The novel coronavirus pandemic has prompted lots of questions and uncertainty this year. How is the virus transmitted? Am I at risk? What is safe to do? But in addition to those immediate concerns, the pandemic is changing our lives forever in ways that are only now we're starting to grasp.
In the first episode of the livestreamed series "Now What?", Jennifer Stayton talks with Jason McLellan, an associate professor of molecular bioscience at UT Austin, about the search for a COVID-19 vaccine.
McLellan was also a postdoctoral researcher at the National Institute of Allergy and Infectious Diseases Vaccine Research Center.
The following transcript has been edited lightly for clarity:
KUT: All right. So, first of all, I have to ask: obviously, the scene behind you is not in your office; it is a depiction. Describe what we're seeing in the scene behind you. What is that?
McLellan: Yeah, it's an artist's rendition of coronavirus virions, probably inside an infected lung. My laboratory determined the first atomic structures of the spike proteins, which are the white projections on the surface of the virus. So we've been working with several companies to try and make some of these visuals as accurate as possible. There have been some movies and animations made.
And this can be helpful in kind of understanding what it is we're going up against, what's causing the pandemic. And I think these types of visuals can be helpful.
KUT: And we're going to get to all of that as we talk today about your research and also about where we are on the road to a vaccine. First of all, I'm going to ask the question that I'm sure you get asked a lot, and what everybody wants to know: When you hear hopes or promises about a vaccine 12 months from now, 18 months from now, or there's even talk of rushing by the end of this year, the administration has Operation Warp Speed – is any of that talk realistic for a timetable for developing a vaccine for COVID-19?
McLellan: Yeah, I think it is. I think early earlier this year, in January and February, we were thinking maybe optimistically 18 to 24 months, but things have progressed really well. Some of the data that's come out has looked very good, so we're already basically through with a phase one clinical trial for one of the groups, Moderna, which is developing a vaccine in partnership with the National Institutes of Health based on an antigen that my lab designed. And the phase one looks good; they're starting a phase two. And I think a phase three in July that could be wrapped up by the end of summer.
The early data looked good; the vaccine appears to be safe at the lower doses and is eliciting the types of immune responses we were hoping for.
Then it just becomes a matter of trying to scale up and making millions, tens of millions, hundreds of millions of doses; how to distribute them; who gets them first. But I think we'll have multiple vaccines developed and be optimistic.
KUT: Is that a problem if there are multiple vaccines developed? I mean, if they're developed – different companies, different countries, sort of all on different timetables – is that a scenario that is helpful or is that a scenario that could create more complications or confusion?
McLellan: I think it will be helpful. I think the benefit is that if we only had one, we'd be putting all of our eggs in one basket. If there is a single issue of a supply chain, then there's no doses. So you probably don't want to have 100 different vaccines. But two, three, four different types of vaccines, all hopefully similar efficacy – I think that allows us to get vaccines to more people quickly and less likely to have any potential issues with manufacturing.
KUT: Now, you were describing a timetable that's been under way since early this year, I'm assuming that's faster than normal vaccine timetable development? I mean, usually we're talking about years, if sometimes not a decade or more.
McLellan: Yeah. Historically, it's been closer to decades – one to two decades.
One of the vaccines that I worked on as a postdoctoral fellow at the National Institutes of Health at the Vaccine Research Center is a vaccine for respiratory syncytial virus. There we created the vaccine antigen in 2013, and it's now just in phase two clinical trials, seven years later, and still probably a couple of years away for phase three. So, that's the type of normal decade-long progression. So to try and make a vaccine and do phase one, phase two, phase three and then start manufacturing all within one year is pretty phenomenal.
KUT: So you mentioned research that you're a part of about antigens and that's related to a vaccine that Moderna is working on. Tell us about that research and what's going on there and how that informs development of that particular vaccine.
