Researchers find yet another way to potentially explain long COVID and perhaps other post-infectious illnesses
One outcome of more or less abundant funding and the worldwide reach of COVID-19 is the creativity that gets unleashed. This Harvard study “Impact of cross-coronavirus immunity in post-acute sequelae of COVID-19” did something that’s never been tried in chronic fatigue syndrome (ME/CFS) but presents some intriguing possibilities for it as well.
Taking advantage of the fact that antibodies can also be used as indirect markers of historical infections, the study “deeply explored alterations” in the antibody response as well as to related coronaviruses and a host of other pathogens in 43 people with rheumatological diseases such as rheumatoid arthritis and psoriatic arthritis (but not fibromyalgia). The goal was to see if the findings shed light on why some people came down with post-acute sequelae of COVID-19 (PASC), e.g. long COVID, and others didn’t.
Antibodies to the following infections and vaccines were assessed:
Vaccine antigens (Tetanus, Rubella, Measles, Mumps), herpesviruses (herpes simplex 1 – HSV-1, cytomegalovirus -CMV, Epstein Barr virus -EBV, Varicella Zoster virus – VZV), other coronaviruses (SARS-CoV-1 Spike/S1/S2, OC43 Spike/S1/S2, HKU1 Spike/S1/S2) and other human-infecting pathogens (Influenza, Respiratory Syncytial virus (RSV), and Staphylococcus aureus) and control pathogens (Ebola).
From Bruce Patterson’s monocytes, to the “original antigenic sin”, to persisting viruses or pieces of viruses, to micro clots, platelet hyperactivation, and amyloid fragments, long-COVID research is opening up new opportunities to understand it and other post-infectious illnesses such as ME/CFS.
- Long COVID research opens yet another new and different possibility for post-infectious illnesses.
- Harvard researchers went beyond normal antibody testing to assess antibodies for the SARS-CoV-2 coronavirus, for a coronavirus that causes the common cold, and for a number of other pathogens in long COVID patients and in recovered COVID-19 patients with pre-existing rheumatological diseases.
- The people with long COVID displayed a distinct antibody pattern: antibodies to the coronavirus causing the common cold were elevated, while antibodies against the SARS-CoV-2 virus that sparked the current pandemic were reduced. Plus the elevated antibodies were triggering an inflammatory response.
- This indicated that something called “an original antigenic sin” or “immune imprinting” had occurred. This occurs when the immune system dredges up an older and less effective immune response to a similar pathogen to fight a new pathogen. This results in the immune system being “trapped” and unable to mount an optimal response.
- The authors proposed that this deficient immune response may have caused the immune systems of people with long COVID to fail to clear the virus, leaving either it or the proteins associated with it, to persist – causing an ongoing immune reaction and inflammation. This process has never been assessed in ME/CFS.
- Viral persistence has been proposed in ME/CFS/FM, and some evidence of viral persistence has emerged in long COVID. The Long COVID Research Foundation – which has strong ME/CFS roots – is devoting substantial resources to see if viral persistence is present and causing problems in long COVID. If so, it has pledged to work on ME/CFS next.
- From Bruce Patterson’s monocytes, to the “original antigenic sin”, to persisting viruses or pieces of viruses, to micro clots, platelet hyperactivation, and amyloid fragments, long-COVID research is opening up new opportunities to understand it and other post-infectious illnesses such as ME/CFS.
Lo and behold, the people with long COVID or PASC, and the people who’d recovered from COVID-19, displayed significantly different antibody profiles. People with long COVID displayed significantly enriched or elevated levels of a cytomegalovirus (CMV) antibody and a coronavirus antibody associated with the common cold (OC43 Spike-specific FcγR3a/3b).
The CMV enrichment was a false lead, as more people with PASC had been infected with CMV in the past, but the high levels of antibodies to the spike protein of OC43 – a common cold coronavirus in the same lineage as the SARS-CoV-2 coronavirus – raised some eyebrows. That prompted a search to see if the antibody response to the coronavirus that caused the common cold had impacted the antibody response to the SARS-CoV-2 coronavirus that’s swept the world.
First, they found that the common cold antibody response was likely triggering inflammation. The antibodies found recruit neutrophils to sites of inflammation and activate them – suggesting that a dramatic increase in inflammation had occurred.
