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A summary of presentations from the weekly Summit partner webinars

January 22, 2026 – The latest Summit Summary

Long COVID Update – Akiko Iwasaki, PhD, Director of Yale Center for Infection and Immunity, Investigator, Howard Hughes Medical Institute, Sterling Professor of Immunobiology and of Molecular, Cellular and Developmental Biology

Akiko Iwasaki, PhD, gave an update about Long COVID and the impacts of vaccination.

Long COVID Update – Akiko Iwasaki, PhD
Long COVID is a debilitating and life-changing disease associated with more than 200 symptoms. The potential impact of vaccination, both pre- and post-infection, is promising and currently being studied.

Generally, there are thought to be three outcomes of infection: recovery, death, or chronic infection. However, new thinking points to post-acute infection syndrome (PAIS) as a fourth outcome. While vaccination can block these pathological pathways, chronic infection can also turn into PAIS via persistent replication, even for pathogens that aren’t often thought to induce chronic infection.

  • Although SARS-CoV-2 is the latest pathogen to cause PAIS, the syndrome has existed for centuries from various pathogens (e.g., Ebola, dengue).
  • These chronic illnesses are characterized by:
    • Exertion intolerance
    • Severe fatigue
    • Neurocognitive impairment
    • Sensory impairment
    • Flu-like symptoms
    • Unrefreshing sleep
    • Dysautonomia
    • Myalgia
    • Arthralgia
  • Globally, the incidence of Long COVID is estimated at 400M people; before COVID, the incidence of myalgic encephalomyelitis/chronic fatigue syndrome (MECFS) was estimated at 65M people.
  • PAIS is more often diagnosed in women.

Root Causes
Because many types of pathogens can trigger PAIS, it likely has overlapping causes, which may not be exclusive to each other, such as:

  • Viral reservoir
  • Autoimmunity (induced by acute phase of infection)
  • Tissue damage and dysfunctions
  • Latent virus reactivation

Understanding Mechanisms to Target Treatment
Studies have been considering disease history and its relation to Long COVID in individuals.

  • The Mount Sinai-Yale Long COVID (MY-Long COVID) study looked at medical charts, symptoms surveys, biological parameters through flow cytometry, antibody reactivity to viruses and self-antigens, and plasma proteomic studies. The study focused on Long COVID that developed after mild disease; days from acute COVID was ~400. Findings included:
    • Age, sex, and acute COVID severity were similar between Long COVID participants and convalescent controls.
    • People with Long COVID are enriched in ages 30 to 60 years. Sex is female dominated.
    • Findings in patients with Long COVID: Complement components and chemokines and cytokines were elevated, and — strikingly — cortisol was much lower versus control.
      • The levels of cortisol were so much lower that another cohort was recruited to study that incidence. The lack of elevation in ACTH suggested that the reduced cortisol level was likely happening centrally or at the hypothalamic or pituitary organs.
      • There is also reactivation of latent herpes viruses: IgG antibody against lytic antigens of Epstein-Barr virus (EBV) and the antibody against glycoprotein E of varicella-zoster virus were elevated in patients that have Long COVID.
        • Collectively, this suggests that patients with Long COVID have recent reactivation of EBV and, potentially varicella-zoster virus.
      • Distinguishing factors (and these are predictive of patients with Long COVID with 94% accuracy) include lower levels of cortisol and reduced cDC1 and CDT cells and higher EBV reactive antibody, CD4 T cells, and galectin.
    • Autoimmunity: When functionality of antibodies in patients with Long COVID was probed using purified IgG injected into mice, those that received saline, healthy control, or convalescent control IgG reacted to a hot plate test (standard, in-vivo preclinical assay used to measure pain sensitivity in rodents) in about 10 seconds; however, some of those that received IgG from patients with Long COVID reacted to a hot plate test in less than 5 seconds. This indicates that these animals had heightened thermal sensitivity which may correspond to Long COVID patients reporting new onset of pain, such as inflammatory or neuropathic pain.
      • Another study demonstrated a reduction in the density and volume of the nerve fiber in the skin post injection of IgG from Long COVID patients that did not occur with healthy control IgG injections.
  • The challenge remains to identify patients who have autoimmune phenotype versus persistent virus versus chronic inflammation versus EBV reactivation and treat them all accordingly.