McLellan: Yeah, so the idea with a vaccine is to expose the human body to the pathogen, either the entire pathogen that's been weakened or inactivated or killed, or a portion of the pathogen. For coronaviruses, the portion of the virus that we want to expose ourselves to is the spike protein, the little white dots on the surface of the virions behind me. That spike protein is responsible for first binding to receptors on our cell surface. And then after binding, the spike protein undergoes this really large conformational change that fuses the membrane of the virus with our membranes, and that allows the contents of the virus to enter the cell.
What we want to do is raise an immune response against the spike and prevent it from working. So, if we make antibodies against the spike, those will bind to the spike, prevent receptor binding, prevent membrane fusion, and then that particle can't infect us.
When you're thinking about that, these proteins can exist in multiple conformations (shapes), and what's the optimal conformation? Well, the optimal conformation is the shape that it exists on the surface of the virus. My lab has been involved in determining the structures of these spike proteins and then, based upon the structural information, rationally engineering in mutations into the proteins that lock them and that confirmation that's shown behind me.
And then when you present it to the immune system, your body recognizes it and makes antibodies. Then when it actually encounters the infectious virus, it's primed and ready to recognize the spike protein as it exists on the surface of the virus. My lab does a lot of the structural biology of the viral glycoproteins and then the protein-based engineering to try and lock them into a particular confirmation that we think is optimal for vaccine development.
KUT: In general, how much do you have to know about a particular disease in order to develop a vaccine? Because, you know, this is a novel coronavirus. This is new. Everything is happening fast. How much knowledge do you need about it before that vaccine work can proceed?
McLellan: Yeah, I think there's a whole range. People have developed vaccines for decades — longer — knowing very little about the actual pathogen and what our approach is, is to try and really use a very rational engineering approach.
So even though this is a novel coronavirus, it's not the first coronavirus. And we've known about coronaviruses since the late 1960s. My lab has been working with Dr. Barney Graham's lab at the Vaccine Research Center at the NIH studying coronaviruses since around 2013. And we did a lot of work determining the structures of coronavirus spike proteins with along with Dr. Andrew Ward's Lab at Scripps Research Institute. So we determine the first structures of these spike proteins. We designed mutations. It worked very well for the MERS coronavirus. And for the first SARS coronavirus.
And so we had all this background knowledge about how to design the antigens, how to present them. And once this novel coronavirus emerged, we could just quickly translate all that prior knowledge. We knew what stabilizing mutations that put into the spike protein and start vaccine development. If we hadn't known that, it could have set us back months or years.
KUT: So that sounds like a bit of an unusual situation, but in a good way — that there was already this work done ahead of time and there was kind of a base of knowledge to work from when the novel coronavirus came along.
McLellan: Yeah. And that's an extremely important point: the idea of basic science research getting funding from the federal government and from philanthropies and associations to broadly study disease, infectious disease, cancer and others. It's very difficult to predict where the next breakthrough is going to come or where the next outbreak is going to be. And so it's really important to broadly study.
Just like having the Zika outbreak several years ago. We need people working on these things before the pathogens emerge. That's not the time to begin five to 10 years worth of basic science research. That's why we need to already know a lot about it so we can quickly begin developing interventions.
KUT: I imagine that's a bit more of a challenge when there's not an immediate public health emergency, though, when vaccines are being talked about a lot and development of them and things are moving quickly. I imagine that between those episodes, that's a lot harder to kind of generate interest for.
McLellan: Yeah, it can be. And that's somewhat our job as researchers and in trying to sell our ideas. And there's limited grant funding, and it's a competitive environment. So we have to put forward a strong case to research the things we're interested in. In our case, we felt pretty confident about coronaviruses. We started working on it after the MERS coronavirus emerged in 2012. That was the second one that emerged into the human population after the first SARS coronavirus in 2002.
We felt at the time that there would likely be additional coronavirus outbreaks. And so we wanted to start working on it. And it turned out that there was another one and we were reasonably well-prepared in terms of the science.
