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Vaccine trials have several phases. The final, phase 3 trial usually includes 30,000 participants. There are now five COVID-19 vaccine trials in phase 3.
The COVID-19 trial vaccines do not include the live coronavirus. Therefore, the studies need sufficient time for people in the placebo group to get sick with COVID-19 — while also being instructed to take disease prevention precautions like mask-wearing — to study whether the vaccine works when compared with the vaccine group.
Russia has approved a COVID-19 vaccine called Sputnik V without finishing phase 3 trials. Previous vaccines for other diseases have looked successful in phases 1 and 2 but have failed in phase 3, not leading to a vaccine.
A vaccine's efficacy depends on two main things: how contagious the virus is and how effective the vaccine is. If the reproduction number of SARS-CoV-2 is assumed to be 2, a 75% effective vaccine would require vaccinating two thirds of the population to stop the spread of COVID-19.
Sharing study data could reassure people that an approved vaccine is safe and effective.
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. Everyone's talking about vaccines. How realistic is it that we're going to have a vaccine perhaps early next year?
To help provide insights, I've asked Dr Paul Offit. He is the director of the Vaccine Education Center and professor of pediatrics at Children's Hospital of Philadelphia. Dr Offit, thanks for joining us again.
Paul Offit, MD: Thanks for asking me.
Whyte: Let's start off with what's in the news. Russia has said they've approved their vaccine. Let's take a step back; can you help viewers understand exactly what the process is for vaccine approval, typically, here in the United States? I think people are confused; we throw out different phases or stages. Can you give us a quick primer on that?
Offit: Sure. Typically when you make a vaccine, the timeline is about 15-20 years. It starts with so-called preclinical trials, meaning you have an animal model where you inoculate the animal, whether it's a mouse or a monkey or a ferret or a Syrian hamster, with the virus you are interested in. It causes the disease you see in people.
Then you give your vaccine and see if you can prevent that disease. And most importantly, you can literally dissect out that part of the immune response that's associated with protection. Those are called proof-of-concept studies.
Then you go to phase 1, which usually includes 20-100 people, and then those are dose-ranging trials, meaning you have the strategy you're going to use. Let's say it's an inactivated virus. Then you give different doses to see which one seems to work the best in people in terms of inducing an immune response safely.
Now you do phase 2 trials, which is now not 20 -100 people but hundreds of people, to make sure that the vaccine consistently induces that immune response you think is going to be protective, but you don't know that yet and that it's safe. So it doesn't have any uncommon side effects.
Then you do the key thing, which is phase 3. That's the only way you can tell whether your vaccine works. So now you're in tens of thousands of people, typically a 30,000-person trial, which is what people are moving forward with now. Some people get the vaccine, some people don't get the vaccine. Then you can see whether or not your vaccine works and at least that it doesn't have a relatively uncommon severe side effect.
That typically takes 15-20 years.
Whyte: Right. So there are at least 27 candidates here in the United States. There are five in active phase 3. But even just in terms of timeline, Moderna and others have talked about — you mentioned the 30,000. Most of them are at 5000, roughly, today. So they still need to enroll more people. And then, correct me if I'm wrong, they're not being injected with the virus. They still have to go out in the community, be infected with the virus, right? And then they still have to be compared with a control group. Is that right, and how does the timeline add up when people are saying early next year?
Offit: That's exactly right. If you, first of all, take Moderna as an example. Moderna is a two-dose vaccine trial. So you inoculate 30,000 people either with vaccine or placebo. If you could do that in a month, you would set the record. I mean, that is ridiculously fast.
Let's assume that. Let's assume that by the end of August — which is not going to happen — 30,000 people are recruited and 30,000 people get dose one. Then you have to wait a month to give them that second dose. Now, let's say in the month of September, everybody gets their second dose, which would also be remarkable. Then you wait 2 weeks because that's when you get this sort of full immune response after dose two.
