Opinion Towards a cure for long COVID: the strengthening case for persistently replicating SARS-CoV-2 as a driver of [PASC], 2024, Scoullar, Crabb+

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Towards a cure for long COVID: the strengthening case for persistently replicating SARS-CoV-2 as a driver of post-acute sequelae of COVID-19
Michelle JL Scoullar; Gabriela Khoury; Suman S Majumdar; Emma Tippett; Brendan S Crabb

New insights into post-acute sequelae of coronavirus disease 2019 (PASC) or long COVID are emerging at great speed. Proposed mechanisms driving long COVID include the overlapping pathologies of immune and inflammatory dysregulation, microbiota dysbiosis, autoimmunity, endothelial dysfunction, abnormal neurological signalling, reactivation of endogenous herpesviruses, and persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

In this commentary, we describe some of these advances that indicate that long COVID may be driven by “long infection” and that persistent replicating SARS-CoV-2 may be the potentially mechanistically unifying driver for long COVID.

Link | PDF (Medical Journal of Australia) [Open Access]
 
My brother had what I think is a good idea when I sent him this study: could the immune response to a persistent virus be "supercharged" with vaccine boosters? Maybe by giving them at more frequent or larger doses than are typically used for prevention?

It seems so simple, but also, as far as I know it hasn't been tested.

One possible example of how this could work: a couple groups at the recent PolyBio conference found lower neutralizing antibody responses to the virus in long COVID. This is potentially a reason the virus can persist.

These quotes are about two different labs:
Those with long COVID had significantly lower neutralizing antibody activity against SARS-CoV-2, but no differences in total SARS-CoV-2 antibodies or antibody-dependent NK cell activation/cytotoxicity. Potentially enables viral persistence.

They looked at the ability of antibodies to neutralize (neutralizing antibodies attach to the virus to interfere with its function) SARS-CoV-2 in vitro (outside the body), and found a reduction of these types of antibodies at both time points compared to controls.

If we give them a large/frequent enough vaccine dose with inactivated virus, maybe the body will respond with larger numbers of these antibodies, among other immune responses, which could be what it takes to control the virus.

One source of data that might exist to support this is a study that looks at long COVID outcomes (remissions, length of illness, severity) as it relates to number of boosters received after the long COVID began. If anyone knows of a study that has this data, I'd love to see it.
 
One source of data that might exist to support this is a study that looks at long COVID outcomes (remissions, length of illness, severity) as it relates to number of boosters received after the long COVID began.

Oh here's something:

Effect of covid-19 vaccination on long covid: systematic review 2023 Byambasuren, Glasziou et al
Five studies reported on vaccination after infection, with odds ratios of 0.38-0.91. The high heterogeneity between studies precluded any meaningful meta-analysis. The studies failed to adjust for potential confounders, such as other protective behaviours and missing data, thus increasing the risk of bias and decreasing the certainty of evidence to low.

See last two sections here:
upload_2024-11-25_21-10-27.jpeg

Here are the outcomes used in the above plot:
outcomes.jpeg
Vaccination after infection and in those with long covid has been more controversial, but the studies we identified are reassuringly consistent in being protective.


And another observational study that showed improvements, though no control group:

Vaccination after developing long COVID: impact on clinical presentation, viral persistence and immune responses, 2023, Nayyerabadi et al.
In this prospective observational cohort study, we evaluated the number of PCC symptoms, affected organ systems and psychological well-being scores before, and after patients with PCC received COVID-19 vaccination.
COVID-19 vaccination was associated with decreases in number of PCC symptoms (pre-vaccination: 6.56 ± 3.1 vs. post-vaccination: 3.92 ± 4.02; p<0.001)


I definitely want to see more research on this. And now I'm wondering about vaccination for ME/CFS depending on what the inciting infection was, if there was one.
 
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Oh here's something:

Effect of covid-19 vaccination on long covid: systematic review 2023 Byambasuren, Glasziou et al


See last two sections here:
View attachment 24308

Here are the outcomes used in the above plot:
View attachment 24307



And another observational study that showed improvements, though no control group:

Vaccination after developing long COVID: impact on clinical presentation, viral persistence and immune responses, 2023, Nayyerabadi et al.




