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Developing a COVID-19 vaccine in 12-18 months would require skipping "major steps," such as proof-of-concept studies, larger dose-ranging trials, and getting FDA licensure.
To begin manufacturing a vaccine in a few months with the currently available data would be doing so at risk.
Any protection from a natural infection of COVID-19 will probably be short-lived and incomplete.
The only way to get true population immunity is with a universal vaccine.
This transcript has been edited for clarity.
John Whyte, MD, MPH: You're watching Coronavirus in Context. I'm Dr John Whyte, chief medical officer at WebMD.
There's a lot of talk about vaccines [against COVID-19]. Some folks are saying it's going to be available by the fall. Others are saying it's years away. To get insight into how realistic vaccine development is, I've turned to Dr Paul Offit, director of the Vaccine Education Center and professor of pediatrics at Children's Hospital of Philadelphia. Dr Offit, thanks for joining me.
Paul A. Offit, MD: My pleasure.
Whyte: So, where are we on the possibility of a vaccine? Is 12-18 months realistic?
Offit: Well, remember that the average length of time it takes to do the research and development on a vaccine is about 20 years. That's typical.
Whyte: Twenty years. Okay.
Offit: I was fortunate to be part of a team at Children's Hospital of Philadelphia that created the strains that became the bovine-human reassortant rotavirus vaccine, RotaTeq. That took 26 years. That's about average.
If you go through all the steps, that's about how long it takes. If you're trying to get a vaccine out in 12-18 months, then you're going to have to skip some steps—major steps.
Whyte: What are those steps that might be skipped?
Offit: Here's typically what happens. Typically, you do a proof-of-concept study. This is a virus that just got in hand only a few months ago. So the question is: How do you want to make the vaccine? Do you want it to be a whole, killed virus like the inactivated polio vaccine or hepatitis A vaccine? Do you want it to be a live, weakened form of the virus like the measles, mumps, rubella vaccines? Do you want it to be just a purified protein like the hepatitis B or papillomavirus vaccines?
Do you want it to be a vector vaccine? Meaning that another virus that is innocuous has the gene that you care about cloned in—in this case, the gene that codes for the surface protein of the coronavirus, the so-called spike protein. That's the way the Ebola virus vaccine is made. That's the way the dengue vaccine is made. Or do you want to try something that has never been done, which is a messenger RNA or DNA vaccine, where you basically give the gene or message that codes for that protein, the spike protein?
Normally, what you would do is a proof-of-concept. You would have an animal model that would get sick when you inoculated it with COVID-19. Then you would try one or other strategies and see which one works. Then you would do dose-ranging trials, trying to see what dose you can give to induce an immune response in at least an animal, to correlate it with protection.
Then you do larger and larger trials, with usually hundreds or thousands of people—a big dose-ranging study. Then you do a phase 3 trial, the definitive FDA licensure trial, which is typically a prospective placebo-controlled trial. For our vaccine, that was a 70,000-child, 3- to 4-year trial. And that's typical. The Rotarix trial was a 60,000-person trial. Conjugate pneumococcal vaccine was a 30,000-person trial. The HPV vaccine was a 35,000-person trial, roughly.
Whyte: So why are we talking about 12-18 months? Some people say, "Well, we had data on SARS, and it's similar." Others will say that the UK is pretty far along. We're really waiting on many of our mitigation strategies with the hopes that a vaccine might be here soon.
Offit: So, what would you skip? I think you skip the animal-model studies. You do small dose-ranging studies, which Moderna, who is making an mRNA vaccine, has already done, or Inovio, which is making a DNA vaccine, is in the midst of doing. And then you say, "Okay, here's a dose that induces an immune response similar to that which occurs after natural infection. I'm going to assume that that immune response is protective, even though I don't necessarily know that."
You wouldn't go and get FDA licensure. You wouldn't. You would do a prospective placebo-controlled trial of 1000 or 3000 or 6000 people, which may or may not be enough to tell you whether it's effective. It's certainly not enough to tell you whether or not you have any sort of uncommon side-effect problem. And then you would roll it out. This is basically the Ebola vaccine model.
