RECOVER: What Clinical Research Comes Next for Helping People with Long COVID
Posted on by Gary Gibbons, M.D., National Heart, Lung, and Blood Institute; Walter Koroshetz, M.D., National Institute of Neurological Disorders and Stroke; Hugh Auchincloss, M.D., National Institute of Allergy and Infectious Diseases
“I connected with RECOVER to be a part of the answers that I was looking for when I was at my worst.” Long COVID patient and RECOVER representative, Nitza Rochez (Bronx, NY)
People, like Nitza Rochez, who are living with Long COVID—the wide-ranging health issues that can follow an infection with SARS-CoV-2, the coronavirus that causes COVID-19—experience disabling symptoms with significant physical, emotional and financial consequences.
The NIH has been engaging and listening to Nitza and others living with Long COVID even before the start of its Researching COVID to Enhance Recovery (RECOVER) Initiative. But now, with the launch of RECOVER, patients and those with affected family or community members have joined researchers, clinicians, and experts in their efforts to unlock the mysteries of Long COVID. All have come together to understand what causes the condition, identify who is most at risk, and determine how to prevent and treat it.
RECOVER is unprecedented in its size and scope as the most-diverse, deeply characterized cohort of Long COVID patients. We’ve enlisted the help of many patient volunteers, who have enrolled in observational studies designed to help researchers learn as much as possible about people who have Long COVID.
Indeed, thousands of research participants are now providing health information and undergoing in-depth medical evaluations and tests, enabling investigators to look for trends. Additionally, studies of millions of electronic medical records are providing insights about those who have received care during the pandemic. More than 40 studies are being conducted to identify the causes of disease, potential biomarkers of Long COVID, and new therapeutic targets.
In all, RECOVER’s research assets are voluminous. They involve invaluable contributions from many people and communities, including research volunteers, research investigators, and clinical specialists. In addition, millions of health records and numerous related tissues and specimens are being analyzed for possible leads.
At the center of it all is the National Community Engagement Group (NCEG). The NCEG is comprised of people living with Long COVID and those representing others living with the condition, and it is truly instrumental to the initiative’s progress in understanding how and why SARS-CoV-2 impacts people in different ways. It’s also helping researchers learn why some people recover while others do not.
So far, we’ve learned that people hospitalized with COVID-19 are twice as likely to have Long COVID than those who were not hospitalized for infection. We’ve also learned that members of racial and ethnic minority groups with Long COVID were more likely to have been hospitalized with COVID-19.
Similarly, disparities in Long COVID exist within those living in areas with particular environmental exposures , and those who were already burdened by other diseases and conditions—such as diabetes and chronic pulmonary disease . We’ve also discovered that the certain types of symptoms of Long COVID are consistent among patients regardless of which SARS-CoV-2 variant caused their initial infection. Yet, people infected with the earlier variants have a higher number of symptoms than those infected with more recent variants.
Patient experiences have guided and will continue to guide the study designs and trajectory of RECOVER. Now, fueled by the knowledge that we have gained, RECOVER is preparing to advance to the next phase of discovery—testing interventions in clinical trials to see if they can help people with Long COVID.
To prepare, we are beginning to identify potential clinical trial sites. This important step will help us to find the right places with the right staff and capabilities for enrolling the appropriate patient populations needed to implement the studies. We’ll ensure that the public knows when these upcoming clinical trials are ready to enroll.
Of course, the design of these RECOVER clinical trials will be critical, and insights gained from patients have been key in this process. Results from RECOVER study questionnaires, surveys, and discussions with people experiencing Long COVID identified symptom clusters considered to be the most significant and burdensome to patients. These include sleep disorders, “brain fog” (trouble thinking clearly), exercise intolerance and fatigue, and nervous system dysfunction affecting people’s ability to regulate normal body functions like heart rate and body temperature.
These patient observations have effectively guided the design of the clinical trials that will evaluate whether certain interventions and therapies can help alleviate symptoms that are part of these specific clusters. We’re excited to be advancing toward this phase of the initiative and, again, are very grateful to patient representatives like Nitza, quoted above, for getting us to this phase.
Effective evaluation of those treatments will be important, too. Early in the pandemic, while many clinical trials were launching, most were not large enough or did not have the appropriate objectives to define effective treatments for acute COVID-19. This left clinicians with few clear options when faced with patients needing help.
