Under the Microscope: How Sequencing Plays Pandemic Detective

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The longer the COVID-19 epidemic persists the more likely we are to see more super-spreader events, even among those vaccinated, and possibly by variants not yet identified.

Health experts have already worked to help prevent and treat COVID – but say there’s more we need to do to track individual cases and community spread.

On this week’s episode, John Connor, MD, an associate professor and researcher at the National Emerging Infectious Diseases Laboratories at Boston University, joins us to explain how they track the introduction of COVID and remnants of COVID infections over time.

The following is an abridged transcript of his interview with “Track the Vax” host, Serena Marshall:

Marshall: Dr. Connor, you’ve been tracking COVID infections over time. Explain for us how this is done and how it’s calculated, and shared because it seems like we don’t really even hear about these variants until they’re a big percentage of the population or are spreading rapidly.

Connor: To explain what my lab is doing in my lab is part of really what is a very large and growing effort in the United States of a bunch of different people, is we are very interested in essentially probing what the virus genomes can tell us. Right? So, in my case, one of the things that we’ve been doing for a long time is working with Boston University, which is doing on campus testing.

So whenever they get a positive sample, we then get a portion of that positive sample. And we extract the viral RNA. We then convert to DNA and through a couple of different machination steps, figure out what the genome sequence is, right? So that’s 30,000 individual nucleotides, and then we study it and the idea behind studying it is that when we look at that genome sequence, you can think of it as a traveler’s suitcase.

So a long time ago, when people would travel to different countries, they’d get a sticker from that different country and they’d slap it on the outside. So you’d see Italy and Spain and Germany, depending on when people went. And people may still do it. I, of course, I’m thinking of old time movies.

But the idea of looking at the genome is that it accumulates changes over time.

And that’s very much like those stickers. So you can essentially keep track of where the virus has been, a little bit about its history. By looking for these different mutations, which in my analogy are our stickers. And so when we get samples and we get the full length genomes, we compare them. And see how similar are they? What do their travel patterns look like?

And there are cases where we can see that at least on the campus, there are viruses that are coming from outside the campus. And that’s usually the overwhelming majority of the cases we see. But then there’s also some situations where it looks like there has been transmission between people on the university campus.

And we know that because then the virus really hasn’t picked up any additional mutations.

Marshall: That’s fascinating. So essentially what you’re showing is exactly how often the virus is spreading and where it’s coming from?

Connor: That’s right. The central question, at least from how we’re looking at it, is within the population that we can look at: how is the virus showing up? We know it’s showing up. But the question is, is it because of things that are going on on campus? Is it because of gatherings on campus or is it because of things that are outside, that can’t be controlled as much?

Marshall: So how many have you identified?

Connor: So at this point we have sequenced more than 2,000 different individual genomes.

Marshall: So there’s more than 2,000 variants of the virus, essentially?

Connor: So no, I explained that poorly. I apologize. So we had sequenced 2000 individual virus genomes, but they then get classified into different lineages. So let’s talk about right now. So in the last month we have sequenced several hundred different viruses. They have all been Delta lineage.

They are various sub lineages within the Delta family of viruses, but they all essentially cluster as Delta.

Marshall: Okay.

Connor: And they all have various different mutations that distinguish them. Right. Let’s say that they have come from various different places and are unique introductions, in most cases.

Marshall: So now, as we’ve learned, Omicron is spreading within a two day span, much quicker than Delta. You’re going to start seeing in your lab that Omicron variants and lineages start to [tick up].

Connor: Yeah. So we expect that will happen. Right now, as of December 6th, we hadn’t noted an individual case within the BU community, but as you and whoever’s listening is probably aware, there has been a very rapid uptick, both in our area and in the nation where more and more of these cases are being identified.

Our university is not going to be a little island untouched. And so, yes, I expect we will see more. We will start seeing Omicron cases. I expect, then the question is going to be can the existing policies in place and good contact tracing as well as us understanding where the Omicron cases are identified, help us limit the spread of the virus?

Marshall: I want to take a step back here, Dr. Connor and just, you know, when we talk about the virus having more opportunity to replicate and spread and get stronger. How it’s really more of an accident of replication, right? The virus isn’t thinking or adapting to try and get stronger and evade our vaccines.

So can you just take a step back and explain for us when you’re seeing these sub lineages, and then you see one gets stronger. How does that evolve?

Connor: Yeah. So I think the way that I usually explain it is that the virus is making a lot of copies of itself when it’s replicating. So right, if I get SARS-CoV-2 and it is hanging out in my nose, it is busily making copies of itself. And it does a pretty good job, but it’s not perfect. It’ll make a mistake.

Really. It ends up making a mistake about once every time it copies those 30,000 nucleotides.

Marshall: So pretty often.

Connor: What it means is that it’s seeking out a lot of different opportunities, right? Some of those mistakes will be harmless. Some of those mistakes will make the virus, that individual virus genome, not work very well, but others may help it work better. And there’s a really intense calculus of what those mutations might bring to the virus.

