Are mRNA therapies the future of pharmaceuticals?

mRNA therapies are having their moment.

Far from being the bust that some had predicted, mRNA therapies have proven to be a savior during the deadliest pandemic in 100 years. Both mRNA COVID vaccines, Moderna’s and BioNTech’s, not only were brought to market faster than any other vaccine, but proved more effective than any other vaccine as well.

This sudden success has spawned legions of mRNA explainers, created billionaires, and generated countless complicated geopolitical arguments over which country gets access to these miracle drugs first. It’s prompted breathless press releases where the application of mRNA to a problem is basically seen as tantamount to a solution, like Yale’s mRNA-based vaccine for malaria, which not only hasn’t been approved, it hasn’t even received a patent yet!. 

Finally, it’s also prompted many observers to ask whether mRNA is the future of all therapies, or at least of all vaccines.

That’s what this article is about. Is mRNA the future of all therapies? Is it at least the future of all vaccines? 

If you’d like to stop reading now, the answer is no to both questions. mRNA is a really cool technology with some remarkable advantages, but it’s just one tool in the toolbox, and a difficult to use one at that. If you’d like more information, read on.

It’s easy to forget, during these heady times, that it wasn’t too long ago that people were questioning whether mRNA was a complete bust. If we venture back to the far past of 2017, Moderna had just failed a high profile animal trial in a rare condition called Crigler-Najjar, and BioNTech’s “cancer vaccines” were still struggling to make it out of phase 1. 

It was actually seen as an admission of failure that these mRNA companies were considering moving into vaccines, given that vaccines are famously bad investments for pharmaceutical companies. Vaccines can’t be sold for a high price, are usually only given once, are subject to very stringent toxicology requirements (as they’re given to healthy individuals), and, ironically, often face a lot of competition from non-profit ventures who see their public health importance. 

It’s also easy to forget, during these heady times, that, with the remarkable exception of the COVID vaccines, not much has changed! Even if we consider all the drugs in Moderna’s portfolio, including vaccines, it only has one other drug that’s made it out of phase 1, a cytomegalovirus vaccine. BioNTech also only has 1, an advanced melanoma therapy.

So, the idea of mRNA as the future of all therapies or all vaccines is, frankly, not well-founded historically. mRNA has a good track record for a complicated technology at the forefront of biotech, but nothing that would warrant that sort of confidence.

Scientifically, it’s also not particularly well-founded. Let’s take a look at the problems with mRNA therapies first, as that’s easier to debunk. Then we’ll take a look at mRNA vaccines.

The first and biggest problem with mRNA therapies is that they make people sick. mRNA cannot be injected directly into the body, as your body has a lot of defence mechanisms against random mRNA floating around (as that’s a tell-tale sign of some kind of foreign invasion). So, mRNA has to be disguised by lipid nanoparticles (LNPs) in order to slip past the body’s defences (note: there are other ways of disguising it, but that’s the most common way right now).

So far, so good. Unfortunately, the body also reacts really poorly to random lipids being injected in the body. So, injecting people with lipid nanoparticles provokes an immune reaction, which can pretty easily be fatal. In fact, there are suggestions that the fever and malaise people get from the mRNA COVID vaccines are just a reaction to the lipid nanoparticles, although nobody knows for sure.

The easiest way to get around this problem is probably pretty obvious. You put less lipid nanoparticles, which is what they did in the COVID vaccines. But, the only way to do that is to use less mRNA.

That’s not an easy thing to do. When I say less mRNA, I mean way less mRNA. Tiny amounts. Now, I couldn’t get exact figures for just the mRNA or just the LNP portion of the mRNA vaccines, but I could for another therapy which uses LNPs, Alnylam’s siRNA therapy for hereditary transthyretin-mediated amyloidosis. They used just 30 mg of their drug (mRNA + LNPs) every 3 weeks to achieve their effects, and still had side effects.

30 mg is tiny! A single pill of azithromycin is 250 mg. It is really, really hard to fit everything you need to in 30 mg, especially if you can only administer it once every 3 weeks. Very few conditions lend themselves to those sorts of size constraints.

Another problem with mRNA is more fundamental to mRNA itself. mRNA can only be used to make the body make proteins that, well, the body can make. This might seem obvious, but it’s a pretty key part of where Moderna’s “software of life” analogy falls flat. It’s a limited software with limited toolkits. You’re not going to use mRNA in humans to make, say, an antibiotic that’s naturally produced in fungi.

