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

Brendan: And I'm Brendan, and we are your hosts. Think Research 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.

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Brendan: As COVID-19 has been upending lives around the world, many people wonder what could have been different, how are we doing now, and what is next. As we turn to researchers in the field for guidance, information continues to change as the weeks and months go by. Now, we speak with Dr. Yonatan Grad of the Harvard TH Chan School of Public Health to discuss his essential work on infectious disease and COVID-19 research throughout this year.

So Dr. Grad, thank you for joining us. And welcome back to the show.

Yonatan Grad: Thank you for having me.

Brendan: So you're an infectious disease epidemiologist. And we're in the middle of the worst pandemic in 100 years. So could you take us back to earlier this year and what your life was like when the virus started spreading around the world. You know, you study this kind of stuff. So what was the-- I don't know. What were you thinking in January, February, when the news started really breaking about this?

Yonatan Grad: So I think, as with many people, I was following closely the reports coming out of China about the new virus, about its connection to the market. And then as it became increasingly clear that it was a notable outbreak and was causing severe outcomes, of course many of us started focusing more and more on it. Knowing that the timing in January, it was a coincident with a time when many people travel in China, that Wuhan is a major travel hub, raised a lot of concerns that this is something that we would start seeing spread both around China and then globally. When we first started seeing cases appear in other countries or in other regions of China and the world, it seems like we were at further risk when there was clear indication of human-to-human transmission.

As you might remember, that was a question early on. It became again increasingly obvious that we were facing something that would spread around the world. And the question was whether the features were going to be like with the SARS epidemic back in the early 2000s when public health efforts were sufficient to keep it under control and eventually eradicate it-- or whether this was going to be like influenza pandemics, where we really see global spread that is unchecked. There were some basic questions from an epidemiology perspective.

What's its basic reproductive number? This is the R-naught that became quite famous and it was much discussed. So how contagious is it-- was really the question. What's the serial interval, so another sense of how quickly does it spread? How severe is the infection? What's the case fatality rate and the infection fatality rate? Again, these are some characteristics of infectious diseases that are critical to know, but hard to know early on in pandemics.

When we first started seeing it spread around, it became pretty clear to me we were going to have an issue here as well. There's no reason why the US would be insulated from this. We were focused on trying to understand the pattern, the spread, and what kinds of interventions would be successful in trying to slow its spread-- quarantine versus symptom monitoring, isolation-- various features that we have used that would inform those kinds of protocols. And we started, in the Center for Communicable Disease Dynamics, having regular meetings to discuss their findings on SARS-CoV-2 and COVID-19, trying to get an understanding of what was happening in China, what the early literature showed, and what the implications are.

Brendan: You mentioned the SARS outbreak in 2000. And that was eradicated because of strict public health measures, but also the nature of that virus is very different.

Yonatan Grad: Right, so one of the key differences, had to do with when are people contagious. So with the first SARS outbreak, it really seems that infectiousness coincided with symptoms. Whereas, with this one people are infectious even before they develop symptoms. So there is a presymptomatic stage in which people are able to spread the virus. And that makes infection control much, much more difficult.

Speaker 1: And it took a while to figure that out. So there was a time when the virus was just spreading unchecked and people didn't know. How long did it take for the public health and medical community to figure that out?

Yonatan Grad: It was it was pretty clear there was asymptomatic disease even with the spreading. But the question was, how much. And then this idea of presymptomatic spread. That people would be infectious and then go on to develop symptoms.

And there was some early work in February that really helps to lay that out. There is another paper in science from Jeff Shaman and some of his colleagues, that I think spelled it out pretty clearly, that I think was first posted back in February. So there are indications even then that this was going to be a much more difficult struggle from a public health perspective.

Speaker 1: And so you've been looking at this a lot. We're talking, it's August 14th now. And so since February, March, you've been studying this. And you've also been interviewed a lot. I've watched a lot of your interviews. And you were also on Anderson Cooper, AC-360 on CNN.

I was wondering if you could talk about what it's like being that in demand all of the sudden and being interviewed on such a high-profile show like Anderson Cooper.

Yonatan Grad: It's funny, for a while there, my inbox was-- and it's still quite busy, although, less busy for me now. I know some of my colleagues, like Michael Mina continue to be totally overwhelmed. He's recently been championing the low-cost rapid turnarounds, low-sensitivity testing, and in doing so in such a high-profile way that I'm sure he is-- [laughs] It's hard to imagine just how busy he must be.


So I think all of us go in cycles. But at the time, things were so busy I was getting email requests. All of us were getting bombarded and we--

Speaker 1: And by all of you, you mean everybody at the Center for Communicable Disease Dynamics?

