The technology that is helping us combat COVID-19 is also poised to help us tackle tough infectious and non-infectious diseases. Immunologist Sarah Fortune explains how these vaccines work, and how the mRNA platform could transform the prevention and treatment of deadly diseases.
In this episode of “Better Off,” Harvard Chan School immunologist Sarah Fortune takes on common misconceptions about COVID-19 vaccines, and discusses the ways that mRNA technology could be used to create vaccines for diseases like TB and cancer.
Anna Fisher-Pinkert: From the Harvard T.H. Chan School of Public Health – this is Better Off, a podcast about the biggest public health problems we face today . . .
Sarah Fortune: Too little immunity is bad. But, actually, too much immunity is also bad, and the wrong flavor of immunity is also bad.
Anna Fisher-Pinkert: . . . and the people innovating to create public health solutions.
Sarah Fortune: And so what we’re going to learn out of all of this is sort of which platform has the ability to hit the “Goldilocks” spot.
Anna Fisher-Pinkert: I’m your host, Anna Fisher-Pinkert.
When the first COVID-19 vaccine was given an Emergency Use Authorization by the FDA back in December, a lot of us, myself included, breathed an enormous sigh of relief. This was the moment we’d been waiting for – a breakthrough, a light at the end of the tunnel. But after the excitement dissipated, a lot of people still had questions: What is the new mRNA technology behind these vaccines? What does it do inside our bodies? And how do scientists know that it’s safe?
If you or someone you know is not just thinking about when they will get the COVID-19 vaccine but whether they will get vaccinated – this is the episode for you. We’re going to talk about what mRNA is, what it isn’t, and how this technology can help us fight other deadly diseases.
This week, we’re better off with immunologist Sarah Fortune.
Sarah Fortune: So my name is Sarah Fortune. I am the chair of the Department of Immunology and Infectious Diseases at the Chan School.
Anna Fisher-Pinkert: So what is an mRNA vaccine? And how is it different than the vaccines that I would have received in childhood for the measles or polio?
Sarah Fortune: So when we vaccinate people, basically we take a little chunk of the pathogen, in this case SARS-CoV-2, and we give people (in a safe form) – we give people that little chunk of pathogen. Vaccination started with actually the pathogen itself in some crippled form. And then we’ve moved to safer and safer iterations of that by whittling down the parts of the pathogen that we give to people. And so the traditional way of giving parts of pathogens is to give the whole protein. So, many vaccines that people would have received in childhood are protein vaccines. And this is sort of the next frontier of vaccine technology in which instead of giving the protein, you’re giving the sort of message, the map for how the body makes that protein, which is called mRNA, and you’re making the body make that protein.
Anna Fisher-Pinkert: Before we dive into the new mRNA vaccines, let’s back up a second and think about where vaccines started.
Sarah Fortune: Vaccination actually has a very long history. And it begins, actually, with smallpox.
People just gave tiny, tiny doses of smallpox and hope that the very small dose of smallpox, delivered in a controlled fashion, would give you smallpox in just a very limited fashion, which would then make you immune. And then people subsequently recognized that there were cousins of the smallpox virus that would give you, really, a much milder clinical syndrome that then would also make you immune. And so those were the original vaccines from which really our understanding of vaccinology has derived.
Anna Fisher-Pinkert: In 1796, a British doctor named Edward Jenner inoculated an 8-year-old boy against smallpox, using cowpox, a less-deadly cousin of smallpox, and voila – the beginning of vaccination as we know it. But that’s not the kind of vaccination that a child would receive in a doctor’s office today.
Sarah Fortune: Well, you know, if you think about how many vaccines you’ve gotten in childhood, there are lots of different flavors of that. And so, I’m just going to start with one that I know really well, actually, that many people in the United States don’t know as well, but that’s BCG. It’s the most commonly given vaccine in the world. It’s the vaccine for tuberculosis. And so it is a vaccine that was made in 1920, originally. And basically what they did was they just took the pathogenic form of the organism and grew it and grew it and grew it until it lost all the little bits that made it pathogenic. And then they had a sort of “crippled cousin” of the organism that you could give to people. It would generate an immune response, but it wouldn’t make people sick. As vaccine science got more and more sophisticated, they moved on from that form of vaccine to sort of just trying to identify and then take the pieces of the pathogen that were most important for the immune response and just making those in some safe form and then just delivering those. And so those sort of second and third generation vaccines are just part of the pathogen as opposed to the crippled form of the pathogen.
