Published on May 04, 2020

  • Average research and development time for a typical vaccine is about 20 years.
  • To bring a vaccine to market in 18 months, developers will have to skip some research steps and "manufacturer at risk."
  • A new COVID-19 vaccine shouldn't be given to children until in-depth testing is done to determine it's safety in that age group.
  • To make a COVID-19 vaccine available quickly, manufacturers will "scale up without knowing if the product is safe and effective, in the hopes that it is."

Video Transcript

JOHN WHYTE: You're watching Coronavirus in Context. I'm Dr. John Whyte, chief medical officer at WebMD.

There's a lot of talk about vaccines. 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. He is the Director of the Vaccine Education Center and Professor of Pediatrics at CHOP, Children's Hospital of Philadelphia. Dr. Offit, thanks for joining me.

PAUL OFFIT: My pleasure.

JOHN WHYTE: So where are we on the possibility of a vaccine? Is 12 to 18 months realistic?

PAUL OFFIT: Well, remember, the-- the average length of time it takes to do the research and research of development on a vaccine is about 20 years. And that's typical.

JOHN WHYTE: 20 years. OK.

PAUL OFFIT: [INAUDIBLE] 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 rota vaccine-- rotavirus vaccine, RotaTeq. That took 26 years. That's about average.

Um, if you go through all the steps, that's about how long it takes. Um, if you're trying to get a vaccine out in 12 to 18 months, then you're going to have to skip some steps, major steps.

JOHN WHYTE: OK. What are those steps that might be skipped?

PAUL OFFIT: So-- so, here's typically what happens. Typically what you do is you--you do so-called proof-of-concept study. This is a virus that just-- we just have in hand now 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-- the inactivated polio vaccine, with 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--


PAUL OFFIT: --papillomavirus vaccines? Do you want it to be a vectored vaccine, meaning a-- a virus-- another virus which is innocuous that you then sort of clone in the gene that you care about, which is, in this case, the gene that codes for the surface protein of coronavirus, uh, the so-called spike protein. And that's the way the Ebola virus vaccine is made. That's where the Dengue vaccine is made. Or do you want to try something that's never been done, which is a messenger RNA or DNA vaccine where basically you give the gene or message that codes for that protein, the spike protein. So you don't know.

And so normally what you would do is you would do 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 another strategies and see which one works. Then what you would do is you would do dose-ranging trials, trying to see what dose I can-- can give to induce immune response in at least in animal models correlated with protection.

Then you do larger and larger trial-- trials, usually hundreds or thousands of people.


PAUL OFFIT: Do a big dose-ranging study. Then you do a phase-three trial, the-- the definitive FDA licensure trial--


PAUL OFFIT: 3 typically is a prospective placebo-controlled trial. For our vaccine, that was a 70,000 child-- uh, uh--

JOHN WHYTE: 70,000?

PAUL OFFIT: --three-, four-year trial. And that's typical. The ROTARIX was 60,000-person trial down.


PAUL OFFIT: Conjugate pneumococcal vaccine was a 30,000-person trial. The HPV vaccine was a 35,000-person trial, roughly.

JOHN WHYTE: So-- so why are we talking about 12 to 18 months? Is it-- some people say, well, we had data on SARS, and it's similar. Others will say that the UK is-- is pretty far along. And we're really waiting on-- on many of our mitigation strategies with the hopes of a vaccine might be here soon.

PAUL OFFIT: So-- so what would you skip? I think you skip the animal-model studies. You do small dose-ranging studies, which Moderna, which 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, OK, here's a dose that induces an immune response similar to that that occurs after natural infection. I'm going to assume that that immune response is protective, even though I don't necessarily know that.


PAUL OFFIT: Then would you would do is you would-- you wouldn't go and get FDA licensure. You wouldn't. You would do, um, a-- a-- a trial, a prospective placebo-controlled trial of 1,000 or 3,000 or 6,000 people.


PAUL OFFIT: Which is-- is-- 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 without-- this is basically the Ebola vaccine model.


PAUL OFFIT: That vaccine was rolled out into West Africa without FDA licensure.


PAUL OFFIT: And-- and 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. It was sort of [INAUDIBLE].

JOHN WHYTE: And how long did that take? How long did that take?

PAUL OFFIT: How long did it take to do that? It still-- still took a couple of years to do that, to get all [INAUDIBLE].

JOHN WHYTE: And was it effective? How effective was it?

PAUL OFFIT: It was effective. It was saf-- effective. It had one mild safety problem, but it was an effective [INAUDIBLE].

JOHN WHYTE: [LAUGHS] Safety is always an issue, as you know, particularly on vaccines. So we take all of this into consideration, and there are current, you know, phase-one trials currently underway for various vaccines. What about the fact that folks are saying, you know what? We can look at the data as the most that we have, and we can make some decisions in a few months about manufacturing? Because otherwise then we're pretty far out. What are your thoughts on that?

PAUL OFFIT: Yeah, I think what they would do is manufacture at risk. In other words, they would manufacture, scale up without knowing whether or not the product that they're making is safe and effective in the hopes that it's safe and effective.

And, you know, the-- the government can mitigate some of the risk there. BARDA has had-- which is part of Health and Human Services-- has given $500 million to each of five different companies--


PAUL OFFIT: --and mitigate some of that risk.

JOHN WHYTE: And-- but again, wha-- what are your best estimates? Because in many ways we say if all the stars align-- which they don't usually, right? It usually is trial and error. We often don't get things right the first time. Do you have a sense of timelines, of what-- how you think it will play out?