Plus, the overall antibody response (OC43-specific FcγR2a, FcγR2b, FcγR3a) to the common cold coronavirus ratcheted up – indicating that the long-COVID patients’ immune systems reacted to the new coronavirus by dredging up a response to its less dangerous cousin. This coincided with an inhibited antibody response to the current SARS-CoV-2 coronavirus. Not only that, but this antibody switch appeared to turn on an inflammatory response as well.
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Original Antigenic Sin
This process – called the “original antigenic sin”, “immune imprinting”, or the Hoskins effect, has been called “the downside of immunological memory“. It occurs when instead of creating a new immune response that specifically targets the current pathogen, the immune system dredges up an older and less effective immune response to a similar pathogen. This results in the immune system being “trapped” and unable to mount an optimal response when confronted with a new virus.
It’s been known to occur with influenza, HIV, dengue fever, and other viruses, and was found to occur in some hospitalized COVID-19 patients last year. The impact of this “back-boosting” or “immune imprinting” attempt by the immune system to fight the coronavirus is unclear. This study, though, suggests it may be unhelpful, indeed, as an “immune imprinting” response was associated with long COVID in this patient group.
Viral Persistence Explained?
The authors noted that this strange immune response could explain why either the spike protein or the SARS-CoV-2 virus itself may persist in people with long COVID. The inability of the long-COVID patients’ body to mount a strong immune response that’s specific to the new coronavirus may cause the virus in one form or another to remain.
A new and quite different immune hole from what we’ve seen in ME/CFS has been uncovered and the specter of viral persistence raises its head again. Could a combination of imprinted immunity / viral persistence also be opening the door to ME/CFS in some people?
Some evidence of viral persistence in long COVID has emerged. Bruce Patterson has evidence indicating that SARS-CoV-2 proteins may be sparking an ongoing immune response in long COVID. Another study found residual virus in appendix, skin, and breast tissues of 2 long-COVID patients. Other studies have found it in the gut, plasma, and stool. One case report brought a possible new treatment approach to bear when it found nirmatrelvir/ritonavir and tocilizumab treatment reduced symptoms in a long-COVID patient with coronavirus persisting in her throat.
Health Rising recently reported on a major new effort from the Long COVID Research Foundation – which has strong ME/CFS roots – to determine whether viral persistence plays a major role in long COVID. If viral persistence is found, PolyBio has pledged to look for it in ME/CFS.
From EBV and herpes zoster to enteroviruses, viral persistence and reactivation has been something of a theme in ME/CFS/FM, yet aside from Dr. Chia’s and Dr. Pridgen’s gut samples, it has been little addressed. Should viral persistence be shown to play a role in long COVID, it will surely be addressed in ME/CFS as well.
Whatever the answer ultimately turns out to be, long COVID is doing what we hoped it would do – bring new and creative approaches to the study of post-infectious illnesses. From Bruce Patterson’s monocytes, to the “original antigenic sin”, to persisting viruses or pieces of viruses, to micro clots, platelet hyperactivation, and amyloid fragments, long-COVID research is opening up new opportunities to understand it and other post-infectious illnesses such as ME/CFS.
Has anyone been able to get rid of sore throat after Covid ?
Kelly, this persistent sore throat could also be a dysautonomic response or vagus nerve dysfunction. I have had a hoarse voice that comes and goes for the whole 31 months of my long COVID. Two different ENTs found nothing structurally wrong with my throat or vocal cords. I do also have EBV reactivation.
I’m reading a good book now called Activate Your Vagus Nerve by Dr. Navaz Habib. It might be worth checking out. And he definitely recommends vigorous gargling with warm water twice a day.
Thanks for another great article Cort! I get excited whenever they start really digging into the immune/autoimmune component of this disease. I get hopeful for a cure for post exertional malaise when they start talking about root causes.
I get a horsey voice/throat every afternoon and I’m alone until then, so I haven’t been talking. I have ME/CFS but never had COVID.
try red tea and,camomile tea, warm up orange,get better soon
It sounds like The Epstein Barr Virus (EBV) might be rearing it’s head, activated from Covid ?
