Led by researchers at UCSF, the research program plans to validate promising candidates for noninvasive tests that can be used to advance clinical trials.
Key points you should know:
- Long COVID’s heterogeneity and range of clinical presentations have made the search for biomarkers extremely complicated and resource-intensive.
- With a $1.35 million donation from PolyBio Research Foundation, the University of California, San Francisco has recently launched VIPER, a program designed to coordinate and accelerate the biomarker search. VIPER stands for Viral Immunopathogenesis and Persistence Repeat Donor Cohort.
- VIPER’s initial focus is on biomarkers related to viral persistence, although the project expects to expand to other possible biological pathways in future efforts.
- The program will include a “well-defined” cohort of 150 participants — 100 with Long COVID and 50 who had COVID-19 but recovered.
- Researchers are planning fast-track promising candidates for noninvasive tests into clinical trials and, if the results are good, to scale up dissemination as quickly as possible.
In March 1985, less than four years after the first report about the disease that became known as AIDS, the Food and Drug Administration approved a commercial test for detecting HIV infection. That initial diagnostic biomarker was followed by many other tests that became essential tools for monitoring, treating, and researching HIV/AIDS. In particular, the advent in the mid-1990s of blood-based assays to measure and track HIV viral load was transformative for drug development.
In comparison, Long COVID is lagging behind in the search for biomarkers. Despite the many reported findings about possible pathophysiological pathways, investigators have not yet identified reliable and useful biological tests — a situation that frustrates everyone involved, including clinicians and people with Long COVID waiting for answers.
“We would all have liked this to have gone faster,” said Michael Peluso, an infectious diseases doctor at the University of California, San Francisco (UCSF). “But a lot of the work in this field involves developing tests from scratch. That’s really hard, and it takes time.”
At UCSF, Peluso leads a new project designed to expedite the development of noninvasive Long COVID biomarkers called the Viral Immunopathogenesis and Persistence Repeat Donor Cohort, or VIPER. After a planning stage, VIPER was formally launched in March with an initial $1.35 million from the PolyBio Research Foundation, a nonprofit focused on the link between infectious disease and chronic illness.
The VIPER approach is patterned after a project called the HIV Reservoir Assay Validation and Evaluation Network (RAVEN). Launched more than a decade ago, RAVEN pioneered the strategy of running head-to-head comparisons of potential biomarker assays from a range of labs. Steven Deeks, a professor of medicine at UCSF and a key investigator in RAVEN, was already involved in the HIV field when viral load testing emerged as a game-changer. He is also deeply involved in VIPER.
“Having witnessed how a single test can transform a complex disease like HIV, I am fully committed to doing my part to develop tests for Long COVID,” said Deeks in a statement when VIPER was launched.
The heterogeneity of Long COVID
Biomarkers are traits that can be measured in blood, tissue, and other bodily samples and excretions. By providing data about physiological processes, biomarkers play a key role in research as well as in the care of many medical conditions. In particular, surrogate indicators — biomarkers that accurately predict clinical outcomes — are important for tracking the impacts of medical interventions.
“The holy grail of all of this is the concept of surrogate markers, where not only do we know how to change them, we know that changing them is going to alter how you are a year from now,” said Peluso. The availability of such biomarkers, he added, could play a major role in persuading pharmaceutical companies to invest in the search for Long COVID treatments.
VIPER will focus initially on investigating biomarkers related to SARS-CoV-2 persistence, which remains a leading hypothesis for what might be driving the disabling symptoms of Long COVID. This persistence could be in the form of viral fragments in blood and tissue, which have been reported in many studies.
There could also be hidden reservoirs of intact virus, said Mady Hornig, a physician and longtime myalgic encephalomyelitis (ME) and Long COVID investigator, and a visiting scientist at Feinstein Institutes for Medical Research. “You could have small amounts in tissues that are deep and difficult to access,” she said. If reservoirs can be identified, she explained, the goal would be to seek proxy indicators that reflect those findings in more accessible samples, like blood.
In the early days of the pandemic, it became clear that the perplexing syndrome soon to be known as Long COVID lacked biomarkers. Standard tests were of little help in diagnosing or treating it. Multiple factors have hampered the search for alternatives.
