Q&A: NIH Director Dr. Monica Bertagnolli on next steps for RECOVER, future Long Covid research plans, and more

Betsy Ladyzhets spoke with Dr. Monica Bertagnolli, director of the National Institutes of Health (NIH), in a wide-ranging interview discussing the agency’s efforts to further research into Long Covid and related diseases.

The interview follows Betsy’s reporting about the NIH RECOVER initiative, the agency’s flagship Long Covid research program, for The Sick Times as well as STAT News and MuckRock. These stories uncovered widespread criticism of the initiative for moving slowly into clinical trials and failing to produce novel research after receiving over $1 billion in federal funding.

In the interview, Bertagnolli described a new phase of RECOVER, called Treating Long Covid, which responds to the Long Covid community’s criticism with a renewed focus on innovative clinical trials. The Treating Long Covid program will launch next month with a three-day research meeting to discuss trial proposals, Bertagnolli said. This meeting will also be instrumental in planning how to use $515 million in additional funding allocated to RECOVER earlier this year.

Along with RECOVER, the interview covered developments in Long Covid and Myalgic Encephalomyelitis (ME/CFS) research, the need for continued federal funding, acute Covid-19 precautions, and more. This interview has been lightly edited and condensed for clarity.

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Betsy Ladyzhets: I wanted to start with the RECOVER-Treating Long Covid program that was announced recently. How will the new wave of clinical trials that this program going be different from the initial ones? I know it’s still being developed, but I think people would appreciate any updates.

Dr. Monica Bertagnolli: First of all, let me put the first round of trials into perspective a little bit. We were hit with this disease [Long Covid]. The bad thing about this disease is that we don’t understand it — we don’t understand it at a molecular level. Through all the people who signed on to the [observational] cohorts, you know, 30,000 people, both affected and not affected, and through the assistance of so many clinicians who are taking care of ME/CFS in the past, too, I think that we have started to get an idea about the clinical presentations of this disease. But we really are lacking still in understanding it on a molecular basis.

So we’re left with a real dilemma — what do we do for trials? Because we want everybody to be cured. We want this disease to be gone, either prevent this or cure it. And with Long Covid, as opposed to ME/CFS, we actually know the agent that has done this. We know the virus [SARS-CoV-2].

The first round of trials were based on hypotheses with partial knowledge. The VITAL trial [testing Paxlovid] was based on work where, we don’t know that we’ve got persistent virus, but we’re going to assume — that’s our hypothesis. That we need to treat an active virus. We didn’t know it for sure, we still don’t know it for absolute sure, but [research] is getting closer and closer. We also didn’t know whether [symptoms were caused by] persistent virus that the body couldn’t clear, or whether it was damage that the virus did that now we’re left with. And so some of the interventions in the other trials were trying to attack [that damage].

The last thing I want to say about the current, first round of trials is that every single one of them has biospecimens and biology along with it. These answers that we still don’t have, we’re going to know so much more when those tissues are analyzed and the results of those trials are known. I also want to say to the community, I know people were a little disappointed at some of the trials. [People thought:] “This is just a treating a symptom. It’s not really getting us our cure.” But interwoven with the treatment is also deep a understanding of the biology that we’re going to need to get to the next round. 

Now, what’s different about the new trials? Well, we are moving fast. It seems like we’re not, for the people who are suffering, but we’re moving really fast. We stood up this whole first round of trials based on our best guess as to what was going on, in our best approach to learning more. The next round of trials, we want to be based on all the knowledge we’ve gained so far.

So what’s going to happen? We are having a meeting, September 23 to 25. Three days. We want everyone who has an approach to trials to participate. We put a call out to all the current investigators [in RECOVER], and absolutely anybody out there who has ideas, to participate in the meeting. It’s going to be hybrid. We should be able to engage the broadest possible audience. It’s going to be about taking a very serious look at, “What do we know today? And what smart trials can we design? What are we ready to start doing in new trials going forward? What don’t we know yet?”

That meeting is going to be absolutely critical. I want to emphasize, we want that meeting to be really inclusive. And after that meeting, there’s going to be a lot of really serious, hard work to be done, to plan for where we go next. We’re not waiting for any of [the first round of] trials to read out or anything else to happen, because we know we’ve learned a lot. I think that we’ll come out of that meeting with some new, exciting trial proposals, but I have no foregone conclusions.