The Impact of COVID Vaccination on Long COVID Outcome
A meta-analysis on pre-infection vaccination on Long COVID outcome showed a reduction of about 30% for developing Long COVID if a person were to be vaccinated prior to getting COVID. This shows that vaccination is one of the layers of protection — in addition to ventilation, masking, and other strategies — against COVID and Long COVID.

Regarding the therapeutic impact of vaccination on Long COVID after diagnosis, small studies have shown either no or some symptom improvement after vaccination. It’s mixed. After post-diagnosis vaccination, some patients develop severe side effects and others completely recover from Long COVID. The heterogeneity of results likely has to do with differences in root cause. A very small prospective study on basal levels of cytokines showed that after post-diagnosis vaccination a lot of people felt better, but some had a worsening of symptoms. After the vaccination, the cytokine profile did not change much, but people who reported worsening symptoms had elevated levels of interferon beta and other cytokines.

QUESTIONS & ANSWERS

Q: Do you have any data about, or do you know if there’s a way to look at, if you’ve had acute COVID and you recover and you get vaccinated, does that still have an impact on potential Long COVID developing further down the line if you get a second acute attack?
Akiko Iwasaki (Yale, HHMI): Reinfection seems to carry cumulative risk for developing Long COVID. So, unlike other infections where you recover from one infection one time and you’re protected for life, that seems not to be the case for Long COVID.
Q/Follow-up: So, for every acute attack, you run the risk of Long COVID again; therefore, vaccination makes a lot of sense in that case?
Akiko Iwasaki (Yale, HHMI): Exactly, and in the data that I didn’t have time to share, the booster vaccines — booster shots — also provide added benefits for reducing the risk. So, yes, I get all the boosters I can.

Q: Is there a cure for some of these effects that you’re seeing, whether it be latency reinfection or reactivation, etc.?
Akiko Iwasaki (Yale, HHMI): I believe there’s a cure: Some of them are existing cures, others need to be developed. But for instance, if a person has persistent viral replication, we did a clinical trial using 15-day course of Paxlovid, which unfortunately did not show any benefit. And that’s consistent with the Stanford trial as well. But it doesn’t mean that other, more potent targeting of the virus wouldn’t work. For instance, the monoclonal antibodies that are potent in targeting the spike protein — those things really need to be tried for people who have this persistent viral gene type. In the case of autoimmune phenotype, I also think there are so many wonderful medicines that have been developed in autoimmune fields, such as the FcRn inhibitors that reduce the antibody levels. And that may be very beneficial for those people who have these elevated autoantibodies. And things like B-cell depletion therapies and many other great medicines in the autoimmune space can be tried in patients with autoimmune disease that we’re seeing. Chronic inflammation, yes, you can also target that using things like JAK inhibitors or immunosuppressive drugs. And the EBV, we don’t have a vaccine, but if we had a shingles vaccine equivalent for EBV, we could also try that. So at least understanding the basic biology of disease will allow us to at least think about what is needed for future targeting.

Q: Have you measured anti-NFL neurofilament peptides in patients with various forms of Long COVID? And could you help folks understand why NFL peptides are important?
Akiko Iwasaki (Yale, HHMI): We didn’t really invent this assay ourselves. Neurofilament light peptide is an integral part of the neuronal axon, and usually you don’t see these peptides in circulation. But when there is damage, such as in the case of multiple sclerosis or some neurodegenerative diseases, you can find elevated levels of neurofilament light peptides in your blood. So, we should be measuring neurofilament light peptides in the patients. We only did it with the passively transferred animals, but ultimately, we need to look at this. And there are many great clinical tests that are being developed for diagnosis of other diseases. So, again, we can use that tool to apply to Long COVID patients. It’s a great idea.

