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[OBY: From the campus of Harvard Medical School, this is ThinkResearch, a podcast devoted to the stories behind clinical research. I'm Oby.

[brendan]: And I'm Brendan, and we're your hosts. ThinkResearch is brought to you by Harvard Catalyst, Harvard University's Clinical and Translational Science Center.

[oby]: And by NCATS, the National Center for Advancing Translational Sciences.

[brendan]: In a year unlike anything we have experienced before, scientists and doctors have become essential heroes more than ever. As COVID-19 cut across 2020, clinical researchers around the world began committing their life's work to finding a vaccine.

Now, with the search for a vaccine underway, Dr. Katy Stephenson talks with us about the unique experience of being at the front lines of infectious disease research and what she has seen and learned this year. Dr. Katy Stephenson is an assistant professor of medicine at Harvard Medical School, an infectious disease physician, and director of the Clinical Trials Unit at Beth Israel Deaconess Medical Center.

Dr. Stephenson, thank you for joining us. Welcome to the show.

[katy stephenson]: Thank you for having me.

[brendan]: You're the director of the Clinical Trials Unit at the Center of Virology and Vaccine Research at Beth Israel. Can you tell us about what the Clinical Trials Unit does?

[katy stephenson]: Sure. We're embedded within CVVR, which is a translational research center. Our group, our center, has about 10 different principle investigators, most of which are actually PhDs. So they have large laboratories in our center. We do quite a bit of wet lab research, meaning at the bench, and then a number of researchers also do animal research.

But within the group, we started in about 2016 a Clinical Trial Unit, because we realized that we were developing a lot of interesting, novel interventions for the treatment and prevention of infectious diseases that we were then handing off to other groups to test in clinical trials.

And for me, personally, I have never loved animal research. I much prefer to do work with patients. So we started this unit in order to do our own Phase I clinical trials. Phase I is the first step, when you're translating a discovery in the lab to humans.

So we started our unit here. And we work within the context of the hospital, so our research division is just-- you can walk indoors through a couple bridges and get to the hospital, which is where our clinic is located.

[brendan]: You did your postdoctoral work at Beth Israel, and your mentor was Dan Barouch. Could you tell us about your postdoc work and how that prepared you for what you're doing now?

[katy stephenson]: Sure. I'm a clinician initially, so I'm an M.D. I did my internal medicine training at Columbia, and then I came up here to Mass General and Brigham and Women's Hospital to do my infectious diseases specialty training, which is clinical training. But the program here has a research component to it, so you can do an additional three to four years of training to do a postdoctoral research piece to it.

During my clinical training, I was very interested in HIV vaccine research, which has been a long-standing interest of mine. That is part of the reason why I came to Boston for this training, because there were many people here who do vaccine research, including Dr. Dan Barouch.

Dan Barouch was initially, actually, one of my clinical attendings on the wards. But through talking to him and realizing that we had some aligned interests, I came over to do my postdoctoral research years at his group at Beth Israel Deaconess. When I started there--

And I have continued to see patients to today. I'm still an active physician.

But what we decided, and what I felt like I needed to do, was to get a better handle on the basic science and vaccinology. I wanted to always go forward and do translational work in product development, but I just really felt like I needed to understand the mechanisms of how vaccines work, better understand the immune system.

So my postdoctoral years I did bench work, all bench work, stemming immune responses to vaccines and infection in animal models.

[brendan]: Tell me a little bit more about how that evolved into how you're approaching your research now?

[katy stephenson]: I started as a postdoc, working on analyzing the immune responses to this-- a concept of a mosaic HIV vaccine, which is genetic recombination of multiple different sequences. As I was working on that vaccine, looking at immune responses in rhesus macaques who had been vaccinated, it looked really good in these animal models.

As a result, it got picked up by an industry partner which at the time was called Janssen, which was ultimately purchased by Johnson & Johnson. So Janssen was a smaller group that worked with us in the beginning. They were encouraged enough by the animal data in this vaccine to actually take it into human studies. This was also funded by the NIH. The NIH had a very big grant that Dan had for translating these bench concepts into human studies.

This is a big theme for me, which I'm learning from constantly, is how do you make that leap. Because it's quite hard in research to do that. You need a lot of funding. And Dan has had that funding.

So that began going into Phase I studies in people, and that's when I said, OK, well, I am a clinician. I work with patients. I understand the immunology really well of this vaccine. I would really like to run my own study in humans, in patients, to look at their immune responses.