BL: I see. To clarify, you said it will be current investigators at that meeting — will there also be opportunities for researchers who are not currently part of RECOVER, but have also been working on Long Covid, ME, other diseases —

MB: Absolutely. A few of them have reached out to us, who weren’t part of RECOVER… I hope we’ve gotten to everybody, but I also put it out on social media, to try to announce this meeting so people who are interested could attend. The other thing I get asked is, “Are people affected by Long Covid invited?” Absolutely. As are people who take care of people with Long Covid, people with ME/CFS, people who are smart on the clinical care. I suppose if we get 30,000 people at the meeting, it will be a problem, but that will be a lovely problem to have.

BL: Do you have a sense of what the meeting will include? Will people submit proposals for different interventions, stuff like that?

MB: We’re asking for one or two pages [proposals], I need to get back to you on exactly the format… But we do want to make the meeting as productive as possible. So there is going to be a callout for ideas in advance of the meeting, in very short form. Again, I’ll emphasize that the meeting will aim to hear from everyone and have as many good theories and ideas as we can talk about during the meeting — but it’s only the start. After the meeting, there will be intense activity to decide how we go forward, in an inclusive way.

People also ask, what about industry [pharmaceutical companies]?

BL: Yes, I got a couple of questions about that, too.

MB: Yeah, very important to include them as well. I’ll say, I think we’ve not seen a huge rush of pharma into this space, right? … Believe me, they want to be in this space, this is a really fruitful, fertile area for the pharmaceutical industry. But they’re in exactly the same place we all are. We have to understand the fundamental pathobiology.

And we’re getting there. It’s a critical part of the cohorts, the specimens. It’s a critical part of the trials that are ongoing. And it’s a critical part of the rest of the research community, not just RECOVER. I think it’s going to be a really exciting meeting, I hope it can also be an inclusive and productive meeting where people know we’re listening, because we really are.

I appreciate these kinds of venues [like the meeting] to be able to communicate better. I also anticipate, after the meeting, some good ongoing communications… If you had to ask me, what’s one mistake, one thing I think we really want to do better on, that’s being better communicators. [Communicating] what the fundamental problems are and everything we’re doing to try to overcome them.

One thing I think we really want to do better on, that’s being better communicators. [Communicating] what the fundamental problems are and everything we’re doing to try to overcome them.

BL: I wanted to ask more about that underlying biology piece, because I know people have a lot of questions about this. What do you see as some of the most promising research right now on disease causes, biomarkers for Long Covid, and ME and other related diseases as well? And what do you see the continued efforts of RECOVER and other NIH work doing to push this forward?

MB: We are looking very comprehensively, and we’re focusing on areas that seem to have promise for treatment. The two, I think, leading areas right now that we’re really focused on are viral persistence — accumulating data that there’s still virus, that this virus homes to particular tissues, and the body’s trying to set up a chronic immune response and that’s causing some of the pathobiology behind [symptoms]. There’s not incontrovertible evidence yet, but getting there.

The other is the immune system and the immune system’s response. We know this from other diseases that are chronic — there’s a dynamic with the immune system that then the body doesn’t seem to be able to resolve properly. I have a cancer immunology background, which means I know about Epstein-Barr Virus and how it can cause cancer. Viruses can be incredibly destructive.

BL: I know there have been studies looking at reactivated Epstein-Barr Virus with Long Covid, too.

MB: Right. Epstein-Barr is a good example. Why do some people get it and it never bothers them again? Other people get it, and even when it reactivates, it doesn’t bother them. And others who have it latent, it turns into something terrible. What are the characteristics? Why can some people overcome it and others can’t?…

The leading thing here is, what is [SARS-CoV-2] doing to the immune system? Is it causing the body to attack tissues that it should be leaving alone? Or is it true viral persistence, meaning we need antivirals? We have one study of an antiviral, it was designed to give the maximum dose of Paxlovid that FDA could tell us was safe. But is that the right dose? Do we need to do more? Do we need a different, stronger antiviral? Are we ready to start going forward with more aggressively pursuing antivirals? I think this is going to be a really active discussion at the time of the meeting.