Yonatan Grad: Yeah, there are a number of us who have been active from early on are vocal. So the Center is led by Marc Lipsitch, who's really become one of the most prominent voices and most trusted voices, I'd say. He's both one of the leading lights in the world of infectious disease epidemiology. But also, he is just super smart, a really lovely guy, and really, I think, clear headed and a great science communicator. So he's been championing this effort and working with a variety of different sectors and many others.

But at the time, things were so hectic. And there were so many emails flying back and forth that I didn't pay attention to ones where I didn't know the people sending emails often. And I got an email from AC-360. And I had no idea what that was. I don't watch [laughs] television. I had no idea what it was. And ended up getting in touch with one of the administrators in my department, who got in touch with me.

And eventually I connected them. I had never-- I have to admit-- never watched Anderson Cooper. I think I knew who he was because of him playing himself in movies, like The Avengers or something.

[laughing] Or the one about to discuss world events and threats to the globe. And it's like, [inaudible]. You know, maybe it's fitting. It's been a learning process.

Trying to move from the usual professorial mode of pontificating and having a platform. Right? Most of my science delivery is at a podium, where I give a seminar or give some lecture. But this is a very different mode of communication, where you want to come in with your three-main points and learn how to short bursts. So it's been an education.

Speaker 1: Yeah, talk more about that. When you're giving a seminar at a podium, you have the luxury of time. And you can elaborate. And you can get into nuance. And you have an audience responding to you and stuff like that.

But when you're sitting at your desk in a remote interview with Anderson Cooper, that maybe only lasts two and half minutes or something, you don't have that time. And I think there's the potential to be misunderstood if you're not careful. So How did you make that adjustment?

Yonatan Grad: It's a little bit weird to be told, look at the green dot and not focus on the person on your screen, so that you can actually appear to be looking at the viewer. So that was one with a lot of adjustment. But the others really have to do with identifying the points you want to make and figuring out how to make them sync.

Sometimes I would ask for at least a general sense of what the questions would be beforehand. And then think about what kinds of short, accurate, and informative answers I could provide with the understanding that this is not a discursive mode of interview, but one intended to briefly communicate key points.

Speaker 1: And so you've been doing a lot of communication through papers and through articles. And in March, you published a paper about social distancing and looking at some models saying that, depending on how well we do with controlling the virus, we'd have to continue some form of social distancing kind of on and off until 2022.

And it's now August, and we've seen different places reopening and infections resurging in some of those places. So could you tell us, where are we now in that scheme and what that looks like.

Yonatan Grad: So the framework that undergirds that projection is based on the idea that pandemics either end because you can eradicate the virus, which is what we saw with SARS back in the early 2000s, or because enough people have been infected that you've achieved herd immunity and we won't see a continued epidemic spread of the virus. So thinking back to the early days of the virus, we saw everywhere these graphs that showed these epidemic curves. And we talked about, that our goal is to crush the curve, or all of the language around trying to limit the spread with the hope that by doing so we would reduce the pressure on hospitals and the health infrastructure generally.

And the notion there of these curves is that you will see the virus spread, people get infected, and then eventually infections would subside as enough of the population is immune. With that as the [inaudible] could then ask, OK, if we use different types of mitigation efforts-- social distancing, for example-- and we slow the spread, and knowing that we won't be able to maintain the community quarantine, these lockdowns, for a sustained period-- you know, if we were to do it for one time and then as long as there are enough susceptible people in our population, we'd see virus surge again.

And then we'd have to implement the same kinds of social distancing interventions. What would it look like if we were to have to do this repeatedly? And the notion that we articulated in that paper was that if we end up having these cycles or these intermittent social distancing efforts, how long would it take until we hit herd immunity so that we wouldn't have to do this. And this again was in the absence of other types of interventions and thinking about how do we adjust our capacity of intensive care units, and so on. So it really is just one view of what might happen given tools at our disposal.

And that's what led to the somewhat notorious 2022 prediction or projection. In fact, what we knew then, but really what has become even clearer and I think for a policy perspective is quite important because that the experience of the pandemic is really hyper vocal. And the experience in each community is distinct. And it's really shaped by the decisions made by those communities and jurisdictions.

We can see that globally. New Zealand now, somewhat famously, and aided perhaps by it being an island, was able to control community spread through aggressive measures very early on for a long time. They went over 100 days without evidence of community spread. A combination of making sure that every visitor went through quarantine testing, and doing aggressive contact tracing, and quarantine for contacts.

So that was one example. And then in other examples what we've seen in northern Italy where the pandemic raged for a while until they had, again, very aggressive community lockdown for some period of time. Similar Wuhan in China, where they were able to institute both travel restrictions, and lockdowns, and eventually able to stop it once they had halted community spread.

