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A COVID-19 Q&A with B.Next

B.Next is IQT’s bio initiative committed to identifying and accelerating biotechnologies to help detect, manage, and mitigate epidemics of infectious disease, which hold the potential to affect national security. B.Next has been on the IQT Podcast breaking down the COVID-19 outbreak and the role technology can play in ceasing the pandemic. The series includes discussions about tools and testing, crisis standards of care, synthetic biology, and using visualization to understand the data available and presented. The latest pod explores listeners questions, and this post recaps the Q&A as answered by B.Next Drs. Kevin O’Connell, Dylan George, and Dan Hanfling. (Answers have been condensed for length and clarity.)

Q: Is the antibody test worth trying to get? And if you’re immune, can you go back to work? If you’ve built up an antibody response to the virus, are you then no longer able to transmit the virus to others?

Kevin O’Connell:

These are all really important questions. The problem is that it’s unclear whether an antibody test actually answers any of them at the moment. Part of this is because we still have a limited understanding of the biology of the virus and of our immune response to it, and part is because there’s a very wide variability in the quality of the tests that are being developed. We currently don’t know whether the presence of an antibody actually provides immunity to the virus, and we don’t know, if in fact you do get that immunity, how long that will last.

In the presence of antibodies in response to viral disease, you frequently develop an antibody response, but it varies from disease to disease, from virus to virus, and the significance of that antibody response. On the one hand, if you have an immune response to the measles it means that if you catch the measles or you get the vaccine for it, you typically receive lifelong immunity to measles after that time. However, on the other hand, if you either have the flu or you get a flu vaccine, the immunity to the flu, even to that same strain, can wane over time. There also are some viral diseases for which there is no vaccine at the moment, and that’s a whole other branch of biology we won’t go into today. So, again, the message here is that we just don’t know.

More research needs to be done to determine how long-lasting immunity to this coronavirus infection could be, and of course, we’ve only had this disease around since late last year, so we won’t know for a while. We need to continue to learn more, and the people developing the tests need more time to refine them.

Q: What changes would you recommend to hospitals to reduce the spread of the coronavirus?

Dan Hanfling:

Excellent question, and I will put my clinician hat on since I’m a practicing emergency physician. I’ve been in and around the virus in the hospital setting, and the first thing I would say is this is an incredibly transmissible virus. It is very easy to spread, and that is why we’re seeing such concerning presence, evidence, if you will, of clusters of patients who are coming in, particularly those who are susceptible and vulnerable, for example, when we see a spread in nursing homes or within household contact. Hospital-acquired infections have an entire protocol that are applied that is based on the fundamentals of infection control and prevention, and this is where preparedness really matters most, where you know what supplies, equipment, and training is required to be able to affect those principles and practices most efficiently. I think one of the challenges has been, as Kevin said in response to the last question, this is a new virus, and so for many, even in the hospital setting, it is not usual that they encounter highly transmissible, highly viral pathogens in patients who can transmit those or who may be harboring them.

It is somewhat unusual for the entirety of the healthcare workforce to have to engage in the use of personal protective equipment (PPE) with masks and gowns and gloves, and the processes for correctly putting them on and taking them off. I think that this is where training is most important, and we’re getting better as we go along, but that continues to be an area that needs a lot of attention. We are seeing a lot of different ideas, and we’re hearing a lot of different recommendations, and this really speaks to the importance of having some kind of unified data reporting system and the means for analyzing the data within that system to be able to share best practices.

I’ll conclude by saying that one effort that we did have a hand in helping to support early on in the outbreak was the promotion of a telementoring platform that is run out of the University of New Mexico. It goes by the name of Project ECHO and week in and week out, there are two, sometimes three sessions devoted to critical care and emergency department care. Last week, there was a special session on nursing home care. At the end of the day, given that we are still learning about this disease as it continues to ravage our communities, best practices and sharing of those best practices is really what we have to count on in order to address some of the concerns that you raised.