These two problems combined explain why mRNA therapies have had so many problems. mRNA therapies face very difficult design constraints: they have to be tiny, and they have to produce proteins that the body can make. The difficulty of these constraints is probably why Moderna, at least, has switched over to vaccines, calling it part of their “core modality”.

Now, vaccines are also difficult, but they’re easier for mRNA than other therapies in a few ways. 

First, provoking an immune response in a normal therapy is a problem. Provoking an immune response in a vaccine, as long as it’s not overwhelming, is part of the solution. Second, as long as the body can produce effective antibodies against the pathogen when naturally infected, some vaccine should work to provoke those antibodies unnaturally. Finally, vaccines are normally only given once (or at least spaced out), so it’s a lot easier to give a small amount rarely.

With these elements combined, does that mean mRNA vaccines are destined for success? Should all other vaccine companies give up or change tactics completely?

Eh…not really. mRNA vaccines can be very effective, but they’re not guaranteed to be. To see why, let’s take a look at the big kahuna, the COVID mRNA vaccines.

It’s easy to think that the COVID mRNA vaccines are more successful than other vaccines solely because of their mechanism. That’s not quite true. What the vaccines target is a huge part of their success.

Let’s go over how vaccines work really quick, in a very general sense. Vaccines provoke the body to make antibodies against the target. A successful vaccine needs to both successfully provoke antibodies and pick the right target.

If you look at the mRNA COVID vaccines, they were successful in both of these endeavors. Both mRNA COVID vaccines target a slightly modified version of the spike protein. It’s slightly modified because that makes the body produce higher levels of antibodies. Meanwhile, the spike protein part is important because that’s a highly conserved part of the virus, making it difficult for the virus to mutate and avoid being targeted.

It’s not a coincidence that the slightly modified spike protein is also the specific target of Johnson and Johnson’s vaccine and of Novavax’s vaccine, neither of which are mRNA based and both of which have shown high efficacy in humans (66% and 89% respectively). The COVID mRNA vaccines are more efficacious, but it’s clear that the target matters a lot.

This didn’t have to be the case. It is very possible for a vaccine, even an mRNA vaccine, to provoke low levels of antibodies. This is easier to check in animal trials, though. What’s more difficult to check in animal trials is whether you’re targeting the right thing. Antibodies are targeted incredibly specifically towards very specific parts (antigens) of a pathogen, not the pathogen as a whole.

To see how complicated that is, let’s go back to the Yale malaria vaccine. When these scientists made their vaccine, they had to choose which of 14 different functions they wanted to target. Each of those had numerous antigens associated with it. If you target the wrong function, you can end up producing antibodies that do not prevent infection. For example, in malaria, if you target the replication of merozoites (part of the life cycle of the parasite), you will not effectively prevent infection in older children.

Even if you do successfully target the right antigen, there’s no guarantee of success. This is because vaccines, again, work only as well as the body’s antibodies do. Human beings cannot develop effective enough antibodies against malaria to prevent future infection. The best we can hope for is partial immunity after repeated infections, meaning that we no longer develop severe sickness on contracting malaria.

This is not unique to malaria. The same problem arises with human cytomegalovirus, which is Moderna’s furthest advanced vaccine right now.  Our immune system cannot clear cytomegalovirus, it can only make us asymptomatic. Moreover, natural immunity doesn’t prevent placental transmission of the virus, which is problematic, as that’s the chief problem that vaccines are attempting to solve. Cytomegalovirus is rarely a problem in adults, but can be serious in babies.

So, there are serious difficulties in developing an effective vaccine that are not solved by mRNA. Furthermore, mRNA vaccines still have to be really small and administered with a fair amount of space in between them.

This is not to say that mRNA isn’t a cool technology, because it is. Vaccines are infamously difficult to develop and manufacture, and mRNA makes that process a lot easier. However, it’s not the only technology that makes development and manufacturing of vaccines much easier. For an obvious example, DNA vaccines have proven to have many of the advantages of mRNA vaccines. 

Finally, we still don’t know enough about the immune system to throw less rationally designed vaccines, like inactivated virus vaccines, out the window. Not all conditions are as well studied or understood as COVID.

mRNA’s cool, but I think it’s time to step back from the hype.