The Past, Present and Future of mRNA Vaccines : Short Wave The Pfizer-BioNTech and Moderna COVID-19 vaccines are the first authorized vaccines in history to use mRNA technology. The pandemic might've set the stage for their debut, but mRNA vaccines have been in the works for more than 30 years. Host Maddie Sofia chats with Dr. Margaret Liu, a physician and board chair of the International Society for Vaccines, about the history and science behind these groundbreaking vaccines. We'll also ask, what we can expect from mRNA vaccines in the future?

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The Past, Present and Future of mRNA Vaccines

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MADDIE SOFIA, HOST:

You're listening to SHORT WAVE from NPR.

The Pfizer-BioNTech and Moderna vaccines are truly historic and not just because, you know, they're saving lives during this pandemic. They're also the first authorized vaccines to use mRNA technology.

MARGARET LIU: In a sense, it wasn't surprising that it worked.

SOFIA: That's Dr. Margaret Liu, a physician and board chair of the International Society for Vaccines.

LIU: I think what was surprising to everyone was that they work so well.

SOFIA: We're talking around 94, 95% efficacy in clinical trials - incredible. And here's another thing that might surprise you about mRNA vaccines. This pandemic might be their big debut. But...

LIU: The technology really goes back over 30 years. So this isn't something that is just so brand-new and scary. People have been working for a really long time to turn these technologies into useful vaccines and drugs.

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SOFIA: So today on the show, we look at a bit of the history and science behind mRNA vaccines and ask about their future, what diseases they could eventually be used to treat and their limitations. I'm Maddie Sofia, and you're listening to SHORT WAVE, the daily science podcast from NPR.

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SOFIA: When I called up Margaret, I had a lot of questions for her about mRNA vaccines. So we started at the beginning. I was thinking, Margaret, I want to do, like, a little bit of a history of, like, how long this technology's been around. And if you don't know, like, the super details of that, that's totally fine.

LIU: I do know the super details...

SOFIA: Oh, I love this.

LIU: ...Because I've actually written scientific papers about it (laughter).

SOFIA: OK. Amazing.

LIU: OK.

SOFIA: Now, a lot of scientists have worked on mRNA vaccines over the years, Philip Felgner, Katalin Kariko, Drew Weissman, just to name a few.

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SOFIA: The work really started in the '70s. But it wasn't until the '90s that scientists started testing out the first mRNA vaccines in mice. Most vaccines, like the flu shot or whooping cough vaccine, use bits and pieces or a weakened form of the virus or bacterium to build up immunity. But...

LIU: The mRNA vaccines are not a whole virus or a whole bacterium. What you're putting in is a piece of mRNA, just a piece of coding sequence, that then has your body make that single protein.

SOFIA: For instance, one of the coronavirus' proteins, which causes an immune response that will protect you later when your body encounters the real thing. So that's the idea. But there were two big challenges researchers had to deal with to get to where we are now with mRNA vaccines.

LIU: One challenge was that the mRNA is very unstable and gets degraded very quickly. And so it doesn't last very long. And so the first challenge that has had to be overcome was to find the right way to formulate it. So I like to think of this as M&M'S. So if you were to hold plain chocolate in your hands, that chocolate would melt because your hand is warm. And so what happened was M&M'S are a way of putting a candy coating around it so that you can now hold them in your hands and it doesn't melt.

SOFIA: So that's what scientists kind of did. They incased the mRNA in tiny spheres of fat called lipid nanoparticles.

LIU: And that protects the mRNA from being pretty much instantaneously degraded. But it also helps deliver it. It's kind of like a shuttle system that helps deliver the mRNA into this cell after being injected.

SOFIA: So that innovation was monumental. But Margaret says there was another major hurdle to clear.

LIU: The other problem is that the mRNA, when it's made for, like, a vaccine, actually, has a lot of inflammatory characteristics. So it kind of revs up all sorts of responses. Now, of course, that's actually really a good thing for vaccines. But nevertheless, you want to have what we call the Goldilocks level, which is you don't want too much information. You don't want too little. You want just right.

SOFIA: Inflammation is part of your immune response. So a little bit is not a bad thing. And scientists finally figured out how to get it just right in 2005. So eventually, you know, a lot of this technology was kind of there, you know, before the pandemic. So, you know, why didn't we see it in use before, Margaret, or was it? Or, you know, what was the situation there?

LIU: So the situation was that, in fact, there were a number of clinical trials already going on for vaccines, for different vaccines - influenza, diseases like Zika. But what had happened was they just weren't moving along as quickly because normally, people don't have the sorts of resources that were applied to pushing along the vaccines in those other situations. People just weren't as worried about it. And there wasn't a pandemic going on. So it wasn't that work wasn't being done. In fact, there were a number of clinical trials. And they were getting some promising results. They were just kind of moving along at the usual pace rather than all of the sudden saying, oh, we need an all-hands-on-deck.

SOFIA: Right.

