Nathan Grubaugh: Genomic Surveillance

Harlan Krumholz: Welcome to Health & Veritas. I’m Harlan Krumholz.

Howard Forman: And I’m Howie Forman. We are physicians and professors at Yale University who are trying to get closer to the truth about health and healthcare. Harlan, what has caught your attention this week in healthcare?

Harlan Krumholz: Well, I wanted to bring up an issue that had come up maybe about two weeks ago that I thought people might be interested in. It was an approval by the Food and Drug Administration of a drug called inclisiran. And people may not have heard much about this before. It’s kind of a drug that I think folks are going to be hearing more about. It’s called an RNA interference drug. It’s about the interference of the translation of the DNA into the messenger that then ends up moving to create protein. So essentially, it’s a way to silence genes. And in 1998, there were two investigators, a guy by name of Andrew Fire, and another one, Craig Mello, who started looking at this mechanism while working on, believe it or not, nematodes. And they eventually won the Nobel Prize for it in 2006. But it’s taken a little bit of—

Howard Forman: Tell us what nematodes are.

Harlan Krumholz: Yeah, those are worms, aren’t they?

Howard Forman: Yes, they are. Yeah. Yeah.

Harlan Krumholz: So these guys are working on worms, and they come up and they find that there’s a way to silence certain genes. And of course the pharmaceutical industry starts thinking about this. Well, there are certain genes that are causing mischief, and if we could silence them, maybe we could help folks out. And this drug is a way of silencing a gene that actually is associated with elevated cholesterol levels. And if you can use this drug, it’s a sort of novel approach to silencing that gene and lowering bad cholesterol levels by maybe 50%. The interesting thing about it and the reason I wanted to bring it up, because it sort of gets to this new age, which is that these are administered as shots. But unlike the shots that are being given now, there are injections of what’s called PCSK9 inhibitors.

These are new drugs that came out a couple years ago, where people can go into the doctor’s office, get injections every couple weeks and really lower their drugs. It doesn’t silence the gene, but it interferes with that gene product. So for the folks who are listening, I think the most important thing to say is that it hits it at a different point, but this med, inclisiran, that’s being now approved, you can get a shot every six months. So even you could get a shot, maybe just once a year, depending on what you’re trying to achieve. And folks are thinking that this is like a vaccination.

So for cardiometabolic disease, I don’t have to worry about swallowing a statin every day. Now there’s still a lot to work out. And these haven’t proven yet that they lower the risk of dying or heart disease, but they do lower cholesterol. They’re approved for that. And I think this is kind of a new wave, Howie. We’re concerned about what does it take for people to remember to take their pills? There are similar kinds of drugs that are out there now for blood pressure and for a wide range of other issues. So people might just go to the doctor once or twice a year, get a shot, and that’s going to have the same effect as if they had to take a pill every day. So it’s going to be interesting to see how that unfolds.

Howard Forman: Yeah. It’s so interesting. And you know, you and I are completely aligned because when I was trying to think about what to talk about this week, the FDA just came out with their annual report, just summarizing what they’ve done in the last year. And I’ve been particularly eager to look at the report this year because a lot of people think that the FDA is 100% focused on vaccine development and therapeutics for the pandemic. But the reality is the FDA has a lot of work that it has to continue doing with or without a pandemic. And as you mentioned, this is one of the 50 drugs that the FDA approved this past year. And that’s not a low number. That’s more than the average over the last decade. We’ve now talked about one of them, inclisiran. We talked a few weeks ago about another one with a lot less enthusiasm, that being Aduhelm.

Of those 50 new drugs, 27 were “first in class,” meaning it was a new mechanism or a new disease to be treated. And inclisiran is considered a “first in class.” The first time a drug with this type of mechanism is being introduced. I think 26 of them are orphan drugs, meaning they treat diseases that affect populations less than I believe 200,000 people. The FDA continues to do a lot of heavy lifting for the overall healthcare of society—even during a pandemic. Now we’ll hopefully come back to this topic in the future because there’s a lot to be said about the approval process. We’ve talked about it with Aduhelm and others, but I am deeply admiring of these public servants and the FDA itself for being able to continue this process even under the worst of circumstances.

