The Vergecast - We ask a biostatistician about the timeline of a COVID-19 vaccine

Episode Date: September 15, 2020

There’s a lot of information coming and going about the coronavirus, and the next steps for vaccines and treatments for COVID-19 — The Verge even has a newsletter dedicated to it. But how do we asses all this information in a logical way, to prevent confusion, chaos, or something worse? The Verge’s Nilay Patel, Mary Beth Griggs and Nicole Wetsman talked to Dr. Natalie Dean, assistant professor of biostatistics at the University of Florida, about what we know so far about the timeline of a COVID-19 vaccine, and the best way to evaluate the flood of information coming in every day. We are conducting an audience survey to better serve you. It takes no more than five minutes, and it really helps out the show. Please take our survey here: voxmedia.com/podsurvey.  Learn more about your ad choices. Visit podcastchoices.com/adchoices

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subscribe ahead of the launch by just subscribing to RICO decode now. They're running highlights of Kara's last interviews. It's pretty fun. So hit subscribe over there. On this feed, you know, it's hardware season. So on Tuesdays, uh, Deter's going to host a handful of special episodes that do deep dives on different products with different guests, different reviewers. We're really excited about that. That's going to start happening as of next Tuesday. The interviews are going over to the decode feed is Decoder. So that is all of the news that's happening in October.

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joined me to interview Dr. Natalie Dean. She's an assistant professor of biostatistics at the University of Florida. She specializes in infectious disease epidemiology. She worked on the phase three Ebola vaccine trials. We wanted to talk to her all about vaccines, where they come from, how they're made, how they're manufactured, how we get them out to people. She talked a lot about just collecting the right information to make sure vaccines are effective and safe, how hard it is to make sure they're effective. You want to make sure a vaccine is effective. but if you don't have enough of the disease around it, it's actually quite hard.

And we talked about public confidence in vaccines, how you make sure people are confident in taking the vaccines. It's obviously a hot subject right now. Super fascinating conversation. My role here, you'll hear it. Nicole and Maribathar obviously are very smart science reporters. I just asked a lot of dumb questions along the way. I thought it was really fun, really interesting.

Check it out, Dr. Natalie Dean. Dr. Natalie Dean, you're an assistant professor of biostatistics at the University of Florida. you specialize in infectious diseases. Welcome to the Vergecast. Hi. Thanks so much for having me. And I'm joined by our science editor, Mary Beth and our science reporter, Nicole. How are you guys? Hi. Hey, we're doing good. Well, I wanted to start Dr. Dean by talking about COVID, sort of the general state of it. What I really want to talk about and why I have Matt Beth Nicole here is to talk about vaccine development and how it works,

because that seems like a large-scale research development, engineering, distribution problem. These two know, I think all products are kind of the same. Like, they have the same kind of challenges along the way. I think it's really interesting to think about vaccines in that context. But let's start with the general state of the virus in this country. Where are we? Where are we going? It seems like some of the numbers are trending down.

I'm from the Midwest. It seems like there's outbreaks in the Midwest. College is obviously a big deal. How are things going? It's hard to tell exactly how things are going. I mean, we definitely had a rough period with things taking off in Florida and Texas and Arizona. And that seems to have turned around, but exactly as you said, you know, it's a big country and not everything is going the same way everywhere and in places in the Midwest. And then the fact that college campuses are open and many schools are reopening and that we're heading into the fall and the cooler months.

And we really just don't know exactly how seasonality is going to impact the spread of the virus. And certainly with people spending more time indoors, that can lead to more transmission. So there's just a lot of uncertainty about how the next few months are going to play out. Do you think the sort of flu season, that sort of stuff is going to cause an acceleration of chaos the way that we've predicted? Or do you think that is being sort of managed ahead of the curve? I really can't tell. I mean, it will depend upon exactly how much seasonality impacts the spread of the virus and moving indoors and whether we can mitigate the spread through certain. measures. I think a lot of the things we are doing are going to help reduce the spread of

influenza. I mean, in the Southern Hemisphere, they saw a much milder, very little flu spread this year. And so, I mean, it makes sense that things that stop one respiratory virus will also stop another. But when there's more respiratory viruses spreading, I think it's going to contribute to a lot of confusion. So people are going to have symptoms and they're not going to know what to do. And if there's not readily accessible testing, then, you know, does that mean people have to miss school, miss work. I just think unless we have really good and easy to access diagnostics, it's just going to be very confusing for people. What's your read on the state of diagnostics here in this country? Obviously, statistics is right in the name of the field that you

work in. Do you feel like you're getting clean data? Do you think that you have an accurate view into the virus right now? Well, we know that we're still missing a big chunk of cases, or a big chunk of infections at least. I mean, certainly there are some portion of people who are not able to access testing, and then there are some portion of people who may not have symptoms at all. And then so certainly those tend to be missed unless we're sort of doing something like what certain college campuses are doing where they're frequently testing people regardless of their symptom status. So we know that we're missing information and also that the information we're getting is not going to be great from every area. There are going to be communities that tend to be,

I mean, there's places where they're doing a lot of testing, like college campuses or certain workplaces. But then we know that some of the communities that are at highest risk, like certain occupation groups, some migrant workers, you know, we're maybe not doing as much testing. And so we may be getting a lot of information, but not necessarily evenly distributed everywhere. So it can give you a misleading picture of what's going on. It seems like we're also generally getting more data about the people who've had the virus who have recovered, who are long haulers. What is the current state of treatment? Is that something that we're beginning to understand better? Yeah. So early on in the pandemic, definitely the focus was on treating people who were severely ill enough to require hospitalization.

