Brigham researchers are tackling long COVID from every angle, addressing critical questions about how the condition affects such wide-ranging aspects of health and laying the groundwork for preventing and treating symptoms. This story is part of a new, special series about collaborative research efforts underway across Mass General Brigham.

Bruce Levy

Brigham researchers and their colleagues across the Boston area, the country and the world have been working to address key questions to understand and define long COVID. Now, together with their clinical colleagues, investigators are embarking on the next chapter: the launch of clinical trials to test interventions to treat and prevent long COVID and address its constellation of symptoms.

“Long COVID affects people in multiple ways, resulting in a need for specialists in multiple disciplines,” says pulmonary and critical care specialist Bruce Levy, MD, interim chair of the Department of Medicine and chief of the Division of Pulmonary and Critical Care Medicine. “It’s natural that the research to reverse long COVID would be a collaborative effort that crosses disciplines and departments. We’re very fortunate to work in such a collaborative research environment at the Brigham.”

Lindsey Baden

The Brigham is the lead clinical trial site for RECOVER-VITAL (NCT05595369), an initiative funded by the National Institutes of Health (NIH) that will test the antiviral treatment Paxlovid for treating patients with lingering symptoms from COVID-19 infections rather than acute infection. RECOVER-VITAL is the first clinical trial to launch with several more trials in the pipeline as part of this national effort. The trial is expected to last for 12 months, and approximately 70 RECOVER-VITAL sites around the country will participate.

At BWH, a multidisciplinary team led by principal investigator Lindsey Baden, MD, vice president of Clinical Research, has been working behind the scenes to use their research expertise and clinical experience to create a foundation for the clinical trials, leading the development of the RECOVER-VITAL protocol for the NIH.

Hard Evidence of Viral Persistence

David Walt, PhD, co-principal investigator for RECOVER-VITAL, laid the groundwork for identifying long COVID as a persistent virus lingering in individuals through his research. Initially, this work began in Walt’s research lab but transferred to a Brigham clinical lab.

David Walt

In July 2022, Walt and his collaborators published a study indicating that some long COVID patients have a minute but detectable level of SARS-CoV-2 spike protein circulating in the blood in an unknown reservoir up to 12 months after diagnosis of active infection. This biomarker is critical for two reasons: It indicates that a low-lying infection could be causing some cases of long COVID, and it gives investigators a quantifiable measurement that they can use to enroll and assess patients in a trial.

“When we reported a circulating viral spike protein, it was the first piece of hard evidence that there was a persistent viral reservoir lingering in these individuals,” said Walt. “Identifying this biomarker in the blood gives us a handhold on this condition, provides a potential therapeutic target and may help us identify people with long COVID who are most likely to benefit from new treatment approaches.”

Walt has collaborated with Baden and Levy since the pandemic began, and over time the three have discussed the implications of a persistent viral infection in these patients. Through these conversations, they began thinking through how to design a rigorous clinical trial that could definitively test the effects of an extended antiviral treatment, such as Paxlovid, to fully clear the virus.

Testing Therapeutics

Levy, co-principal investigator for RECOVER-VITAL, plays a key role in treating patients with long COVID in the clinical setting. He has witnessed how the condition affects his patients, which motivates his participation in the first-of-its-kind clinical trial. “The trajectory for recovery for patients with long COVID is over months, not days,” says Levy. “Some of these patients still struggle with long COVID years after acute infection, so it’s critical to identify therapeutics that ameliorate their symptoms.”

Rachel Putman

Similarly, as a pulmonary and critical care specialist who has cared for patients with COVID-19 in both the ICU and outpatient settings, co-investigator Rachel Putman, MD, is also aware of the invisible ways that long COVID impacts patients’ daily lives.

“What we’ve learned from long COVID is there isn’t always a great correlation between how a long COVID patient looks and their symptoms,” says Putman. “For example, you may have a colleague who once exceeded expectations and suddenly stopped. They appear healthy looking at them, but they’re underperforming in the workplace due to brain fog from long COVID.”

Currently, the antiviral Paxlovid (nirmatrelvir and ritonavir) is approved for treating acute COVID-19, and patients take the medication within five days of symptoms onset, twice daily, for five days. But in RECOVER-VITAL, patients with long COVID will be grouped into different clusters based on their reported symptoms and will take the study drug or a matching placebo for a longer period — up to 25 days. The study will measure changes in several symptoms associated with long COVID, including changes in cognitive function and autonomic function, as well as the safety of taking the drug for an extended duration.

The study is based on the hypothesis, supported by Walt’s findings, that a persistent viral infection and the body’s disproportionate immune response to it may be causing some cases of long COVID. An extended regimen of an antiviral treatment may help improve long COVID symptoms by clearing the viral reservoir.

Amy Sherman

Infectious diseases specialist Amy Sherman, MD, co-investigator for RECOVER-VITAL, brings her research and clinical perspectives to the trial’s design, including insights into how viral infections like COVID-19 and long COVID can cause significant effects for infected individuals. “I’m excited to be part of this interdisciplinary team,” said Sherman. “A multifaceted approach to both patient care and research for these individuals is essential. I hope this study will help to elucidate the pathophysiology of long COVID and identify potential treatment modalities.”

What’s Next

The Brigham RECOVER-VITAL team has enrolled the first person in the study and will continue to recruit participants around the nation. Samples collected from RECOVER-VITAL sites across the country will be sent to the Brigham for analysis, and their findings will help researchers understand the effectiveness of a regimented treatment dosage of Paxlovid in patients with long COVID.

“Long COVID impacts patients’ lives and their productivity, and I’m hoping that we can get answers not just for the people who are enrolled in the study, but for all the millions of people in the U.S. and around the world who are struggling with this,” said Levy.

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