Q: What’s the impact of plasmapheresis on Long COVID?
Akiko Iwasaki (Yale, HHMI): Plasmapheresis has been used in a subset of patients, and some patients do well after plasmapheresis, while for others there’s no impact, and in others there’s worsening. So, if we can identify people who would benefit from plasmapheresis, which I think these elevated autoantibody levels are a key marker of that, then we can really focus on those patients and give them plasmapheresis. There’s a lot of anecdotal evidence that people do better after plasmapheresis, but not everyone. What we are currently lacking in the field is a diagnostic, as well as a therapeutic, biomarker that can distinguish patients into different drivers of disease.

Q: In the real world, how can you identify what the underlying basis is for the Long COVID that a patient has? Is there a consistent way to identify, and then pursue a treatment?
Akiko Iwasaki (Yale, HHMI): That’s the biggest gap right now: We don’t have those biomarker panels that other diseases have. For example, lupus: You can order a lupus panel and test the patient’s blood to see whether they have lupus. That’s where we need to be, but we’re not there yet. Part of it is because Long COVID is a collection of multiple diseases. We don’t know how many diseases there are, but we know that it’s not just one disease. So, if we can have a panel of biomarkers that can say, “Okay, you have type A Long COVID, type B Long COVID that is distinguishing because of the root cause driver of disease,” that would be the ideal scenario. To develop those biomarkers, we first must understand what is going wrong with the patient. We are developing a lot of insights, but they haven’t translated into those panels of markers yet.

Q: There is a question about whether you had measured antibodies against NFL, and it sounds like you haven’t, because you said that would be a good idea to look at.
Akiko Iwasaki (Yale, HHMI): Yes, exactly, we have not.

Q: Is there anything to add for someone who’s had Long COVID for 4 years? [The doctor asking the question has a patient in this position and is seeking advice.]
Akiko Iwasaki (Yale, HHMI): First, thank you for caring for that patient. One of the struggles of this field and the patients is that there aren’t enough doctors who take the patients seriously and treat them appropriately, and oftentimes they’re being dismissed as having psychosomatic disease. So, I appreciate you taking care of this patient. The problem is that there is this condition, myalgic encephalomyelitis, or chronic fatigue syndrome, that has pre-existed prior to the COVID-19 pandemic, and some of those patients have been suffering for decades with this disease. So, it’s an inflection point, now, to finally try to figure out the reasons for these diseases, but we have missed the opportunities from the past. I wish I could say, “Yes, we can now diagnose these patients with these panels and treat them with these medicines,” but we’re not there yet. But as I said, I still have hope for treatment and cures for these diseases. I think we’re just lacking that step of identifying the right patients for the right treatment.

Q: To your point, now there seems to be biological plausibility with some of the things like brain fog, because of the neuronal impact. Maybe there will be more sympathy for people who are coming in and saying, “I have brain fog.” Because if there’s a neuronal basis that you have identified, it might make it easier.
Akiko Iwasaki (Yale, HHMI): Absolutely. A whole study I didn’t have time to talk about is kind of to map out of what happens from acute respiratory infection, even with very, very mild disease. In this animal model, they don’t lose any weight, you can’t see any sickness behavior, and yet these animals develop reactive microglia 7 weeks post-infection. That is collaborative work that we did with Professor Michelle Monje at Stanford. It seems that there is a chronic change that happens in these macrophages of the brain, the microglia, that is just continuous, and we can’t really turn them back to the homeostatic phenotype. So, intervening with these kinds of immune cells in the brain itself may be another avenue for dealing with things like brain fog and lots of pathology that may be also happening in the brainstem that then, through the vagus nerve dysregulating not only the autonomic nervous system but the immune system itself … There’s a very tight regulation of the immune system by the vagal system, vagal nerve, so we can’t really separate the brain and the nervous system from the immune system. I mean, we shouldn’t be doing that. But I think this is an opportunity where immunologists and neuroscientists can come together to try to figure out how we can treat this disease.