What recommendations can we make to reduce the spread of this virus? I think it’s going to take everyone’s participation, staying home when you can stay home, or adopting safe practices when you are in those frontline positions to protect both yourself, your family, and those around you in your community.

Q: What evidence is (or isn’t) there to support whether or not this virus will be seasonal, like the flu?

Dylan George:

This is a really tricky one, and as we’ve pointed out in both of the preceding questions, this virus has only been around for a handful of months in the human population. We just don’t know a lot about it right now. We’re learning on a day-by-day and a week-by-week basis. Marc Lipsitch, who is a world-renowned epidemiologist at Harvard, wrote a wonderful piece on the potential of seasonality of COVID-19. In the piece, Mark talks about four main factors that influence seasonality in pathogens, including: environmental factors, human behavior, host immune system, and then, last but not least, the status of susceptibles (susceptible persons).

Regarding environmental factors, there’s been some good research showing that absolute humidity is correlated more with transmission. Some experimental work has shown that the drier it is, the more transmission that happens between people for respiratory pathogens. But even with that kind of information, it should be noted that transmissibility does happen in humid areas. In countries that have high humidity, they do still see the flu. They do still see respiratory pathogens being distributed about. We also see transmission of flu throughout the year. It’s just not as high in the summer months as it is in the winter months. That’s not to say that it’s the only driver, but absolute humidity is an environmental factor.

Human behavior can influence seasonality as well. Those of us in the temperate zone of the United States know where we spend time in the winter versus in the summer. During the winter, most of us are either in school or at work, so we’re inside where the quality of the ventilation and the size of the rooms that we spend time in really matters. We do see patterns of infections, particularly measles, flu, and chicken pox that are strongly correlated with school terms. You have higher infection rates when kids are in school versus when they’re not.

This is a well-known pattern in the military as well. When you bring in recruits and bring them all together from various parts of the United States, you see a spike in respiratory infections, adenoviruses, and various other influenza sorts of things. For COVID-19, there is a little bit of discrepancy here because we know that kids get infected. We’ve seen this from the data from China, Italy, and even now here from the United States, but we don’t have that good of an understanding of how well kids transmit the infection or spread it themselves. In regards to the flu, it’s well known that kids are just major vectors of spread. But we do need to learn more about COVID-19 transmission and the role that kids play to have a better assessment of whether or not schools are a function. Our human behavior — how we come together, where we spend our time, our proximity with one another, or are we outside where respiratory pathogen transmission is not going to be as big of a concept going forward — is a big factor.

And then we have host immune system as a factor. We generate vitamin D when we’re exposed to ultraviolet light, and when we’re outside in the summer we actually get more of it. There’s some evidence that it does a good job of stimulating our immune system. So, while that undoubtedly is a factor, it’s probably a smaller factor, but that’s something to think about as well. However, it is well-established that overexposure to UV and sunlight is a cause of skin cancer, so please be very careful with that.

The last factor is this idea of how many susceptibles there are in the population. With COVID-19 we know that the human population is not immune because this is a newly emerged infectious disease, so we know that there’s no preexisting immunity, or at least that’s the assumptions that we’re making for this particular virus. As we see infectious disease epidemics rise, that means there will be fewer and fewer susceptibles in the population. Then once we hit this level that’s referred to as herd immunity, the portion of the population that is largely infected, or has been infected and is immune, and can no longer actually carry on the change in chains of transmission. So, you see this sputtering out of what’s happening going forward in the outbreak, which can happen seasonally. If there’s any seasonally-forcing function, you will see that amplified because of this change in susceptibles through time, and so that will reinforce some of that seasonality.

Here’s an interesting side note here is with animal populations. Humans reproduce all the time, whereas many animal species reproduce just once in a season. In the springtime you see a lot of newborns in wildlife populations, which allows for a whole new segment of wildlife populations to be susceptible, and that drives a lot of seasonality in wildlife diseases because they have seasonality of births, seasonality of susceptibles, and seasonality of disease following after the susceptibles and chasing them and driving them.