Learning from this experience, the RECOVER trials will be harmonized to ensure coordinated and efficient evaluation of interventions—in other words, all potential therapies will be using the same protocols platforms and the same data elements. This consistency accelerates our understanding and strengthens the certainty of findings.
Given the widespread and diverse impact that the virus has on the body, it is highly likely that more than one treatment will be needed for each kind of patient experience. Finding solutions for everyone—people of all races, ethnicities, genders, ages, and geographic locations—is paramount.
RECOVER patient representative, Juan Lewis, of San Antonio shared with us, “In April 2020, I was fighting for my life, and today I fight for my quality of life. COVID impacted me physically, mentally, socially, and financially.”
For people like Juan who are experiencing debilitating Long COVID symptoms, we know that finding answers as quickly as possible is critical. As we look ahead to the next 12 months, we’ll continue the studies evaluating the underlying causes, risk factors, and outcomes of Long Covid, and we anticipate significant scientific progress on research leading to Long COVID treatments.
Keep an eye on the RECOVER website for updates on our progress, and published findings.
 Identifying environmental risk factors for post-acute sequelae of SARS-CoV-2 infection: An EHR-based cohort study from the recover program. Zhang Y, Hu H, Fokaidis V, V CL, Xu J, Zang C, Xu Z, Wang F, Koropsak M, Bian J, Hall J, Rothman RL, Shenkman EA, Wei WQ, Weiner MG, Carton TW, Kaushal R. Environ Adv. 2023 Apr;11:100352.
 Identifying who has long COVID in the USA: a machine learning approach using N3C data. Pfaff ER, Girvin AT, Bennett TD, Bhatia A, Brooks IM, Deer RR, Dekermanjian JP, Jolley SE, Kahn MG, Kostka K, McMurry JA, Moffitt R, Walden A, Chute CG, Haendel MA; N3C Consortium. Lancet Digit Health. 2022 Jul;4(7):e532-e541.
RECOVER: Researching COVID to Enhance Recovery
Long COVID: Ask NIH Leader about Latest Research (YouTube)
NIH Builds Large Nationwide Study Population of Tens of Thousands to Support Research on Long-Term Effects of COVID-19, NIH News Release, September 15, 2021
Understanding Long-Term COVID-19 Symptoms and Enhancing Recovery, NIH Director’s Blog, October 4, 2022.
NIH RECOVER Research Identifies Potential Long COVID Disparities. NIH News Release, February 16, 2023.
NIH RECOVER Listening Session, June 2021 (NIH Videocast)
NIH RECOVER Listening Session: Understanding Long COVID Across Communities of Color and Those Hardest Hit by COVID, January 21, 2022 (NIH Videocast)
Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes, Centers, and Offices to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 25th in the series of NIH guest posts that will run until a new permanent NIH director is in place.
Gratitude for Biomedical Progress and All Those Who Make It Possible
Posted on by Lawrence Tabak, D.D.S., Ph.D.
It’s good for our health to eat right, exercise, and get plenty of rest. Still, many other things contribute to our sense of wellbeing, including making it a point to practice gratitude whenever we can. With this in mind, I can’t think of a better time than Thanksgiving to recognize just a few of the many reasons that I—and everyone who believes in the mission of the National Institutes of Health (NIH)—have to be grateful.
First, I’m thankful for the many enormously talented people with whom I’ve worked over the past year while performing the duties of the NIH Director. Particular thanks go to those on my immediate team within the Office of the Director. I could not have taken on this challenge without their dedicated support.
I’m also gratified by the continued enthusiasm and support for biomedical research from so many different corners of our society. This includes the many thousands of unsung, patient partners who put their time, effort, and, in some cases, even their lives on the line for the sake of medical progress and promising treatment advances. Without them, clinical research—including the most pivotal clinical trials—simply wouldn’t be possible.
I am most appreciative of the continuing efforts at NIH and across the broader biomedical community to further enable diversity, equity, inclusion, and accessibility within the biomedical research workforce and in all the work that NIH supports.