While cases are triggered by infection with SARS-CoV-2, Long COVID is not a single clinical entity. An umbrella term, Long COVID covers a broad range of manifestations, with many dozens of possible symptoms involving multiple organ systems. Researchers are investigating any number of possible causes, including viral persistence as well as immunological and neurological dysfunction, vascular abnormalities, and reactivation of latent viruses.
Given the range of manifestations of Long COVID, researchers “have really struggled” to identify useful biomarkers, said John Swartzberg, an infectious disease physician at the University of California, Berkeley. In general, a lack of biomarkers can hamper clinicians’ ability to make timely treatment decisions, he explained.
“Having biomarkers is enormously important in changing medicine from being a reactive profession to being a proactive one,” he said. “With HIV, testing someone’s viral load tells us whether the medication is working. We don’t have that with Long COVID.”
With HIV, testing someone’s viral load tells us whether the medication is working. We don’t have that with Long COVID.
John Swartzberg, UC Berkeley
Another problematic factor is that Long COVID is a fluctuating condition. Biomarkers that appear to be prominent early on might play no role at later stages, said Hannah Davis, co-founder of the Patient-Led Research Collaborative (PLRC). “If your study has patients that are all over the place in terms of illness duration, that’s going to complicate the findings,” Davis said.
A recent study, for example, challenged the idea that the SARS-CoV-2 virus’s “spike protein” could serve as a reliable Long COVID biomarker. Earlier research had found evidence of it in plasma for up to a year after the acute infection. However, in the new paper, which was published in June, investigators from Spain reported that the spike protein was generally undetectable after two years.
“Current evidence does not support its use to guide clinical monitoring or treatment decisions in Long COVID,” they wrote.
Because Long COVID is so complex, no one expects to find a single diagnostic biomarker that identifies all cases. Investigators generally agree that lumping everyone together in studies is likely to impede research, and that separating participants into subgroups is critical to success. The hope is that a combination of assays, like those being assessed in VIPER, could ultimately distinguish between the various types of Long COVID, said David Putrino, a neuroscientist at Mount Sinai Health System in New York City.
“It is possible that, on a five-year horizon, you would be able to give a blood sample and we could say, ‘Yes, based on these three markers, we can confirm that you have Long COVID and it is the autoimmune phenotype, for example, and these are the treatments we’re going to give you,’” said Putrino. (Like VIPER, some of Putrino’s research at Mount Sinai’s Cohen Center for Recovery from Complex Chronic Illness (CoRE) is supported by PolyBio; PolyBio’s co-founder and president, Amy Proal, also serves as scientific director at CoRE.)
To date, efforts to study biomarkers have largely been scattered and uncoordinated. Studies have recruited participants with varying definitions of Long COVID and have different laboratory methodologies, making it difficult to compare results. Funding for this research has generally been scarce.
The VIPER program seeks to address some of the obstacles. “We recognized the very fragmented and ad hoc way that these efforts were coming together,” said Peluso. “And we really wanted to provide a central organized structure within which that work could take place.”
How VIPER will work
The VIPER team is setting up a well-defined cohort of 150 participants — 100 with Long COVID and 50 who had COVID-19 but recovered. Some might be recruited from UCSF’s existing Long-term Impact of Infection with Novel Coronavirus project, which has gathered specimens from more than 1,500 participants and is also supported by PolyBio.
Peluso expects the group to include people infected with different variants of the virus. “We are paying careful attention to the diversity of the cohort in terms of both demographics, characteristics of the COVID infection, and clinical phenotype of Long COVID,” said Peluso. As examples of key phenotypes, he specifically referenced post-exertional malaise, autoimmune dysfunction, dysautonomia, and neurocognitive, cardiopulmonary, and gastrointestinal symptoms.
The team will take extensive samples — enough for the biospecimens from each individual to be divided into hundreds of smaller units for easier handling and distribution. The samples will include blood, saliva, and stool, as well as tissue from several sites in the gut. Participants will have to undergo colonoscopies as part of this tissue-sampling process.
VIPER will blind the samples and send them to a number of labs with promising platforms for testing biomarkers, allowing for head-to-head comparisons between the results. The plan is to fast-track promising candidates for noninvasive tests into clinical trials and, if the results are good, to scale up dissemination as quickly as possible.