And there's been progress there. And certain clinical trials have identified better treatments. It's ranges from just better sort of treatment protocols to also understanding that it's a multi-system disease and the role of clotting and then the use of steroids. And so there's been a lot of focus on people who have been severely ill. And so far we've had to use treatments that have been kind of off the shelf available. But now we're starting to see more targeted treatments like I think just today or just recently these targeted monoclonal antibodies are starting to go into clinical. trials. So that's great. But then we also know that there are a set of people who aren't sick

enough to require hospitalization, but may benefit from some sort of intervention. That either, you know, if we can get them earlier on in illness, maybe we can prevent them from progressing to become more severely ill or we can prevent some of these long hauler symptoms. So more focus on outpatient care and trying to intervene earlier. I think that's very promising. But just difficult to do because the numbers are really big. Have you started to see, do you think, transition to some of those trials on outpatients? Because obviously the earliest focus and the easiest focus is on the severely ill and the hospitalized. That's kind of the critical starting point.

How we started to see trials move more into the outpatient, do you think? And how far are we along in those? I'm not sure exactly where we are. I've definitely heard it discussed from the NIH and that they're thinking about a timeline of there's patients at different phases. and can we think about trials at different phases? And so trying to intervene earlier. The challenge is that you want to find some way to triage that you're identifying the people

who would benefit the most because we don't want to just start treating a lot of people who may recover on their own. And so then there's there are always some risks with the treatment. And so we really want to target individuals who are most likely to benefit. And so identifying what the risk factors exactly for who may become most severely ill. I am not sure of the status of those trials. I know they're being explored, but it's such the landscape is changing so quickly. I'm not sure.

So that feels like a good view of where we are now with the virus, testing, tracing, treatment. We have a sense of it. But what I really wanted to talk about was vaccine development, how it works, how it's going, for better or worse, it feels like everyone's holy grail of this entire situation. I think we all have a lot of feelings about that. But that's sort of emerged as the sort of gestalt emotion about it. Talk to me about how a vaccine comes about. And then I want to let these two kind of dig into the details.

But give me just a broad overview. How do you begin to make one? Who makes them? How do you test them and make sure they're effective? And then ultimately, how do you manufacture and distribute them? Yeah, well, do my best. So vaccines, they follow through this development pathway that starts in the lab. And a lot of the vaccines that we're seeing that are furthest along, they're using technologies that we can sort of modify.

So they're existing technologies that have been used for other diseases. So for example, the RNA vaccines, those are specifically designed to be used in pandemics because you can plug in the genetic code for the virus. and then you can get something up and running quickly. So there are certain vaccines that are designed to be, you know, that can be used for multiple different diseases. There are some vaccines that are, maybe you're actually growing the virus and weakening the virus or you're killing the virus. So there's going to be more specific to the actual virus, but there are technologies that we

have more experience with. So there are all these different way, you know, types of vaccines. and then they move through this pathway, evaluation pathway, it includes animal studies. And so one challenge has been that we don't have validated animal model or early on the pandemic, we didn't have an animal that replicated the symptoms. So usually you do your animal studies and then you do your inhuman trials. But one thing, one way we were able to shave off time is that for certain vaccines that we had enough safety data, the FDA allowed those products.

to be evaluated in animals and in people simultaneously. So you're running the trials in parallel. You're still collecting the animal data, but you can do that in parallel. And so they move through where we get the most data is in the clinical trials. So these are inhuman trials. And these move from very small,

where you're just, you know, including just a few people, just to make sure the product is safe or start getting safety data and you're looking at the immune response. And then those get, progressively bigger, we learn more about, you know, we can enroll different types of populations. We can see, are they, or they're listening in immune response.

But then the real proof is what we get from these large phase three trials, where you have thousands or tens of thousands of participants who are individually randomized. They receive either vaccine or placebo. And then they're followed up, and they go about their daily lives. And the fundamental question is, does the vaccine actually prevent those people from getting disease to prevent them from getting sick. And so we can, you know, have a promising immune response, but we don't always know that that translates into actual real protection. Vaccines are complicated and it's hard to predict. So these phase three trials are, this is what supports decisions

about whether a vaccine can be used in a wide population. Is it actually preventing disease? And also, they're very big studies. So they give us a lot of data, data on safety. And this is what will be used to support regulatory decisions, like from the FDA, about, you know, who can the product be used in. And you've got a lot of experience working on and designing phase three trials. You were working on the Ebola vaccine and designing the phase three trials for that. You know, this is a different disease and a different pandemic. But can you tell me a little bit about what is different between the two? And also are some of the things that you used in designing the Ebola vaccine?

are some of those same techniques going to be used in these phase-through trials which are ongoing? We've absolutely learned a lot about how to run trials in pandemics in public health emergencies, and there's a different set of considerations. Everything is just at an accelerated pace. I mean, it's just protocol writing. You may have less information about the vaccine, all the details you want. So you need to accelerate a sort of every step. But then specifically when it comes to outbreaks, I mean, one of the big challenges is that it's very

unpredictable where there's going to be transmission. And so, and a hot spots can change. I mean, it's different from endemic diseases like malaria where you know that every year, you know, there's going to be a certain number of cases. I mean, if you think about trying to set up a vaccine trial, a few months ago, you may have started in New York. But then now that wouldn't be the best place. Rates are really low in New York, and the hot spot has changed. And so one of the big things we've learned is the value of flexibility. And so being able to move the trial to reflect the changing epidemiology. And so having multiple sites, being able to add new sites over time,