So I got a what they call a K23 grant, which is an NIH career development grant-- it's a five year grant-- to look at immune responses in humans following vaccination. Then, working with this group, we initiated our first clinical trial, which was in 2016.

To do that we had to hire all new staff. This is not a typical operation for a lab, so we had to hire nurses, for example. It's very different. And clinical research assistants. And we work with a clinic, and build up our infrastructure for that. It's just a totally different set of skills than the lab. But surprisingly, it went rather smoothly.

But what was interesting in terms of how this all relates to the current pandemic is that we started that vaccine study, and then, simultaneous with starting our very first trial, the Zika outbreak occurred.

[brendan]: And that was back in 2016?

[katy stephenson]: Yeah. Exactly. So at the same exact time. And Dr. Barouch's group was working with a number of collaborators at Walter Reed Army Institute of Research, because they also do HIV work. It became clear that this epidemic was moving very, very quickly, and that a vaccine was going to be really critical, which we still believe.

So we got involved very early on in testing these Zika vaccine constructs in the animal models, exactly what we'd been doing for HIV. But now we had something different, a different tool, which was we had a Phase I Clinical Trial Unit.

So in about February of 2016, that's when, really, vaccine work started in earnest for Zika. And by October, we started our first Phase I clinical trial for a Zika vaccine, which if you think about is actually similar timelines to COVID-19, except we're faster. At that time, that was probably the fastest that we could think of that anyone's really done that. At that time that seemed-- it was unprecedented and was incredibly fast. Yet here we are in August with COVID19 and doing our Phase I studies.

That created a system for us that was very, very important when COVID-19 hit. So that was a very foundational moment, and it was a very crazy time for us because, of course, it was my second vaccine study ever, and it was starting simultaneous with our first. We had a completely new staff, completely new group of people, but it was very exciting as well.

[brendan]: Yeah You mentioned the COVID-19 pandemic, and your group is working on a vaccine trial for COVID-19 I want you to take us back a little bit to earlier this year, because I think, for most people in this country at least, COVID started in March. Early March things started shutting down. Tell us about the first meeting you had at the hospital about COVID.

[katy stephenson]: So because I'm super interested in emerging infectious diseases-- Zika, and Ebola, and all of those-- I follow on Twitter basically everyone, every scientist out there that's in that space. There are a lot of groups like Flu Tracker and some other websites, and groups that report-- almost every day they report on various little outbreaks that occur throughout the world and put them on the radar for everyone else. And that always bubbles along.

But this one in Wuhan seemed to pop up, and each day there was a new update. That caught my attention, as well as other virology people in this space. So I was following that along, and we had our lab meeting-- Dan Barouch's group. It was actually January 10th, because I was looking back at my calendar.

January 10th we had our lab meeting. At the front of the lab meeting-- I always sit up in the front because I give the updates about the clinical trials. It was Jinyun, who's one of our staff scientists, Diane, and myself, and we were sitting there. Jinyun had actually come back from Wuhan like a month before.

Dan and I were talking, basically like, have you seen? Did you hear about this outbreak? Talking about it, and we're like, we need to start working on a vaccine for this thing, because it looks like it's going to be bad. We start talking about like, Jinyun, do you have any friends back in Wuhan, right? How can we get the data? How can we get the virus? How can we get the information?

So we were talking about that, and then we had our lab retreat that day, where we were doing our presentations about our work. Then I was getting ready to go on vacation and I was back on Twitter, and it was in the evening. I remember I was going through it, and I saw that the scientists in China had posted the sequence to what became SARS-CoV-2 online.

That was really a game changer, probably one of the biggest milestones in this entire epidemic. Now, there's a lot to be unpacked about how transparent or not transparent China was during this period of time. But these particular scientists-- whether they were doing this on their own or not, I don't know-- but the fact that they publicly posted this sequence for the entire world to see and use was an incredible moment of scientific transparency.

So when they posted that, I sent the link to Dan. I said, look, we don't have to send Jinyun to Wuhan. They actually posted it. And that night is when Dan sent an email to the group and said, OK, let's convene. We have to get started.

And I think by the next week Dan's group had started working on about five or six different concepts, so DNA-based vaccines, had already sent in the orders to the companies to build peptides based on that sequence. All of that was in motion. And that wasn't just Dan's group. If you go back and look on Twitter, because that's where all of science is talking, the diagnostic tests started then. It's interesting to look back at that now and see.

