On Friday, a number of prominent Long COVID scientists are set to present updates on their work at the PolyBio Research Foundation’s fall research symposium. PolyBio is a leading organization in supporting formative Long COVID science; it has backed research into Long COVID’s biological causes as well as clinical trials aiming to address those underlying issues.
Through its Long COVID Consortium, PolyBio has funded innovative scientists in the U.S. and globally who are studying everything from microclots, or small blood clots, to SARS-CoV-2 persisting in the gastrointestional system. People with Long COVID often point to the consortium’s projects as formative in better understanding the disease.
Following results of earlier PolyBio-funded projects, the consortium’s current work aims to get more specific about biological processes and test potential treatments. “Phase one looked at, ‘Is persistence happening?’ And phase two is looking more at, ‘Why and how is persistence happening?” Dr. Amy Proal, president of PolyBio, told The Sick Times earlier this year. The consortium also fosters collaboration between different scientific disciplines, with researchers sharing samples and methods across organizations.
Current projects also include clinical trials, studying potential Long COVID treatments such as Paxlovid, other antivirals, monoclonal antibodies, repurposed HIV drugs, an enzyme that may help with microclots, and the immune-suppressing drug rapamycin. The Cohen Center for Recovery from Complex Chronic Illnesses (CoRE), a new center that recently opened at Mount Sinai in New York City, leads several of these trials.
The Sick Times team will be following the presentations throughout the day. Check this article and our social media pages to find our takeaways from the presentations.
— Betsy Ladyzhets
Editor’s note: The PolyBio Research Foundation, like The Sick Times, has received support from the Balvi and Kanro funds. Our newsroom operates independently of financial supporters.
4pm to 5pm EDT
Nadia Roan, senior investigator at Gladstone Institutes and professor at UC San Francisco, presented on SARS-CoV-2 persistence and T-cell activity in the female reproductive tract. She acknowledged that women, particularly pre-menopausal women, are more likely than men to experience Long COVID. There are sex differences in immune responses, which could be driven by chromosomal and hormonal factors. In an upcoming study that just began and is currently recruiting, their team is hoping to interrogate T-cell responses against SARS-CoV-2 and other similar diseases, knowing the endometrium might be a unique tissue to study SARS-CoV-2-specific T-cells.
Dr. Alessio Fasano discussed the peptide larazotide in the treatment of SARS-CoV-2 spike protein translocation, and ”leaky gut” — his team found that SARS-CoV-2 reservoir can leak viral spike proteins from the gut to the blood, driving hyperinflammation. Fasano’s team worked on a clinical trial using a larazotide with “open-label compassionate use” and double-blind placebo trial for multisystem inflammatory syndrome (MIS-C). The trial is being adapted now for Long COVID.
Dr. Sara Cherry at Penn Medicine talked about defining a viral reservoir in the GI tract with regard to Long COVID. In bronchial cultures and kinetic cultures, Cherry’s team saw the kinetics were different in terms of their persistence. They looked at cellular responses to SARS-CoV-2 infection. They found the genes induced in the gut were different than the ones induced in the lung. Aside from trying to find out how SARS-CoV-2 alters the gastrointestinal tract, her team is also trying to find out the effectiveness of varying antivirals.
Next, Amy Proal, president of the PolyBio Research Foundation and the science director of CoRE at Mount Sinai, talked about the Long COVID low-dose rapamycin clinical trial starting at CoRE now. The clinical trial is double-blind, randomized, and placebo-controlled, and enrolls 80 Long COVID participants in a dose of 6 mg once-weekly that they’ll titrate up to. There will be whole blood, saliva, and EndoPAT data analyses measured once before the study, once at week 12, and once at 24. It “might help us design a larger trial of more tightly phenotyped participants,” Proal said, and hopefully it will grant people “a read on how well this dose is tolerated.”
The last speaker of the day was Dr. David Putrino, the Nash Family Director at CoRE. He shared that there are a number of clinical trials underway and planned for 2024/2025. In particular, he talked about an in-human trial in partnership with Humanity Neurotech around cognitive impairment. Roughly 60% of people with Long COVID report cognitive impairment significant enough to affect daily function, he said, and that scale of measurement is “aligned with the same level of impairment we would see in traumatic brain injuries.”
Neuroinflammation is a driver of Long COVID-related cognitive impairment, and while there are therapeutics targeting neuroinflammation, Putrino said “the track record for most of these drugs has been spotty at best,” citing Low-Dose Naltrexone as an example. The Humanity Neurotech trial will use a device that emits a low-energy magnetic field to neurons and has already been used to treat animals, showing safety and efficacy. Recruiting starts in January 2025 and there will be four weeks of at-home intervention, along with measurements (patient-recorded outcomes, blood biomarkers of neuroinflammation, cognitive Ax) taken at baseline and follow-up.
