The PolyBio Research Foundation recently hosted its fall research symposium featuring project updates from some of the leading Long Covid scientists in the field, including Dr. Akiko Iwasaki, Dr. Michael VanElzakker, and Dr. Amy Proal.
Long Covid media outlet The Sick Times live-blogged the event and noted that the consortium “fosters collaboration between different scientific disciplines, with researchers sharing samples and methods across organizations.”
A recording of the event will be made available, and you can read our summary of the Symposium presentations below. Read other entries in our Solve Science Spotlight series here.
FALL 2024 POLYBIO SYMPOSIUM SCHEDULE – PART 1
Dr. Amy Proal (PolyBio Research Foundation)
Dr Proal gave a brief overview of PolyBio-funded research & clinical trials, using a new interactive visual aid on the PolyBio website that connects each body system with related PolyBio-funded studies which is meant to aid researchers in collaboration. The updates from PolyBio supported researchers show that they have been able to effectively share their samples and other resources with each other.
Dr. Nicolas Huot (Institut Pasteur, Paris)
Dr. Huot reviewed his research on THEMIS (a protein traditionally associated with T cells) and looked at its impact on natural killer (NK) cells response to SARS-CoV-2 infections. By looking at the blood and bone marrow in monkey models, he found that THEMIS made the natural killer cell response different in pwLC compared to recovered patients and healthy controls.
He also looked at a cohort of vaccinated patients with SARS COV2 infection for their THEMIS expression and found it to correlate with a type of natural killer cells (NKG2A) after 3 and 6 months post-infection compared to the group without a SARS COV2 infection. He doesn’t know if THEMIS can help or not with Long Covid but is going to continue to investigate if THEMIS can modulate the human natural killer cell immune response.
Dr. David Price (Cardiff University, UK)
Dr. Price looked at two groups of patients with documented SARS-COV2 infections; one who went on to develop Long Covid and those who fully recovered from Covid and did not go on to develop Long Covid.
He found no difference in T-cell response to the spike protein but thought that could have been because of later vaccination in the groups. He also found no difference in the groups in their viral reactivity to viruses such as cytomegalovirus (CMV) and Epstein Barr virus (EBV). He found T-cell exhaustion in the Long Covid group towards proteins (but not the spike protein) particularly towards PD1 and TIM 3, which are “inhibitory molecules that develop with repeated response to antigen exposure in the SARS COV2 virus.” Dr Price said he takes this to mean there is prolonged antigen exposure in Long Covid patients.
Dr. Price also found a difference in the patients’ ability to neutralize the SARS COV2 virus.
Using proteomics, he found a large number of proteins associated with apoptosis and cell death to be upregulated in patients with Long Covid He identified a key marker in patients with the symptom of breathlessness which was a TNF inflammatory molecule called BOX ANA (which he said is also a marker of platelet activation).
He also took lung biopsies in 15 patients with Long Covid and 15 healthy controls and is working on a “Lung Microbiome. He is waiting for data to be run by fellow PolyBio-supported researcher Chris Dupont at JCVI. Dr Price will also run RNA sequencing on these tissues.
Dr. Resia Pretorius (Stellenbosch University, South Africa)
Dr. Pretorius is trying to find a biomarker for Long Covid by looking at blood clots including NETs, Fibrinogen, Biofilms, Syndecan, and extracted clots from stroke patients. She wants to also see if microclots can group into “macroclots” that could cause a stroke.
She spoke about the technology she is using to investigate if NETS are found in microclots using staining techniques. She showed that some microclots have biofilms and mentioned she is working with Alain Thierry.
Dr. Morgane Bomsel (Centre National de la Recherche Scientifique, Paris)
Dr. Bomsel said that patients with Long Covid have a positive correlation with the presence of persistent SARS-CoV-2 (spike, ds RNA, viral RNA) in megakaryocytes. She did not see this in her control group which she calls “Covid Recovered” or “CR”.
Her Long Covid group had more megakaryocytes than HC (healthy controls) or RC (recovered Covid) groups. She found spike was detected in circulating plasma in some patients in her Long Covid group. She also found serotonin/5-HT and metabolites were decreased and said that was “likely due to TPH1 deficiency.”
Dr. Johan Van Weyenbergh (Rega Institute, Belgium)
Dr. Weyenbergh wanted to find a biomarker in the blood or saliva using transcriptomics, He says he found identifiers in patients with Long Covid including something called Antisense. He also found a separate marker (COOP) for those patients with Long Covid reporting anxiety/depression.
Dr. Van Weyenbergh also discussed a patient-led Paxlovid trial and reported:
- A 32% drop in total symptoms after 15 days (although no change in antisense which infers it may not correlate with Long Covid symptoms).
- A decrease in COOP but he did not specify rather anxiety and depression symptoms changed.