Harlan Krumholz: Well, the FDA folks are amazing, but let me ask you this. So in the midst of the pandemic, with so much of the resources being focused on that, how’d they end up approving more drugs than average? Are they changing their thresholds? What is it that led to more than usual? And in that 50, was it because most of the ones for the pandemic were authorized, not approved? So I assume those aren’t in that number.

Howard Forman: That’s correct.

Harlan Krumholz: And “authorized,” just for folks listening, means they lowered the standards for getting it out into public use under an Emergency Use Authorization framework, which meant that that doesn’t really count as an FDA approval. As you may remember, a lot of vaccines people were arguing about, “Are they approved, authorized? What does that mean?” and so forth.

Howard Forman: Absolutely. The monoclonal antibodies, the novel therapeutics, PAXLOVID—all of these are under Emergency Use Authorization. No, I think part of it is, and this is a discussion that we could have that would be longer, but in the early 1990s, the Prescription Drug User Fee Act passed, which allowed the FDA to derive additional funding directly from the pharmaceutical industry to fund the work who do the work on approval. And that scales up, whether there’s a pandemic or not; if a drug company wants to submit data because they already have the data ready, that scales up. It will be very interesting to see in the next year whether clinical trials for non-COVID indications might have slowed down because of the pandemic. That would not surprise me at all, but we’ll start to see that when we see next year’s data.

Harlan Krumholz: So great, Howie. Let’s move on to Nate Grubaugh.

Howard Forman: So, Harlan, I’m really excited for our guest today. Nate Grubaugh, professor of epidemiology at the Yale School of Public Health. He’s been here since 2018. Before that he worked in the biotech industry doing toxicology studies. But since that time he’s worked really on issues around infectious diseases, mosquito-borne virus surveillance, including Zika, and then his lab itself works on using genomics to help us evaluate the risk of emerging threats. And obviously during this pandemic, he’s done a lot of work. He’s been an essential source for me on Twitter. He’s answered questions for me, even when they’re annoying. And I’m just so thankful to have him here today. So welcome, Nate.

Nathan Grubaugh: Thank you so much for having me.

Harlan Krumholz: It’s amazing. You and I have talked about this, how the pandemic has linked together people who wouldn’t ordinarily be working together. One of the great, real joys for me over the course of pandemic was to be able to meet a lot of people and to call them colleagues and friends now who were outside of my immediate research area but became colleagues. And Nate’s one of them. Nate, I want to just go to a couple quick things, because you are really a leading expert in so many aspects of infectious disease and this pandemic.

Let me go to this pre-print that you were on that Howie and I had talked about how people can still be shedding virus, still be infectious for quite some time after the initial infection. And this pre-print that you were on with colleagues suggested that at five days, maybe half the people are still shedding virus, and you’ve tweeted, “Main take-away = ending isolation at day 5 should include a negative rapid antigen test. Otherwise isolation needs to be extended.”

Now this is a little different what the CDC says, but more than that, I’ve had a lot of people ask me this question: “If I get a negative antigen test at five days, am I one of those who are done, or should I still be concerned?” And I wonder if you could maybe get a chance to expand a little bit on your perspective on this.

Nathan Grubaugh: Yeah, thanks for that question and bringing this up. If you have a negative rapid antigen test at day five, that would suggest that you are not infectious. It’s not 100%, right? There’s some small fraction of probability in there that you could still be infectious. And that’s why the CDC then recommends that you strictly wear a mask afterwards. That doesn’t mean you wear a mask except for that happy hour you’re with other colleagues [or] except for when you’re sharing the lunchroom—like, at all times with people outside of your household. So just in case that probability that maybe you are still infectious, that you are reducing the chances for transmission.

Harlan Krumholz: But how much can we bank on the rapid antigen test, especially if people, for example, aren’t taking it from the throat or mouth area? And we’ve been hearing so much, of course you’re an expert on this issue around saliva. So how much should we be able to bank on one rapid antigen test being negative as being sort of a “I can quit my quarantine, and I can consider myself largely not infectious anymore.”