Now you're in the middle of October. Then you have to hope that enough people in your placebo group get infected — not just infected, but sick. Remember, you're looking to prevent moderate to severe disease; that's the clinical endpoint. And at the same time, you're telling them to wear masks, to wash their hands, to maintain social distance. You're not sending them all to Sturgis, South Dakota, to hang out at a bikers' rally. I mean, you're actually instructing them not to get sick, even though, at some level, they're going to have to get sick in order for you to know whether it works. I can't imagine we would have data on this by any earlier than early next year.
Whyte: So how has Russia announced approval of a vaccine? Which, interestingly, as you know, is called Sputnik V. They're approving it right at phase 2. It hasn't even finished phase 3 or started phase 3, to some degree.
Offit: Who knows? I mean, Russia's a black box when it comes to science. And I think it's ironic that they named it Sputnik V because Sputnik was in space for 5 days before we ever knew that it was there. I mean, they're secretive.
My understanding of that vaccine is that it's two separate replication-defective adenoviruses that express that spike-protein gene, given as a two-dose vaccine. Again, they can't possibly have finished the phase 3 trial. That's not possible. So when Vladimir Putin says it's "effective," he can't possibly know that.
What worries me in all of this is that our administration may feel pressure to do something quickly which shouldn't be done.
Whyte: There are many vaccine trials that have failed phase 3 endpoints. Isn't that right?
Whyte: So it's not as if even with encouraging data in phase 2 that the majority are successful at phase 3. Is that correct?
Offit: Yes, probably most egregious was an RSV vaccine. It looked good in phase 1 and phase 2, and then when you got to phase 3 it was an utter failure.
Whyte: You're on the FDA advisory committee that addresses approval for immunizations, makes recommendations. Do you expect this to come to the advisory committee?
Offit: Yes. I base that on Stephen Hahn, who's the FDA commissioner, who made a statement in the Journal of the American Medical Association just in the past few days, and I'll read it to you. This is what he said: "Given the widespread potential use of the COVID-19 vaccine, transparent discussion at FDA's Vaccine Advisory Committee will be needed prior to vaccine authorization or licensure to ensure a clear public understanding of the evidence supporting vaccine safety and efficacy." So as long as he means that, then I think he will go to that committee.
Whyte: But let's get in the weeds a little. And I apologize to some of our viewers, but he has also said that they could utilize emergency-use authorization for the vaccine, right? So that's not a true full approval. How does that impact decision-making about the vaccine?
Offit: That's a great question. I mean, when a vaccine is licensed, it's very clear what the rules are. The FDA, in fact, put out a statement recently. It's a 30-page paper called FDA Guidance to Licensure of COVID-19 Vaccines, but the word was "licensure," not "approval" or "authorization." You had to go to page 19 to look at the emergency-use authorization criteria, which were loose.
And I think that's what worries people, because the typical licensure timeline is about a year. Expedited reviews are 8-9 months. We can't wait that long. So I think it makes sense to do this through the emergency-use authorization.
What worries me is that that may be [seen] by the administration [as a reason] to truncate things — say, phase 3 trials — and say, "Look, we've got thousands of people. Looks like it's safe. The immune responses are good. Let's get it out there because people are dying, without finishing a phase 3 trial," which I think would be a mistake.
Offit: I hope we can do better than that. The answer to the question is, what percentage of the population do you need to vaccinate in order to stop spread? It depends on two things: one, the contagiousness of the virus; and two, the efficacy of the vaccine.
If you assume the contagiousness of this virus, the so-called R0, is 2 — meaning you will infect two people during your day assuming you have your normal day, they're all at risk, and you're sick or you're shedding virus — and if you assume efficacy of 75%, which would be reasonable (I think it's doable), you would have to vaccinate two thirds of the population to stop spread. If the efficacy is 50%, you'd need to vaccinate 100% of the population to stop spread. So 50% would make it hard to stop spread.
Whyte: Do you know if children are being enrolled in the vaccine trial?
Offit: As far as I know, the trials that are currently in phase 3 now are all people over 18. So no.
Whyte: That's what I thought. And what about over 65?
Offit: Yes, definitely. I mean, that's a priority group — not just over 65 but over 65 with certain health issues.
Whyte: What about data that suggest that in people who are overweight and obese, the vaccine may be less effective? Is there any credence to that, or do you think that's just pure conjecture?