Those are the four main reasons why you would see seasonality in COVID, whether it be the depletion of susceptibles, the host immune system, the human behavior of how we generate contacts, and then these environmental factors. But we just don’t know what the main effect any of those are going to have on COVID yet, and I think the consensus right now is that we need to watch and wait, and then it’s probably going to have an effect. To what degree the effect is going to be we don’t know, and there is significant discussion right now about the second wave coming in the fall, and lots of concerns about that.

Q: What are your thoughts on the development of herd immunity as a response strategy?

Dylan George:

There’s been a lot of discussion about it and I’ve seen some reports of people trying to actually get infected. The big concern about that situation is that we don’t have good therapy. All we have right now is supportive care, and Project ECHO as Dan mentioned, but we’re getting much better at understanding how to treat individuals and provide that supportive care because we’re understanding the disease better and how it’s creating pathologies in the individuals. That’s wonderful, but because we don’t have a clear understanding of how to treat, and we don’t have therapies in terms of drugs or vaccines, to me it seems a bit reckless and dangerous to go that route. The preferred way of obtaining herd immunity is through a vaccine. The vaccine is the long-term solution, and that’s why so many companies are pushing so hard to actually come up with something that could be helpful to us to obtain that herd immunity. That’s the safe way to do it, that’s the responsible way to do it, and that’s the way that I would advocate.

Dan Hanfling:

I’ve seen some of those COVID party ideas as well, and to me, that sounds like Russian Roulette –awfully dangerous, because as we know, the vast majority of folks who are exposed will have anywhere from asymptomatic to a mild or moderate course. Some of that may be a little bit rougher than others, but approximately 20% of the population get very sick and we don’t know all of the host factors that might predispose one to having a rougher course than others.

Q: What are your thoughts on the idea of forming a voluntary group would be willing to take the vaccine and then expose themselves to the virus? Thoughts about the ethics or the practicality of those challenge studies, and why they are even coming up in discussion now?

Kevin O’Connell:

Let’s take practicality and ethics separately. As a formal, experimental, practical matter, yes, a challenge study is a very powerful way to get at the efficacy of a vaccine. There’s no doubt about that. We do that, not with humans, but often with animal studies, where we administer a vaccine and then later a challenge and look for an impact on the course of the disease, and on severity and things along those lines. At this moment, I’m not quite sure where to think about ethics. We never do those kinds of experiments on human beings. At least, it hasn’t been a discussion within my professional lifetime about this, up until some of these discussions that have surfaced.

Dylan George:

I’m not an ethicist, and I state that right out of the gate because it’s not my field and I haven’t spent a lot of time thinking about this, but I do think that there is a fundamental difference between doing human challenge studies and doing COVID infection parties. The fundamental difference is that people who would participate in human challenge studies would be closely monitored by medical professionals to make sure that they could receive supportive care very quickly and very efficiently, and they would be monitored for the period of time that you’d be in the incubation period.

I think the major idea behind human challenge studies is if you could have a group of true volunteers to come up with responses, would that mean that there’d be fewer people that would be subjected to the vaccine challenge or the vaccine clinical trial going forward to get answers faster? You’d have fewer people involved in the clinical trial, and therefore, less subjected to adverse effects of the vaccine and that sort of thing. Again, it’s like balancing the pros and cons and the ethics of all of that is a little bit beyond me. It’s not my expertise, but at least on the surface, it’s something to consider in terms of whether or not it could crash the schedule. I know one of our colleagues is strongly opposed to it, and so I think it is a topic that divides or is an area of active debate within the medical profession right now.

Dan Hanfling:

I also find it to be of concern. As Kevin said, we’re not used to doing this in the human population. These challenge studies are usually conducted with non-human primates or other animal species. Only after careful consideration are vaccines provided to a human population, mostly with the intent to look at safety and evidence of side effects and tolerance of the administration. So, I find this to be a concerning topic, and the reason that it sort of triggered in my mind was the notion of, again, let’s all go to a COVID party, get sick, and get it done with. I think that we have to give very careful consideration to intentionally exposing folks. Much the same way that we don’t think the COVID party is such a great idea, I’m not 100% convinced that a challenge study is all that good an idea either.