High on my Thanksgiving list is the widespread availability of COVID-19 bivalent booster shots. These boosters not only guard against older strains of the coronavirus, but also broaden immunity to the newer Omicron variant and its many subvariants. I’m also tremendously grateful for everyone who has—or soon will—get boosted to protect yourself, your loved ones, and your communities as the winter months fast approach.
Another big “thank you” goes out to all the researchers studying Long COVID, the complex and potentially debilitating constellation of symptoms that strikes some people after recovery from COVID-19. I look forward to more answers as this work continues and we certainly couldn’t do it without our patient partners.
I’d also like to express my appreciation for the NIH’s institute and center directors who’ve contributed to the NIH Director’s Blog to showcase NIH’s broad and diverse portfolio of promising research.
Finally, a special thanks to all of you who read this blog. As you gather with family and friends to celebrate this Thanksgiving holiday, I hope the time you spend here gives you a few more reasons to feel grateful and appreciate the importance of NIH in turning scientific discovery into better health for all.
Tuberculosis: An Ancient Disease in Need of Modern Scientific Tools
Posted on by Anthony S. Fauci, M.D., National Institute of Allergy and Infectious Diseases
Although COVID-19 has dominated our attention for the past two years, tuberculosis (TB), an ancient scourge, remains a dominating infectious disease globally, with an estimated 10 million new cases and more than 1.3 million deaths in 2020. TB disproportionately afflicts the poor and has long been the leading cause of death in people living with HIV.
Unfortunately, during the global COVID-19 pandemic, recent gains in TB control have been stalled or reversed. We’ve seen a massive drop in new TB diagnoses, reflecting poor access to care and an uptick in deaths in 2020 .
We are fighting TB with an armory of old weapons inferior to those we have for COVID-19. The Bacillus Calmette–Guérin (BCG) vaccine, the world’s only licensed TB vaccine, has been in use for more than 100 years. While BCG is somewhat effective at preventing TB meningitis in children, it provides more limited durable protection against pulmonary TB in children and adults. More effective vaccination strategies to prevent infection and disease, decrease relapse rates, and shorten durations of treatment are desperately needed to reduce the terrible global burden of TB.
In this regard, over the past five years, several exciting research advances have generated new optimism in the field of TB vaccinology. Non-human primate studies conducted at my National Institute of Allergy and Infectious Diseases’ (NIAID) Vaccine Research Center and other NIAID-funded laboratories have demonstrated that effective immunity against infection is achievable and that administering BCG intravenously, rather than under the skin as it currently is given, is highly protective .
Results from a phase 2 trial testing BCG revaccination in adolescents at high risk of TB infection suggested this approach could help prevent TB . In addition, a phase 2 trial of an experimental TB vaccine based on the recombinant protein M72 and an immune-priming adjuvant, AS01, also showed promise in preventing active TB disease in latently infected adults .
Both candidates are now moving on to phase 3 efficacy trials. The encouraging results of these trials, combined with nine other candidates currently in phase 2 or 3 studies , offer new hope that improved vaccines may be on the horizon. The NIAID is working with a team of other funders and investigators to analyze the correlates of protection from these studies to inform future TB vaccine development.
Even with these exciting developments, it is critical to accelerate our efforts to enhance and diversify the TB vaccine pipeline by addressing persistent basic and translational research gaps. To this end, NIAID has several new programs. The Immune Protection Against Mtb Centers are taking a multidisciplinary approach to integrate animal and human data to gain a comprehensive understanding of the immune responses required to prevent TB infection and disease.
This spring, NIAID will fund awards under the Innovation for TB Vaccine Discovery program that will focus on the discovery and early evaluation of novel TB vaccine candidates with the goal of diversifying the TB vaccine pipeline. Later this year, the Advancing Vaccine Adjuvant Research for TB program will systematically assess combinations of TB immunogens and adjuvants. Finally, NIAID’s well-established clinical trials networks are planning two new clinical trials of TB vaccine candidates.
As we look to the future, we must apply the lessons learned in the development of the COVID-19 vaccines to longstanding public health challenges such as TB. COVID-19 vaccine development was hugely successful due to the use of novel vaccine platforms, structure-based vaccine design, community engagement for rapid clinical trial enrollment, real-time data sharing with key stakeholders, and innovative trial designs.