and so that we can accrue information as necessary from multiple places, because what we really need is definitive, we really need definitive data about whether this works because if you start to just use the vaccine like on an emergency basis and you're not sure, then you can end up in this perpetual state of limbo. That's another lesson we've learned from Ebola. If you're not sure, then you can't go back and become sure. Like once you start using the vaccine and then you can't use a placebo anymore, then you can end up in the state where you never quite know how well the vaccine works. And when we're talking about a vaccine to be used for millions, tens of millions of people, I mean,

we want to be very confident that it is safe and effective. We've seen that limbo with other things so far in the U.S., particularly with the pandemic, with, you know, the hydroxychloroquine issue. We've seen it with plasma, where you have products being pushed out before we know things, and then the data isn't actually, doesn't end up being collected. And that's something that you've brought up on Twitter about kind of the potential drawbacks of an emergency use authorization for a vaccine product. And an emergency use authorization, EUA is something that is not fully approved by the FDA, but it's considered basically better than nothing. There's been a lot of talk about whether that would be a mechanism

used for a vaccine. And yeah, so I'm kind of wondering where you stand on that question and what you see is the pros and cons of using sort of that faster, potentially lower bar from the FDA for a vaccine. Yeah, there's a lot of discussion about an EUA pathway and what its role can be. And I do think there is a potential role. We just have to really think through all the implications because I could see a situation where you have your trial, you do an early, you know, do an interim analysis. So you analyze the data and, you know, we take looks, a certain pre-specified looks along the way. And if there's a very dramatic difference between the groups, we may meet our goal early. And so the question then is, you know, we meet that goal early. Do you need to wait for full licensure

to start using the product? And full licensure is actually quite involved. It involves a lot of follow-up data. It involves data about the manufacturing. It involved. I mean, there's a very, you know, intensive review. And there's a question of during that period, I think, after you, after you have definitive data before you have a full licensure, you know, could you use a product? And I think that that, you know, that sounds reasonable to me, but you just need to think through, are there any limitations? Because you're always sacrificing something and whether it's public confidence in case something goes wrong, whether it's your ability then to generate long-term data, long-term safety or long-term efficacy data. Like, are you giving up something? And to really,

weigh whether that's worthwhile. And I think there's just been a lack of transparency about exactly what, you know, the FDA would consider acceptable for an EUA and a discussion about what those, you know, if we issue an EUA, will we make sure that we still have a way to get the information we need in order to use the product in a wider population? And EUA is just, there's enough benefit that outweighs the risk in a small population. But if ultimately we want to get towards full licensure where we can use the product in a wide population. Do we, is there still, are we making sure we're preserving that pathway? That's what I want to make sure.

We're still going to be able to get the information we need to know that the product can work in. Older adults can work in, you know, in diverse, diverse population, all the people who would want to use the product in. Can you, I promise that I would just ask dumb questions along the way. So here I am. When you say older adults, I think about vaccines. I have a small child, right?

I think the general conception of vaccines is like babies get them over time. Is there a significant difference between vaccinating a child versus vaccinating older adult? Like I don't think we've talked about those risks quite as broadly because we're still in this development phase. What are the risk factors as you get older? What are the changes you need to make to a vaccine for those different age groups? Absolutely. Yeah.

So anyone who says they're going to ask a dumb question never asks a dumb question. So there, you know, there are differences between vaccines. and how well vaccines work in kids and how well they work in older adults because there are differences in immune systems. But we do have precedent for vaccinating older adults. We give people the flu vaccine every year. There is shingles vaccine. But one of the challenges is that since older adults have declining immune systems called immunosiniscence, they may not develop the same immune response that we need for them to be protected in the future. So it can be harder to elicit. an immune response in older adults. And so, and because older adults are exactly who we want to be

targeting, then it's very important that we collect information for them. We also want to make sure that the safety profile is there as well. But, you know, it's, yeah, it's going to be a challenge because it's possible that some of these products won't work as well in older adults. And so thankfully, there are a lot of different vaccines being developed using different technologies. And some companies have specifically targeted and been thinking about an older immune system. And so one of the ways that they screened different, you know, types early on and figured out which one they were going to proceed with was looking at an older immune system. So, yeah, I think that will become a big challenge as we progress, making sure that the vaccine works specifically in these target

populations. What are, you said different technologies, and we obviously talked about the RNA vaccines. What are the sort of spread of technologies and how do they, how would you categorize them? Yeah. So there are, and I'm a statistician, so I have a biology degree. And I understand enough because I've been asked about this enough, but it's not my expertise. But there are, yeah, there are this RNA vaccines and the DNA vaccines that are similar in the sense that you plug in the genetic code. And then there are vaccines where you hybridize kind of part of the, something on the outside of the virus, you hybridize it with another virus. And so the Oxford vaccine,

the AstraZeneca vaccine, for example, it's hybridized that protein with a chimp adenobirus. And so, and so you give someone a lot of that virus. And the virus doesn't actually replicate for that particular vaccine. But because there's, people are exposed to that surface protein, then that can induce an immune response. There are other vaccines where they do this kind of the same hybridization, but the virus actually replicates. So this was like the Ebola vaccine that I worked on, used to vesicular stomatitis virus, just as a cow virus. And that is hybridized, but it replicates. So then that can induce a stronger immune response that way. Other vaccines, you can kill the, kill the virus and activate the virus, but then it will still sort of have little bits