Peluso expects to announce the roster of participating labs later this year. The group could include some already working on PolyBio-funded projects. Investigators at Ohio State University, for example, are seeking evidence of SARS-CoV-2 in extracellular vesicles, small particles that serve as messengers in communication between cells. At Boston University, Shannon Stott is pioneering a process so sensitive it can detect intact virus at concentrations as low as three particles per one milliliter of blood.
So far, said Stott, a biomedical engineer and an expert in the field of microfluidics, her team has been able to detect viral particles three months after infection. Now they are investigating whether these particles can be detected at later time points, and — if so — whether their presence is related to the symptoms of people with Long COVID. “The questions we’re asking right now are how far out do we detect the viral particles, and does that serve as a biomarker that helps inform clinical decisions?” said Stott.
The initial VIPER funding covers a two-year period, said Peluso. He hopes the team can make “meaningful progress” over that time in evaluating several assays.
The initial VIPER funding covers a two-year period, said Peluso. He hopes the team can make “meaningful progress” over that time in evaluating several assays.
Beyond viral persistence
Although VIPER is beginning with viral persistence, Peluso expects to expand the search to biomarkers related to other proposed factors. Akiko Iwasaki, a Yale immunologist who serves on VIPER’s scientific advisory board, said she would welcome efforts from other private funders to create similar programs involving the various other Long COVID hypotheses. “It would be great to have multiple entities out there that support different angles, because we should be looking at them in parallel,” she said.
Grace McComsey, a pediatrician at Case Western Reserve University and a principal investigator for an observational study within the National Institutes of Health’s RECOVER initiative, agreed that research into biomarkers involving other potential biological mechanisms was critical. But she’d prefer that federal agencies, rather than private donors, spearheaded these efforts.
“I think you need the government to fund these things, but the RECOVER money is dwindling,” she said. While she is concerned about the prospects for future funding, she expects some useful biomarker findings to emerge from ongoing RECOVER projects.
And there are many other places to look for biomarkers. A 2024 review of dozens of Long COVID studies identified hundreds of potential blood biomarkers, with the most promising clustered in three areas: immunological and inflammatory dysfunction, endothelial and vascular dysfunction, and metabolic and clotting abnormalities. Because no single indicator stood out as clearly distinguishing Long COVID, the investigators suggested instead that “a profile of biomarkers across various physiological systems may be more clinically useful.”
Investigators are also examining neurological biomarkers. In January, a study from Stony Brook University in New York reported that increased levels of a protein called pTau-181, a known biomarker for Alzheimer’s disease, were associated with cognitive dysfunction in those with neurological manifestations of Long COVID. Similarly, researchers from New York University recently presented a poster reporting higher levels of a related Alzheimer’s biomarker, pTau-217, in the blood of people with Long COVID compared to those who recovered and to controls.
Long COVID investigators are aware that the current biomarker situation provides some fodder for those who maintain that the illness is largely a psychosomatic or so-called functional condition. Not surprisingly, they reject that view.
“It’s a silly argument,” said Hannah Davis of the PLRC. “It doesn’t make any sense. Migraine doesn’t have a biomarker, ADHD doesn’t, autism doesn’t, cognitive impairment doesn’t.” Those making that case, she said, “seem like outliers in their own little world.”
UCSF’s Michael Peluso agreed that the argument doesn’t hold water. “It’s a little premature for anyone to declare that no biomarkers will be identified just because nothing has been clearly identified so far,” he said. “Lots of diseases are really challenging, but we’ve been investing in them for decades. I don’t know why we would hold Long COVID to a different standard.”
“Migraine doesn’t have a biomarker, ADHD doesn’t, autism doesn’t, cognitive impairment doesn’t.” Those making that case [that Long COVID is psychosomatic], she said, “seem like outliers in their own little world.”
Hannah Davis, PLRC
David Tuller is a senior fellow in public health and journalism at the Center for Global Public Health at the University of California, Berkeley. His academic position is supported by crowdfunded donations to UC Berkeley, largely from people with ME/CFS and, more recently, Long COVID.
Editor’s note, The PolyBio Research Foundation and the Patient-Led Research Collaborative, like The Sick Times, have received support from the Balvi and Kanro funds. Our newsroom operates independently of financial supporters.
Editor’s note, August 12, 2:56 p.m. ET. This article was updated to correct that UCSF’s LIINC program has collected specimens from 1,500 participants, not 15,000.
All articles by The Sick Times are available for other outlets to republish free of charge. We request that you credit us and link back to our website.
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