Or Cytomegalovirus activated from Covid?
EBV never seems to disappear. Even if it’s not directly EBV it still shows high titers.
Do a PCR test, not antibody titers
Could OC43 be what is being unleashed when it comes to EBV?
I think we all have thought this was viral. We have never found a cure for the common cold. The problem has been $$$ for research. The NIH was never our friend. Someone like dr. Ian Lipkin at Columbia could have figured this out with grants. Always hoping as we all are.
It’s obvious that I’m encouraged by all the different possibilities long COVID research has been uncovering and think of this – we haven’t even begun to see what the RECOVER Initiative can do. It should dwarf everything going on now.
Correct. The fact that Lipken’s Columbia lab has not been adequately funded is criminal. This man and his associates are highly regarded Biochemists. We really need to push our representatives in Washington to force an immediate change at the top of the NIH. Since the disease seems to have several triggers, ME/CFS will only be “cured” with extensive participation of the NIH
Congress is the one we got to go through if there is ever to be any cooperation on the NIH. It does not look to me like the NIH is even stepping up to the plate on Long COVID. They are sure taking their sweet time about getting the RECOVER initiative off the ground from what I am seeing.
It is absolutely criminal that Lipken is not getting money from the NIH when Lipken is highly regarded. It is also absolutely criminal that Ron Davis is not getting any grants from the NIH when he helped map the human genome. This is something that Congress needs to investigate because the NIH is not doing its job. Quite frankly, it is time for an independent group to work on ME and other chronic illnesses because the NIH can’t be trusted with ME, LC and these chronic illnesses.
Gargle with salt water, Kelly.
Cort: Wonderful article. Maybe I will see a cure before I leave the planet! I am 86 and have had ME/CFS for 35 years, now homebound and not liking it!
Love to all.
Diane, no, it’s not been fun. Thirty six years for me. Love to you, Javen
So from the mid-1980s for Diane and Javen – and me. Perhaps we caught the same cold back then.
Keep the faith! I am hopeful that successful anti-viral treatments will be forth coming! We have all waited/suffered too long.
Fingers crossed perhaps a “cocktail” Treatment (meaning a combination of anti-virals) will get us back to some semblance of living.
Me, too, Javen.
Valganciclovir is more effective than salt water for EBV.
Congress. What a mess. But you are spot on.
I may be off track here but worth mentioning while we’re on the subject of colds.
I wonder if those of us with ME/CFS who suddenly improve to near full energy during the entire period of a head cold, only to relapse back to our prior bad health a day or two after it’s cleared, have a persistent similar coronavirus lurking in us (like Covid does) that the immune system starts incorrectly targeting via ‘Original Antigenic Sin’ during a head cold infection? As may shut down the persistent viral activity for several days.
OR has the immune system made a past error (molecular mimicry) that targets an antigen on a protein for our bodies that is needed for an essential autonomic bodily function? So during the head cold period the the immune system is distracted enough that it mostly focuses on the newly arrived cold virus instead of autoimmune activity. hence the sudden improvement of energy and other ME/CFS symptoms.
I have faith ME/CFS is reversible because I’ve experienced full recovery during the 5 to 7 day period of a cold. The cold is horrible but having near full energy return, although be it temporary, is amazing!
It doesn’t happen with all colds either, which could be because different colds are from different viral families, so the immune response may have a different response or target.
Have any researchers looked into this?
And has anyone with Long Covid experienced the same phenomenon when catching a common cold?
Interesting hypothesis! I would guess that the original antibodies may be triggered towards the culprit virus during a cold.
Oddly enough, I haven’t caught a single cold since coming down with Long Covid, despite being exposed multiple times
Same. Absolutely no colds at all for me. And I have 2 kids in daycare!
I experience this too but again not with all illnesses, just some and I had it with the 1st P vac too. Its ironic isn’t it, to have more energy when ill and the foggy head clears too. I have M.E but Ive seen a few with long covid mention this happening to them on twitter. Seems reversible however the pain in my legs from fibro doesn’t go away.
I have noticed the same thing with me! Not every cold but with some of them I feel the ME/CFS go away until the cold is over. My illness started with a mild cold and I think these theories are onto something.