KUT: Can you remind us a little bit about those other two outbreaks? Because we have been hearing a lot about those in conjunction with the novel coronavirus. Just remind people briefly what those two outbreaks were.
McLellan: Yeah. So the SARS coronavirus emerged in 2002 in China. The primary reservoir for the human coronaviruses are bats — these horseshoe bats. It's likely that the bats, the primary reservoir for SARS coronavirus, then had a secondary reservoir of palm civets, these cat-like creatures. And then that led to an outbreak. The case fatality rate was higher. So about 10% of all confirmed cases led to a fatality, which is actually quite high. And it affected around 8,500 people.
So it was able to be relatively well contained to within China, although there was some spread outside. So it was more of an epidemic rather than a global pandemic.
For the Middle East Respiratory Syndrome (MERS) coronavirus. That emerged in 2012 in the Arabian Peninsula in Saudi Arabia. That's an even more lethal virus — it has a 35% case fatality rate with only around 2,500 people have been infected. It doesn't spread easily person to person, as this novel coronavirus, SARS-CoV-2, spreads.
KUT: We actually have a question from somebody on Facebook asking about herd immunity. Did we ever get herd immunity for any SARS virus or any coronaviruses of non-SARS type? Did herd immunity ever come about for any of those?
McLellan: So there's now seven human coronaviruses, three of which have caused the more serious diseases: SARS-1, SARS-2 and MERS. And then there's four that circulate seasonally. They cause mostly mild respiratory illness, like the common cold. And so for those four, we generally have some degree of herd immunity. Most people have been infected. And that causes then follow up reinfections to be less severe.
For the first SARS, again, only 8,500 people were infected. So there's really no herd immunity. There is no additional transmissions after 2003. Same thing for MERS. And now with SARS-CoV-2, we're still, I think, relatively low percent of people have been infected. Of course the estimates are ranging due to testing issues, but we're probably below 10 percent and it's thought for herd immunity for SARS-CoV-2, we might need to be closer to 60% or 70%.
KUT: I want to get back to the vaccine development process a little bit because we hear about people who have gotten injected with a vaccine in a few of the trials that have already happened. How is it determined when a vaccine is successful? What is the flag in a trial that says, all right, we're ready now to go into that mass production that you were talking about? What signifies that?
McLellan: It first has to pass safety tests and so the phase one clinical trial is really looking at safety. And so that's generally in tens of people, let's say 40 people or so, I think the Moderna vaccine is 45 people. Then everybody, the 45 people, they're all getting vaccines. So there's no placebo. And it's generally escalating doses. So that the first people get the lowest dose, might wait a week or two and see how they respond. That looks OK. The next people get the higher dose. So we're just trying to get an estimate of safety and the dosing.
And then what you really want to look at then is for efficacy, the ability to prevent severe disease or prevent infections. And that's where you really need something like the larger phase three clinical trial where you have thousands of people. One group is receiving placebo. The other group is receiving vaccine. And then you expect to see some difference between the two groups.
The flag itself, it depends a lot on how the particular phase three clinical trial is constructed. There will be primary endpoints, secondary endpoints. People have to decide what they are. Are you trying to decrease infections? Are you trying to decrease severity of disease? Days in hospitalization? Deaths? Those are all different potential endpoints or secondary endpoints. And that needs to be looked at. If you achieve the threshold you are going for and that people think could be useful, then potentially you move forward and begin licensure and manufacturing distribution.
KUT: So I'm curious about those steps. I want to ask a little bit more about each one that that initial step, that safety step, as you were describing that, I just started thinking, well, that's a that's a particular kind of person who would sign up to be a participant, to be a volunteer for that first round of testing. Have you talked to some of those folks before?
McLellan: I haven't personally talked to them, but it's pretty cool in the current age. Some of them are on Twitter and some have actually been tweeting about it. One of the people who had a more severe adverse reaction to the highest dose had a story and kind of tweeted about that a little bit. So it's been interesting to actually obtain some of this information in real time. I think a lot of people were excited to be a part of this.