During a short Q&A after the sessions, Proal also said that CoRE is beginning trials that look at drugs in both acute COVID-19 and Long COVID. She then thanked all the researchers and closed out the symposium, adding that the next one will occur in six months.
— James Salanga
3pm to 4pm EDT
Dr. Chiara Giannarelli from New York University Langone Health presented on her team’s varied research looking at cardiovascular complications of COVID-19, including analysis of COVID-19 autopsy coronaries and neuropilin-1 macrophages facilitating SARS-CoV-2 entry. Giannarelli’s team found that SARS-CoV-2 infects macrophages in coronary lesions and increases plaque inflammation. Now, they’re trying to answer whether there’s a SARS-CoV-2 vascular reservoir and what impact it may have on immune response and cardiovascular complications.
Next, Dr. Christopher Dupont from the J. Craig Venter Institute shared research on the tissue profiling pipeline for infection-associated chronic conditions. Dupont says his team has been working on lining up sites that are understudied, including lung, intestinal, endometrial, skin, and ligament/nerve, to see if they may be reservoirs for pathogens and microbes from previous infections, including Long COVID and endometriosis. “The microbes living in and on our body are far more diverse than we’ve thought,” Dupont said. They’ve also been working with industrial partners to test, develop, and deploy methods for improving microbiome capture.
Dr. Benjamin Readhead from the Arizona State University Biodesign Institute presented on a study validating a cytomegalovirus-based biomarker for Alzheimer’s clinical trials. Readhead compared his research to the story of Bilbo Baggins, saying there was a “meandering quality” to the work he shared.
Readhead’s team found that Alzheimer’s-associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain. They’re now wondering about a clinical trial of antivirals in CD83(+) Alzheimer’s subjects and looking at blood-based biomarkers for CD83(+)/HCMV.
Then, Matthew Frank from the University of Colorado, Boulder, shared his team’s work on a multiple-hit model of Long COVID. The team is focused on understanding neuroinflammatory properties of SARS-CoV-2 antigens, building on the evidence of neuroinflammation in Long COVID.
Frank also said this is linked to glucocorticoids (cortisol), which serve as a brake on the immune system in terms of reducing inflammation (among other things), being reduced in the serum of Long COVID patients.
Dr. Max Qian with the J. Venter Craig Institute talked about his team’s work on machine learning identification of Long COVID endotypes (or subsets of patients). They are using topic modeling of symptoms data to help interpret identified endotypes, and used clinical questionnaire data from 615 Mount Sinai patients on 44 symptoms. Among the groups they identified are endotype #2, which includes pulmonary, neurological, and cardiovascular problems, and endotype #3, which includes more sensory, hormonal, and gastrointestinal problems. Most of the identified symptom clusters and endotypes consisted of more female than male patients. Next, Qian’s team is trying to validate the endotypes using assay data and identifying global and local patterns.
— James Salanga
2pm to 3pm EDT
Opening with a graph showing the lack of studies of Long COVID in children compared with adults, Dr. Lael Yonker briefly reviewed our current understanding of pediatric Long COVID. As a pediatric pulmonologist, she has been studying healthy pediatric controls compared with study participants with Long COVID and MIS-C (multisystem inflammatory syndrome in children, a severe complication of SARS-CoV-2 infection). “We need to include kids in [clinical trials],” she said, pointing out there is only one current drug clinical trial for pediatric Long COVID, Larazotide. “There is no reason to wait.”
Dr. Marcelo Friere of the J. Craig Venter Institute opened his presentation by highlighting the multisystemic nature of Long COVID and speaking about the evidence of multi-modal biomarkers. Multi-modal biomarkers are a combination of two or more measurements that can indicate normal or abnormal biological processes, which would be helpful tools in Long COVID to diagnose and treat the disease. His research has focused on studying an oral cavity biomarker by using shotgun proteomics, “to identify persistent innate immune and clotting dysfunction in saliva collected from Long COVID patients and matched controls.” He also uses cutting-edge technology to look at blood and gut mucosal tissues.
Next, Dr. Rigel Chan of the University of Massachusetts Chan Medical School gave an overview presentation on the impact of SARS-CoV-2 (and other viral infections) on Alzheimer’s and neurodegenerative disease. “Exposure to SARS-CoV-2 spike may alter cell-type composition leading to great susceptibility to [herpes] infection induced Alzheimer’s disease,” he said. Chan also explained that herpes viruses can go into latency within the brains of people and get reactivated. He concluded by addressing future research directions, asking, “Will SARS-CoV-2 infection trigger this reactivation thus causing downstream risk to acquiring Alzheimer’s disease?”