It may make it more stable so that it can now be transmitted better, but that doesn’t necessarily mean that it makes it more pathogenic. It doesn’t mean that it will make people more sick. It just means that now it can be transmitted better.

Every time that there is an infection, SARS-CoV-2 is essentially probing other pathways, other ways that it might get around. And it’s not doing it intentionally. Like if there’s not a little COVID brain that is sitting there directing it; but it does mean that every time there is an infection, there is the opportunity for the virus to change a little bit.

Marshall: So, what do we know based on your research about how quickly COVID is being introduced into communities?

Connor: So what we see is that we have very regular introductions. Because of the way that the university has set up control policies and tracking because there’s regular testing of all the people on the campus once a week, it means that individuals are identified really quickly. And that allows those individuals to then quarantine or to at least stay out of large social gatherings, which really limits the spread.

And so I would make the analogy that at least what we have seen is a lot of embers that come into the community that then get snuffed out.

Marshall: Is there a main source of transmission that you’re finding? You said that more of the genomes are showing up as being from outside the university versus the interior. So is that, you know, a family gathering indoor dining school, like the school itself? It doesn’t sound like the school is the main source.

Connor: Right. So it’s a great question. The data that we have is suggesting that on-campus activities are not the major source of spread. That one of the things that we have looked at intensely, and when I say we, I mean a very large group at the university, I don’t mean to suggest it’s just by laboratory.

We have been interested in: is there classroom transmission?

Marshall: I think many parents want to know.

Connor: Parents want to know, faculty wants to know, students want to know, and we have looked very hard and it does not look like that as a significant source of transmission and other on-campus events don’t repeatedly come up as sources of transmission.

Marshall: Yeah. Other on-campus events like frat parties?

Connor: Yeah.

So great question. I think I would draw a distinction there, right?

When you have situations where people are hanging out for long periods of time and maybe doing so unmasked. That does tend to correlate with transmission, which I think makes a really difficult situation. That these are the things that are an important part of who we are as human beings. We are part of community and the challenge is that this virus seems to be very excited about large gatherings that last for long periods of time.

Marshall: So is that what you’re seeing as the main source of transmission, then like parties themselves or indoor dining?

Connor: So it’s very difficult to say to you that there’s really one source, right? One thing that happens. It’s not that every party leads to lots of spreading. It’s not that any particular event is always going to lead to disease transmission. But it is the case that what we end up seeing is that when we do see a lot of internal transmission, there are a lot of social components associated with it. And those can be different, but it’s always the extended social interactions that are associated with spread.

Marshall: I mean, for many people it’s kind of become when there is a big event [they] term that a super-spreader.

Connor: Right.

Marshall: And so what do we know about why those are still happening? Even as we have more treatments and vaccines available, cases are more mild, but I mean, does that change that definition of what a super-spreader event is?

Connor: So the super-spreader event is usually referred to as something where you can start counting numbers. Where you can see that there is one event or a couple of linked events where a lot of infections came out of it. And there’s been a lot of things that have been changing.

A year ago, we were in a situation where people were largely staying apart from one another. There weren’t a whole lot of gatherings. And when there were a lot of situations where those few gatherings did lead to a lot of spread. But now a year later, I think we’re all really exhausted by the concept of always being segregated and there is a lot more interaction. There’s a lot more interaction that doesn’t lead to super-spreader events.

I think it’s very, again, very complex to really nail down. Okay. When you do this, this is the issue. I think there’s a lot more safety because the vaccines have shown that they can limit spread. And that they can limit severe consequences from infection and that’s really positive. It does not, however, seem that the vaccines are an Iron Man suit that protects us from everything.

There is still transmission to vaccinated people. It appears that there’s still transmission among vaccinated people in certain cases. And I think it’s really difficult to understand exactly why. The super-spreader event is something that we can still see instances where there is a significant amount of spread.

Marshall: I think people thought, you know, once you get vaccinated, those super-spreader events would go away?

Connor: Oh, wouldn’t that be great.

Marshall: Then that’s not the case.

Connor: So it is, I would say it is markedly less for every interaction. Right. So if, let me suggest to you that before vaccines came out, if there were 10 large group interactions, let’s say five of them might’ve led to super-spreader events, and now that’s down to one. But the number of get-togethers we’re having is larger. And so even if it’s more rare, if we’re getting together more often than those two things can balance out.

Marshall: So less big super-spreader events and perhaps more small ones. Is there a number that you put on it to count it as a super-spreader?

Connor: No, I don’t think there’s a hard and fast number for what is a super-spreader event. When we see situations where there are four or more, we really start thinking hard about what caused that many individuals to acquire infection essentially at the same time. But there’s not really a number where I would say: yep, it is a super-spreader if it is five or more and not have it is below that there’s a lot of situation-dependent context for how we think about it.

Marshall: So looking at the variants that you’ve been tracking, you said most of them are Delta. You expect that to tick up to Omicron. How many, though, different variants of COVID do you believe are circulating?