Kevin O’Connell:

I agree, and certainly, the size of the population that’s being exposed now, certainly, there was a concern during the Ebola outbreak that the epidemic might be over before there was a chance to have enough people vaccinated to actually conduct a usable clinical study on the Ebola vaccine. I don’t think we face that situation here, unfortunately.

Q: Is there any way to know that getting a test guarantees whether or not you have it? I’ve heard that some tests are unreliable. Are there any true facts?

Kevin O’Connell:

Well, I would say that the truest fact is that any test that you get won’t guarantee that you do not have the disease. I think that’s a pretty safe assertion. A negative result on a test can occur for any number of reasons. One, you might have only been exposed yesterday and your body has not developed either an antibody response or had enough time to let the virus multiply to the levels necessary to trigger some of the tests. We have heard that, and we believe the news, that there have been some failures in the way that which people are being sampled. Not everybody who gets the swab up the nose necessarily generates a sample that’s viable enough to carry enough (virus), and sometimes people just don’t make it all the way through the sampling process. All of the these tests — whether it’s the RT-PCR test or the so-called molecular test for the presence of genes that belong to the virus, or the antibody tests that tell you in retrospect whether you’ve been exposed — need a certain amount of either the virus or these antibodies to be present in the body. They have what we call a limit of detection. Down to limit of detection in the laboratory, some of these tests are, in fact, quite accurate, but the way that the test behaves under pristine laboratory conditions is different than the way the test behaves in the real world.

So, no, you cannot say that there’s a guarantee that you have it or not. A responsible practitioner uses a test result in addition to other clinical signs including the patient’s medical history, social history, and have they recently been exposed to people that are known to carry COVID-19, as part of a collection of information to assess the likelihood of a COVID infection.

Q: Can I get COVID-19 from mosquitoes?

Dan Hanfling:

Mosquitoes are known to transmit a number of infectious diseases, particularly when we think about Sub-Saharan Africa and South Asia like malaria, yellow fever, dengue, chikungunya, which are all mosquito-born illnesses and infectious diseases. But I think it’s safe to say at the present time that COVID-19 is probably not transmitted by mosquitoes. Of course, where there’s a will, there’s a way, and those mosquitoes are probably looking to get in on the business.

My sense is that what we know of the transmissibility of this particular virus is that it’s primarily either transmitted by a droplet from a cough or a sneeze, aerosol, if it actually stays suspended in the air for some period of time, or a fomite. Fomite is when those droplets land on a particular surface, whether that be on a counter top or a bed railing or paper, what have you, and then the next person comes along and touches those droplets, those particles, and then brings them up towards their mucus membranes, rubbing their eyes, touching their mouth or nose. So, those are really the known and expected means of transmission of this virus right now.

Dylan George:

As we talk about these routes of transmission that would infect an individual, I think it’s really useful to talk about routes of transmission within the population. For example, we need to have better understanding of which groups are more at risk. I mean, if you find a case in the community, is it really the household where that person lives who is more at risk than anybody else? Do they transmit well in the community, or are there particular coworkers that would be more at risk? A recent study documented these transmission events, and they did find that household members are at highest risk, which just is intuitive. It’s the people you spend the most time with and you’re at the closest range.

Then also, with transmission five days after symptom onset, you really start to lose transmissibility after that point. The most frightening thing, and a lot of people have talked about this as well, is this presymptomatic or transmitting before you actually have symptom onset. Most people are talking about two days before you have symptom onset is when you’re starting to see lots of high viral load and lots of transmission and shedding going on. Those things are pretty concerning as well.

There’s this idea of contact tracing or trying to go into the community and chase down the virus and create firebreaks around it so that it can’t go any further in our communities. We also can think about contact tracing as a way to understand or get better data on these major vectors or these major ways of transmission within the population, and that will help us target where we need to focus infection control and isolation of individuals in a more effective way, and so we don’t use this blunt instrument of population-wide physical distancing going forward, but we can try to be much, much more targeted going forward.