Offit: No, I think that's possible. I mean, certainly that is a group that is at greater risk for severe, and occasionally fatal, infection, and it may be because they're not adequately making an immune response to rid themselves of the virus.
Whyte: You've been talking a little bit about monoclonal antibodies, and maybe that's a more effective strategy. Have we missed our timing for that in terms of what we would have to do in order to scale up production? And can you tell our viewers what monoclonal antibodies do?
Offit: Monoclonal antibodies are synthetic antibodies directed against one part of one protein of the virus. So in this case, it's the spike protein. It's that one part of the spike protein called the receptor-binding domain.
We now can make much longer-lived monoclonal antibodies. So instead of having sort of a half-life of only 3 weeks, it can be protective for as long as 6 months.
I think that if these vaccines swing and miss early, then the monoclonal antibody strategy would be potentially workable, but it's hard because you'd much rather have someone making a so-called active immune response [to fight] the virus and make their own antibodies. When you give passively those antibodies, they'll eventually fade, and then you would have to give them again.
Whyte: Would that reinforce the concept that if you have COVID at one point that you do have some immunity afterward? I mean, it's not exactly the same analogy, but there's some basis for that, then.
Offit: No, I think that's right. So, for example, you give this antibody. You can measure the quantity of neutralizing antibodies in the person's blood and see who's protected and who's not, and get a sense of exactly how much neutralizing antibody is necessary to protect. So I think it would, in some ways, also inform the vaccine.
Whyte: Are we putting too much stock in a vaccine and we don't have a plan B? And the reason why I say that is because many people are saying we don't open up the schools until we have a vaccine. We don't return to work until there's a vaccine.
And then we did a survey at WebMD, and it has been replicated elsewhere, showing that more than half of people say they're not going to get a vaccine, or a significant percentage say, "I'm not going to get it in the first 3 months; I'm going to wait because I'm concerned that it's been rushed. So, Dr Offit, I'm going to let you get it and see how you do, and then I'll consider it." How does that help if we don't have a plan B? If, for some reason, we don't have a vaccine, or even if we do but the majority of people don't take it?
Offit: I think we can have a vaccine. I'd be really surprised if, given the neutralizing antibody responses that have been evoked by these vaccines, that these vaccines weren't at some reasonable level effective. I don't know how long they'll be effective, but I think they would be effective, certainly as long as monoclonal antibodies would be effective.
In terms of people who are choosing, saying they wouldn't get a vaccine, I don't think the question is right. If you ask me the question — Would I get a COVID-19 vaccine? — my answer would be no, not until I see the data. And not only just the data, the data in my age group, people who are over 65. What are the data in my age group that make me feel better about getting that vaccine? Because some vaccines don't work very well in older people. Let's see whether this one works well.
So I think the better question would be: Would you get a vaccine that was, say, 75% effective, could protect you for a year, and had been tested in 20,000 people and shown to be safe? And I think there the numbers would be higher.
But it's also going to depend on the virus, to what extent the virus is still doing the kind of damage that it's doing. I don't actually worry about that. I think with a successful vaccine, we'll be able to get it out there.
Also, remember that the people who initially are going to get it are the highest-risk groups. That's phase 1, which is about 120 million people.
Whyte: Do you have enough time to truly assess safety data?
Offit: Maurice Hilleman, who I consider to be the father of modern vaccines, I think said it best. He said, "I never breathe a sigh of relief until the first 3 million doses are out there." That's still true. That's not going to be prelicensure or preapproval. So you just have to make sure there are systems in place — and there are, like the Vaccine Safety Datalink — that when a vaccine now is not just in 20,000 people but in 20 million people, you can make sure that it doesn't have a rare adverse event, as rare as one in a million, and we can pick that up through those systems.
Whyte: Dr Offit, I want to thank you for taking time today to provide your insights and help us understand how vaccine development works and what we should be asking when a vaccine's approved.
Offit: My pleasure. Thank you.
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Cite this: How Likely Is a COVID-19 Vaccine by the End of the Year? - Medscape - Aug 14, 2020.