On May 18, Moderna released promising early data for their Covid-19 vaccine. It’s an mRNA vaccine – it gives a person’s cells the recipe for making a coronavirus protein so the person’s immune system can learn to attack it without the person actually having to get sick. Today I thought I’d tell you more about how this and other mRNA vaccines (hopefully) work, and what Moderna’s found so far. P.S. This post is for you dad (he was asking me a lot about it yesterday!)
note: I am not connected to Moderna in any way and this isn’t a paid endorsement or anything, I’m just trying to help people understand what I understand about what they’ve told us
Moderna’s is just one of over 90 coronavirus vaccines being developed. They all aim to do the same thing – introduce a person’s body to the coronavirus that causes Covid-19 (i.e. the SARS-Cov-2 virus) or some part of that virus in a harmless form. In the case of mRNA vaccines, they give the person copies of the genetic “recipe” for making a viral protein and get the cells to make it. These proteins then allow the person’s immune system to learn what the virus looks like without the person having to get sick. The “learning” involves developing little proteins called antibodies that (by combining unique variable regions with generic constant regions) specifically bind parts of the virus but don’t bind the person’s own molecules. This way, if the virus does try to infect the person, that person’s immune system can flag it right away and destroy it.
When disease-specific antibodies appear in a person’s blood – either after vaccination or actual infection – the person is said to have “seroconverted” (sero- is a prefix people use to refer to blood-y things). Tests like an ELISA use purified viral proteins as “probes” to see if someone’s blood contains antibodies that bind those proteins, but they don’t tell you about whether those antibodies are able to go the “extra step” and “neutralize” the virus by binding in such a way that they block the virus from getting into cells. To know if blood contains neutralizing antibodies, you have to do a more complicated test like a Plaque Reduction Neutralization Test (PRNT), which tests the ability of antibodies to prevent the virus from infecting cells in a dish. The infected cells appear as viral “plaques” on the dish & neutralizing antibodies are able to reduce the number of plaques, hence the creative name. You can learn a lot more about them in past posts I will link to, but I just wanted to introduce you to these, because they’re a couple of the tests that Moderna is reporting data from.
Moderna hasn’t released the full results of the trial, which is still ongoing, hence the “Interim Phase 1 Data” in their press release header: https://bit.ly/2ALQ21v but here’s what we know…
The FDA approval process involves phases of clinical testing – in the first phase you’re testing mainly for safety and dosage, and then in later phases you test larger sample sizes and look for actual effectiveness. Back on March 16, Moderna started a Phase 1 clinical trial, which was really fast – they were the first US company to begin a clinical SARS-CoV-2 vaccine trial. And this speed might worry people, because vaccines usually take decades to develop – but the key to the speed was the technique they’re using – mRNA (messenger RNA). mRNAs are the “formatted” copies of genes, written in RNA, and which protein-making complexes called ribosomes latch onto and make the corresponding proteins. mRNA is much easier to manufacture than other vaccine types, and, more crucial to the early start, all you need to know is the genetic sequence of the virus – you just need the recipe and you can go to work – make a bunch of copies of the recipe and then stick it in a lipid nanoparticle (give it an oily membrane coat that protects it, masks its negative charge, and allows it to easily get through our cells’ own oily membrane coats.)
Of course, they have to choose the right protein and maybe tweak it a bit, but it’s still much much easier that having to actually express and purify the protein! And Moderna had experience doing this mRNA-making-and-delivering – Most people probably hadn’t heard of Moderna before recently, but, as an RNA researcher, I had – I’ve even seen their workers presenting presenting research at conferences. I’m not saying this to like name-drop or anything, just to say that Moderna has been around (but only since 2010) and they’re known for work on mRNA therapeutics (we’re discussing vaccines now, but mRNA can also be (potentially) used to replace or supplement proteins) They have never brought a product to market or even to Phase III clinical trials, but they have a number of them at various stages in the clinical development pipeline (the furthest-along is a vaccine for CytoMegaloVirus (CMV), which is in Phase 2 & includes mRNA recipes for making the CMV pentamer complex & glycoprotein B (gB) protein which are important for cellular entry of that virus.
For SARS-CoV-2, they decided to stick in the recipe for the coronavirus’ Spike (S) protein because this is the one that binds to cellular receptors – if you wanna make neutralizing antibodies, this is the guy you wanna hit. They made a couple of minor tweaks to the recipe to make a couple corresponding protein letter (amino acid) changes in order to stabilize the resulting S protein in the “pre-fusion conformation” (the shape it takes before binding to the receptor, shape-shifting and fusing with the cell membrane in order to dump its contents out into our cells). They named it mRNA-1273 and, after promising pre-clinical results, including the finding that it was effective at inducing protective antibodies in mice – they started their Phase 1 trial.