That vaccine was rolled out into West Africa without FDA licensure. So then, when you gave it to tens of thousands of people, you could see how effective it was. You could see how safe it was. And then you got a license. That's the way that worked.
Whyte: How long did that take?
Offit: It still took a couple of years to do that.
Whyte: And was it effective? How effective was it?
Offit: It was effective. It had one mild safety problem, but it was an effective [vaccine].
Whyte: Safety is always an issue, as you know, particularly for vaccines. So we take all of this into consideration, and there are phase 1 trials currently underway for various vaccines. What about the fact that folks are saying, "You know what? We can look at the data that we have, and we can make some decisions in a few months about manufacturing. Because otherwise, we're pretty far out." What are your thoughts on that?
Offit: I think what they would do is manufacture at risk. In other words, they would manufacture and scale up without knowing whether or not the product they're making is safe and effective, in the hopes that it's safe and effective.
You know, the government can mitigate some of the risk there. BARDA [Biomedical Advance Research and Development Authority], which is part of the US Department of Health and Human Services, has given $500 million to each of five different companies to mitigate some of that risk.
Whyte: But again, what are your best estimates? We say, "If all the stars align," but they don't usually, right? It's usually trial and error. We often don't get things right the first time. Do you have a sense of the timeline, how you think it will play out?
Offit: It depends on what you're willing to accept, if you're willing to accept that when this vaccine is introduced into thousands or maybe even tens of thousands of healthcare workers, frontline responders, grocery store workers, pharmacy workers, mass transit workers—those are who this would be tried in first—that the vaccine is being given without a large safety and efficacy trial. To some level, it may not be as effective as you think or may not be as safe as you think, but you're scared of the virus.
If you're still panicked about the virus because it's killing 1000 or 2000 people every day, then you're willing to accept some level of risk. If, at the time the vaccine is introduced, it's killing 10 people a day, you may not be willing to accept that risk. And so it's all risk versus benefit in medicine, right? We give cancer chemotherapies that can kill people to those who have cancer because you're willing to take that risk, because the cancer could kill you.
Whyte: But we're often not having that narrative in the media. We're just talking about a vaccine being available. And you're right. There will be caveats to that and a discussion of risk versus benefit, and sometimes people misestimate the risks of vaccines.
Offit: Right. So, at some level, you have to manage expectations. If you haven't given this vaccine yet to tens of thousands of people—so you can't say with confidence how effective it is, or you can't say with confidence that it doesn't have an uncommon side effect—then you have to manage that expectation.
The other expectation you have to manage is how well this vaccine will work. It's a coronavirus, so it's going to be like other coronaviruses where the protection even after natural infection is usually short-lived and incomplete, meaning it's not going to last for decades; it may last for a couple years. And it's not going to protect you against asymptomatic reinfection or even mildly symptomatic reinfection. You're trying to just keep people out of the intensive care unit and out of the morgue.
Whyte: Right. Would we give it to children, or do we need to study them separately?
Offit: I certainly wouldn't give it to children until you are very, very confident that this vaccine is safe and effective, because children don't die from this virus. So you better make sure that you have a safe product before you put it into children.
Whyte: You talked about antibodies and immunity, and we're correlating presence of antibodies with immunity—essentially giving protection. What are your thoughts on some of these antibody tests and the discussion about giving certificates of immunity based on whether or not someone has antibodies? Is the science currently there to establish that?
Offit: No. You don't really know what level of immunity is protective. That's why you do prospective placebo-controlled efficacy trials, because then you may know that.
I mean, we never do that. With the rotavirus vaccine, even in 70,000 people, we still never had an immunologic correlate of protection, but we knew the vaccine was safe and effective. And now the vaccine is in millions of people and we know it's safe and effective. But you often don't know that. So I think that to say, "Here's a person who has a certain level of immunity and therefore I know that they're going to be protected," we're not there yet. I think we could get there.
Whyte: How can we get there?
Offit: By doing the kinds of trials where you see: "Here's someone who's gotten the vaccine. They're protected, and we know this. They have this immune response. Here's someone who got the vaccine but didn't have that immune response. It wasn't protective. So here's the immune response you need."