that the immune system can observe, and that's like what the in China, the Sinovac and SinoFarm use that technology. And then you can also weaken a virus. But that takes a long time to do. And there actually aren't that many in development because you need to make sure that it's safe. And that's harder to quality control. And there's probably another type. There's like proteins. But I think that's a reasonable summary. Yeah. And you mentioned AstraZeneca. You know, there's been a lot of talk about that vaccine, the other sort of big ones that have been getting a lot of people have been talking a lot about, you've got Pfizer, you've got Moderna, AstraZeneca. Those seem to be those sort of leading the pack, at least in terms of timelines for their phase three data. And there was big news with the AstraZeneca trial,

with the adverse event, the trial had to be paused. Can you talk a little bit about, you know, how that all went down, how unusual it was and sort of what the kind of fallout could be kind of continuing going forward? Yeah, I mean, so trials have a lot of oversight because you're giving, these are healthy participants and they're receiving some product that has not been approved, it's not been licensed, it's still, you know, experimental, candidate, you know, we're investigating it. And so these people are monitored very closely. And so if they have anything that goes on that's, that's serious, then it is captured within the context of the trial and then it can trigger an investigation. And so, you know, I think it's important for people. to understand that that is an important part of trials is this oversight and it can be very reactive. But that's meant to, that's intended to safeguard participants. And so I, you know, we don't have enough information to, we don't know all the details. We don't know whether it's linked to the vaccine. And so, so we don't have enough information. But, but, you know, I think people should understand, right, this is part of the learning process and the safeguarding process.

But certainly if we saw, you know, anything more than, right, that that could signal trouble for that vaccine or, you know, or for other vaccines that use a similar pathway, use a similar mechanism. And it's important that we learn because certainly if we saw something that was concerning in, you know, for one vaccine, then we would pay more attention with all the other vaccines. And so, and so there is this interaction interplay between all of the, you know, the different. products. But then also, I think, very important, the public confidence part. And so, you know, it's going to be very challenging, I think, because everyone's dissecting everything so closely. They're not used to how clinical trials run. And so educating people about the process like you're doing here is really important. Yeah. And one of the things that you mentioned is just, you know, we don't know all the details of this particular case. And I don't know how likely it is that we're

going to know all the details, or at least that the general public will know all these details immediately. And that's something that I've been seeing is kind of criticism that, you know, we're not seeing all the data from all of these trials. You know, how important is it during a situation like this, during an emergency and a pandemic, for people to be sharing information? It seems like it's really hard because there are a lot of companies that this is proprietary information and they're wanting to hold on to it really closely, but that's not an option necessarily when you have public health. It feels like there's a conflict there. Yeah, it's a, there's a complicated balance in what should be shared and made available. And I think, right, we are in this extreme situation.

And so, um, so one thing we should have more of is information about the, the protocols and the process and what they've decided, how they're planning to. to analyze the data, how are things defined? And we want to be able to compare notes across trials. We want to be able to understand differences. We want to feel confident that the process they laid out is reasonable. We agree that it will generate the data that we need. Because right now, it's kind of very bare bones details that are available on there's a clinical trials registry that gives you some basic information. And then there's press reports. And there's the company websites themselves. but there is a lot of detail that's missing.

And so I think that that's really important. I think safety data is very important to be transparent about. I mean, that's very critically important to the public. But it does need to go through some channel, like proper channel, because I worry the leaking and the, you know, getting covered by the press, that can lead to a lot of confusion and chaos. And so I think people feeling confident that there are, There is a process by which this information will come out through proper channels where it's like been reviewed by doctors,

you know, clinicians and it's interpreted in context. I think then people wouldn't be as desperate to pick apart everything. I'm just a little nervous about how the public response to stuff like exactly what just happened. We don't even know if it was related to the vaccine, but it definitely is going to have some impact on confidence. And then with regards to the efficacy data, though, I do have a concern that will release data too early. So then we do have a lot of experience with other trials where if something looks promising, but it's not definitive, but then it's released, people do not know what to do with that information. And sometimes that can lead to trials grinding to a halt, but then we don't have a pathway

to collect that information and to get to a definitive answer so we can end up in this limbo. So I have a different feeling about efficacy data than I do about safety data. efficacy data, I want it to go through the pathway where it's fully vetted and it's only released when there's a clear answer. So let me be a little cynical, realistic. I don't know that there's a lot of institutional trust in the United States of America right now. This is like a huge problem that affects everything. We are seeing a lot of leaks. We are seeing a lot of politically motivated data discussion.

If you are an individual smart person consumer, how should you evaluate it? the flood of information that's coming at you. Should you just ignore it and wait for Nicole to write a story? Should you go to the source? Should you demand the preprint yourself? Like, or should you just walk away and just trust? Like, I find myself struggling with that and I have a lot of access to smart people who can help me. I think for the regular person, it's even harder. What advice would you give them? I think it's important for people to remember that, you know, this process is moving really quickly, but it's not going to happen overnight. So if a trial reads out or we get something out of a trial, it doesn't mean that you're going to be able to access the vaccine

tomorrow. So, you know, let the dust settle a little bit because it'll take time from the time that you get some data to the time it's, you know, it's been reviewed by experts to the time that there is a regulatory decision to the time that then the vaccine becomes available or is even approved and then to the time that you could even access it. So there are these steps along the way. And so some very smart people, some of my colleagues wrote this article for journalists a while back. And they said, you know, information that's a few days old is more reliable than information today. And I really think that's going to be true because there's people are, you know, people are so voracious for information. But it's when it comes out in these strange ways, it can tend to be very misleading.