And there are many other possibilities [for trials], some of them have to do with, why target one type of tissue in one person and another type in another? Why does one person get POTS and another have really prominent chronic fatigue? And should we have therapies directed at particular tissues or cell types… All of these are important, active questions.

The last thing I want to say about treatment is, we’re always mindful that treatments are powerful and treatments can have harmful effects, too. Although we don’t want to be hesitant to move forward with treatment, we also want to do it in a way that doesn’t also create harm. These are powerful systems, when you’re modifying immunity and modifying the vascular system — we have to be very careful.

BL: Another thing I wanted to ask about in the context of trials, but also a bit of a broader question, is including people who have more severe manifestations of Long Covid and related diseases in this research. Some people are bed-bound, or have a really hard time leaving their houses for the amount of time that it takes to go to a center and participate in clinical research. Today also happens to be Severe ME Day, an awareness day in the community. So I wanted to make sure I brought that up and asked, with the new round of trials and more broadly, what are you thinking about in terms of things like decentralized trials or remote participation, ways to include these people more?

MB: Absolutely, I’m glad you asked that. It’s a goal for all of NIH and all the trials that we do — we want to bring trials to the people who need them. Obviously, the first goal of a trial is to make sure the trial is effective and make sure the trial is safe. But we’ve learned that we can reach out and get to people with the proper support and the proper structure. And so I think that would be a very important part of the conversation that we have for our trials going forward, specifically trials for those people with the most severe disease.

BL: Good to know. I wanted to ask also about pediatric clinical trials, because I know there’s the pediatric component of the observational study, but I think people, like caregivers of children with Long Covid, also are very interested in what might be the latest progress there.

MB: I would have to get back to you on that one… I can say that we have a commitment to understanding this disease in young people. And it’s absolutely critical. ME/CFS, this could be a disease that if a young child gets it, it could affect them for the rest of their life.

(Editor’s note: In a follow-up email, the Director’s Office said that pediatric trials will be included in the September RECOVER-Treating Long Covid meeting.)

BL: Yes, I have talked to people who have had ME for 20, 30, 40, years.

MB: We absolutely have to address that… I know it’ll be a part of the discussion at the meeting. We’re really focused on moving forward as quickly and wisely as we possibly can, and not wasting any opportunity to get to understanding this disease and building some approaches to successful treatment. And that means every person, every age, and every symptom manifestation. That’s why you see five platforms [in the initial RECOVER trials]. I think that was a smart first attempt to not only hone in on what could help, but hone in on the pathobiology as we’re doing trials.

BL: One of those is the autonomic platform, which I had a question about as well. One researcher who is a dysautonomia expert sent in a more specific question that I thought was important to bring up about autonomic function testing in the observational protocols. Her question was why standard autonomic function testing hasn’t been included in the broad protocols that everybody in RECOVER is doing, even though studies have shown that POTS and other forms of dysautonomia are very common [with Long Covid]. This might be too specific of a question for you, but I wanted to ask — at least about this connection between dysautonomia and Long Covid.

MB: I can say, in general, this testing is important, and it’s important that it’s done by qualified people so that it is carefully standardized and we get the best results. Let me get back to you to be definitive, [but] it is my understanding that the reason that testing hasn’t gone broadly to everyone is because of challenges in being able to do it and do it right. It’s more of a resource issue than a, we’re ignoring it issue. But let me get back to you… 

(Editor’s note: In a follow-up email, the Director’s Office shared: “An autonomic suite of testing, including gastric emptying, is performed on a portion of participants in the adult protocol (see page 70 and 77 of adult protocol).  Additionally, a portion of participants in the children’s cohort protocol undergo an autonomic dysfunction assessment with an active standing test repeated 5 times at 6-month intervals (see page 19 of the pediatrics protocol).”)

BL: Thank you.

MB: We’re struggling with balancing resources, as you can imagine. This has been — 30,000 people, commitment to diverse populations… Firing up the trials that we have started with, the pathobiology behind them, it’s just incredibly expensive. And so we’re at the stage where, frankly, we have to start making some resource decisions. We’re already there, even with the $515 million we have going forward for the next couple of years.