Very interesting, Brendan. I don’t think anyone has looked into this but I know it happens sometimes in ME/CFS. I’ve experienced reduced pain and increased mental clarity at times with a cold.
I have ME/CFS and always experience temporary improved symptoms immediately after my cold clears.
Also, what I think is really interesting is that after I got the Pfizer vaccine I was temporarily cured. It IS like my immune system got distracted from the shot. Sadly, after my body adjusted I was more sick than my baseline and remain that way. Hard to believe no one has researched this.
This is exactly what happens to kids with PANDAS and strep throat infections. Stanford is studying it.
Here’s something worth noting, though not from the actual common cold virus…a friend of mine who already had ME/CFS became ill with the chicken pox (a herpes virus) AND then recovered from ME/CFS! Though not a 100% recovery, he definitely felt a whole lot better, 80-90% improved! Can anyone explain that?
I too am a longtime sufferer-29 years. Funny I never seem to catch colds, though sometimes the flu, but rarely.
This reminds me of a peculiar thing long before I caught ME. Ihad a very stressful autumn and got shingles, reactivation of chicken pox as a result. I was not severely hit but it is quite prolonged compared to a common cold. So it persisted that autumn until I caught influenca then the shingles disappeared!
I guess, by the way, that it is quite common that when stressed you catch several kinds of infections, and also that it can induce autoimmune reactions? Maybe it is several processes that are going on at the same time, and that is one of the reasons that it is so hard to find an unifying hypothetis?
One or several underlying things, that get triggered by a multiple of things alone or together? Sometimes when I read about causes in this “micro perspective” I do loose the entire picture.
It is the same with many diseases, like the reumatological ones, we do not know why someone got it? We know that it is autoimmune, but what triggered it? And why? I wonder, there must be alot of reasearch in other diseases that can help ME reasearchers? Our bodies only have that many ways to react?
I will have had ME for 56 years at the end of this month. Whenever I’ve had a cold, there has been a marked lessening of my symptoms, to the extent that if a cold is doing the rounds, then I go out of my way to catch it. Many other people with ME that I know are also aware of this, yet there has been so little research into it.
This thread is very interesting—had to chime in after reading so many of those here that have caught a virus and had improvement in their ME symptoms.
I was diagnosed with ME/CFS (d/t EBV) in 2003. I was housebound. By 2011 I had recovered enough (kind’ve) to go back to work—had to nap during all breaks—I was still very exhausted all the time—lost a lot of friends. But I n Oct 2013 I caught a cold. I remember this because it’s the last time I’ve ever been sick to this date. But after I recovered from my cold virus, I had completely recovered from my ME/CFS. So much so I was able to ski again and I got into mountain biking. Eventually I was riding 50 to 100 miles, 3-4 days a week. Plus I was kayaking, going to concerts, etc. my energy had no bounds. Sept 2017 it all ended. Now I struggle to walk 1 mile and need a week to recover. But I still have not caught another cold or a flu virus since that Oct back in 2013. And I have been around plenty of sick grand kiddos during cold and flu season. I thought there had to be something to this…?
Thanks Cort for all that you do!
I have noticed the same thing with me! Not every cold but with some of them I feel the ME/CFS go away until the cold is over. My illness started with a mild cold and I think these theories are onto something.
Brendan, for me it is the day or so before I actually start getting the symptoms of the cold – I have SO much more energy than usual that I inevitably do too much and crash myself. This is the one and only single thing that has ever given me more energy in 19 years of this life destroying illness. A common cold. So weird.
This is what happens to me, it’s always the day before I get sick. It’s gotten to the point that when I suddenly feel much more normal I know a cold is coming … I tell my family I’m about to get sick and they think I’m nuts.
I was first diagnosed with ME/cfs in China in 1985. During the interviewing 37 years there have been good years and very bad years. I do not recall a bad head cold in all that time until COVID FOUND me. My case was relatively mild with head cold sinus symptoms. It cleared in a week and I was feeling good with good energy. The first outing a calm easy canoe paddle I began coughing. The next day was an uphill hike 4 miles, I coughed the whole way. The 3rd day was a bus ride in misery. Days 4-7 were in bed misery with constant cough, searing sore throat, a jump in temp from 95.5 to 101. Jump in resting heart rate from mid 50s to 90s. Clearly to me this seems like COVID meets PEM.