So, I mean, I think if you're, if you want reliable information, then letting the dust settle a little bit because it's not like the vaccine's going to be available to you tomorrow. Like, you don't need to make your decision. You know, like decisions are not being made overnight. So just letting things, getting the full picture first. And just out of curiosity, how does our approval process for vaccine in the United States compare, integrate, differ from the process in countries worldwide? Are we going to be the leader? Do we have the most stringent standards?

or if tomorrow a vaccine appears in Italy or Germany, and we're like, okay, that's it. That's the one. Usually there's pretty good alignment. Well, it depends. So different countries will have different processes. And we've seen this play out already with Russia approving a product based on less data. And China approving a product for certain populations based on less data.

So that's a lower standard. But you reference some countries that are covered by the European Medicines Agency, the EMA, which is similar to the sort of the same function as the FDA. And I'd say usually there's pretty good alignment between them, but it's not perfect. And so an example is hydroxychloroquine. And that received, you know, an emergency use authorization back in the spring. And that was actually, so that received authorization in the U.S., but that was criticized by the EMA. And I agree with the EMA in that case.

There was not sufficient evidence in order to, you know, to give that type of authorization. And it should have continued to be evaluated in the context of well-controlled trials with some limited exceptions. And that was basically what the EMA had laid out. So generally, the agencies are very similar in how they evaluate evidence. But we've seen so far in this pandemic that it's not always an exact concordance. Yeah, and I mean, I think one of the things that is so fascinating about this is that there is this timeline and it is longer than we expect. It's longer than a lot of people expect when it comes to the vaccine, which is what you're talking about. This is also going so much faster than the vaccine process normally does.

Can you talk a little bit about like how we have gotten to this point where, you know, we're in phase three trials already? this is, it seems to me from an outside perspective, pretty unprecedented when it comes to vaccine development. It's absolutely unprecedented. I mean, it's really just a real feat and for, for modern science. And I mean, we should all, I'm just so impressed by how people have come together and worked so quickly. And I mean, I think it really shows when people are very highly committed and there's, well, and also when there's a lot of financial support to achieve something, how quickly something can happen. because it's been achieved in a few different ways.

I mean, like I said, some things have been able to proceed in parallel, some of the vaccines, they were, they're modified versions of existing vaccines. And so that's allowed the process to accelerate. But then also just eliminating a lot of downtime. And it's usually kind of a period between trials where you're deciding what you're going to do next. You're planning the next trial.

You're getting it through the regulatory review. You know, you're getting the ethical review. You're doing all these steps. But now we're sort of planning the next step before we've even finished the first step. And so you can, so you're kind of ready to go right away. And the same with the manufacturing is increasing the manufacturing in parallel with while the trials are still ongoing. And so you're assuming more financial risk. Because if something goes wrong and you decide you can't proceed, well, then you, that's a, you've wasted money.

you've spent that money and you can't get that back. But the advantage obviously is making a product available sooner. So I think it's reassuring to see that it's been done in a way that doesn't cut corners with respect to the evidence that we're generating and the safety and the efficacy. But it's, yeah, and I think it will have implications for how we evaluate future vaccines and shows what's possible if we really put everything towards, goal. So you worked on that phase three trial for the Ebola vaccine. What is the, this is just like a straight management question. What does that team look like? What are the roles? Is there a manager? Is there,

are there like four researchers? Is there a, like a accountant? Like how does, how do you structure that team and like how does it operate? And then how do you make it operate faster? Yeah. So again, I'm a status tissue. So I'm, I'm part of the team, right? And so, so there's, there's someone in charge. and this is it was run out of the WHO and along with with Guinea, which is where the trial took place. So there is a team of Ghanians and folks at WHO are kind of in charge of everything. And so there are different teams. I was on the team that was writing the protocol. And so you're laying out the details and designing the analysis.

And so I helped with the statistical analysis and analyzing, interpreting the results, planning what it would look like, you know, all the details of the trial. And then there are teams who there are teams who are actually out in the field doing the trial. And so they are, it was a mobile trial. So it was used a special design where these teams would go to different communities where there have been Ebola and then literally set up tents in communities and enroll and vaccinate people there and then go back to those communities at regular intervals to do, to monitor and to see whether people had any safety concerns or whether people have been infected or become sick. So there was this, there were teams that were doing the follow-up. There are teams that are

monitoring safety. There's, yeah, there's a communications team that that figures out, you know, how do we build community trust? There's a lot of distrust about clinical research. And so, you know, how do we communicate in a way so that we can properly receive informed consent so that people are participating and they understand, you know, they're willing to do so. They're on board with that. So, yeah, there are a lot of different teams and I was one part of it. Is that 100 people? Is that 200 people? I'm just trying to get a sense of, you talk about a phase three trial and obviously we're in the details of the data you might collect and how it might work. but the mechanics of it seem fascinating to me as well, right?

You need to gather some large number of people. You need to go out to a community. You need to make them agree in an informed consent manner. They need to do it. They need to figure out. The mechanics of that seem very difficult. Is that something you can, that you think is being sped up effectively in the coronavirus context?

Is it just you add more people? You add twice as many people on the communications team and off you go. Or is it there are actually techniques or efficient? that are available? Yeah, I mean, these are huge enterprises. And most of these are being run directly by the companies. And so they have their large teams and they have their contractors. And one way we can speed things up is by having lots of sites participate.

