Three prominent clinical trials targeting viral persistence in Long COVID with Paxlovid and monoclonal antibodies have failed to demonstrate significant health improvements for participants, according to researchers involved in the studies. However, scientists view these early results as important stepping stones toward more targeted treatments for the complex condition.
The unsuccessful trials include two studies testing Paxlovid at Yale and Stanford universities, and a University of California, San Francisco (UCSF) study examining the monoclonal antibody AER002. All three studies found no significant difference in health improvements between treatment and placebo groups.
Viral Persistence Theory Faces Early Setbacks
The trials were based on the viral persistence hypothesis, which suggests that SARS-CoV-2 or its components continue replicating in the body, causing chronic symptoms. Michael Peluso, an infectious disease clinician and researcher at UCSF who led the AER002 trial, acknowledged the challenging results but remained optimistic about future research directions.
"I think the first round of trials answered the question about whether it would be easy to hit a home run, and the answer was no," Peluso said. He noted that researchers expected this outcome, though they had hoped for different results.
The Stanford Paxlovid trial included 155 participants, while Yale's study enrolled 100 people. Both tested 15-day courses of the antiviral, longer than the standard five-day treatment for acute COVID-19 but relatively short for chronic illness management. UCSF's AER002 study was smaller with 36 participants and specifically recruited people whose Long COVID symptoms followed infection with variants the drug targets effectively.
Study Design Challenges and Limitations
None of the trials followed what researchers describe as an "ideal scenario" of recruiting only participants with confirmed SARS-CoV-2 reservoirs and measuring changes in those reservoirs before and after treatment. This approach hasn't been feasible due to the lack of clear biomarkers for viral persistence.
Bornali Bhattacharjee, who led Yale's trial, identified the lack of specific recruitment criteria and short treatment duration as "possible interpretations" for why the study didn't find symptom improvement.
Studies from UCSF, University of Pennsylvania, and other research consortium members consistently find that around 25% to 35% of people with Long COVID have viral fragments in their blood or immune markers of persistence, according to Peluso.
Amy Engebretson, a physician with Long COVID who participated in Yale's decentralized trial, noted a potential confounding factor in the study design. Both Yale and Stanford trials gave placebo groups ritonavir, which provides Paxlovid's distinctive metallic taste but also has antiviral properties that may contribute to symptom relief.
"That actually happened with me," Engebretson said. "In fact, I'm still taking this drug [ritonavir] because it improved my symptoms quite a bit." She suggested this improvement in placebo groups could have affected trial results.
Next-Generation Trials Show Promise
Researchers are now designing more targeted studies based on lessons learned from these early trials. Nancy Klimas, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University, is leading a phase 2 trial of sipavibart, a preventive monoclonal antibody designed to protect people for six months.
"I think we picked the right product, I think that we have the right group, that we're measuring the right stuff, and we'll know from this study if it's worth pursuing or not," Klimas said. Her trial includes about 100 participants and features more than 20 outcome measures to comprehensively assess treatment effects.
Marc Elia, Chairman of the Board at biotech company Invivyd, explained why monoclonal antibodies might be better suited for Long COVID than short-course antivirals. While Paxlovid mainly stops viral replication over short periods, monoclonal antibodies "can essentially sit over the very long term" and continually "try to pull [the virus] out and eliminate it."
Larger Studies Await Results
Two major Paxlovid trials have completed data collection but haven't yet reported results. The National Institutes of Health's RECOVER-VITAL study included nearly 1,000 participants and tested both 15-day and 25-day treatment courses. A similar trial from Sweden's Karolinska Institute has also finished collecting data.
The larger sample size and longer treatment duration in RECOVER-VITAL may help identify which patients benefit from antiviral treatment, though some researchers remain skeptical given similarities in study design to the earlier unsuccessful trials.
Future Research Directions
Researchers are also developing next-generation treatments specifically for Long COVID. Invivyd is working on VYD2311, a monoclonal antibody designed to work against recent variants, and exploring easier delivery methods including muscle injections or subcutaneous self-administration.
Japanese pharmaceutical company Shionogi's ensitrelvir, which works similarly to Paxlovid but may have preventive potential, is being tested by UCSF researchers in a trial expected to complete by the end of 2025.
Other ongoing trials are repurposing treatments from different diseases, including larazotide (originally developed for celiac disease) at Massachusetts General Hospital and HIV/AIDS drugs maraviroc and Truvada at Mount Sinai's Cohen Center for Recovery from Complex Chronic Illnesses.
Peluso emphasized the need for parallel testing of multiple therapeutic pathways rather than sequential studies over decades. "We need to be going a lot farther down these various mechanistic pathways, and doing it a lot faster," he said at the Keystone Symposia meeting in Santa Fe.
The early trials established important proof of concept that rigorous clinical trials could be performed for Long COVID and demonstrated the safety of these treatments in research settings, providing a foundation for larger, more targeted studies ahead.