I thought that the diagnostic tests and lab testing was going to be the easy part of this, because they already had PCR-based tests. People were working on them in their lab by the next week, and the World Health Organization had them ready. That's not my space, exactly, diagnostic testing, but I would have thought that that problem would have been solved immediately. So it's kind of amazing that we're still struggling with that.

So timeline-wise, the vaccine work really started in earnest in January. Then all of February we were working on vaccines here. Now I'm doing the clinical trials, right? So I am in the background during this period of time, listening in, and thinking about which of these vaccines constructs are most likely to go into Phase I testing and how can we be ready for it.

What we very early on-- what everyone in our group felt-- and Dan Baruch and others of course, leading this charge-- was the most likely candidate for us to work on would be based on that adenovirus 26 vector.

The reason for that is because we had a long-standing relationship, years, working with industry on translating this concept into Phase I human studies. So we had already done it with HIV, and in fact, we'd done it with Zika, as well. We were working on-- at the time, and it's now under review-- our Ad26 Zika vaccine first-in-human trials.

[brendan]: Yeah. So for people who don't know the adenovirus, you talked about it earlier, but it's sort of like you send a-- the vaccine is encapsulated in a virus, or? Maybe I don't understand it that well. Could you explain it?

[katy stephenson]: All viruses work by binding to some sort of receptor that's on the surface of a cell-- our own cell, different types of cells. It binds to that receptor and is brought into the cell. Once the virus is brought into the cell, it unravels within the cell and uses our own host machinery within the cell to make more copies of itself.

It does that by-- various enzymes within the cell translate the genetic sequence of that virus and turns it into various proteins. Vaccines can use various different ways to introduce the body to these proteins so that the body can learn about them. You can either just make the proteins in a factory and inject them, and that's the very common way to do it.

Another way that you can do it is to use a different virus to transport the sequence for those proteins into the cell. So what you can do is take something like adenovirus 26, which is a serotype of adenovirus. Adenoviruses are really good for this, because they're kind of big pro-- you can take out chunks and replace it with other sequences, and it's a hardy little virus. It doesn't die when you do that.

So you can take adenovirus, in our case, we make it replication incompetent. We take out enzymes in there that would be required to make the adenovirus replicate, and instead we swap in, in this case, the sequence for the spike protein from SARS-CoV-2.

So Ad26, it binds to the cell, the human cell. It's brought up into the cell. The cell starts making the proteins. It makes a whole bunch of adenovirus proteins, which are never reassembled into a real virus, because it doesn't have all of the genes for it.

And along the way, it just goes on automatic pilot. It makes the spike protein for SARS-CoV-2, because we kind of snuck it in there. It makes this spike protein. It's only one protein, so you can't make the whole SARS-CoV-2 virus.

And then, that protein is secreted from the cell or posted up on the surface of the cell. And that's how the immune system sees it. For whatever reason, this often creates a nicer immune response, or we think it does. It sees the protein in a more natural way than if you just injected it into the bloodstream. It sees it as the body would see it if it was infected with SARS-CoV-2.

[brendan]: So you're involved in a clinical trial of this vaccine now, based on this adenovirus 26 vector. As you were starting to look into the vaccine, starting to develop the vaccine, you're also managing clinical trials for other things related to COVID-19.

One of them was Remdesivir, which is an antiviral treatment that has shown some promise. So, maybe, you could just quickly tell us about that clinical research, and what were some of the challenges of doing that.

[katy stephenson]: Yeah. So my day job, I guess you would say, had always been working on these vaccines, like we've just been talking about, in a kind of calm, methodical manner. And in the background that has been occurring. The Ad26-based vaccine was going through this whole process of development through March and April, and there was nothing much for me to do for that at that point, because it wasn't ready for clinical testing.

But March 3rd, I think is-- when I look back on my calendar-- I went on service in the hospital. And that's where we saw the very first cases. I'm an infectious diseases doctor, so we had to see those cases. And that was when things really broke wide open. We started to see a lot of cases. In some of the cases, we saw within a week we had cases in the ICU.

One way to do research is to do something called compassionate use research, which means that you have a patient, an individual patient, and you can request to give them an experimental drug, not in the context of a trial but one-on-one. You can request it from the company that makes that drug and from the FDA, and you can get emergency-use approval to do that.

So we had a patient in the ICU, and we requested to do that for Remdesivir. So that was my first, and our hospital's first, experience using Remdesivir. We requested this because, for myself, working at the Center for Virology and Vaccine Research and being in the thick of this, I knew already about Remdesivir.