Connor: So there are a large number of variants and most of them are ones that we have a relatively good handle on. And the reason for that is that there is a lot of surveillance sequencing going on around the country. And that means that we are in a good position to catch things that are circulating.

Even if they are rare, the likelihood is that if they are continually transmitted, that over this regular sequencing, we will see it. What we are seeing is that over time, the variants that are circulating have changed. If you remember back to the beginning of the year, everybody was very concerned about Alpha. Everybody was concerned about Beta and some of that bore out. Alpha became a major aspect of the circulating virus in the country. Beta never really did. Gamma never really did. But it definitely made an appearance.

The interesting thing about Alpha is that it was very strongly transmitted at the beginning of the year, but by the summer, it was pretty much gone. On our campus, we saw very few cases in June, overall. Right. It looked like the sun was coming out. It was great. I was super happy.

And then what we saw was that Delta arrived and cases started going up and we have essentially seeing Delta, not exclusively, but overwhelmingly.

Marshall: Yeah, I think the CDC put it originally like a week ago or something at 99%. Now Omicron is at 3% of that.

[Editor’s note: CDC data now lists Omicron as responsible for 73% of new cases.]

Connor: Right. Yeah. We have seen waves of the different variants, and I think we are paying attention to the major variants when they exist, but we are also always looking. The reason for doing the surveillance sequencing that we are doing is in case there is something odd that shows up, we’ll catch it early.

Just like in South Africa and in Botswana, the first identification that it was circulating was fairly early on and the identification that it was something new was something that was done fairly early on because of the ability to do this surveillance type of sequencing.

Marshall: A lot of epidemiologists, though, say we need more real time surveillance and sequencing, like your lab’s doing, but on a national level.

Connor: And I agree with them. I think that it is something that is proven to be very informative in multiple ways. There’s a general populational way in which it’s informative. When we think about: okay, diseases circulating, that’s one way of thinking about it. But understanding that the virus is changing over time is also helpful for us knowing what treatments should we use. Which treatments are not going to work because the virus is evolving and having fast sequencing, can be really useful in that.

Marshall: Is fast sequencing really the way to end the pandemic? I mean, we know the vaccines have been huge, but even now with Omicron, we’re seeing that you now need the booster in order to really be protected. And it sounds like given how many variants are probably out there that that’ll change again.

Connor: Yeah, I agree. I think I’m an “all of the above” person on how to address the pandemic. I think that sequencing is critical, but sequencing alone is not going to solve the entire set of problems. There needs to be an ability to understand how the virus is changing, but there also needs to be a good set of tools to treat those who are infected and symptomatic. And there need to be good vaccines.

I think we’ve made a good start. I’m hopeful that we will continue to develop better and better vaccines and that all of these things are necessary. And that if we don’t do that, then we will continually be fighting a seesaw battle.

Marshall: Do you see given how many variants you’re tracking and how many are nationwide that this vaccine will eventually turn into an annual shot like the flu?

Connor: Yeah. So it’s a great question. If it becomes an annual shot, I am going to line up and get it. But I am always hopeful that we would be able to identify a vaccination strategy where it could be longer-lasting.

I think I am always excited about the idea that we could develop a vaccine for this virus that is similar to measles or mumps or polio. Where they are longer-lasting.

Marshall: Do we have as many variants with those illnesses though, as we’ve seen with this virus?

Connor: No, and we also don’t have as much transmission.

One of the complicating aspects of SARS-CoV-2 of this pandemic is if you have millions and millions of people that are infected with and transmitting the virus, each one of those individuals is a chance for the virus to try a different path.

Marshall: So we’ve seen because of this transmission, because of the new wave that is expected, at-home testing made more available. Do you think that’ll make it more challenging to gather the data and get ahead and stay ahead of the variant?

Connor: I think that at-home testing is really exciting. I think it’s something that can be really important for helping people understand their situation personally, and help influence their behavior. And so from that standpoint, I think it’s a really important part of successfully addressing spread during the pandemic.

I don’t think that is going to derail anything necessarily. I think that having at-home tests will allow people to know more. I don’t think it will mean that they will never come in and get tested in other ways. And I think that as they come in for other tests, like the RT-PCR test, that if it feeds into a good surveillance sequencing approach, will still give us the information on what is circulating and that’s going to be important.

Marshall: Would it help to beef up surveillance if we had everyone’s at-home test include a prepaid envelope and they sent them to a lab like yours?

Connor: Right. If you are positive, will you please swab your nose again and send that off?

Marshall: Is that a realistic scenario?

Connor: So I would say if that could be done, even in a fraction of cases, that would be really useful.

Marshall: How would that happen though? Would you have to include a special container? Is it literally just dropping that swab in an envelope? I mean, what would that look like?

Connor: Yeah, right. It’s a great question. There are already some approaches where there are mail-in tests. And so I think it could build off of that, but you’re asking a great operational question and a logistics question that unfortunately I can’t answer.

Marshall: Well, this is just so fascinating, doctor. Thank you so much for joining us and we’ll continue to watch these super spreaders and variants. And hopefully at some point they’ll stop.

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