Q: There are many comments about how the coronavirus is not as infectious as the flu. Can you explain universal truths about viruses and how scientists determine the rate of infection, how the doubling of cases every few days can depend on the virus characteristics, and the population density, and so on? People just don’t seem to get that trajectory and how predictable it is for viruses. So, as a result, they have a hard time believing that the stay-at-home orders are even doing anything.

Dylan George:

I think this question really helps us understand that there’s no fundamental or universal aspect of the pathogen. It’s the combination of the characteristics of the pathogen, the population that the pathogen is in, and how people are moving about and actually interacting with one another. And to some degree, the environmental characteristics of where that population is as well. All three of those broadly influence pathogen spread, and one concept that we’ve talked about in other podcasts is about how epidemiologists actually characterize spread. It’s the famed R0 (r naught), or reproductive number, which is an estimate of the average number of individuals that become infected from an initial case in an immunologically-naïve population. So, when you see a number of an R0 above 1, you would expect spread to happen unbridled. If you see it below one, that means it’s starting to sputter out within the population, and hopefully with die out. So, when epidemiologists think about this R0 concept, it’s really three main components:

1. The probability that a susceptible individual will come in contact with an infectious individual;

2. The probability given that contact of an actual transmission of the virus happening;

3. The duration of infectiousness of an individual.

Combine those three components in a mathematical way and you can actually drive this R0 function or this R0 estimate of this parameter estimate. That contact in that definition and in those components is critical. When we change behavior, like physical distancing, that means we’re changing the capacity of the disease to spread within the population, and how much it impacts.

When we saw what was happening in China, Italy, Spain and other places, the initial estimates of this R0 was anywhere between 1.5 and 3.5, meaning anywhere from one to four individuals were being infected from somebody that got COVID, and you can see how fast that would pile up going forward. Now, if we contrast that with seasonal flu, seasonal flu has an R0 of 1 to 2. So, there is a significant overlap there, but definitely, COVID-19 was spreading much more quickly than what we would see in seasonal flu. As I mentioned at the top, these estimates definitely depend on context and will change through time as new data and interventions are put into place.

One of the things that’s been very exciting, and you can see this from the data in New York state and in Washington state, they’ve actually been estimating R0 every week to see what is happening with the dynamics, and you can see a downward trend through time, which is exceptionally exciting and encouraging. What that means to me is that social distancing is working. We’ve spaced ourselves out more. It means that the disease can’t spread as much, or the pathogen can’t spread as much, and now it’s bouncing around in that kind of 1-ish area, or lower than 1 in some places. That’s the encouraging thing. So, we do have some evidence that is correlated with the physical distancing and with the decrease in spread.

When we think about flu, we’re thinking about not just one virus, but we’re thinking about many viruses. There’s many different types of flu viruses and they all have slightly different sorts of components to them. So, it’s definitely transmitting more than what we’ve seen in flu, and then also, the case fatality rate is multiples or maybe an order of magnitude more than what we’ve seen in seasonal flu, and that’s what’s very concerning going forward.

I think it’s hard for people to fully appreciate that many times we have this mental model of what we’re experiencing as a natural disaster, and natural disasters are very quick events that happen, and they’re destruction that happens very quickly, and we move into a recovery phase fairly quickly as well. As we’ve talked about in past podcasts, a pandemic is a slow-moving event that is having impact over weeks and months, and the uncertainty about what’s happening is really challenging, and it’s uncertain as to know what’s happening, because many times you have to make decisions much earlier than what you actually can see in the data. Because you have exponential growth of cases, and you have linear response capability, meaning your response capabilities will be outstripped by the pressure of the outbreak coming forward, and those components come together in very hard ways for people to feel that they’re contributing, feel that something’s happening, and respond to it in a meaningful way.

Q: What are the best sources to check for new, credible scientific information?