Great article Cort!
Sorry if I missed it but do you have a link to the paper itself? It would be great to read.
Here you go – https://www.medrxiv.org/content/10.1101/2022.09.25.22280335v1.full – Impact of cross-coronavirus immunity in post-acute sequelae of COVID-19
Any way you could post the article link?
Just got it in there – “Impact of cross-coronavirus immunity in post-acute sequelae of COVID-19” – https://www.medrxiv.org/content/10.1101/2022.09.25.22280335v1.full
To me, this theory is consistent with the wide-spread observation of high IgG and IgM titers on many many different viruses. Are there any serious ME/CFS clinicians or researchers who do not think our immune systems are confused? Various antivirals have been given to ME/CFS patients with mixed results. Maybe the better results are from when the antiviral given treated a triggering virus.
One of the more interesting things that I think will come out regarding long COVID and COVID-19 is the development of better antivirals. I heard from an ME/CFS researcher that there’s increased interest in the development of better EBV antivirals. She told me the current antivirals aren’t really targeted at EBV.
Research into better antivirals for EBV. That would be fantastic!
How does this gibe with the fact that even very mild cases end up with long COVID? It seems to me that, if the immune system mistakes COVID for something else, you’d end up with more severe case.
Prolonged inflammation from misfiring immune system triggering long COVID is still an interesting idea. Prolonged inflammation is what’s common between mono, overtraining and chronic stress, three of the most common pathway to ME.
Good question…That whole issue of asymptomatic COVID-19 cases turning into long COVID is fascinating. It flies in the face of a lot. Untangling that is going to be interesting.
Interesting. Yet, they fully expect that every child’s immune system will simultaneously produce specific antibodies to 4 or 5 different pathogens when they give them those combo vaccines.
I was glad to see they figured out the presence of CMV was a false lead. I myself never had CMV and yet I developed, CRPS, FM, neuropathy and dysautonomia following a common cold or flu in 1994. They didn’t mention this either but, I believe there must be a genetic predisposition for long covid and similar conditions. Early childhood trauma can also damage the nervous system and cause it to be susceptible to further damage that can lead to an autoimmune response such as this. Not much is known about autoantibody attacks on the vagus nerve and the autonomic nervous system but I think researchers would do well to take a closer look at that. My personal quest has been to discover nutritional ways to bring myself back to health. Week-long extended fasts markedly improve many of my symptoms especially neuropathy, pain, sleep disorder and mast cell activation. I also have a lot more energy and clear thinking during a fast. So, I think it’s possible to reduce some symptoms through autophagy. I’m beginning a ketogenic, lectin-free diet for the next 6 months to see if this can reduce inflammation enough to push everything into remission once and for all. The body really wants to heal itself if we give it the opportunity.
Thanks for the gist. Cort, your on a roll! 🙂
I am not aware of any antivirals that cure any virus, particularly herpes family viruses (EBV, CMV, herpes zoster, HHV6 A & B, HHV7, HHV1 & 2, etc.) These are the viruses most often implicated in ME/CFS.
Antivirals also have significant and serious side effects. I broke three bones because of falls from dizziness caused by Valtrex.
Finding ways to boost immune function seems to hold more promise in treating ME/CFS. None of the viruses above reactivate in a robust immune system.
Seems to me that the weaker arm of the immune system needs to be brought back to where it can do some good while the overly strong arm of the immune system needs to be brought back to a level where it can do its job efficiently without getting overly carried away. A modulated immune system in the proper balance basically.
Betty, I agree. I am skeptical about the utility of antivirals for ME/CFS.
It takes years to bring new medications to market safely. Ideally, an existing drug would be found, but that is unlikely to happen unless patients fund the research.
Additionally, how would an antiviral stop the immune system from creating an erroneous response? Would we have to call our doctor every time we felt a cold coming on or would we have to stay on an antiviral indefinitely? Perhaps I am missing something.
If some people are prone to chronic viral infection and others are not – what are they missing? Or, what puts a person at risk? I think this is what would be most helpful to sort out (but probably not most lucrative).