Anna Fisher-Pinkert: Over the last 225 years, scientists have been trying to make vaccines safer by making them less and less similar to live, dangerous pathogens. mRNA vaccines are a new technology in that very long project. What’s different about an mRNA vaccine is that you aren’t receiving the pathogen at all.
Sarah Fortune: No. And it’s not really alive, actually! So it is the roadmap by which the body makes proteins. Every cell in your body has DNA, which is transcribed into RNA. And we call those mRNAs. And then those mRNAs are then further translated into protein.
Anna Fisher-Pinkert: The “m” in mRNA stands for “messenger.” And there is a ton of mRNA in your body, right now, instructing your cells to go make the proteins that, in turn, allow your cells to function and keep you alive. The new mRNA vaccines take advantage of this biological system that already exists in your body.
Sarah Fortune: And so here you’re just giving the body that roadmap, the mRNA, and it is making the protein that is then generating the immune response.
Anna Fisher-Pinkert: Ok, so if that seems confusing, think of it this way. Let’s say you’re in a town in the Wild West, and you’re trying to stop this big gang of dangerous outlaws. The old school vaccines that you got in childhood – those are basically giving your body a big WANTED poster with a picture of the whole gang, minus the really dangerous ringleader.
Sarah Fortune: And then you’re saying, “Get every one of those members of the gang.” Right? And here you’re just saying, “Every one of those members of the gang is wearing a black hat.” And maybe you’re just actually really just giving them a picture of the black hat. And then your body’s going off and capturing everybody with a black hat.
Anna Fisher-Pinkert: That kind of makes sense because it’s actually like leveraging the things that are the most distinguishing about this particular pathogen.
Sarah Fortune: Yes. Okay, so this is the big challenge that your body faces – is trying to understand what’s the pathogen and what’s you, right? That is the central problem of immunity. And so what the immune developers are doing is trying to figure out the bits of the pathogen that really are uniquely “pathogen,” that don’t share any similarities to you, and then giving those to you and your body has all these other filters to say, I’m going to only recognize those bits of that pathogen that are very, very distinctly the pathogen and don’t share any similarity to you and generate robust immune responses to those very unique features.
Anna Fisher-Pinkert: And the unique features in the case of SARS-CoV-2, that’s the spike protein, right?
Sarah Fortune: That is the spike protein. In this in the case of this vaccine and not just the mRNA vaccines, but actually every vaccine that is close to clinical approval in the United States is focused on this spike protein.
Anna Fisher-Pinkert: So, why have mRNA vaccines come out on top in the fight against COVID-19? Is it because they are the best method of protecting us against SARS-CoV-2, or just because they were developed faster?
Sarah Fortune: I think that we will understand that better with time. In part, we are seeing these mRNA vaccines come out first because the technology was developed to be nimble. In fact, post- 9/11, we recognized that we had a huge vulnerability in terms of developing vaccines against new bioterrorist threats and that our traditional mechanisms of vaccine development were too slow and we were going to have to develop platforms that were going to be faster. And one of those appealing platforms that was sort of translatable across a whole spectrum of pathogens, potential bioterrorist threats, was the mRNA vaccine platform. So we invested a lot in building those platforms over the subsequent two decades. And then coincidentally, one of the few groups that was working on coronavirus vaccine development was at the NIH, they were working on MERS vaccine development. So this was Barney Graham and his colleague Kizzmekia Corbett. They happened to actually have partnered with Moderna and were developing and using mRNA vaccines for their work in MERS coronavirus vaccine development. And so they were super well poised to be able to pivot and generate a SARS-CoV-2 vaccine.
Anna Fisher-Pinkert: This concept that we could use synthetic mRNA for vaccines, you’re saying it’s decades old but this is the first time that one of those vaccines has been produced. So what are the reasons that it hasn’t it hadn’t happened until now?