BL: That funding is something else I wanted to ask you about. One reader who sent in a question specifically asked, ahead of the September meeting, might it be possible to see a breakdown of the funding so far and what the proposal is for this $515 million that was allocated in February, in the interest of transparency? In my reporting, I’ve seen a lot of concern and confusion from the Long Covid community about where all the funding has gone so far. And I think people are really interested in this $515 million, really want to know what it’s being spent on.

MB: I can be very transparent about it. We do not know exactly how that $515 will be spent. We really don’t. It is an active area of discussion and strategizing and planning.

Part of it is this meeting [in September] — what can we put into trials now? How can we resource those? This meeting will also help us take a deep-dive into all the [underlying biology] issues. There is a constant discussion as to, are the resources going to the best possible place? When have we learned enough from one project, and we can move on? I can be very clear that [the $515 million] is not allocated yet, and we will allocate it toward the very best use of getting to health for everybody…

What we anticipate is going to be needed is continued efforts, round after round after round of learning from studies and learning about pathobiology, because not everybody with Long Covid or ME/CFS is going to be the same. I predict we’re going to start making progress, but we’re going to continually have problems we still need to solve for people. There’s not going to be a magic treatment here.

We’re going to need round after round after round of more biology, more trials, and I think we’re going to be doing that together for the foreseeable future. I am very optimistic that we’re going to make progress. But are we really going to get to the bottom of this long, long-term problem? Not as quickly as any of us want.

The last thing I will say is that NIH has a commitment to these diseases and these patients. We have a commitment, we will use whatever funding we can and are allocated by Congress, to conquer this in the best way we know how.

BL: What do you see as some of the future asks for Congress, or the path for continuing Long Covid research and continuing this broader area of study, past the current RECOVER funding? Do you anticipate this being part of the regular NIH budget going forward, or what other options are there?

MB: I am very encouraged by interactions that have come from our legislators to me, encouraging us to keep going. Legislators are telling me to do the same things that we want to do… We’re seeing support for Long Covid.

[RECOVER] was a one-shot, two-shot funding. I think we’re not going to solve the problem with the current funding we have. Transitioning into a long-term project will teach us so much that we need to learn about the post-infectious complications for Covid, and ME/CFS, chronic Lyme disease, all of these chronic conditions. A long-term program that’s really robust in these conditions is going to be important, and I think it’ll also deliver benefits for the rest of medicine. If you learn what these viruses are doing to the immune system, we’re going to learn about better ways to use the immune system.

[RECOVER] was a one-shot, two-shot funding. I think we’re not going to solve the problem with the current funding we have.

BL: With those long-term goals in mind, I wanted to ask both about the Moonshot Act that Bernie Sanders just introduced last week — how would that impact these plans for a more robust future program? And another thing a lot of people are asking about, along similar lines, is a new office or a new specific, dedicated program at the NIH, for infection-associated chronic diseases, or whatever you want to call this area of research. To what extent would these kinds of proposals help achieve that vision you’re talking about?

MB: We are grateful for Senator Sanders’ support of this particular issue. There are others who I think are also helping. And we will do the best we possibly can with what the public has given us to conquer these conditions. Along with the funding from Congress, the support we get from the people who have these conditions — I don’t want anybody to think that we do not value or don’t keep top of mind the contributions that people make, the people who help us do this research.

When it comes to the operational organization, we’re going to do what’s best for the overall program. You see one shift right now, we decided it’s time to get the whole broad community and take a deeper dive [on trials]. That’s when the Director’s Office got involved. We also see NIAID [National Institute of Allergy and Infectious Diseases] taking on real responsibility for the trials, coordinating and organizing the trials.

BL: So the exact directions are still up in the air, it sounds like.

MB: I think we know this is the right thing to do right now [with the September meeting]. And then we’ll see where it takes us.

BL: Also in the realm of funding, I know there’s been a lot of interest from the ME/CFS community, of course, in Long Covid research, because of all the overlaps between these diseases. But there is also a real desire for more funding, specifically, for ME — causes, biomarkers that may be different from Long Covid due to a different viral trigger. A couple of people asked specifically about a need for more ME/CFS funding that is commensurate with the burden of the disease, in the regular NIH budget. I’m wondering if that’s something you could talk about, along with the ME/CFS Research Roadmap — people want to see more funding and long-term research come out of that.