Q: Is there a way that a person with Long COVID could determine if they might have symptoms worsening post-vaccination? For that reference definition of Long COVID, is there possibly a spectrum?
Akiko Iwasaki (Yale, HHMI): Yes, that is why we did that study. We wanted to have hundreds of people, but unfortunately, we only had 16. That’s what we’re missing right now. If we can predict if a person is going to get a very bad side effect from the vaccine, or if they’re going to improve and recover from Long COVID, wouldn’t that be great? Most patients are afraid to get boosters, because they’ve had such a bad reaction to the vaccine in the past. Can we predict using biomarkers who is going to respond and how? But so far, with that very small study, all I can say is that there are some cytokines that are elevated in those who do worse with vaccination, including interferon alpha and beta and others, soluble IL-6 receptor being elevated, but this must be expanded into a much larger cohort.

Q: How can we take this information that is compelling at the scientific level and make it simpler for patients, or people with lower literacy. Are you, at Yale, trying to do something like this? Or, as a basic scientist, trying to get your information out to the less literate public?
Akiko Iwasaki (Yale, HHMI): That’s a great idea, and we should be working on that. We have this Yale Center for Infection and Immunity, where we are trying to develop communication tools to be able to disseminate this information in a much more digestible form. I have been just talking at the scientific level, but you’re right, this needs to be disseminated and understood by the public. And, you know, any help you can give me, I will take it. But it’s very important.

Q: From a clinical perspective, the symptoms are non-specific. What would you suggest for clinicians in practice to help them have more confidence in diagnosing Long COVID versus other, overlapping clinical syndromes.
Akiko Iwasaki (Yale, HHMI): I’m not a clinician, but my clinician colleagues have put together a handbook for other clinicians to use to diagnose Long COVID properly. Because, a lot of times, what needs to happen is to exclude other potential causes of these nonspecific symptoms. For instance, I have this wonderful clinician colleague, Lisa Sanders, who’s running the Long COVID clinic here at Yale, and she has accumulated a lot of experience and knowledge; she’s telling me that a certain percentage of the patients are certainly suffering from something else, like, it could be cancer, it could be autoimmune diseases. And once they have that diagnosis, they can get the proper care. But many of the patients that she sees have this sort of classical, typical Long COVID phenotype, and it’s hard to put that in one sentence. But there’s a handbook out there, so I’m happy to share that with this group, if interested.

Please find link to the handbook for diagnosis and treatment for Long COVID and related illnesses.  It was shared by Dr. David Putrino. Credit to Dr. David Purtrino and CORE at Mount Sinai for the resource.
https://www.coresinai.org/manual

Q: A unifying theme for Long COVID is that SARS-CoV-2 virus promotes vascular inflammation, which leads to the various organ system dysfunctions — brain, heart, lungs, kidneys — that can be long-term. Would you agree that vascular inflammation is a starting point with this hypothesis, or is it more everything kind of just reflecting a latent virus infection or persistent virus infection?
Akiko Iwasaki (Yale, HHMI): Vascular inflammation, mitochondrial deficit, many of these things are concurrently happening in the patients, and if we can… for example, if we treat the vascular inflammation and cure patients, that’s great. Who cares what the root cause is, right? So, ultimately, we are going for the cure and symptom improvement in patients, but we also see vascular inflammation in all our patients to some extent, different extent. So, it’s clearly one of the, if not the, initiator; it’s one of the amplifiers of this disease. And that’s something that we also need to study seriously and see whether patients might benefit from reducing that inflammation. And there’s also complement activation that’s happening in subset. So, if we can just sort of draw a map of all the different pathologies and say, “You are landing in here, you’re landing in here,” that would be useful.

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