Sarah Fortune: It’s not technically true that this is the first time that one of these vaccines has been produced. It’s just it’s the first time that one of these vaccines has made it through the full regulatory cycle and gone into people in large scale. So actually, the mRNA platforms have been used for both different infectious disease vaccines and cancer vaccines. And so those vaccines had been through early phase trials in several different settings, but none of them had made it all the way through a phase three trial such that it could be used in at a large scale in people.
Anna Fisher-Pinkert: So in essence, when we talk about the vaccine development for SARS-CoV-2, it doesn’t begin at the moment that SARS-CoV-2 is found. It’s actually something that is based on technology that’s been in the pipeline, that was being used on other things and has been tested in various ways.
Sarah Fortune: And I think that that point is actually exceedingly important because part of the narrative has been SARS-CoV-2 appeared and then we started to generate a vaccine and miraculously, six months later, we have a vaccine and we’re testing it in people. And while some of that narrative does reflect the incredible heroic efforts on the part of the scientific establishment to get a vaccine turned around in a very short period of time, I think it does create a sense of anxiety in people who might receive the vaccine that the vaccine is not safe because how could anything that started in January and arrived at people in July have been fully vetted for safety? And so I think that it is important to acknowledge that there were decades of work involved in mRNA vaccine platforms and in fact, in testing different kinds of vaccines for different coronaviruses, starting with SARS-CoV-1 and then MERS. So we knew a lot going into this. So when SARS-CoV-2 first appeared at the end of 2019, actually we had a huge foundational knowledge that accelerated that vaccine development.
Anna Fisher-Pinkert: So, here’s the big question: how do we know that these vaccines are safe?
Sarah Fortune: That is the purpose of clinical trials. So there are phase one, phase two and phase three clinical trials where in phase one we do a gross assessment of safety. In phase two, we kind of assess immunogenicity, for example, for this vaccine.
Anna Fisher-Pinkert: Assessing immunogenicity means figuring out whether the vaccine produces an immune response.
Sarah Fortune: And then phase three, we tested in tens of thousands of people to understand whether it is both efficacious and whether there are safety signals that we missed in the phase one trials that we should be aware of. So, you know, at some level we know for these vaccines because we’ve tested them now and not just tens of thousands, but hundreds of thousands of people.
Anna Fisher-Pinkert: So clinical trials give us a ton of information about safety and efficacy – and any COVID-19 vaccine that you can receive in the U.S. has been through that process. But, there are a LOT of rumors going around about the COVID-19 vaccine. So let’s talk about them!
One fear that keeps coming up is that something else that we want in our bodies will look too much like that spike protein on SARS-CoV-2, and get attacked by the immune system. Sarah says that’s unlikely because our immune system is really sophisticated. To go back to the Wild West, if the mRNA tells your immune system to “go look for the guys in black hats,” it’s not going to identify all hats as a threat.
Sarah Fortune: The exquisite specificity of your immune system is hard to overstate. . . It might be like saying, look for the particular shade of dirt from this gang’s campsite on the black hat. And in fact, the immune system is not very good at even saying this coronavirus spike protein might look like another coronavirus spike protein with the closest cousin. It doesn’t even see those two things as similar. It’s just incredibly, incredibly specific for the specific immunogen that it has seen.
Anna Fisher-Pinkert: Sarah Fortune says that there is no evidence that mRNA vaccines or other vaccines cause autoimmune disorders, and that mRNA vaccines are actually safer to give to immunocompromised people.
Sarah Fortune: So, in fact, many vaccines that we give, you know, those crippled shadows of pathogens . . . Many of those are not so easily given to people who are immunocompromised. But the vaccine platform, because those mRNA vaccines are not alive, is safe. And so that’s one of the great things about this vaccine platform.
Anna Fisher-Pinkert: Another rumor floating around the internet is that mRNA vaccines could alter your DNA. And it turns out that’s just not possible.
Sarah Fortune: So you think about your cell, you should think about essentially there’s a one-way conversation whereby your DNA is the roadmap to make RNA is the roadmap to make proteins. So you have very few copies of DNA in your cell. You make hundreds to thousands to hundreds of thousands of mRNAs, and then you make even more proteins and in each of those processes is a little error prone and so you don’t want any mechanism by which those accumulated errors, get translated back into your DNA. And so your body has worked very hard to make those conversations one way.