Nathan Grubaugh: Yeah, well, I think there’s a difference between the time of infection and the sensitivity of rapid antigen tests. So even before Omicron, we’ve always known that during early parts of infection, a rapid antigen test is just going to be far less sensitive than a PCR test. We’ve even known that via saliva, that you tend to test positive a little bit earlier than you would with a PCR test from a nasal swab. I think Omicron is exacerbating that a bit. And this could be in part due to the fact that this is more of an upper respiratory tract infection. I think you’ve talked to Anne Wyllie, who’ve probably gone into a lot of detail into that. So I don’t need to dive into that part.

But further into infection, the difference between whether you’re doing it via nasal swab or a throat swab, I think are pretty minimal. And in that point, I think that the nasal swab rapid antigen test is probably a pretty good assessment. And if you are negative there, you’re likely not infectious because the saliva or the throat swab will actually probably come down a little bit before that. You might actually test negative a little bit sooner with the throat swab. So yeah, again, there’s always some probability that you’re still infectious, but I’m really okay with that policy of a single negative test to test out of isolation. Would we like to have more? Yeah. A better policy would be two days in a row of a negative test, but then we have to think about, do we have access to those?

Harlan Krumholz: I want to leave it open to Howie, but let me just follow up just one more quick one, which is, I also understand that there are some people who will have a positive antigen test for a long time, that they will have viral remnants that will end up being positive. Are those people just screwed because they’re going to assume that they’re going to be infectious? And when, then, if I have a positive test, can I consider that that’s a positive test that’s not infectious anymore on the rapid antigen?

Nathan Grubaugh: It’s far more likely to happen with a PCR test than a rapid antigen test. This is why I’m not recommending a PCR test to get out of isolation because you will test positive for longer. There might be some individuals that test positive for longer via a rapid antigen test. And I’m not here making the policies, and I don’t envy the people in those positions to have to do it. You only have access to one test. If you test positive on day five, then you do a 10-day isolation would be my recommendation. And then I think after 10 days, there’s very little probability that you would still be infectious by then. So whether or not somebody is screwed depends on what you mean by “within those five days,” how important those are to being able to return to work and other things.

Howard Forman: Can you give us a little sense about the heterogeneity of all the different tests that are out there among just the antigen tests? Because we now know, and I went online yesterday, I ordered my four rapid tests that are to come to me. I think a lot of us have already done that at. The U.S. government has the website up so that you can order it yourself. But I don’t even know what they’re shipping, what type of test. I presume it’s a rapid antigen test. We know that there’s quite a bit of heterogeneity. There are some rapid tests that are PCR tests or nucleic acid tests. Do you have any advice to give people about what they should be looking for if they’re buying it themselves or about what types of tests they might be getting?

Nathan Grubaugh: Yeah. I ordered those tests yesterday too, and really excited to get them and really happy that the government is finally putting this in place. I think it would be so helpful. We get questions about this a lot, of the different sensitivities of rapid antigen tests. At Yale, the Environmental Health and Safety group gets questions about this a lot too. It’s kind of difficult to actually determine. I think the advice that we’ve been primarily getting is, use the tests that are available and note that being negative does not mean that you’re not infected. It decreases the probability that you are, but it’s not perfect, but being positive is a pretty good indication that you are infected and infectious. So I don’t really have a great answer for you, Howie. I’m sorry, but it’s the heterogeneity that we have to live with. And I don’t think it’s that great between tests that I would say, “Don’t use this one here.” It’s similar with PCR tests. There’s differences in the sensitivity on these, but overall they work fairly similar.

Harlan Krumholz: I wanted to ask you was about the surveillance work you’re doing. You’re really maybe the Connecticut maven on surveillance and in the sequencing to help us understand what’s going on. I wanted to ask you one thing, which was on December 22nd, you said that at that point 56% of the outpatient testing in New Haven were Omicron, and you expected it to continue to go higher. You were right about that, right? It was on a pretty steep slide. A lot of people have wondered, “Why aren’t we doing more sequencing?” And then you’re also at the forefront of this kind of shortcut to sequencing using the S gene dropout. I just wonder if you could just explain how you see the role of sequencing and surveillance now and what you’re doing to do the shortcut, maybe explain in lay language for folks what you’re doing to try to make this more efficient than having to actually do the entire gene sequence of these viruses.