Working with medical examiners, Dr. Zian Tseng leads the POST SCD autopsy study, which performs autopsies after sudden cardiac death, focusing on how SARS-CoV-2 persistence — including tissue damage — may impact Long COVID. The study has hundreds of specimens from both pre-and post-2020, which is important as many of these tissues are not available from biopsies. The study has collected tissue samples from numerous parts of the human body, including brains, lymph nodes, hearts, gut, and bone marrow.
Lastly, Dr. Gene Tan of the J. Craig Venter Institute gave an overview of how suboptimal antiviral immune responses to the coronavirus may be related to causing Long COVID. Analyzing hundreds of blood samples from participants with Long COVID and healthy controls, Tan’s ongoing project plans to define the viral antibody response in Long COVID blood, detect viral antigens in Long COVID blood, and evaluate virus-induced intestinal permeability. Tan concluded that neutralizing antibody activity was “significantly lower in Long COVID cases” from the research to date.
— Miles Griffis
1pm to 2pm EDT
Dr. Michael Peluso kicked off the third hour of presentations by shining a light on the work coming out of the UCSF (University of California, San Francisco) LIINC cohort. His research centers on targeting the SARS-CoV-2 reservoir in Long COVID clinical trials and has expanded to include people who were diagnosed with ME/CFS prior to COVID-19. He hopes to expand to include other infection-associated chronic conditions in the coming months. One of the main struggles of the UCSF LIINC cohort has been people with Long COVID becoming reinfected during their participation in their studies. He believes in-study reinfections also need to be researched, and he also spoke about designing trials with various eligibility determinations. You can read more about his project, including his commitment to open science, at PolyBio.
Timothy Henrich, who also belongs to the UCSF LIINC cohort, said that his main goal is to “stamp out viral persistence.” We now know Long COVID can persist in the gut for years (“coronulomas” is what they’re calling the clusters), and Dr. Henrich suspects he would find similar evidence of viral persistence in bone marrow. His research suggests that Long COVID is a tissue-based process that requires more imaging to understand the difference between people with Long COVID and those who have recovered. His team has made “significant strides” in PET images, and he believes that progress will continue to the benefit all infection-associated chronic conditions (IACC) patients. “Seeing is believing,” Dr. Proal encouraged after his presentation.
Dr. Esen Sefik of Yale University presented her work studying a humanized mouse model of SARS-COV-2 RNA persistence. Her team’s goal was to create is a consistent human immune system in mice, specifically to look at the way human neutrophils form NETs in response to SARS-COV-2. “Can neutrophils be infected?” she asked. “Can we block NETosis?” Her team will continue to experiment to determine how different therapies can eliminate viral RNA in mice.
Harvard University’s Dr. Michael VanElzakker is working with Long COVID and pre-COVID ME/CFS patients to try to better understand brain fog. He noted that the severity of this neuroinflammatory process isn’t really captured by the phrase “brain fog,” but it is the currently accepted nomenclature. Dr. VanElzakker described the testing his team is working on: Dual MRI-PET scans for neuroinflammation, whole body imaging for fibrin accumulation, neuroimaging for vagus nerve function and CSF flow, pupillometry, and even sleep studies. Pre-COVID ME/CFS patients and Long COVID patients with brain fog have similar scans and similar pupil diameter constriction. He said the images are “something like what you’d expect in a concussion.” For more, check out his interview with Dr. Amy Proal.
Dr. Petter Brodin of Karolinska Institutet shared his research on immunological sex differences in IACCs. He said that women are more likely to develop Long COVID, just as they are more likely to develop autoimmune disorders. Gender-affirming testosterone therapy supports this theory, as immune systems adapt and recalibrate as hormonal levels change. The branches of our immune system seem to be calibrated by sex hormones. He hopes to use this research to uncover important components of disease development, pathogenesis, and illness subtypes. You can read more about his work at PolyBio.
— Heather Hogan
12pm to 1pm EDT
Dr. Van Weyenbergh presented on his research on digital transcriptomics to capture SARS-CoV-2 persistence in whole blood, a potential and promising biomarker. The early study by Van Weyenbergh is currently being replicated in an independent cohort with support from PolyBio as well as donations organized by Long COVID Foundation. He also gave an update on a new “grassroots” patient-led study on Paxlovid that also uses transcriptonomic analysis, measuring the blood of participants both before and after the use of the treatment. “It is pressing to have a Long COVID biomarker,” Van Weyenbergh said.