So you're not, you don't have people, you're not enrolling people in just one place in the country. You have lots of sites. And so you can think about a parallel effort there that by having lots of participating sites, then you can enroll lots of people at different locations at the. same time. So you'll have a team then for each site that is enrolling people. So that thinking about ways that we can parallelize the, you know, the effort. And so I think, because you can only enroll so many people at one site per day, but if you have lots of sites. And so that's, so, I mean, the enrollment numbers have been really impressive, how quickly they've been able to enroll

tens of thousands of people. I mean, that's really incredible. And that's, that is, yeah, the all hands on deck effort. Yeah. Usually there's not that type of, funding for these types of trials. Do you think that, I mean, the enrollment has been really fast and they've hit their targets like pretty quickly, which is, you know, I know there was a little concern at the beginning. Do you think that is reflective of like the investment on the clinical trials team more so or of just, you know, people's interest in potentially getting a vaccine as part of a trial? Like how is there a way to kind of weigh out the impact that those things can have and like

the mechanism of moving these things forward? Yeah, I'm not sure of the exact details. My general sense is that there are a lot of people who are willing to participate, but it may not be the types of people that we want to enroll in a trial because we want to achieve a certain type of representation. And we also don't want to enroll people, you know, people like me that can spend a lot of time, you know, at home or like you need to enroll people where they're actually at some risk and can benefit. And so, so first of all, getting different types of populations, getting the broad, I mean, there's to get certain distribution across racial ethnic groups. And so that's been a big focus because we want to make sure that vaccines work well across age ranges, racial ethnic groups. I mean, we want broad representation. And so I think that's been a challenge because people who are willing to participate, you know,

may be from certain communities, but not from everywhere. And so if you really want to achieve the representation, you have to put in extra effort. And so I think that has been a challenge, but I don't know all of the details. Yeah. We've also seen if Pfizer bumped their enrollment goal, they're planning to expand, but I think it's 10,000 more people, which statistically, you're the statistician, but my understanding is that gives you additional power in your study to be able to kind of find results. But are there other reasons that they would expand numbers like that? And did that surprise you to see? It didn't surprise me to see, I mean, I'd like to see more details, but I think it's good. We have this period where we can

generate a lot of randomized evidence. And so getting as many people participating as, you know, as possible, I can see an advantage to that. The power of the trial is not driven by the total number of participants. It's really driven by how many people in the trial actually gets sick. And so that really depends on the outbreak and who is participating in the trial. And so, And so I think it's, I see it like an insurance policy to, to be able to be more likely to get towards that, that goal. I mean, clinical trials during outbreaks are also interesting in the sense that it's, they're also kind of like a, an access mechanism in a little bit. You know, you're, people have some chance of getting a 50% chance of getting placebo. But it's also a way, right, to get, yeah, to generate more data and get about, about the vaccine and, yeah, get more information.

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That's upw-R-K.com. Upwork.com. So once we're through, I mean, this is very optimistic. Let's go with it. Let's be in an optimistic place for a minute. So once we're through the trials and we say, okay, these are the two candidate of vaccines that we think are the, that have the highest efficacy and the highest safety. Then you enter a phase of manufacturing and distribution, which is actually kind of like the

hardest part of any product, right? You have to like make a lot of it and get it to all the right people at the right time. What is the scaling? How do you, once you have it, you've done it, the people in the white coats have like done test tube stuff. Again, I'm here to ask the dumb questions. How do you scale it? Is there a manufacturing process or there are robots that are available to you. What is the challenge? Because that seems like almost a harder problem. Yeah, it's definitely a challenge, particularly for some of these products. We have less experience with manufacturing them. I mean, I've seen people comment, like, how would we manufacture that much RNA? And so, and some of these vaccines have very extreme storage and transport requirements.

So they need to be kept at a cold chain that's really, really cold. And so, yeah, right, what are the, what is the plan in place, how we're going to distribute that, make that work. Yeah, I know a little bit less about the manufacturing side and all the details there, but, but I mean, if it's some of these early products, if some of these are successful, then there are going to be very real practical challenges in getting that out to people. And so, you know, right, we have to think about all steps and and so planning, you know, trying to use existing frameworks that we have, like for distributing flu vaccine, but of course they're going to need additional layers because just the logistical challenges of it having to be kept so cold. Or maybe you need more consent or you need to monitor

these people somehow to continue to monitor them for safety. And like, so what are all the extra steps that are going to need to go with it? So yeah, it's going to be challenging. Was there a method of vaccine development right now or a vaccine in development right now that has less of those challenges than others, or are they all kind of, they all need to be kept cold, and that's just the way it is. I think that the really extreme cold chain is unique to some of these early products, and some of the other ones have less extreme requirements. But I am not sure of the details for all of the vaccines.

It's not just the cold thing, right? It's not just that they have to be kept really cold. it's also that there are some vaccines, including some of the ones that are kind of furthest along and in phase three trials, they're also two-dose vaccines. Yeah, that's a great point. You have to get two of them. So it's not just a matter of manufacturing a single dose in these cases. It's getting two.

And so that's one reason that people are also looking into getting like single-dose vaccines and continuing to work on those even as we're progressing with this first round, to say at least. Yeah, and people don't always return for the second dose. I mean, we've seen that with all different types of vaccines, HPV vaccine. I mean, there's things that you have multi-doses. So how do you, what is the structure in place to get people back? And you need to be back at a certain time. And, you know, like, yeah, so that always adds a lot of complexity as well.

And of course, cuts down on how many people you can vaccinate if you need two for every person. The two doses are to boost immune response because one, on its own often does not give like enough of a jolt to your immune system to make what your body needs to, to, you know, in theory, protect itself. And yeah, I think like some of them, it's like three, four weeks in between. So it's not like you're coming back tomorrow. It's a planning thing. Yeah. And we don't know if maybe that first dose provides some partial protection or something, but really where, you know, what we're trying to measure with these trials is how well does the vaccine work under optimal conditions.