LIU: We need to actually, really, expand our clinical trials since it looks safe. We need to then test it more, move it along more quickly, specifically for coronavirus.

SOFIA: Yeah. Yeah. Yeah. The money always helps for sure (laughter).

LIU: You know, it's interesting because money is, in fact, the biggest issue of - when people have talked about what was called Operation Warp Speed in the U.S., it wasn't really that any safety steps were being skipped. What was done was that the vaccine manufacturers, some of them on their own money, like Pfizer, and some of them getting money from the U.S. government, like Moderna, invested early in, for example, manufacturing. Normally, you'd wait...

SOFIA: Right.

LIU: ...Until you had a really good idea. So the real risks were financial risks. They weren't human or safety risks.

SOFIA: Got it. Got it. OK. So a lot of people, including me, are really excited about the future of this technology, you know, beyond the coronavirus. So - but before we get into, like, some specific examples, can you talk to me about some of the general pros of mRNA vaccines, you know, like, including the manufacturing?

LIU: Sure. So first of all, let's start with they've been very effective. So it's a great technology, as we've seen, for coronavirus. Secondly is that the manufacturing, as you've said, is really straightforward. So some vaccines - for example, if you need to make a weakened version but that's still live - have taken years, even decades, to figure out, how do you cultivate this virus so that it's still alive but not dangerous? So these, in fact, if you want to change the vaccine, all you do is you just make up a new sequence of your mRNA. So in the future, whether it's for coronavirus and making new vaccines for mutants or for some other diseases, that aspect will be very rapid.

SOFIA: You know, is there a specific disease that you're excited about, you know, potentially for this vaccine to be - you know, to mRNA vaccines to be effective? Like, is there, like, one, you know, disease or virus where you're like, oh, that's - your next, buddy, you know? What do you think?

LIU: Well, I have to say the SARS-coronavirus-2 is, to me, right now, the most important one...

SOFIA: (Laughter) Sure, sure, sure.

LIU: ...Particularly with all these mutants going on. I would say that there are other - the other ones that are clearly huge issues right now are influenza because influenza does still kill many, many people. But then I think the targets that have been so intractable, such as HIV and tuberculosis and malaria, we need new...

SOFIA: Yeah.

LIU: ...Approaches and new vaccines for. I will add, though, if we're expanding this to talk about other diseases that, in fact, mRNA before recently had most been tested for cancer. And one of the advantages is - because you can make the construct so easily, is that people are actually trying to make personalized cancer vaccines.

SOFIA: OK. OK. So let's talk a little bit about mRNA technology limitations. You know, one that's been really clear during this pandemic to me is that, you know, what's authorized right now requires ultra-cold storage, which is a real challenge - right? - when you're aiming and striving for vaccine equity.

LIU: Right. That's absolutely right. I mean, it's not even just a question of vaccine equity around the globe. Even within the United States, there are limitations because the amount of time that you can thaw the vaccines and then still use them. And that's why there have been all these issues of people saying, oh, I've already thawed all these. I have to go find people because you don't want to waste any of these precious doses. That just makes it more challenging than if you could just have it there in your refrigerator for whenever people came in or, frankly, if you could administer it through a patch or spraying it in someone's nose or something. Everything we can do to make a vaccine administration easier makes it more broadly useful for people.

SOFIA: Absolutely. Absolutely. OK. So I'm going to ask you to predict the future right here, which I know scientists are super-comfortable doing all the time.

LIU: (Laughter).

SOFIA: When - I mean, when do you - (laughter) when do you think mRNA vaccines will start to be more and more common, like, we'll start to see new treatments, vaccines? I mean, this has been such a mobilizing event for this technology. I mean, are we thinking years, decades? And I apologize for asking you to predict the future here.

LIU: Yeah. I, actually - you know, my answer to that that I read - somebody says, well, as a scientist, I can't predict the future. That's what journalists do. But I'm just kidding.

(LAUGHTER)

SOFIA: And some of us are both. And I'll tell you what, it's a very uncomfortable dynamic.

(LAUGHTER)

LIU: Yeah. Exactly. So this is not a prediction. This is just an analysis. I think that, you know, it's - this is fabulous that we have this new tool to use. At the same time, we actually don't have a full understanding of HIV or malaria or TB and, certainly, not about cancer. We don't know everything about how the immune responses will be either protective or therapeutic for these different diseases. But certainly, it should advance all of our applications, whether for prevention or for therapy, because we just have this easily, rapidly made entity that you don't have to find a new way to manufacture it every time that you make a new one.

SOFIA: OK. Margaret, this was an absolute delight. I appreciate you and your brain. Thank you for coming on the show.

LIU: Sure. This was a fun discussion. Thank you so much.

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SOFIA: This episode was produced by Rasha Aridi, edited by Viet Le and fact-checked by Berly McCoy. The audio engineer for this episode was Gilly Moon. I'm Maddie Sofia. Thanks for listening to SHORT WAVE, the daily science podcast from NPR.

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