However, critical gaps remain in our armamentarium. These include the harnessing the immunology of the tissues that line the respiratory tract to design vaccines more adept at blocking initial infection and transmission, employing thermostable formulations and novel delivery systems for resource-limited settings, and crafting effective messaging around vaccines for different populations.
As we work to develop better ways to prevent, diagnose, and treat TB, we will do well to remember the great public health icon, Paul Farmer, who tragically passed away earlier this year at a much too young age. Paul witnessed firsthand the devastating consequences of TB and its drug resistant forms in Haiti, Peru, and other parts of the world.
In addition to leading efforts to improve how TB is treated, Paul provided direct patient care in underserved communities and demanded that the world do more to meet their needs. As we honor Paul’s legacy, let us accelerate our efforts to find better tools to fight TB and other diseases of global health importance that exact a disproportionate toll among the poor and underserved.
 Global tuberculosis report 2021. WHO. October 14, 2021.
 Prevention of tuberculosis in macaques after intravenous BCG immunization. Darrah PA, Zeppa JJ, Maiello P, Hackney JA, Wadsworth MH,. Hughes TK, Pokkali S, Swanson PA, Grant NL, Rodgers MA, Kamath M, Causgrove CM, Laddy DJ, Bonavia A, Casimiro D, Lin PL, Klein E, White AG, Scanga CA, Shalek AK, Roederer M, Flynn JL, and Seder RA. Nature. 2020 Jan 1; 577: 95–102.
 Prevention of M. tuberculosis Infection with H4:IC31 vaccine or BCG revaccination. Nemes E, Geldenhuys H, Rozot V, Rutkowski KT, Ratangee F,Bilek N., Mabwe S, Makhethe L, Erasmus M, Toefy A, Mulenga H, Hanekom WA, et al. N Engl J Med 2018; 379:138-149.
 Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis. Tait DR, Hatherill M, Van Der Meeren O, Ginsberg AM, Van Brakel E, Salaun B, Scriba TJ, Akite EJ, Ayles HM, et al.
 Pipeline Report 2021: Tuberculosis Vaccines. TAG. October 2021.
Tuberculosis (National Institute of Allergy and Infectious Diseases/NIH)
NIAID Strategic Plan for Tuberculosis Research
Immune Mechanisms of Protection Against Mycobacterium tuberculosis Centers (IMPAc-TB) (NIAID)
Partners in Health (Boston, MA)
[Note: Acting NIH Director Lawrence Tabak has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the seventh in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.]
NCI Support for Basic Science Paves Way for Kidney Cancer Drug Belzutifan
Posted on by Norman "Ned" Sharpless, M.D., National Cancer Institute
There’s exciting news for people with von Hippel-Lindau (VHL) disease, a rare genetic disorder that can lead to cancerous and non-cancerous tumors in multiple organs, including the brain, spinal cord, kidney, and pancreas. In August 2021, the U.S. Food and Drug Administration (FDA) approved belzutifan (Welireg), a new drug that has been shown in a clinical trial led by National Cancer Institute (NCI) researchers to shrink some tumors associated with VHL disease , which is caused by inherited mutations in the VHL tumor suppressor gene.
As exciting as this news is, relatively few people have this rare disease. The greater public health implication of this advancement is for people with sporadic, or non-inherited, clear cell kidney cancer, which is by far the most common subtype of kidney cancer, with more than 70,000 cases and about 14,000 deaths per year. Most cases of sporadic clear cell kidney cancer are caused by spontaneous mutations in the VHL gene.
This advancement is also a great story of how decades of support for basic science through NCI’s scientists in the NIH Intramural Research Program and its grantees through extramural research funding has led to direct patient benefit. And it’s a reminder that we never know where basic science discoveries might lead.
Belzutifan works by disrupting the process by which the loss of VHL in a tumor turns on a series of molecular processes. These processes involve the hypoxia-inducible factor (HIF) transcription factor and one of its subunits, HIF-2α, that lead to tumor formation.
The unraveling of the complex relationship among VHL, the HIF pathway, and cancer progression began in 1984, when Bert Zbar, Laboratory of Immunobiology, NCI-Frederick; and Marston Linehan, NCI’s Urologic Oncology Branch, set out to find the gene responsible for clear cell kidney cancer. At the time, there were no effective treatments for advanced kidney cancer, and 80 percent of patients died within two years.