You get the full dose. Remembering, though, that when we talk about the trials and how we analyze the trials, there's usually a little period between when you get that second dose and when we start, when we actually attribute, we count disease events in our trial. Because if I got a vaccine and then I got sick tomorrow, I think I was probably infected before and the vaccine had no chance of protecting that. So there are these delays. and that slow down the trial, which is that you, in order to tell how well it works, you need to

get vaccinated the first time, the second time, and then there's a little extra delay, and then you can start measuring efficacy. Once you roll out the vaccine so unprolably, and you've kind of alluded to this several times, there's a public confidence problem, there is making sure everyone takes it, there's obviously this compliance problem and making sure you get two doses. How widely distributed do you think vaccine needs to be before it is actually effective in the way that when I said at the very beginning, sort of emotionally everybody wants it to be effective. Snap, we went back to normal. Is that a realistic thing to think about in the time frame for these vaccines? Or is there

more development of a next generation of vaccines? We're going to iterate past the cold chain problem. Where do you see? I mean, that's a lot of factors that are combining, right? There's an anti-vax movement in this country that is going to insist that Bill gave them 5G or something. How do you see that all playing into just how much vaccines need to be distributed and taken correctly before they're effective? Yeah, it's challenging. So we have this concept of the herd immunity threshold, which is sort of how many people need to be vaccinated, to be immune in order to prevent new outbreaks from forming because we can break chains of transmission if enough people are immune that we can protect people even who are not vaccinated.

And but, you know, roughly we estimate that's like around between like 50% and 67%. I mean, that's a lot of people. Of course, there's still, there's more complications to that. And that's just sort of a rough average. But, you know, the way that I think we need to think about it is the vaccine is one tool and what are our other tools. And all of these combined together is what drives our numbers lower and helps us live safely and helps protect us. And so there are some tools that we have that are not so sustainable, like closing things. And, you know, like we don't want to have to keep that up forever.

But there are some things I think we can do, like having a robust testing, having contact tracing in place, having better ventilation, things like that. We may have these different discoveries that can give us some level of control that will help us so that the vaccine doesn't need to do the full lift. Another challenge, though, is that uptake of the vaccine may vary across different populations. So where there are pockets of populations that don't take up the vaccine, then those pockets will remain at risk. Or there may be populations where the vaccine doesn't work as well. So if we find that the vaccine doesn't work as well in older adults, then those populations will remain at risk and right. And that's where we're really going to need potentially layering different vaccines

that have different attributes to sort of fill in the gaps. But yeah, I mean, it's definitely going to be a challenge if there is a lack of public confidence and there are populations that just refuse to take the vaccine no matter what. And then, you know, and then we really have to focus on our communications plan and the transparency of the process. And I mean, that's, we've in, you know, Operation Warpspeed has invested so much money in developing vaccines, but very little in the social and behavioral sciences that we need to actually communicate with publics about vaccines. And so I hope there's more emphasis on that. And then figuring out all the other ways that we can continue to keep people safe while resuming as much normal life as possible. So all the other

layers that help protect us. How have you seen the anti-vax movement in this country? I mean, this is for better or worse, right? This is just fuel on that fire. Have you seen it grow? Have you seen it affect the development of vaccines? Have you seen any responsiveness from the people in your field to the fact that, yep, the thing, assuming that all goes well, we eventually had this product and it will be met

with exactly this kind of resistance? Is that something that crosses your radar? or is it something that your community is thinking about? Absolutely. I mean, there are researchers in my field whose entire research focuses on vaccine confidence and vaccine hesitancy. And my concern is that we don't want to give people

any more reason to be concerned about vaccines for this disease or any diseases. So we want to make sure that the process is playing out in a transparent, trustworthy way so that we don't risk uptake of childhood vaccines. I mean, uptake of all the other things. So I am nervous that if something does go wrong, that it would have downstream effects

that are much broader than even COVID because we've already seen rising vaccine hesitancy just in general, these trends. So I do think about that, and that's why that we can't rush the process. I mean, I think it's an emergency and we want to get something out quickly, but it really has to follow a certain set of steps

because if anything goes wrong, it's really hard to, you can't put that genie back in the bottle. And so I do worry about that. Is there a difference, do you think, between, you know, you have sort of anti-vax sentiment, vaccine hesitancy around sort of our well-established vaccines.

And then we have this, which is a brand new product, which has never, you know, never existed before a couple months ago. you know, is there a difference between how people might be hesitant about like a measles vaccine versus hesitancy about this vaccine? And how can we communicate the difference between those types of hesitancy? Absolutely. I think we have to acknowledge that this is moving very quickly and that can bring up some anxiety. And, you know, and we can, these are not anti-vax people. These

are people who believe in science. I think we just have to acknowledge that it is moving very quickly. And people, you know, want to feel confident. I mean, this, a vaccine is something that healthy people take. And so, you know, this is why we need the risk-benefit profile to be immaculate. So you're going to give something to tens of millions of people. I mean, you need to be very confident that it's right, that it looks good, that, you know, confident in the data. So, so, yeah, I think this is why communications plan is so important because it is, it does make sense to me that people have concerns and just the way things have played out in the medium been discussed and pressures on the FDA and and so yeah we need a communications plan that identifies yeah what are

people's concerns and integrates that back into our process i mean if people if there's something that we can be doing better in the and how the process is playing out so that to increase transparency that would help build confidence then we should we should be doing that so we mentioned you know about how the company, what data the companies are releasing. So maybe that means they need to be releasing more information up front so that we can increase confidence. So this is why this social and behavioral research is so important. Can we use the same communication strategies that we use for like anti-vax sentiment that is kind of pegged to like autism and measles and conspiracy that can we can we transfer those strategies or is this just something different because as you said, there are kind of valid