This trial was small (as is the point of Phase 1 trials – you want to make sure it’s super super safe before you go injecting it into a bunch of people). In this case, there were 45 trial participants, split into 3 dosage groups (the second point of Phase 1 trials is to find the right dosage – here they wanted to find the “goldilocks” dose that would induce strong antibody production without side effects). Note – they were only able to provide partial data for the later timepoints because the trial’s still underway and not everyone got injected on the first day.
Speaking of people getting injected, the trial involved healthy volunteers in the 18-55 age range. They were given either 25μg (micrograms), 100μg, or 250μg, starting with a “prime” injection and with a subsequent booster injection 4 weeks later.
Even at the lowest dose, antibodies for the SARS-CoV-2 S protein appeared in their blood by 15 days, and 2 weeks after the booster shot (43 days after initial injection), the levels of these antibodies were similar to the levels in the blood of people who had actually been infected with, and recovered from, the coronavirus (so-called convalescent sera). For those who’d gotten the 100μg dose, the antibody levels were even higher.
But, all that was just talking about “binding antibodies” – antibodies that can bind to the viral protein and can be detected by ELISA – but the really important question is whether binding to those antibodies actually blocks the virus from infecting cells. To answer this, they did those PRNT tests I was telling you about earlier – they only had data to report for the first 4 injected people in the 25 & 100μg groups (I’m hoping the data for more will be available soon!) – but all 8 of them had neutralizing antibodies in their blood.
They didn’t provide much info about the 250μg dose other than that, after the booster shot, 3 of them developed side-effects like fever, muscle pain, & headaches. With the lower doses – the only side-effect reported was a little redness & soreness at the injection site – in 1 person. All these side-effects resolved themselves and there were no serious “adverse events” – but they decided to ditch the 250μg dose and replace it with a 50μg dose – they’re adding a 50μg group to their Phase 1 trial & they’re also adding additional age groups (55 to 70) & 71+ https://nyti.ms/36b73O8
They got the green light for this Phase 2 trial, which will start soon and include 600 people given 50μg or 100μg doses to see which is best.
Assuming that Phase 2 goes okay, once they figure out the best dose, they’re planning to start Phase 3 trials in July in order to see if it really is effective at preventing infection. This is hard because you need a really large sample size in order to have enough people vaccinated AND exposed to be able to see if the vaccine prevented infection. And you have to follow up and follow up and follow up… Because you don’t know when they might be exposed. To get an earlier indication, you can do “challenge studies” in lab animals where you vaccinate some and don’t vaccinate some (the control group) then you purposely try to infect them and see if they get sick. Moderna did this with mice – and they found that it worked – it prevented the virus from replicating in the mice’s lungs. And, encouragingly, the levels of neutralizing antibodies Moderna found in people where comparable to those we know worked for the mouse. But we don’t know if the same will hold true for humans – and we don’t know how long the immunity will last.
If Phase 3 is successful, the challenge will be ramping up production and delivery. Moderna itself is pretty small and, on its own wouldn’t be up to this monumental task, but on April 16, the federal Biomedical Advanced Research and Development Authority (BARDA) gave them a big investment to help accelerate development & manufacturing https://cnn.it/2KYDbKQ And they signed a worldwide development agreement with the Swiss pharmaceutical manufacturer Lonza. https://bit.ly/3d9RkRO ⠀
So the early results are promising, but there’s still a long way to go and we have very very little to go off of now – we don’t even have the official phase 1 results, just the press release with midway results. So, be hopeful but hopefully not hyper-hyped. I know it’s easy to latch onto any good news but, unfortunately, we’ve gotta wait and see…
Another note: Moderna may be first, but it isn’t the last – multiple other companies are also developing mRNA vaccines for SARS-CoV-2. BioNTech has deals with Fudan and Pfizer for mRNA vaccines. They’re trying a few different ones – a few have modified RNA letters thought to help make them and a fourth is a “self-amplifying mRNA with has the gene for a replicase protein which makes more copies of the mRNA once inside the cell. https://bit.ly/3d9RkRO ⠀
The mRNA technology is really new, so there actually are not yet any FDA-approved mRNA human vaccines for any disease, but hopefully one of these will be the first!
more on the ELISA: https://bit.ly/covid19testtypes
more on PRNT: https://bit.ly/neutralizationtests
more on other vaccine types: https://bit.ly/coronavirusvaccinetypes
more on the vaccine development & approval process: https://bit.ly/coronavirusvaccinetesting
more on clinical trials: https://bit.ly/clinicaltrialterms
more Covid-19 resources: https://bit.ly/covid19bbresources
more on topics mentioned (& others) #365DaysOfScience All (with topics listed) 👉 http://bit.ly/2OllAB0