But there are other places, like what we've seen in Florida and Texas, for example, where the governor has decided not to implement social distancing efforts, at least upfront. And so we saw what you might expect to see, which is the widespread virus.

And so it really depends on each jurisdiction, each municipality, each hyper-local area's response to the virus. What efforts can these places put in place to slow its spread? And where they have been successful in slowing spread, or even eliminating community transmission, how do you proceed.

Well, you have to maintain a vigilance so that, the huge population that remains susceptible to infection does not see a surge in infections. So it's been a different story all around the world, community by community. The main continuing threat here is the simple math of epidemics, which is that as long as there are enough susceptible individuals to the sustained spread of the virus and opportunity for the virus to spread among those individuals, it will do so.

Speaker 1: It was interesting, when talking about different places in the world and how local it is. You mentioned countries like China, and New Zealand, and cities Wuhan, and region, like northern Italy. But when we get to the United States, it's really state by state we've seen the response varying.

And we saw that from the beginning there was never a concerted federal effort to try and do stuff like New Zealand did, or like China did, or South Korea, where you track and trace everybody that comes in. You test and there was no forced quarantine or anything. So I don't know what the question is there.

Yonatan Grad: Well, I'll make a couple of comments. I want to just add, I should have included it before, but I haven't mentioned vaccine. But vaccine is really-- if you choose to crush the curve and maintain your population as being susceptible, you're basically choosing a path that requires that we develop an effective vaccine. Because otherwise your populations may remain susceptible to this virus circulating around the world.

So really that path is one that in some ways is hopeful that science will be able to come up with an effective answer. Then once a vaccine is available, you can vaccinate your population and achieve immunity that way, rather than immunity through exposure to the disease itself. So vaccine, I regretted not mentioning it earlier, but it is a fundamental part in thinking about how each of these communities are making decisions about their response and we will play a really big role going forward.

The need for an effective vaccine for protection is immense in those countries that have successfully crushed the curve and reduced community transmission. They're not getting out of this without, either seeing virus spread in a population, or an effective vaccine that they can provide to members of their community.

The story isn't done yet. We've got a ways to go for each of these populations. The fragmentation of the response in the United States is just a sordid tale. It reflects the abdication of responsibility by the federal government. Worse than abdication, I think there's just been horrendous mistake after mistake and missed opportunity after missed opportunity.

There's been an absence of leadership and in some ways a subversion of an appropriate response. Saying that the virus was just going to go away magically, it was nonsense from the beginning. Saying that we were willing to consider bleach, the advocacy for hydroxycloroquine-- I mean, a lot of these things were downright dangerous, and not taking a lead for a national response in some ways seemed cowardly.

I mean, it's not wanting to take on the responsibility of having to care for the entire population, throwing it onto someone else's shoulders, and then not lifting a finger to really support them with providing PPE and providing sufficient disease tracking, making enough diagnostics. This has just been-- it's almost an incomprehensible failure of the federal government's response.

Speaker 1: So we've talked about testing early on in the pandemic. One of the issues with testing that came out was the CDC had tests that were defective. And that set us back. Have we resolved those issues? And do we have enough testing capacity in the country now?

Yonatan Grad: No. No, we don't. We don't have enough testing capacity at all. Test turnaround times have been in the news a fair bit recently because they are just unacceptably long. Useless, they've basically rendered the tests useless. If you want to make a decision as to whether someone should stay in isolation, or move from quarantine to isolation, or you need to do contact tracing on potential contacts-- getting data seven days, 10 days later, essentially it's way too late.

So you need rapid turnaround tests. And Michael Mina as I mentioned earlier in our conversation, has been very much a prominent and public. He has desperate pleas for the FDA to approve these cheap rapid tests that even if they are of lower sensitivity, would be particularly useful for surveillance purposes. And really just help us get to the point of being able to slow the spread of the virus.

But it continues to be the case that we just don't have enough testing of any kind. If we had had good available testing with rapid turnaround, we would be nowhere near where we are right now. The repercussions have been so dramatic. And we are still not at a point where we can have the kind of testing we need. People need to be able to, if they want a test, they should be able to get a test, and get an answer very quickly.

And for all those who are engaged in public health interventions, all the contact tracers, and so on, they should be able to test people and retest them. And we don't have the infrastructure and capacity for it.

Speaker 1: And that's something that has been depleted over many years? Or is that something we had the capacity to build up in January?

Yonatan Grad: Certainly, it was something we could have done. And we were set back pretty dramatically by the CDC error, where instead of using available tests the CDC decided we wanted to make its own and sent it out. But it was a flawed test. And so there basically we were behind by a month. Which, for this pandemic and the speed with which this virus spreads, was just catastrophic.