I think depending on the vaccine in general, we aren't expecting really too many too severe adverse events. Generally, some redness and some other things, maybe fever. But yeah, I think they’re pretty brave people to volunteer to do this.
KUT: Talk a little bit more about then the second step, the efficacy step. You said there are three different groups and getting a placebo and different doses. Talk about, then, exactly more specifically how that is tested. What are researchers looking for in that efficacy step?
McLellan: Some of the things we can do initially, even in the phase one, is we can draw the blood of the vaccinees and see if they're making antibodies against the virus or against the protein that are potentially neutralizing. So we know that with the vaccine, we're trying to elicit an antibody response and particularly an antibody response that can neutralize or inhibit the virus from entering.
And so we can get the concentration of those antibodies, the titers, we can get a sense of how well we're working. We know that people that have been infected with SARS-CoV-2 and recover, they have a certain concentration of antibodies. We would like the vaccine to elicit a similar concentration or potentially even higher. So we can get some of that initial information.
For some of the trials, it's looking quite good. We are eliciting those types of antibodies. But ultimately, you want to know whether there's protection, whether we're protecting from severe disease. And that's where you might look if you had several thousand people in one group received placebo and one group received the vaccine, you could potentially look at, after several months, the number of people hospitalized in each group and compare those and see if there's a statistical significance. Or days in the hospital, those are the types of metrics you're looking at.
KUT: I want to veer off the vaccine course for just a second, because when you mentioned antibodies, I know people who have been following your research and following some of these developments closely are probably thinking about research they may have heard about involving llama antibodies. Now, that's for a treatment, not for a vaccine. But talk a little bit about your research there, because obviously it's llamas and people are interested in what on earth are you studying llamas for and how is that related to all of this?
McLellan: I think broadly you can think about interventions for viruses, for this particular coronavirus, in three different modalities: vaccines, antibodies and small molecule inhibitors. So for vaccines, as I mentioned, we are trying to inject a virus or a portion of the virus into a person and then let their body generate an immune response. Antibodies and T cells. So that's an active immunization. It requires the vaccinee to actively make an immune response.
For antibodies, we can actually purify antibodies from either a llama or from a human and express them and then inject them into a person. And immediately after injection, the person then has a very high concentration of this protective antibody circulating in their system, and they should be protected. The concentration of the antibody will wane over time because their body isn't making more of it. And so then they might need a boost every one to two months.
But this can be useful, for instance, for protecting health care workers, for people that we know are going to be exposed to a lot of virus. You could immediately inject them with an antibody and have them protected for a certain amount of time and potentially they can be used for treatment. If somebody gets infected or is likely to have been infected, you could then administer the antibody and hopefully that would resolve the infection or decrease this disease severity.
So there's a lot of work going on now to isolate monoclonal antibodies from people who have survived COVID-19. And then we've also been working with with llamas. Llamas make two types of antibodies. One is very similar to antibodies we make, conventional antibodies. Another is a much smaller antibody that is really unique to the camelid family. So camel llamas, alpacas. And the portion that recognizes the virus is much smaller than the human homolog. This allows it to fit into small pockets and crevices that maybe the conventional antibodies can't, and then these small antibodies can be really stable. They can potentially be nebulized into an inhaler delivered directly into the lung, into the respiratory tract where the infection takes place.
And we've known that camelids can make these types of antibodies for decades. There's entire companies started around this type of technology. And we began working on this in 2016, trying to isolate a camelid nanobody that broadly binds to all coronavirus-like proteins.
We failed in that aspect of it, but we were able to isolate these nanobodies that can find and neutralize MERS. And the first SARS coronavirus. And it turns out that then one of the ones that binds to the first SARS coronavirus also binds to the spike protein of SARS-CoV-2, and it can neutralize. And it looks really well. It's finding a pretty conserved site. And our colleagues in Belgium are rapidly moving that forward for preclinical development.