Dan Hanfling:

That it’s a great question, and even for experts like us, it’s a real challenge sorting through so much information. If anything, this has shown us what data explosion looks like and what an information explosion looks like, and what a challenge it is to be able to make sense of everything that is coming at us fast and furious. So, from the clinical perspective, I’ll start, and then I’ll turn it over to see where Dylan and Kevin are looking for sources of information.

Regarding clinical aspects, there are three websites that I have put up on my bookmark bar at the top of the page, and I look at fairly regularly. The first is from the National Institutes of Health, and they have coronavirus diseases treatment guidelines, so for clinicians like myself, it is really a good place to start with regards to looking at what is acceptable, what is being trialed, what does or doesn’t have some data behind it, and therefore, cannot be recommended as a strategy going forward.

That’s the first place I go. The second place that I like to go is a place called the Institute for Healthcare Improvement (IHI) who have put together a tremendous dashboard on all things COVID-19-related, including links to a lot of the material that is now being made available outside of the paywall in some of the most prominent medical journals across the globe, including the New England Journal of Medicine, JAMA (Joural of the American Medical Association), The Lancet, British Medical Journal, etc..

The third place that’s specific for the kind of work that I’m doing in the emergency department, comes from essentially a wiki effort that was homegrown. It started out of the Harvard UCLA Department of Emergency Medicine, called WikEM, and is also another useful clinically focused repository of information. I think one of the lessons learned going forward is we’re going to have to figure out what tools can we use, including some tools that we look at from within our vantage point at In-Q-Tel, what tools can we use to help us sort the wheat through the chaff and be able to allow AI or other web crawlers to help us and guide us to the information that is most credible and most relevant for the questions that we’re asking.

Kevin O’Connell:

The world that I live in is pretty nerdy, and a lot of the data that I look at are fairly down in the scientific weeds, and may be a little hard to access for the general reader. I think a good overview of the status of the outbreak can be seen at the Johns Hopkins coronavirus dashboard website. That site is very rich in data that they collect not only inside the United States, but from around the world. I also spend a lot of time thinking about the status of COVID testing, and that’s a bit of a wild west right now, but there are some websites that are collecting and collating data on tests that are being developed. When you are on these websites be very cautious about the claims for the sensitivity and specificity of these tests. Very, very few of them have been tested extensively. Even those that have received emergency use authorization from the FDA have not been tested to the extent that we would in non-COVID situations.

Dylan George:

There’s a handful of people that I follow. My colleagues here on B.Next are absolutely world-class and wonderful, and I think we take advantage of that a lot. I mean, Tara O’Toole, who leads our group, is phenomenal. Dan here is just an amazing resource. Every time there’s something about testing I always go and talk to Kevin here because he’s just a wealth of knowledge. Lu Borio understands medical countermeasure development and testing better than any of the rest of us in our group. And our other colleagues, Joe and JJ, are phenomenal as well. They really help us have a better understanding of what’s going on in these particular spaces. So, some valuable resources there, without a doubt.

Dylan George:

A couple other people I wanted to highlight that you can follow on Twitter, Caitlin Rivers from Johns Hopkins University is just a phenomenal epidemiologist. As is Marc Lipsitch from Harvard University who I already mentioned. Another colleague that I follow almost religiously is Steven Riley, who works at the Imperial College in the UK. He does some very beautiful modeling and is a voice that I lean on and rely on quite heavily going forward.

Dylan George:

The other person that I’ve loved recently, and I’ve never met in-person, is John Burn-Murdoch from The Financial Times, a visualization expert who has put out some beautiful visualizations of different aspects of COVID-19. I love the visualizations and they’re easy to interpret, they help me understand things very quickly, and they’re just an example of how to communicate data more effectively, and how to do that in a concise and powerful way.

This post is not intended to convey medical guidance or provide recommendations regarding the outpatient management of presumed or confirmed COVID-19 patients. It is intended as a supplement to support the ongoing efforts of currently managing COVID-19.

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