Speaker 1: Why did the CDC want to use its own tests?

Yonatan Grad: Great question. I don't know. And why didn't it have their procedures in place to-- if it's going to make something, to make sure that it's made up the standards and to insure against this kind of error? There I don't know either. It seems like some of that is just systems issues.

Some of that may also well be attributed to the regular deep-limited funding supplied to the CDC or reductions in funding. It's a good question. How did this happen to begin with?

Speaker 1: And so, based on that, we're still looking for testing. There's some talk about a rapid-- or you're talking about your colleague is talking about these antigen tests. Is it the--

Yonatan Grad: Yes, so they're--

Speaker 1: --antigen or it's a less sensitive, but quicker test. So the idea is that you test more often. And if you're testing more often, you're going to catch more people.

Yonatan Grad: Yeah, it's also the idea that people are most infectious when the burden is high. And that the sensitivity of the tests depend on how much of the virus is around. When there's a lot of the virus around, the tests can pick it up. When there's less virus around, the tests are less likely to pick it up.

But if people are really contagious, you can see that someone is in the stage when there is a lot of virus around. And then you can act on that information. And you can interrupt spread. So even though sensitivity tests may be useful given the dynamics of viral loads over the course of infection in the relationship between those viral loads and infectiousness. So the hope is that even the rapid low sensitivity tests that are pretty cheap, and again the technology exists. A number of companies actually have made these-- getting those widespread may have a great impact for surveillance purposes.

Speaker 1: And so if we can do that, say we get the rapid tests to enough places that we need them, I think , as we look towards the fall, we're talking about schools reopening, some universities reopening-- do you think schools reopening in-person or hybrid is a good idea at this point. And how do you see this playing out through the fall if, in fact, schools do reopen some in person-- people's economic necessity is going to dictate that some parents send their kids back to school and/or back to daycare, or have daycare provider come into their home or something. So how do you see this playing out through the fall?

Yonatan Grad: I think it's really going depend on where and what their community prevalence is. So we saw what happened as a first indication in Israel, where opening schools led to, again, another lockdown. Because there started to be widespread disease. We saw what happened recently in Georgia, as schools opened, and people didn't engage in masking or social distancing. And there were outbreaks and led to the school being shut down.

So if you try to open without any mitigation measures, it goes back to this idea that the virus is going to spread where you have susceptible individuals and opportunity for the virus to spread. If there is very low prevalence or, ideally, there's no community transmission, then it seems like opening schools is reasonable.

But where there is community transmission, and you are not able to engage in the various non-pharmaceutical interventions-- like masking, and distancing, and put people together in poorly ventilated spaces where the air isn't going through Hepa filters, and so on-- there will be opportunities for spread. And we should expect there to be outbreaks.

I think one of the other main concerns that I have is-- I was talking about this with colleagues over the past couple of days-- there's a mass migration that's about to happen in the United States. And that is of college students going off to universities and different places.

In the Boston area, something like 170,000 undergraduates who normally descend on the greater Boston area each fall. It's going to be a much smaller number because many universities are no longer holding in-person classes, or told students not to come back, or have done some kind of in-between model.

Harvard, for example, telling the freshmen to come, but only upperclassmen that need to be on campus. They cut it back to something like 40% of the undergraduate population. But still, that's going to be people coming from around the country. And if you look at where there is a large fraction of the population in the US, that's Florida, Texas, California, places where the prevalence right now is pretty high.

So we're going to see introductions of cases into Massachusetts, a large influx all at once in the last bit of August, beginning of September. That's going to happen. What is the impact then on community transmission? A lot of that depends on what colleges and universities are going to be doing in terms of testing and quarantining all of their incoming students.

How many of them are living on campus? How many are going to live in apartments rented in communities? Where are they going to get their food? How are they going to start interacting?

I think it's a fair expectation that we're going to see more cases over the next month. What impact is that going to have then on all of the other schools, elementary schools, middle schools, high schools, when you have an uptick in community transmission or those schools are going to be at risk?

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As we move into the fall, and there's less opportunities to hang out outdoors where transmission is less likely to happen, because of good ventilation. Then I worry, we're going to see quite a bit more spread come the fall and moving into winter. So it's not just school openings for community schools, it's really just this mass migration of students that happens with the beginning of the college and university terms. That I think we're going to feel the impact of.

Speaker 1: Well, Dr. Grad, thank you very much. It was a pleasure to have this conversation with you.

Yonatan Grad: Thanks, and nice to speak with you again, Brendan.

Speaker 1: 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.

Speaker 3: To learn more about the guests on this episode, visit our website catalyst.harvard.edu/thinkresearch.