Dr. Marcus Buggert (Karolinska Institutet, Sweden)
Dr. Buggert wanted to look closer at tissues in the gastrointestinal and upper respiratory tracts (tonsils, colon, ilieum, cecum).
His study looked at 6 patients with Long Covid and 6 healthy controls, he took biopsies of the colon, ilieum, and cecum, and looked for SARS-COV2 reservoirs and changes in immune and epithelial cells using transcriptomics.
He is also going to look to see if antigens in tonsils could trigger ongoing T-cell activation. His tonsil samples include 60 patients who had a Covid infection (with no vaccination), 30 patients who had the Covid vaccines (but no Covid infection), and 40 patients who had neither the vaccine(s) nor a history of a Covid infection!!
He is working with David Price on a Long Covid biomarker by looking at protein assays to find which proteins correlate best with each Long Covid symptom and is using OLINK and says he already sees markers that correlate with the symptom of breathlessness.
Dr. Michela Locci (University of Pennsylvania)
Dr. Locci collected lymph node samples from the necks in patients with Long Covid using a fine needle and then a sonogram method that already exists for vaccine testing to look for “vaccine draining” into lymph nodes. She looked to see if the “germinal center responses” –which generate antibodies–are connected to the development of Long Covid.
She found that Long Covid patients have less germinal center responses in B-cells than recovered patients which she refers to as “convalescent” or “CONV” in her slides below.
Dr. Akiko Iwasaki (Yale University)
Dr. Iwasaki looked at the many latent viruses that we acquire and live with, such as the herpes virus family, and the many viruses that have integrated into our genome from our ancestors which are called Human Endogenous Retroviruses or HERV. She cited studies linking Epstein Barr Virus (a herpes virus) to Long Covid and says that reactivating Epstein Barr is one of four predictive factors for developing Long Covid.
She also cited her own 2018 paper mapping Human Endogenous Retroviruses and a 2021 paper covering antibodies against Human Endogenous Retroviruses and stated that antibodies against these are higher in Lupus patients. She sued the “ERVmap” to show this.
Dr. Iwasaki said that antibodies have two parts:
- The variable region, or the antigen binding site, which specifies the reactivity of a particular antibody and
- The function, or FC, region which determines the antibody’s function.
Dr. Iwasaki is using funding from PolyBio to collaborate with a company called SeromYX. From www.seromyx.com: “Seromyx correlates antibody effector function to product efficacy and humoral immunity to develop potent antibody therapeutics and vaccines”. She is looking to see if there is a relationship between antibodies to Epstein Barr virus or Endogenous Retroviruses in patients with Long Covid.
She is also testing to see if antiretroviral HIV drugs (Truvada and Mavaviroc) alleviate Long Covid symptoms in a clinical trial with David Putrino at Mt Sinai.
Dr. John Wherry, PhD (University of Pennsylvania)
Dr. Wherry found that CD8 T-cells are working differently in response to “breakthrough infections” (a Covid infection after vaccination), and also in response to Epstein Barr virus and Varicella Zoster virus (the virus that causes Chicken Pox and can reactivate later in life and cause Shingles). He wants to find out why CD8 T-cells are acting differently in response to these situations. He is using BEAM (“Barcode Enable Antigen Mapping”) to track CD8 T-cells and says he “should be done in 4-6 weeks.”
He is collaborating with Dr. Iwasaki and said most of this work is being done by Marc Painter in his lab (the Wherry Lab at PENN).
Dr. Michael Peluso (University of California San Francisco)
Dr. Peluso talked about the UCSF LIINK study that is funded by RECOVER. He said they have samples, patients enrolled, imaging, and trials going. He mentioned several recent papers:
- Early biological markers of post-acute sequelae of SARS-CoV-2 infection (Aug 2024) – Acute covid patients have higher amount of virus that can be recovered from the nose in the first couple weeks and test positive longer in the first couple weeks.
- Measurement of circulating viral antigens post-SARS-CoV-2 infection in a multicohort study (Sep 2024)
He went to talk about the LIINC tissue program which has gut biopsies and is also supported by PolyBio.
Dr. Peluso stated, “With the support of PolyBio, we are also expanding to other IACCIs … starting with post-Covid ME/CFS and non-Covid ME/CFS in early 2025 … and will do rigorous biospecimen collection.” He said they have already submitted the ME/CFS trials for IRB and has a paper coming out about this on November 13, 2024 in “Science Translational Medicine” with Drs Hanson and Deeks. He discussed other LIINC studies which are detailed on the slides below.
Finally, he discussed the different types of viral persistence for consideration in reservoir trial designs and different therapy ideas for each instance; Persistence of viral RNA with no proteins should be treated with Immunotherapy. Active replication but no virome should be treated with Monoclonal Antibodies. Active infection with ongoing replication should be treated with Antivirals, and some patients–and trials–may need a combination of these.