Remdesivir was a drug that was developed for Ebola. It was actually an all-purpose antiviral, and had been tested for Ebola. It was already well-known among scientists at that time that it was potentially the most-- we had the most optimism about it. So that was a natural choice to ask for for compassionate use. So that was our first experience actually using it.

Then shortly thereafter, probably a week, I was able to connect with Gilead to actually do the formal trial of Remdesivir at the study. I really wanted to get our hospital involved in the NIH-funded study, but they had already picked sites for that.

So it's a bit of a scramble, is what I've learned in this experience. You're just going to have to hit the phones and reach out to as many people as you can to try to get your hospital to be a site. We were super fortunate, and I'm very happy that we were able to be a site for those studies, which started right away. Basically in mid-March we started those studies.

[brendan]: You were able to be a site for the Remdesivir trials, even though originally you hadn't been because it'd already been chosen?

[katy stephenson]: Well, there were different mechanisms by which people were testing it. The NIH had started a placebo-controlled trial, which ultimately became the basis for the data that showed that it actually had a benefit. That study had a placebo arm to it. And parallel with that, the company also ran their own studies looking at different questions-- five days versus 10 days, et cetera.

So those were the studies that we were able to get in on, and that was really great for us. Because for a while, that was kind of the only way that we could get patients treated. The compassionate use is one-by-one. It's really time consuming, labor intensive, and not scalable.

We did continue to do compassionate use through the Remdesivir trials for pregnant women, because they were excluded from the study-- or ineligible for the study. So we actually did enroll pregnant women for compassionate use, and that was also a really interesting experience for me.

Our little clinical trial team, which I mentioned to you is just this tiny team that we created in 2016, only ever did outpatient work. Suddenly we were doing an inpatient study. Very, very different situation. Incredibly sick patients, patients in the ICU, patients that you couldn't talk to, patients with devastated family members trying to make decisions on the fly.

We had to do everything at that point remotely, doing informed consents remotely, working with the house staff and the nursing staff to get the drug to patients, getting IRB approval turnarounds within 24 hours, all of that stuff. We had to create a system overnight for this entire thing.

It was actually very inspirational, I should say, to see my team adjust to that-- nurses who hadn't been doing that kind of work for years, our research assistants straight out of college that had never interacted with an incredibly sick group of people like that before.

And, of course, we had many patients die during that period of time, which is not something we'd experienced before in any of our studies. They died from COVID-19. Young people died. And to have to work with a research group that's typically very academic-- we just do immunology seminars and do our experiments, and to suddenly have to work with families at that level and go through our own grief was a very different experience. That lasted until about the end of May.

[brendan]: Wow. Two months of really hard experiences that you've never gone through before. How did your group deal with the grief and just the magnitude of everything?

[katy stephenson]: It was hard. We didn't really talk about it for a while, because we were just running at full speed. The research nurses in my group had to bring it to my attention. I mean, I'm a physician, right? So I've trained in ICUs before. I've gone through some of this before.

So they had to kind of sit me down and-- or, virtually sit me down-- and remind me that the rest of our team had not really been through anything like this before, especially the younger research assistants, and they needed time off. And that the research nurses themselves really needed-- I mean, we'd been working every single day.

When there's a pregnant woman who is in the ICU, and they page you at 3:00 AM in the morning to start the application for compassionate use, you don't ever say, call me in the morning. You don't say, what, I'm a research-- I only work 9:00 to 5:00. You don't do that. You assemble this whole team, and the pharmacist comes in and hand delivers the drug to the team at 5:00 AM, or whenever.

So after probably a month of that kind of thing, we had to stop doing it like that, for our own mental health. I mean, we would do it for that situation, but we just had to slow down. So like, we would take Sunday. We'd say, OK the team is going to be off on Sunday. I'll hold the pager, and if there's an emergency I'll handle it. Or we would say, OK-- I would check with people like, did you take a walk today? Did you leave your house today?

It took some time, and I think we're actually, to be honest, we're still recovering from that. Going into the vaccine studies, we're just really checking all the time. Are we getting swept up again? Are we going to-- we can't do that again. So we're spending a lot of time talking to each other about it. I'm very thankful that I have a team that communicates with me and is very honest with me when things are getting totally insane.

[brendan]: You talked about running full speed, and I wonder if that-- was it similar to what you felt in 2016 with Zika, or it was just way more?

[katy stephenson]: It was completely different. Zika we were running nonstop, but-- I remember for the Zika vaccine trial I submitted our application to the FDA from a tent. I was camping with my kids, and couldn't get Wi-Fi, and I had to go find it so I could press submit.