Whyte: But how do we truly know that they're protected? Do we retest over periods of time? What's the analysis there?
Offit: I think you know it in efficacy trials. By doing large, prospective, placebo-controlled safety and efficacy trials, I think you can know what level of immunity you need because you're looking at that; you're looking at their immune response before they get the vaccine and after they get the vaccine. You'll see who's protected and who's not. Then you can hopefully have an immunologic correlate of protection.
Whyte: Everyone's talking about reopening society and how we [should] do that. You had a very interesting editorial in The New York Times where you talk about crowding and the coronavirus, and the key to reopening. Essentially, you talk a lot about population density and that that's how we need to think about reopening. Can you walk us through that analysis?
Offit: The one thing that came through again and again is the degree to which the virus is being transmitted from one person to another. How common is it in that population? If it's a population that's fairly spread out, you're at lesser risk in reopening, whereas a population that's very close together—as seen in large cities—will be at greater risk. Or a population that's close together in a meatpacking plant in South Dakota will be at greater risk.
David Rubin, who is the head of the PolicyLab at Children's Hospital of Philadelphia, put this together, and I think he's made an important contribution.
Whyte: And a key component to that is testing, correct? We have to do much more testing, much more frequent testing to sort some of these issues out.
Offit: That certainly would help. We're going to find that we're not going to be doing that testing because we've been talking about getting testing for a long time, and it hasn't happened. So I'm getting pessimistic about whether we'll ever have it.
Whyte: The Rockefeller Foundation says we can do 30 million a week by June if we invest $100 billion.
Offit: I'll look forward to that. But in the meantime, I don't think it's going to happen. You have a sense of what the case rate is in a particular setting and how dense that setting is, and I think we're just going to see. You know how certain states like Georgia or certain parts of Florida or Texas or South Carolina are opening things up? I think we're going to learn a lot in this. We're seeing New York open things up much more in the Germany model. New York has kind of acquired the Angela Merkel–Germany model of "let's do a lot of testing, both serologic testing and who's shedding virus," and knowing that will bring people out into the community. I think that is what New York State is doing, so I give Andrew Cuomo credit for that.
Otherwise, I think we're just going to learn as we go.
Whyte: Sweden announced this week that they think they have 30%, 40% herd immunity already, and that by June it may be as high as 50%. Is that realistic when we don't have a vaccine, we don't have effective treatments, and we're behind on testing? How do we really know that?
Offit: I think Sweden made a mistake. I mean, they certainly have the largest number of deaths per million people in the world by choosing to do what they did, which was to take a laissez-faire attitude. Their bet, their gamble, if you will, is that they'll have enough population immunity from natural infection that they will then stop the spread of the virus. I don't think that's going to happen. Remember, of the four human coronaviruses that circulate every year in the United States, they [all] circulate every year in the United States. I think the only way we're going to get true population immunity, as Bill Gates says, is with a universal vaccine. I think that's right.
Whyte: Finally, you've been mentioning that this is an RNA virus, and most of the time they're not that complicated. But there's been discussion lately about reinfection. Do you think reinfection with coronavirus exists, or do you think that it's a failure of accuracy of testing?
Offit: No, I think it may exist. I do think, though, that natural infection probably protects you against moderate to severe disease associated with reinfection, which is true about a lot of these viruses—respiratory or intestinal viruses—that have relatively short incubation periods, where viremia is not part of pathogenesis. Usually you get protection that's short-lived and incomplete, but it is protection.
A natural rotavirus infection will protect you against moderate to severe disease associated with reinfection. The same thing is true with the vaccine. I think you're not going to have a vaccine that does better than natural infection. That's typically true. It's the rare vaccine that does better than natural infection.
Whyte: Dr Offit, I want to thank you for taking the time today to share your insights.
Offit: My pleasure. Thank you.
Whyte: I want to thank you for watching Coronavirus in Context. I'm Dr John Whyte.
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Cite this: The COVID Vaccine Timeline: Is 12-18 Months Realistic? - Medscape - May 04, 2020.