Next, Marcus Buggert of the Karolinska Institutet presented on the impact of SARS-CoV-2 on Long COVID gut and lymphoid pathology. Using cutting edge technology, Buggert is studying if persisting SARS-CoV-2 in the gut or tonsils can “drive immune activation and microbiome changes.” He noted that many viruses including Zika, Rhino, and Polio can affect multiple tissues in the body. “SARS-CoV-2 is no exception”. His study looks at over 200 samples of tonsil tissue. He stressed the importance of tissue samples in Long COVID research stating, “If you’re just looking at the blood you might miss this.”
Similar to Buggert, Dr. Michaela Locci of the University of Pennsylvania is also assessing tissues in Long COVID. Her research looks at the lymph node immune responses in the disease, primarily how “aberrant germinal center responses are connected to the development of Long COVID.” Using Fine Needle Aspirate (FNA), Locci and her team have collected cervical lymphoid tissue from Long COVID study participants. She has found a major reduction in B cell responses to SARS-CoV-2, that SARS-CoV-2 antibodies are less neutralizing and wane faster, and that memory B cells have aberrant interferon-stimulated gene signature.
Then, Dr. Akiko Iwasaki of Yale University gave a presentation on the role of endogenous and latent viruses in Long COVID. “The most so insidious or prevalent virus that we live with is the endogenous retrovirus [HERV],” she said, explaining that Epstein Barr Virus (EBV) is also very prevalent, in about 95% of adults. She explained that anti-retroviral drugs like Truvada and Maraviroc may help alleviate Long COVID symptoms, since Truvada has been shown to interfere with EBV replication and because Maraviroc is being will block inflammatory cell migration to tissues. These clinical trials are underway with co-lead David Putrino at Mount Sinai’s CoRE.
At the end of the hour, Dr. John Wherry of the University of Pennsylvania gave a presentation on T cells as biosensors of viral persistence in Long COVID. In his summary, he stated that there is evidence of SARS-CoV-2 antigen sensing in 25-45% of individuals with Long COVID and that SARS-CoV-2 virus or viral protein may be detected by T cells. Similarly, other persisting viruses like EBV may be “awakened” in Long COVID.
— Miles Griffis
11am to 12pm EDT
Dr. Amy Proal kicked off the symposium by expressing gratitude for people with Long COVID who have been integral to the research that PolyBio funds, and to all of the researchers whose collaborative work has continued to contribute to a better understanding of the causes of Long COVID and potential treatments. Dr. Proal unveiled the new Consortium Project Explorer, which allows the public to explore PolyBio’s research by different body parts, organs, and systems — and to see the different programs collaborating on research in each area. It’s an exciting piece of interactive technology, and it emphasizes the collaborative, iterative research that PolyBio is using to build its knowledge base and design its trials.
Every researcher today will have ten minutes to present on their topic.
In the first hour, we heard from Nicolas Huot from Institut Pasteur whose work focuses on THEMIS, a protein that might be able to modulate SARS-CoV-2 persistence. Much of Hout’s research has been done with blood and bone marrow from a monkey, and then on blood and bone marrow from human patients. His team found 15 different natural killer (NK) cell clusters, one of which changed over time in infected people, indicating that THEMIS could play an important role in NK cell regulation.
David Price from Cardiff University presented on infectious, immune, and microbiome signals in the lungs of people with Long COVID. Signs of T-cell exhaustion in people with Long COVID could indicate ongoing antigen exposure, signaling viral persistence. Despite the fact that many people with Long COVID have spike-specific antibodies, they do not seem to be able to neutralize SARS-COV-2. This viral persistence could be causing ongoing tissue damage. Dr. Price said he expects to have “a slew of data by the time we get to the next symposium.” He expressed gratitude to patients who underwent the biopsy procedures, noting that he didn’t think he’d be brave enough to do it.
Resia Pretorius’ work centers on optimizing methods for biomarker identification. Microclots are promising biomarkers, but Dr. Pretorius believes there are more biomarkers that should be explored. She is working to identify biomarkers and match them with specific Long COVID symptoms. Her team has developed a new biofilm process that enabled them to see syndecan-1 as a marker of endothelial damage. Microclots can develop into macroclots, which can cause strokes.
Morgane Bomsel from the Centre National de la Recherche Scientifique presented her research on SARS-CoV-2 persistence and its impact on Long COVID megakaryocytes and platelets. Dr. Bomsel has studied infected platelets in both people with Long COVID and those who did not survive SARS-CoV-2 infections. Megakaryocites could be causing persistent infection, she suggested. Dr. Bomsel also noted that dysregulated energy metabolism and hormonal changes are also often common in the people with Long COVID that she has studied.
— Heather Hogan
Leave a Reply