PAUL OFFIT: It depends on what you're willing to accept. I mean, if-- if you're willing to accept that when this vaccine first is introduced into thousands or maybe even tens of thousands of health-care workers, front-line responders, grocery-store workers, pharmacy workers, mass-transit workers-- so I think that's who-- who this would be tried in first. Um, if you're willing to accept that-- that when those vax-- that vaccine is being given you haven't done a large safety and efficacy trial-- so 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. I mean, you're still panicked--


PAUL OFFIT: --about the virus because it's still killing a thousand or 2,000 people every day, then you're willing to accept some level of risk. Is-- if, at the time, the vaccine is-- is introduced it's-- it's killing, say, 10 people a day, may-- you may not be willing to accept that risk. And so I think it's all de-- it's all risk/benefit in medicine, right? I mean, we give cancer chemotherapies--


PAUL OFFIT: --that can kill people to people who have cancer because you're willing to take that risk because the cancer could kill you.

JOHN 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-- and sometimes people misestimate the risks of vaccines.

PAUL OFFIT: Right. So I think you, at some level, have to manage expectations. You know, I think that if you haven't given this vaccine yet to tens of thousands of people-- so you can't say with confidence that-- how effective it is, or you can't say with confidence 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. And I think it's a coronavirus, so it's going to be like other coronaviruses where the protection even following 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.

JOHN WHYTE: Right. Would we give it to children, or do we need to study them separately?

PAUL 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-- you better make sure that you have a safe product before you put it into children.

JOHN WHYTE: You talked about antibodies and immunity and were correlating presence of antibodies and immunity-- essentially give protection. What are your thoughts on some of these antibody testing and a discussion that we can give out certificates of immunity based on whether or not they have antibodies? Is the science there right now to establish that?

PAUL OFFIT: No. You need to-- 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-- with the rotavirus vaccine, even in 70,000 people, we still never had an immunological correlative 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 usually-- you-- you often don't know that. So I think that to say here's a person who has a certain level of immunity, therefore I know that they're going to be protected--


PAUL OFFIT: --it's-- it's-- we're not there yet. I think we're-- will-- I think we could get there.

JOHN WHYTE: How can we get there?

PAUL OFFIT: Oh, by-- by doing the kinds of trials where you see--


PAUL OFFIT: --OK, here's someone who's gotten the vaccine. They're protected, and we know this. They have this immune response. Here's someone who-- who got the vaccine but didn't have that immune response. It wasn't protective. So here's the immune response you need.

JOHN WHYTE: But how do we know they're-- how do we truly know they're protected? Do-- do we, uh, retest over periods of time? What-- what's the analysis there?

PAUL OFFIT: I think you-- you know it in efficacy trials. I mean, by doing large, prospective, placebo-controlled safety and efficacy trials, I think you can know what level of immunity because you're-- you're looking at that. You're looking at their immune response before they get the vaccine, after they get the vaccine. You'll see whether-- who's protected and who's not. Then you can hopefully have an immunological correlative protection.

JOHN WHYTE: Everyone's talking about reopening society and how we do that, and you had a-- a very interesting editorial in The New York Times where you talk about crowding and the coronavirus, the key to reopening. And essentially you-- you talk a lot about population density, and that's how we need to think about reopening. Can you walk us through that analysis?

PAUL OFFIT: Well, that's 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-- that population? But 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 in-- as seen in large cities, you're at greater risk. Or a population that's close together in a meatpacking plant in South Dakota, you're at great-- greater risk.

So I think, um, David Rubin, who really is the head of the PolicyLab at Children's Hospital Phila-- Philadelphia put this together, and, um, I think he's made an important contribution.

JOHN 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.

PAUL OFFIT: Yeah. I mean, that certainly would help. I-- I think the final analysis, we're going to find that we're not going to be doing that testing because we've been talking about getting testing now for a long time, and it hasn't happened. So I'm getting pessimistic about whether we'll ever have it.

So I think what you need--

JOHN WHYTE: Rockefeller foundation says we can do 30 million a week by June if we invest a hundred billion dollars.

PAUL OFFIT: I'll look forward to that. But in the meantime-- JOHN WHYTE: [LAUGHS] PAUL OFFIT: --I don't think it's going to happen. So, I mean, I think you have a sense of what the-- the case rate is in a particular setting and how dense that setting is, and I think we're just gonna see. You-- you know how certain states like Georgia or certain parts of uh, you know, Florida or Texas or South Carolina that are opening things up, and I think we're going to learn a lot in this. Well, we're seeing New York open things up much more in the Germany model. I mean, New York has kind of acquired the Angela Merkel Germany model of let's do a lot of testing, both serological testing and who's-- who's shedding virus, and then-- then we'll-- knowing that will bring people out into the community, which I think is what New York-- New York state is doing. So I give Andrew Cuomo credit for that.

But otherwise, I think we're just going to learn as we go, which, sadly, is all [INAUDIBLE].

JOHN 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, we're behind on testing? How do we really know that? PAUL 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. I-- I mean, remember, of the four human coronaviruses that circulate every year in the United States, they 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.

JOHN WHYTE: And then finally, you've been mentioning this is an RNA virus. 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's a failure of accuracy of testing?

PAUL 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 a lot of these incu-- 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-- that's short lived and incomplete, but it is protection.

I mean, you know, 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.

JOHN WHYTE: Well, Dr. Offit, I want to thank you for taking the time today to share your insights.

PAUL OFFIT: My pleasure. Thank you.

JOHN WHYTE: I want to thank you for watching Coronavirus in Context. I'm Dr. John Whyte.