MB: I agree to that. We want to be able to conquer ME/CFS and do it in the best possible way. I hope that the ME/CFS community will see much of the research that’s happening now, spurred on by Long Covid, to benefit them. We’re going to look for the similarities and differences between these different types of viral triggers that can benefit both sides. And we have a small but mighty team of long-term ME/CFS researchers who’ve been interested in this problem, some internal to NIH, that we intend to continue to fully support.

The funding issues, that’s always a moving target. It’s difficult for me to speak to that other than to say, we’re going to do the best we can with what funding we receive.

BL: Thank you. Also about ME/CFS, people had questions about the intramural study that was published earlier this year. There have been a lot of criticisms from the ME community, particularly around the “effort preference” finding. There have been some calls for retraction for that part of the study from different patient-advocates and researchers. Is this something you’re paying attention to, or do you have a response to that?

MB: I’ve certainly read the study. And I’ve said, we want to hear from the ME/CFS community. We want to hear these concerns. Crafting a direct response is not something I myself can do without engaging the research team, but I can also get back to you on what’s happening. We absolutely want to hear the feedback from the community and respond to it appropriately… They’re taking it very seriously.

(Editor’s note: In a follow-up email, the Director’s Office confirmed that NIH is “reviewing the study to determine if the methods justified the conclusion.”)

BL: Thank you, that’s good to know. Also, you earlier mentioned the need for more collaboration with pharmaceutical companies, I wanted to ask more about that. I know some of this in the realm of the FDA, but I’m curious, are there specific actions planned, maybe as part of RECOVER, to do things like public-private partnerships around drug development for Long Covid and related diseases?

MB: I can tell you that, yes, these discussions are very much underway. I’m not able to announce a new public-private partnership right now, but these are very actively being pursued. Our pharma partners have the same goals we do — we’ve got to understand the biology. We’ve got to share whatever knowledge we have that can lead to development of new, effective treatments. NIH’s position is to always, whenever possible and appropriate, to engage academia and the private industry to move faster.

BL:  People [in the Long Covid community] are also very invested in acute Covid prevention — we know the best way to prevent Long Covid is to protect yourself against acute Covid, right?… A lot of people are asking about this. There’s a lot of fear in the community as we’re seeing things like mask bans. Like, I live in New York City, and Nassau County, adjacent to us, just passed one of these. People are very concerned about continuing to protect themselves. 

MB: We think that, on balance, vaccination is really critical. Maintaining vaccination status, maintaining boosters, getting your boosters — that’s really important. And there’s good data to show that it is protective against Long Covid. And it’s protective against hospitalization and death, which is critical. So that is important.

(Editor’s note: Studies have found that vaccination reduces the risk of Long Covid, but is far from fully “protective.”)

The other dynamics, someone who has immune dysfunction, or a pregnant person — there’s data emerging, that came out of RECOVER, that pregnant people have more complications if they get Covid. So those people, we think, should take more precautions…

I will add this personal comment. I’m a surgeon. I wore a mask for 37 years every day in the operating room. Because it was really important to protect my patients. And so masks in some circumstances can be very important.

BL: Yeah. One other thing I wanted to ask about is the area of medical education, public health education. Something I know is part of the realm of other agencies as well, but something that people are concerned about — even as we’re five years into this, people are having a really hard time finding providers who know about Long Covid, who know about ME, who know about POTS. And it relates also to the resource issue you talked about. The doctors who are aware of these conditions are so hard to find, often, and in such high demand. How do you see the work of RECOVER or work of NIH on these diseases translate to partnerships with other agencies or other offices on this topic [of education]?

MB: I think you said the operative word there, which is partnership. NIH is a research institution, but if we’re going to do our research properly, we have to work with those who know how to take care of people with these conditions and really partner with them. That’s been absolutely critical in the early parts of RECOVER, and will be critical forever going forward.

It’s something that I’m very passionate about, is having close ties between the clinical care environment and the research community that are mutually supportive. It has to be these two communities working together, not unilaterally… 

At the end of the day, every patient is different, and every patient needs a caring clinician who can really help them through this. From my position at the NIH, we want to deliver the data and the tools that allow that caring clinician to really do what’s best for patients. But everything we try to do in medicine comes to a halt if we don’t have those individuals there to help us.

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