institutions. The 10,000 m view of the results showed that the Moderna coronavirus vaccine showed that patients produced antibodies that appear to neutralize the SARS-CoV-2 virus. However, it showed that the vaccine also caused some minor side effects in many patients.
The study also showed a dose-response relationship with patients who received higher doses of the vaccine anti–S-2P antibodies, so that’s encouraging. The authors wrote:
After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens.
In other words, the second vaccination (let’s call it a booster) was required to generate the best antibody response. This may be related to the mRNA technology, but it’s hard to tell.
There is a concerning number of adverse events, although because it’s not a double-blind, randomized study, it’s hard to determine if they are actually vaccine-related. We will get a better grasp of whether the level of adverse events is a concern after phase 3 trials.
With respect to adverse events, the authors wrote:
adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events.
Although this study is encouraging, let’s remember something – antibodies are not equivalent to immunity against the disease. Since these were not “challenge studies,” where participants are intentionally exposed to the disease, we do not know if the participants were actually immune to COVID-19.
Moderna has registered a phase 3 clinical trial which will include over 30,000 participants split evenly between the vaccine and placebo groups. The study is randomized and quadruple-blinded (Participant, Care Provider, Investigator, Outcomes Assessor). The study is planned to be started on 27 July 2020 with an end-date of 27 October 2022.
Even though the endpoint is over two years from now, they might be able to get approval much sooner if results look encouraging.
Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need. The purpose is to get important new drugs to the patient earlier. Fast Track addresses a broad range of serious conditions.
It does not mean that the Moderna coronavirus vaccine gets approval without showing that it is safe and effective. It doesn’t mean that Moderna can skip clinical trials just because. It just means that Moderna can get an expedited review along with more frequent meetings with the FDA to go over issues. In bureaucratic parlance, Moderna’s NDA goes to the top of the pile, which can reduce the time to market by a few months.
And going back to what I mentioned above, all I care about is scientific evidence that I can read from a neutral, unbiased source. We don’t have that.
So here are my issues in somewhat order of skepticism:
- Moderna press releases. Moderna is a small biopharmaceutical company, so they have an incentive to boost their stock prices. Larger pharmaceutical companies, also working on coronavirus vaccine candidates, are very quiet, because they are more conservative about public commentary about drug development – it doesn’t mean that they aren’t doing anything, it just means that they know the consequences of missing on promises. I wish they would quit the hype because it makes a lot of people looking at the data concerned about what they’re doing.
- Operation Warp Speed. As I’ve discussed before, rushing vaccine development has a lot of consequences from missing safety signal and long-term effectiveness to causing concerns from people who are on the fence about vaccines. Of course, committed anti-vaxxer opinions about new coronavirus vaccines will not be relevant since science is irrelevant to them. Ironically, a former Moderna executive and board member is heading Operation Warp Speed for Donald Trump. Let that sink in.
- Donald Trump. Speaking of the President, if you are following the election polls, we know that Trump is in serious trouble. Given the politicization of the CDC and FDA by him, I think it’s plausible that he will pressure the FDA to announce the approval of a vaccine without adequate data. Or even bad data. All this to try to get re-elected.
- Manufacturing. I’ve written extensively about manufacturing a new vaccine – I think that it’s going to be difficult to produce hundreds of millions of doses of vaccines easily, because of the lack of excess capacity in the world. I constantly worry that the capacity that goes to make the MMR or other vaccines will be switched to the coronavirus vaccine. And building new capacity could take years, because manufacturing lines take months, if not years, to spec out and acquire, along with the limited capacity of raw materials like pharmaceutical-grade glass for syringes and vials.
- mRNA technology. I am not opposed to new biotechnology – I am firmly in favor of GMO biotech because the science says it’s safe and useful to humanity. On the other hand, using mRNA to harness the cellular manufacturing process to create the antigen is a new technology that hasn’t been thoroughly vetted for long-term complications, although I don’t expect any. Since anti-vaxxers already whine about “DNA in vaccines” based on pseudoscience, I can imagine their complaints about mRNA in these vaccines. If Moderna is really in the lead with their vaccine, they need to get ahead on messaging
- Antibodies do not equal immunity. This is still an important consideration, but given the variety of conflicting information we have about reinfection by COVID-19, we should not consider antibody production from a vaccine to be an endpoint. It must be actually preventing the disease.