concerns about the safety of something new? Like, do we have to be developing a new strategy that's different from the one we have already for vaccine hesitancy? I admit this is not in my, this is just not my, this is like people's whole area of research and it's just not mine. So I'm, so I'm reluctant to comment too much. I will say this is, this is definitely a unique situation. And so whatever tools we have likely will need to be modified, uh, because it is just a different set of, set of concerns, a different set of challenges. There are people working on that, but I hope they're receiving the funding and support that they need to be able to implement that very important research. Sometimes that's very neglected. That's something that's come up a few times during

this conversation is funding. And funding for the vaccines, funding for the social science research. And you've talked a little bit about how much funding we have put into this particular effort. Can you talk a little bit about what happens when that funding isn't there and or it disappears? Because I think that we've seen that happen in the past with previous vaccine efforts. Yeah, I mean, there's a reason we weren't further along with the SARS vaccine. I mean, there's a reason we weren't further along with the MERS vaccine. Part of it is that there's not a clear pathway for how to evaluate a vaccine because, well, there's no more SARS. How do you tell if it ever works?

And so they're, I'm talking about the original SARS. And with MERS, Middle East Respiratory Syndrome, it's also very difficult to evaluate a vaccine because cases are so sparse. But that is a, so there have been groups like there's the Coalition for Epidemic Preparedness and Evasion Sepi, which has funding from Gates and Welcome Trust and these other groups. And they, and so they're trying to pick up some of the funding for some of these neglected vaccines. because what happened with the SARS vaccine is, you know, there wasn't a pathway, but also there just wasn't any more funding. So we didn't make as much progress. There's more progress we could have made before, like with some of the looking at what the immune system response would have been, we could have gotten further. But it was just stalled out.

And so, yeah, so funding ends up being definitely a challenge, particularly for some of these sort of early phase trials, getting all the duct. So I've been working with the World Health Organization for the last five years on this research and development blueprint initiative. And part of it is about there's more that we can do in advance of epidemics to be prepared to evaluate diagnostics, treatments, and vaccines. And so doing some of that work, that like phase one, phase two work before an outbreak occurs so that when an outbreak occurs, we can go right into phase three. and so we can go right into the field trials where you're vaccinating tens of thousands of people. And so, but that requires funding and support to do that. You've talked a lot about this in the public health context. That's obviously some of the work you've done.

It also just, it feels like if you're, I don't know, the CEO of Pfizer, you're looking at a pot of gold if you can get there first. Is that kind of market dynamic having an effect on the rush to print stuff early or to leak information and say we're going to win? because it does seem like we're seeing some of that play out, and it feels like it's harder and harder to evaluate the information because that kind of financial motivation is there, that business motivation is there. Yeah, it's there in one way, but then if the way they get there is by accelerating too quickly, then there's a risk that it could really backfire. So I think the companies are probably, there is definitely a level of caution because their whole reputation is at stake. if you don't want to be the company that moved a vaccine very quickly and then there was some sort of safety issue. I mean, they have big profiles, these companies, so they don't want that to go out the window because of a bad vaccine. The bad PR for these companies can linger for a very long time.

So there's competing incentives. All right. So we're just at the end here. Thank you for giving us so much of your time. What happens next? If you're looking at this and you've listened to this conversation and you know, you know, you should wait a couple days before evaluating the information. Maybe you're rushing to sign up for one of those 10,000 people with Pfizer trials.

Like, what happens next? What are the next steps along the road that the average person should be looking for? The next few months should be very interesting. I think we're going to start to see readouts from trials. And I, yeah, I mean, depending on what happens with any of these trials. I mean, do they meet the thresholds we have set? Are we adhering to the thresholds we've set? I mean, I, we basically, we're looking for a vaccine that is more than 50% effective at reducing

disease. And we want to feel confident that it's not less than 30% effective. So these are the, this is what has been set out by the FDA. And so, we want to make sure that that's the, yeah, that's the level of evidence that that we're adhering to. But yeah, we are going to start to see, you know, if any of these trials are able to stop early because they get a very compelling result early, then we'll start to see that data. And then, Then we could see something like an EUA. And I really am not sure what impact it's going to have on all of the other products and development.

I think it's going to be a bit chaotic because this is a very unique situation in that there's so many trials, companies working on this same thing at the same time, and where we're talking, you know, they're overlapping. The results could come out within weeks of each other. So, you know, I really am not sure. I think it might be a little chaotic in the vaccine world. But again, from the individual perspective, right, you're not going to suddenly be able to access the vaccine, although you may see a lot of drama playing out in the news. Well, Dr. Dean, thank you so much for your time.

It was really great. We'll have to talk to you again soon. Great. Thanks. Take care. All right, my thanks to Dr. Natalie Dean for joining us talking all about vaccines. Also, of course, thanks to Maribeth and Nicole for actually knowing what they're talking about, doing good. great interview. And just a reminder, Marybeth's newsletter, Antivirus is out now. You can sign up for it at

the verge.com slash antivirus. It's super interesting. She's tracking all the latest research and development of vaccines and ways to fight the virus. It's an engineering challenge, a science challenge, community information challenge. Super interesting. Once again, the verge.com slash antivirus. We'll be back on Friday with a chat show. And like I said at the top, next Tuesday, Deeter's taking over for some special episodes around hardware season. And later in October, interviews come back, is Decoder with the United Patel over on the Recode Decode feed. Subscribe to that now. Let's not care us highlights.

So great. And we'll see you in October with Decoder. Thanks a lot.