Anna Fisher-Pinkert: People also worry that the vaccine could have long-term health effects five or ten years down the road. Sarah Fortune says that there are cases in the history of vaccine development where a vaccine had to be pulled from the market after approval – but those are very rare.
Sarah Fortune: The most common side effects that people are going to experience after vaccination are flu like symptoms, a short period of flu like symptoms, an achy arm, a day of fever, headaches for a day or two. Those are the most common side effects. And they are actually evidence of your body mounting an immune response and they go away and it’s important to be transparent about them, but they’re not dangerous.
Anna Fisher-Pinkert: Another concern is that the immunity given to us by the new vaccines won’t last very long. So I asked: Is this going to be like the flu vaccine, where we have to get a new one every single year?
Sarah Fortune: We get a flu vaccine every year because the flu virus wholesale changes its coat every year. And so it’s basically a new pathogen every year. So that’s why you get a flu vaccine every year. Now, we get tetanus boosters every ten years because, in fact, you get your tetanus vaccine and then the immunity wanes and wanes and wanes, and then you get the new tetanus vaccine and then it wanes and wanes and wanes. So I think we will be somewhere in between flu and tetanus and thinking about these coronavirus vaccines, because there will be some waning of immunity. I don’t exactly know how fast. And there may be, in fact, some drift of the virus itself, which is not going to be like flu. It’s not going to just wholesale reassemble itself, but it may change a little bit, too. And so those two factors may mean we’re going to need to have a vaccine effort that’s not just this one and one and done deal.
Anna Fisher-Pinkert: The variants of concern, in particular the South African variant that appears to have changes in its spike protein. Is that the kind of thing where we would need to go back and like a flu vaccine, tweak it again so that it works better?
Sarah Fortune: Yes. And I think that we should just understand that that is very, very, very likely because, in fact, if you think about how much coronavirus there is in the world right now and if you understand that basically the way the little coronavirus makes itself, by design, replication is imperfect to generate diversity. And so there’s just a whole sea of little coronaviruses that differ in their spike proteins ever so subtly out there. And most of those are not long for the world because they’re not actually very successful unless they’re the ones that are able to escape vaccine mediated immunity – or natural immunity. And then all of a sudden, they’re the ones that are able to sweep through our population. And so I think that we should just understand that this is not going to be over with this vaccine.
Anna Fisher-Pinkert: But what’s remarkable about mRNA technology is that these adjustments can happen faster and more accurately. mRNA technology is being applied to a lot of different diseases right now – from targeted cancer therapies, to developing a vaccine against tuberculosis, or TB.
Sarah Fortune: The core body of my work actually looks at TB infection, tuberculosis, which is another respiratory infection, and in fact, until this year, was the leading infectious cause of death in the world.
Anna Fisher-Pinkert: It turns out that TB is actually incredibly difficult to vaccinate against.
Sarah Fortune: And part of the reason for that is TB is a kind of infection where there’s a sweet spot of immunity. Too little immunity is bad. We know that, and that makes a lot of sense, but actually too much immunity is also bad, and the wrong flavor of immunity is also bad. And so what we’re going to learn out of all of this is sort of which platform has the ability to hit the Goldilocks spot for a vaccinated immune response that might be right for TB.
Anna Fisher-Pinkert: For 225 years, scientists have been manipulating pathogens, trying to coax out that perfect immune response. mRNA technology offers a new hope to people fighting very challenging diseases around the world.
Sarah Fortune: So this has been an incredible moment for vaccine development because it has shown what is possible and what can happen quickly, and it injects a sense of both creativity and optimism into vaccine development for other infectious diseases. It gives you a sense that because of the sort of Lego opportunities involved in using mRNA vaccines, we could actually, in a Lego-like fashion, create the vaccines that we need for the infectious diseases and for the non infectious diseases that have been very hard to target through vaccination.
Anna Fisher-Pinkert: If you want to learn more about COVID-19 and the COVID-19 vaccines, visit hsph.harvard.edu/news to find the latest from researchers at the Harvard T.H. Chan school of public health.
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I’m Anna Fisher-Pinkert, host and producer of Better Off a podcast of the Harvard T.H. Chan School of Public Health.