Nathan Grubaugh: Yeah. So initially there wasn’t a lot of interest around sequencing in SARS-CoV-2 infections, and I’m talking primarily about 2020. We sequenced the first nine cases in Connecticut and kept up on it for a bit. The state didn’t have a lot of interest. The CDC, while they would appreciate people doing sequencing, there still wasn’t a lot of interest there and a lot of places around the world, because what we are primarily doing with it were like spatial epidemiology, and of course we’re attracting evolution, but at that point, public health agencies I don’t think really appreciated the role that evolution has in the pandemic, which I think we all appreciate now. I think everybody knows now why we need to do genomic surveillance, because otherwise you have no way of really differentiating between variants.

Harlan Krumholz: And just for folks, these viruses are basically snippets of gene sequences, and those sequences can change. And so when you’re doing the sequencing, you’re actually characterizing with precision, what exactly is nature of the virus? Because the label of virus encompasses a large number of different sequences. They’re common enough that they’re categorized together, but they’re still quite different. That’s how we got to Omicron versus Delta, right?

Nathan Grubaugh: Yeah, exactly. So the primary use with the sequences is just to bend them into categories based on specific mutations to say that you are this variant or that variant. And we do a lot more with it that maybe I don’t have to explain right now, but that’s the basic use is like, “Is this Alpha? Is this Beta? Is this Gamma?” So with the emergence of Alpha in the U.S.—this was late 2020, early 2021—did this need arise, or did the public health agencies actually recognize this need, and so we rapidly created a group here. It’s the Yale SARS-CoV-2 Genomic Surveillance Initiative. We did a lot of sequencing for the state for free, for about five or six months, just knowing that this is needed to be done. We ramped up efforts, and our goal was to always sequence above 10% of the cases, right?

We can’t sequence everything, and we don’t really need to sequence everything for population surveillance purposes. Really between right around 5% or so is enough to get a good enough indication of what is circulating of variants that are at frequencies at less than 1%. So we’ve been able to maintain that. And now the state actually funds this. This is a coordinated program with many other labs across the state. Collectively there’s about now maybe between 10 and 20% of the cases that are sequenced, that it obviously depends a lot on the amount of transmission that is happening. Why aren’t we sequencing more? Because actually I think we sequence enough. But your question about then using PCR. So sequencing is absolutely needed to be definitive on, is this variant Omicron or Delta or something new that we don’t know of yet, but sometimes we can use shortcuts.

So Omicron has a deletion in its spike gene that might actually be associated with transmission and other things, but for us, that deletion, just by chance, happens to sit right in one of the PCR targets from a specific assay called TaqPath that Thermo Fisher makes. Now the TaqPath PCR assay has three targets: one in the ORF gene, one in the nucleocapsid, and one in the spike, and so you only need two of those three to be positive to call it a positive infection. So it doesn’t decrease the actual sensitivity of the assay, but by looking at the detection in the spike gene, compared to the other genes, we can differentiate Delta and Omicron, because Delta does not have that deletion. And so far our results have matched up really nicely with the samples that we do sequence. Because I don’t want people to think we just do the PCR and that’s it. We actually sequence them too, but it just takes longer. But now I get an update every single morning at 8 a.m. with the TaqPath results from the day before. And so instead of being about two weeks behind with the sequencing data, I’m a day behind.

Howard Forman: One of the things that you all have done, “you” meaning your lab, but other genomic surveillance labs have done is to sort of give a hint as to whether a new lineage is something that we worry about. Is it going to become a variant of interest, a variant of concern? And I’m fascinated by that because people have been able to preemptively say, “We think this is going to make it elusive of vaccine-induced immunity,” or so on. This is grand work that you’re working with people all over the world on this. How collaborative is your work, and how much do you all actually talk to one another about what your concerns are about a new variant?