KUT: So, Jason, you use a word fail in talking about an earlier attempt with this or attempt to sort of get something ready for all coronaviruses. But I imagine that the word fail probably has a different meaning in your line of work, because a failure here, though, might open a door somewhere else or lead to knowledge for something else. So I imagine that something that may seem like a failure isn't always necessarily a failure, though, when you're talking about research and vaccine development.
McLellan: Yeah, you know, we actually feel a lot in science. There's a lot of things we're trying to do, trying to get experiments to work and they just keep failing. And then eventually there's a breakthrough and we move it. That's a little bit of how science works. And you kind of get used to that. A lot of people coming into the field are used to always being successful. And it takes a while to realize most of your experiments are going to fail. But there's usually net progress, and that's what works. In this case, we didn't achieve our our main goal, but we ended up still making some molecules that look efficacious against coronaviruses and one that potentially could intervene in this pandemic.
KUT: Do you have any concerns about the timetables here that we're hearing about? You said you are optimistic about something being developed maybe within this year, but then we also chatted about how that is a very compressed timeline compared to usual vaccine development. Does that concern you at all that this is going so quickly because obviously we have a public health crisis under way right now? Do you have any concerns about that, that compressed timetable?
McLellan: You're always concerned about safety. But again, we're leveraging a lot of prior information, both on coronavirus vaccine development that's occurred for about the last decade, people making SARS-1 vaccines, MERS vaccines. Those have never been licensed. But there's been a lot of animal work and some early clinical trials. The different modalities of vaccines, whether it's an mRNA-based vaccine, DNA-based, adenoviral-based.
There's a lot of research on those platforms in general. So we know quite a bit about that. We know generally the safety profile, and we are going through the steps, phase one, phase two, phase three, being cautious. And we're learning as we go. I think there's always some concern, but we're not doing this for the for the first time. There is a lot of prior research where you're able to leverage.
KUT: Jason, I feel like I should ask you: We're talking about vaccines, we're talking about safety. I imagine you encounter on social media and other places people who have concerns about vaccines, don't believe they work, have worries about them. How do you respond to people who don't believe in vaccines at all as a vehicle for help in this arena?
McLellan: Yeah, we don't really deal in beliefs. There's science, there's data that shows they're safe and effective. I think that's the best thing we can do as scientists is generate the data. Whether people believe it or not is not something we can really control.
KUT: So I don't want to pin you down to a particular number, but you said you're optimistic about the timetable for this year, about something happening this year. Could you put a percentage to that or a likelihood that by the end of the year we might see a vaccine? I think this is something that people are obviously very focused on and very concerned about and hopeful about.
McLellan: Yeah. I think it's likely 90% that that a one or more vaccines will be approved. Now, that's different than having everybody vaccinated by the end of the year. That could still take another year or two to generate enough doses and distribute them all.
KUT: So let's talk about then that step in the process, which you had mentioned earlier, which is once a vaccine is developed, it's approved, it's safe, it's ready to go, what happens then? Obviously it has to be widely distributed and administered,.
McLellan: Yeah, it has to be manufactured and distributed. Right. And a lot of that's going to depend on the companies, what their capacity is, whether other companies will help out the manufacturer, you know, sort of mergers and groups working together on that. I think some of the targets are initially generating a million doses per month by the end of this year, ramping that up to 10 million doses per month next year. But we still have 300 million plus people in the country. So that's still going to take a long time. And we've got to figure out who gets it first in an orderly fashion. And I think those are discussions that probably are happening now and should happen.
KUT: So we have another question from the audience regarding vaccines. Is there any guarantee that all of this work will lead to a vaccine? Or is it possible that it could take a very, very long time or that there just might never be one?
McLellan: I think it's unlikely there would never be one. I think it will lead to a vaccine. What we don't know, for instance — well, I guess, one of the big questions is the duration of immunity afforded by the vaccine or even the natural infection. So we know that people infected, they generate an immune response. But we don't know how long after that they could potentially be reinfected. So that's a big question. It's not going to be the same for every person.