From what I understand Ron Davis at the OMF is trying to use currently existing medications off label to see if he can find something that will hit when it comes to ME.
It will be interesting to see what Team Proal and the Simmaron Institute as well as the researchers in Germany find out. I am interested in the ATG-14, the microclots and the sludge that is not being cleaned out by autophagy. I wonder what can be done to address that. I’m betting a cocktail will be what is needed.
There is this idea that molecular mimicry is responsible for people experiencing food sensitivities; the body doesn’t correctly recognize molecular parts of certain ‘good’ foods and instead thinks they resemble a food that the body has decided is harmful. (Poor explanation, but it will have to do…)
Now when Brendan Rob mentioned the mimicry, it got me wondering if people with ME/CFS, like your article says, are actually reacting to some other (possibly more benign) virus, and the body has lost the ability to distinguish between infections–and maybe they have trouble with FOOD SENSITIVITIES too. It’s like the body can no longer discriminate correctly so the immune system goes after anything that looks remotely similar–so that system is always ‘on’ (inflammation) looking for the wrong thing.
As many people have mentioned, I am also one who hardly ever gets any kind of cold or flu–but have had ME/CFS for about 35 years.
Nancy, same here. I haven’t had a cold or flu for at least 10 years (beyond that I can’t remember). I live in a senior independent retirement apartment that also has assisted living, enhanced assisted living, and memory care. There are colds going around all of the time.
I got covid in January of this year. It was mild in the sense that I didn’t need hospitalization, but fever and misery. I had all three vaccine shots. Although I had some lingering feelings of shortness of breath, I didn’t have serious enough issues until I got the second booster in late April. From there I got significantly worse, getting a confirmation that it is long-covid after many tests, etc. When i got my flu shot recently, I had a huge flare-up, with exhaustion, joint pain, diarrhea….that took about 5 days to get back to base-line. So now I am wondering if I should get the latest covid booster, given that the 2nd likely triggered my condition. It feels like being between a rock and a hard place. Would love any input.
This “original antegenic sin” and the Hoskins Effect makes me wonder if that is why one arm of the immune system is weaker while the other arm of the immune system is stronger. I also wonder if this is why the NK cell count is lower in people with ME. If a common cold virus primed the immune system to unleash OC43 for the COVID-19, what can be done to convince the immune system to address the COVID-19 itself with an effective response. What kind of medication could put the immune system on track. I would be willing to bet that there is a viral persistence in Long COVID and that viral persistence is in ME. There could even be bacterial and other pathogens involved in different forms of ME. I wonder how OC43, ATG-14, microclots, and broken down mitochondria–the “sludge” that is not cleaned up–are connected.
“This results in the immune system being “trapped” and unable to mount an optimal response when confronted with a new virus.
It’s been known to occur with influenza (…)”
<– Where can I read about this? How to test it and how to fix it? I got from mild to severe precisely with influenza almost a year ago. So I am dying to know!!
This is nothing new. ME/CFS is a post-viral fatigue syndrome. So, in theory, it can develop after any viral infection. But it can also develop after other infections, such as a bacterial or fungal infection. Severe or prolonged stress can also trigger ME/CFS. What do these triggers have in common?
The immune system is undermined, which can be caused by an infection, but also because the stress system is on too often or for too long.
Personally, I think ME/CFS is a smoldering chronic infection that resides in the nervous system with all its consequences.
Thanks Cort, this would obviously also be an interesting connection to look at in post vacc Long Covid: possibly, these unfortunate patients also have an OC43 imprint?
Also, this paradigm may be of interest to explain vulnerability to ME/CFS in general. Why do some pts develop ME/CFS after a bout of infuenza and others don´t? One factor may be that the ones who do may overreact to the current strain because of a “fitting” imprinting exposure.
you know why we are so difficult to get money fom HIN for CFS/ME and our reqeusts for more funding from NIH, always been rejected, who as powerful as him, Bill behind all this! around 20years ago he was between rock and hard place for monoply by accusation by US congress, then become insane, stared this horrible thing wirh a mercy persona. hope more people wake up before too late
If patients with long COVID (or those of us with ME/CFS/FM) are carrying uncleared viruses, are they (we) able to spread those viruses?