Nathan Grubaugh: Yeah, I think the most important aspect of our work is what you just described there, putting sequences into categories and reporting the frequencies is like the easy things to do. The main part of it is to determine, do we need to be concerned about this? Do our policies change because of this? And obviously a lot of eyes are on vaccines and therapies. So at least in the U.S., we have a CDC-coordinated group called SPHERES, and we meet every week actually at this time; I’m missing the meeting to chat with you all right now. But we meet every week. We keep in constant communication, and it’s one of the most rewarding things to be a part of.

Harlan Krumholz: So one of the things I noticed that you tweeted was maybe something to watch as the rise of the spike, R346K mutation in Omicron. Can you expand on that a little bit?

Nathan Grubaugh: Yeah. So again, now that things are becoming mostly Omicron, we are now looking within Omicron to see what else here could be of concern. And you mentioned earlier in the podcast about how we have connections with people that we didn’t have before. My primary collaborators are people I didn’t even know two years ago. And a lot of those for me exist in the hospital. And Rick Martinello and David Peaper and Chris Pettker and Marie Landry, I talk to all the time. And what I’m concerned about right now are things that are going to impact mutations that will impact monoclonal antibodies.

And so this R346K mutation, the spike happens to sit in one of the antibody-binding domains for the last remaining monoclonal antibody that is effective for Omicron. And I always forget what it’s called. It starts with an S. This is why I have to have my clinic partners here. And it’s also known or thought to decrease the effectiveness of other monoclonal antibodies. So anything that happens in the spike gene, any mutation there, especially in some of the binding domains, we try to track the frequencies, and we report that back to our colleagues at the hospital as quickly as possible. So could this be a concern? It might be, we don’t quite know yet, but our job is to alert people of what we’re seeing.

Harlan Krumholz: Yeah. I think that was EvoShield, right? Something like.... That’s the antibody that’s still coming from Lilly.

Howard Forman: So I’m curious, is there anything that actually keeps you up at night right now in terms of the overall pandemic response? There are people on Twitter who say that, “If we don’t do this in six months, we’re going to be in a disaster.” And then there’s the other extreme of people who say, “We are synchronized. We have immunity now. So much less to worry about. It’s endemicity at this point.” I’m curious, where do you stand on what the future holds for us, knowing what you know about the evolution of these viruses and the variants that flow from that?

Nathan Grubaugh: Yeah. Well, over the last two years, a lot has kept me up at night. What primarily keeps me up is my kids and being able to keep them in school. And anything that happens now impacts them. And in Omicron, right, is almost like a worst nightmare in terms of those fears. And it’s like, yes, I know that disease severity on the whole is lower, but the increased transmissibility in all of the infections, and this was the worst part of the pandemic. And I was really afraid of what was going to happen to classrooms come January. Whether or not there’s even going to be enough staff in the schools, transmission and infections among kids and keeping them out and having to go to remote. Luckily, our school has done fairly well, but many, many, many haven’t.

Harlan Krumholz: Well, we want to thank you so much for joining us, and if we’re in a better position going forward, honestly, it’s in part due to your efforts. And I just want to signal that to me this is just what public health research is supposed to do, combine the deep scientific with the pragmatic. And that’s what you’ve done. You’ve brought together I think the very best, but to see the tools applied in almost real time.

I just want to tell folks, too, that according to your Twitter description, you said you’ll “sequence for beer (and funding).” So if anybody has some sequencing to do.... And the one last thing I wanted to just say is, and I’m curious, because the way you’re doing with this S dropout, which is lots of people who are infected with COVID want to know what variant they have. And maybe that kind of shortcut is going to open the path towards testing that routinely can tell people what they’ve got rather than for us to say, “That’s only used for surveillance, and we can’t really tell you what variant you have,” but, thanks so much. I really appreciate it and look forward to seeing more good work out of your group.

Nathan Grubaugh: All right. Thank you so much for the time.

Howard Forman: We really appreciate you. Thanks so much.

Harlan Krumholz: Thank you.

Howard Forman: Harlan, what’s something that inspires you or keeps you up at night?