Zbar and Linehan started by studying patients with sporadic clear cell kidney cancer, but then turned their focus to investigations of people affected with VHL disease, which predisposes a person to developing clear cell kidney cancer. By studying the patients and the genetic patterns of tumors collected from these patients, the researchers hypothesized that they could find genes responsible for kidney cancer.
Linehan established a clinical program at NIH to study and manage VHL patients, which facilitated the genetic studies. It took nearly a decade, but, in 1993, Linehan, Zbar, and Michael Lerman, NCI-Frederick, identified the VHL gene, which is mutated in people with VHL disease. They soon discovered that tumors from patients with sporadic clear cell kidney cancer also have mutations in this gene.
Subsequently, with NCI support, William G. Kaelin Jr., Dana-Farber Cancer Institute, Boston, discovered that VHL is a tumor suppressor gene that, when inactivated, leads to the accumulation of HIF.
Another NCI grantee, Gregg L. Semenza, Johns Hopkins School of Medicine, Baltimore, identified HIF as a transcription factor. And Peter Ratcliffe, University of Oxford, United Kingdom, discovered that HIF plays a role in blood vessel development and tumor growth.
Kaelin and Ratcliffe simultaneously showed that the VHL protein tags a subunit of HIF for destruction when oxygen levels are high. These results collectively answered a very old question in cell biology: How do cells sense the intracellular level of oxygen?
Subsequent studies by Kaelin, with NCI’s Richard Klausner and Linehan, revealed the critical role of HIF in promoting the growth of clear cell kidney cancer. This work ultimately focused on one member of the HIF family, the HIF-2α subunit, as the key mediator of clear cell kidney cancer growth.
The fundamental work of Kaelin, Semenza, and Ratcliffe earned them the 2019 Nobel Prize in Physiology or Medicine. It also paved the way for drug discovery efforts that target numerous points in the pathway leading to clear cell kidney cancer, including directly targeting the transcriptional activity of HIF-2α with belzutifan.
Clinical trials of belzutifan, including several supported by NCI, demonstrated potent anti-cancer activity in VHL-associated kidney cancer, as well as other VHL-associated tumors, leading to the aforementioned recent FDA approval. This is an important development for patients with VHL disease, providing a first-in-class therapy that is effective and well-tolerated.
We believe this is only the beginning for belzutifan’s use in patients with cancer. A number of trials are now studying the effectiveness of belzutifan for sporadic clear cell kidney cancer. A phase 3 trial is ongoing, for example, to look at the effectiveness of belzutifan in treating people with advanced kidney cancer. And promising results from a phase 2 study show that belzutifan, in combination with cabozantinib, a widely used agent to treat kidney cancer, shrinks tumors in patients previously treated for metastatic clear cell kidney cancer .
This is a great scientific story. It shows how studies of familial cancer and basic cell biology lead to effective new therapies that can directly benefit patients. I’m proud that NCI’s support for basic science, both intramurally and extramurally, is making possible many of the discoveries leading to more effective treatments for people with cancer.
 Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, Oudard S, Else T, Maranchie JK, Welsh SJ, Thamake S, Park EK, Perini RF, Linehan WM, Srinivasan R; MK-6482-004 Investigators. N Engl J Med. 2021 Nov 25;385(22):2036-2046.
 Phase 2 study of the oral hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 in combination with cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC). Choueiri TK et al. J Clin Oncol. 2021 Feb 20;39(6_suppl): 272-272.
Von Hippel-Lindau Disease (Genetic and Rare Diseases Information Center/National Center for Advancing Translational Sciences/NIH)
Clear Cell Renal Cell Carcinoma (National Cancer Institute/NIH)
Belzutifan Approved to Treat Tumors Linked to Inherited Disorder VHL, Cancer Currents Blog, National Cancer Institute, September 21, 2021.
The Long Road to Understanding Kidney Cancer (Intramural Research Program/NIH)
[Note: Acting NIH Director Lawrence Tabak has asked the heads of NIH’s institutes and centers to contribute occasional guest posts to the blog as a way to highlight some of the cool science that they support and conduct. This is the first in the series of NIH institute and center guest posts that will run until a new permanent NIH director is in place.]