So, I'm working a lot, but I'm still in a tent with my kids having fun. It's a different thing than this. This was putting on full PPE, going into the hospital ward. It's just very different. This was a totally different experience, and I hope never to be repeated in my lifetime.

[brendan]: So that brings us up to now. You're currently involved in the vaccine trial that's being funded through this federal program Operation Warp Speed. Maybe you could just tell us a little bit about that, and what stage you're at with the vaccine trial.

[katy stephenson]: So as I mentioned, we knew pretty early on that the Ad26-based platform was going to have the most potential. The reason why is because we had an industry partner that had proven manufacturing ability, and ability to scale up to global distribution.

So this particular vaccine moved very quickly, kind of out-of-our-hands very quickly, into a much bigger effort as you mentioned, part of the whole Operation Warp Speed, which is a national vaccine effort that involves, actually, multiple different prevention-- not just vaccines but also monoclonal antibodies and other forms of prevention.

They have the whole research effort, and that's what we're involved in, but the other side of this Operation Warp Speed is the manufacturing funding. The funding for all the manufacturing. A lot of this is on a train that has left the station, so that we sometimes have to, for me anyway, look at it from afar. Like, wow, look where that's going. Just kind of trying to hold on to it, almost. I want to stay with this to the end.

But we were fortunate enough, because of our relationship, to be able to do a small study in our group that is very scientifically focused with 25 individuals. It's a study where we can collect a lot of really cool and different samples that will help us answer some interesting scientific questions that will ultimately also inform the development of this vaccine.

For example, we can-- one of the studies we did with Zika that was really cool, and we're going to do it again for this one, is to isolate antibodies that are generated by our patients, and see if those antibodies actually protect animals from infection in different animal models. so that's a kind of ex vivo way of looking at the protective ability of these antibodies.

That's not something you can do in a 700 person study, but we can do it in our little study. Actually, because of some of the infrastructure that we built where we have this Phase I clinic that's in the lab, we can get those samples and walk them down. We literally walk them down, and I hand them off to Jinyun and the rest of the team, and say, analyze this. Then we get the data back like three days later. So that's what we're doing.

And I have to say, after being-- we had about a month where we were really remote. Remdesivir was done, the cases dropped off, our team were all remote just doing, like, data cleaning, and query resolving, and all that for research. When the vaccine study finally opened, it opened with a burst. We opened, and then we had two days to recruit everybody, and we had 10 days to vaccinate everybody, all 25.

But when everybody on my team came back together, and we're physically together again on the floor, it was amazing. It was just so uplifting. We were working on a project that was not a salvage therapy for patients who were incredibly sick, but instead a super optimistic, positive project that we hoped was going to actually get us out of this mess.

All of the volunteers that wanted to be in the study were all like that, too. They were super pumped. There was just a buzz in the air, all of this stuff. Just everyone was so happy to work on-- and it's still the case. We're just all so happy to be working on something positive and optimistic. It's really actually very therapeutic for us right now.

[brendan]: Yeah, I can imagine. So many people are so tired of this, and people have lost loved ones. And people who've been very sick and had really bad outcomes-- and for you to be able to come into the lab and to work on the vaccine that could possibly end this, that must be amazing.

[katy stephenson]: Yeah it is. It's really amazing. It makes it easier. It definitely makes it easier. I think I had mentioned to you previously, I have kids at home, and they're really bored this summer. They have nothing to do, and camps are all closed, and they're just sitting around playing Fortnite for, like, nine hours in a row.

It helps to come home and say, well, I'm working on something. They know all about what I'm working on, and they're excited about it. I sometimes hear them talking to their little friends, texting with them or whatever, and mentioning that I'm working on a vaccine. I can feel that they're proud of it, and that they're proud to be a part of it.

Everyone who talks to us, or friends or family, they always ask about it. How's it going? We really need you. Thank you for doing this. And I think it just really helps my kids, I hope. I don't know. I'll ask them when they're older. But I feel like maybe it helps a little bit, to feel like they're involved and that we're not helpless in this pandemic.

[brendan]: Dr. Stephenson, thank you very much for joining us. It was a pleasure to have this conversation with you.

[katy stephenson]: Thank you. Thank you so much for having me. [music playing]

[brendan]: Thank you for listening. If you've enjoyed this podcast, please rate us on iTunes, and help us spread the word about the amazing research taking place across the Harvard community.

[oby]: To learn more about the guests on this episode, visit our website catalyst.harvard.edu/thinkresearch.

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