Harlan Krumholz: Yeah. I don’t know if this is inspiring or keeping me up at night, but I like to keep us on topical things. And the FDA just came out within an announcement that says.... Listen to this language from the FDA: “It doesn’t intend to object to the use of qualified health claims regarding the consumption of magnesium and the reduced risk of hypertension, high blood pressure.” You have to really realize since we’re on a kind of a theme of the FDA today, given our earlier comments, that the FDA is far beyond drugs and devices. It’s of course cosmetics and food, and food is huge. And you walk down the aisle of the grocery store, you see all these claims, and I don’t know if you’ve ever scratched your head and said like, “Wow, I can’t believe that.” I saw that Kellogg’s, some sugar cereal that they were producing said this is great for your immunity.

And all of this is made possible because the FDA has actually a much lighter touch on food claims, and they allow these companies to make claims where they say something may have it. Now they do have a process, and these qualified health claims are supposed to be supported by scientific evidence, but they don’t meet the same more rigorous significant scientific kind of evidence that’s required for an authorized health claim. These are called qualified health claims, and they can be something like, “Food low in saturated fat—and that includes soy protein—may reduce the risk or might reduce the risk of heart disease.” And I think from the point of view of the public, it’s hard to parse this stuff because on a regulatory science point of view, they’re very careful to say you can only say “may” or “might.” You’re not supposed to say something stronger.

But for example, in this magnesium, they’re saying, “So we’d like you to say something like, ‘Inconsistent and inconclusive scientific evidence suggests that diets with adequate magnesium may reduce high blood pressure.’” Okay. That sounds fine. Because it leads with, “There’s a lot of inconclusive evidence,” but they’re also allowing, “Consuming diets with adequate magnesium may reduce your risk of high blood pressure.” And that’s not really strong. They say you can add a sentence. FDA has concluded that the evidence is inconsistent and inconclusive, but I worry people just read the beginning of that sentence or that there’s a communication here around food and risks and benefits that slides through essentially this qualified health claims loophole.

And then on the marketing side, it gets out of control. So I’m just flagging it. It just came out about this magnesium. By the way, if you’ve got high blood pressure, you want to take magnesium; probably won’t hurt you. There is some evidence that it might lower your blood pressure by one or two points, but most of those studies are small, inconclusive, and there’s a need for bigger trials. That’s the bottom line on magnesium. How about you, Howie? What’s on your mind? I know you’re thinking at a higher level than that.

Howard Forman: I don’t know if I’m thinking at a higher level, but I’m being pensive and wistful in the days after this celebration of Martin Luther King’s birthday and his legacy. And I was a huge fan, I guess I still am a huge fan of Sidney Poitier, and I keep coming back to how much he accomplished in his career as an actor, an activist. He died two weeks ago at the age of 94. I was a really big fan. And even though a lot of the early viewings of his movies happened when I was quite young, it was just not lost on me that the roles that he played helped move the needle on societal awareness and acceptance of our common humanity and our struggles, and race was a central factor in the roles that he played. And he was not given the artistic freedom that actors have today.

And I loved so many of his movies. My favorite though was In the Heat of the Night, Rod Steiger. And so many scenes in that movie were great, but there were also some that were shocking to audiences. And even today when you watch them, you realize that they were shocking at the time, and the world is just a much better place for having had Sidney Poitier among us. His legacy continues to live on through so many others who continue, as do you, to advance equity among all of us and to hopefully get to a more just society. So just in the wake of Martin Luther King’s birthday, that’s what comes to mind and gives me hope.

Harlan Krumholz: Great. So, Howie, we should tell folks they’ve been listening to Health & Veritas with Harlan Krumholz and Howie Forman.

Howard Forman: So how did we do? To give us your feedback or to keep the conversation going, you can find us on Twitter.

Harlan Krumholz: I’m at @hmkyale. That’s H-M-K Yale.

Howard Forman: And I’m at the Howie. That’s @thehowie.

Harlan Krumholz: Health & Veritas is produced with the Yale School of Management. Thanks to our researcher Sherrie Wang and to our producer Miranda Shafer. Talk to you soon. Howie.

Howard Forman: Thanks very much, Harlan. Talk to you soon.