- Safety and effectiveness. These issues take time. Like I mentioned above, I am so worried that Donald Trump, in his vain effort to show some leadership with his plague and with an ex-Moderna executive running point, will push the FDA to approve a vaccine that doesn’t work or has some dangerous short-term adverse effect. Or both. We need a lot of time to determine if a vaccine is effective – unless every single participant is exposed to the virus, we need time to make sure that they have been exposed. That could take months or years. Furthermore, we need to know if the immune response lasts more than a few weeks, which is just about the time frame of the phase 1 trial.
- Moderna’s track record with vaccines. Moderna has nine mRNA vaccines (not including their coronavirus vaccine) in clinical trials. Only one is recruiting for phase 2 trials. To be fair, past performance is not an indication of future results, but companies like Pfizer or Merck, who have coronavirus vaccines in development, have a long record of successfully bringing safe and effective vaccines to the market.
I am frustrated by companies like Moderna (but they aren’t alone) who are making grandiose claims about their new vaccines. Many people believe that there is a vaccine “just around the corner,” which makes people believe we can end our public health concerns about COVID-19.
Moderna should be less worried about their stock prices – they should provide measured, accurate, and evidence-based commentary about their coronavirus vaccine.
I believe that we need a vaccine to have herd immunity against COVID-19. And I want one as soon as possible. But I cannot stress this enough – we need robust, repeated, statistically significant evidence that there is a long-term immune response against COVID-19. It is troubling that anyone thinks we would have this kind of data within a few months.
And one last point, because I’ve seen anti-vaxxers quote-mine my articles about coronavirus vaccines. If the Moderna coronavirus vaccine gives us powerful evidence in phase 3 clinical trials that it is safe and effective, I will be first in line to get it, if they can actually produce enough supply.
I only want everyone to demand the same level of safety and effectiveness that we have for every single vaccine available today – it’s settled science.
Do I want the vaccine to get to market as fast as possible? Absolutely yes, because every day that passes before we have a vaccine may mean thousands of deaths.
Do I want to cut corners? Absolutely not. That’s why I am very happy that Pfizer, a real company with a real background in producing drugs and vaccines, has started a large phase I/II clinical trial in the USA for a vaccine candidate.
We should do everything to get a new coronavirus vaccine, that’s why this one is being fast-tracked by the FDA. But that designation doesn’t mean Moderna gets to cut corners, it just means we can save months on regulatory approval.
I want Moderna to succeed. But I’m very skeptical of their claims at this point. I used to say “call me when phase III clinical trials are completed and published.” I still want that, and maybe they can deliver on that. But right now, they haven’t.
As the LA Times has written:
One hates to be the bearer of bad news, which in this case means placing Moderna’s announcement in context, but the truth is that Moderna hasn’t announced a vaccine and the path to developing one remains long and tortuous.
Whether Moderna’s early trial will result in a vaccine, or when, remains highly uncertain; most drugs that deliver promising Phase 1 clinical trial results end up failing in the final analysis. There’s no reason to expect that this one will necessarily buck the odds. Moderna’s vaccine is one of many being tested.
There are over 110 coronavirus vaccines in development, along with many in clinical trials – even though most will probably never see the light of day, a few will meet the exacting standards of safety and effectiveness. Those of you who want hope, that’s where you should place your bets – on the whole field.
There are days when Moderna doesn’t pass the sniff test. I wish they would quit hyping their results and provide us with actual data. They’re starting to do that, but I’m still giving them the partial stink-eye.
- Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN, McCullough MP, Chappell JD, Denison MR, Stevens LJ, Pruijssers AJ, McDermott A, Flach B, Doria-Rose NA, Corbett KS, Morabito KM, O’Dell S, Schmidt SD, Swanson PA 2nd, Padilla M, Mascola JR, Neuzil KM, Bennett H, Sun W, Peters E, Makowski M, Albert J, Cross K, Buchanan W, Pikaart-Tautges R, Ledgerwood JE, Graham BS, Beigel JH; mRNA-1273 Study Group. An mRNA Vaccine against SARS-CoV-2 – Preliminary Report. N Engl J Med. 2020 Jul 14:NEJMoa2022483. doi: 10.1056/NEJMoa2022483. Epub ahead of print. PMID: 32663912; PMCID: PMC7377258.
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