We see that people are making a range of immune responses, some fairly weak, some fairly robust. People with more asymptomatic infections would be generating a weaker immune response than people with severe disease who've been exposed for a long time to a high amount of virus.
So I think that's one of the things that we're really most interested in in terms of vaccine development: how long would you need a vaccine? Every year? Could you go every couple of years? And I think that's one of the major questions. But all the data suggests so far that several of the vaccines being developed are immunogenic, are eliciting antibody titers and immune responses that are comparable to what's been observed by natural infection. And that's a very good sign.
KUT: Jason, you're talking about that response. I know people know what you're mentioning. You know, there are vaccines that you get once in your lifetime. There's a flu shot you're supposed to get every year, and there's some in between. So part of this work must be figuring out what kind of response is generated and what kind of vaccine we would be looking at.
McLellan: Yeah, part of that is we might just have to wait a little bit to see whether you can get reinfected after a year or after two years, and maybe some of those studies can start to be done in animals to give us a sense of that. But it's true for influenza, the virus changes a lot. It kind of evades our immune response. So when you're getting vaccinated each year, it's not exactly the same vaccine components. It's changing to try and predict the changes of flu.
We know this coronavirus is changing a little bit. Spike proteins may be accumulating one mutation per month. It's a very large molecule. We don't expect it to escape from vaccines being developed now anytime soon. But these are all things we're sort of investigating, trying to figure out as the virus evolves. And what sort of antibody responses and vaccine responses we're getting from each of the different vaccines that are being developed.
KUT: I was just going to ask you about that change, if you've seen the coronavirus changing, this novel coronavirus changing. You said it's changing about once a month or what is that part looking like right now?
McLellan: Yeah, there's really great studies going on. When people are infected, the virus can be isolated from them. The entire genome can be sequenced. And we can start to look at the changes in the genome that are accumulating and how they diverged from one of the very first strains. And for the spike protein itself, we're seeing some mutations occurring. Maybe one particular substitution seems fairly prevalent, like maybe it's been selected for. And it's something to keep an eye on and see just how many changes the surface of the spike is accumulating because that could affect vaccine and antibody responses. But so far, it's not changing too much where we're worried about it.
KUT: So, Jason, I want to ask you to step back a little from the specifics of your work. And I'm just curious: the kind of work that you do, especially now, you're researching, you're working on a vaccine, development is rolling along. And right now, we also know that the death toll from COVID-19 in the United States is very close to 100,000 people. And I'm wondering if you could just talk a little bit, I guess, more personally about what it's like to work on projects in research like this that literally are life and death. What is that like for you?
McLellan: We find it very interesting, which is why we do it. We potentially could work on anything, and I've chosen to investigate infectious disease and trying to develop interventions for it. It's nice that our lab may have a role in helping to combat this pandemic, whether it's a vaccine antigen design and vaccine development, or we're doing a lot of work with the antibody isolation and characterization. And, yeah, it's been hectic.
The students and postdocs in the lab have just been working nonstop. We've got some people just working around the clock trying to get things out, shipping reagents and plasmids to researchers all over the world to try and help them. We've shipped out well over 100 packages of some of our proteins and plasmids to try and facilitate other people's research. So it's been interesting. It's been good. This is the type of research we want to do.
KUT: And just talk a little bit more about what it's like to be working in this field right now. When you talk with your colleagues, what kinds of stories do you all share? What what do you all talk about?
McLellan: We haven't found that much time to talk. We're all pretty super busy. We'll catch up later.
KUT: Jason, thank you so much for your time and your discussion today.
McLellan: Thanks for having me. It was fun.
"Now What?" is a weekly livestreamed event in partnership with UT and the Dell Medical School. Each week, KUT reporters will talk with leading scientists, researchers and thinkers from across the university about what we need to know about COVID-19.
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