I definitely want to see more research on this. And now I'm wondering about vaccination for ME/CFS depending on what the inciting infection was, if there was one.

Just for completeness (not that it tells us much) there was also a small study without control group by Iwasaki on this subject Impact of COVID-19 vaccination on symptoms and immune phenotypes in vaccine-naïve individuals with Long COVID.
 
One source of data that might exist to support this is a study that looks at long COVID outcomes (remissions, length of illness, severity) as it relates to number of boosters received after the long COVID began.
A couple of other papers (only looked at the abstracts). Of course, with long COVID being defined so broadly, it's difficult to determine any particular relevance to LC-ME/CFS:

"The effect of pre-COVID and post-COVID vaccination on long COVID: a systematic review and meta-analysis" (J Infect, November 2024)

"Impact of COVID-19 and effects of booster vaccination with BNT162b2 on six-month long COVID symptoms, quality of life, work productivity and activity impairment during Omicron" (J Patient-Reported Outcomes, July 2023)
I definitely want to see more research on this. And now I'm wondering about vaccination for ME/CFS
There was some historic (mostly fringe) interest in the use of vaccinations as a treatment for ME/CFS; in particular I remember there was a Swedish psychiatrist, many years ago, who trialled a staph vaccine (one paper: "Immunotherapy of Fibromyalgia and Chronic Fatigue Syndrome by a Staphylococcus Toxoid Vaccine", Bulletin of the IACFS/ME 2009-10;17(4):168-183). If I recall correctly trials in this area were not particularly robust.
 
Just for completeness (not that it tells us much) there was also a small study without control group by Iwasaki on this subject Impact of COVID-19 vaccination on symptoms and immune phenotypes in vaccine-naïve individuals with Long COVID.

Thanks. Not great evidence for it, but it's at least not evidence against it.

In this prospective cohort study of 16 vaccination-naïve individuals with Long COVID and significant symptoms at baseline, it was observed that most people improved or stayed the same during follow-up, but some experienced worsening.

This study lacked concurrent controls and was small, so it is challenging to make definitive statements about the effect of vaccination, particularly since many people with Long COVID have fluctuations in their symptoms.

However, the fact that symptom burden decreased on average and more people improved than worsened suggests that the vaccination was not overtly harmful. Future studies with controls are needed to understand the effect of vaccination on Long COVID symptoms.


And it lists more studies that have been done:
Our findings are consistent with other studies and systematic reviews reporting improvement or non-significant change in self-reported health among people with Long COVID who were vaccinated for the first time.18,4345

A single-center observational study in the United Kingdom identified 44 Long COVID patients (reporting a median of 4.1 and 3.6 symptoms per patient) who had received at least one dose of a COVID-19 vaccine and interviewed at 1 month and 8 months post-vaccination with the SF-36 and Warwick and Edinburgh Mental Wellbeing scores.46 After adjustment, health status measured with these instruments at 8 months did not differ compared to Long COVID patients who were not vaccinated.

In an online cross-sectional survey study of 2,094 people in Switzerland, 35.5% of participants reported that their Long COVID symptoms improved, 28.7% reported their symptoms were stable, and 3.3% reported their symptoms worsened after vaccination.47

In a French target trial emulation study from the ComPaRe Long COVID cohort, COVID-19 vaccination was associated with a reduction in Long COVID severity and symptom burden at 120 days compared with those unvaccinated.48
 
A couple of other papers (only looked at the abstracts). Of course, with long COVID being defined so broadly, it's difficult to determine any particular relevance to LC-ME/CFS:

"The effect of pre-COVID and post-COVID vaccination on long COVID: a systematic review and meta-analysis" (J Infect, November 2024)

"Impact of COVID-19 and effects of booster vaccination with BNT162b2 on six-month long COVID symptoms, quality of life, work productivity and activity impairment during Omicron" (J Patient-Reported Outcomes, July 2023)

Nice, thanks. I've made threads for those.
This one seems to just be for preventing long COVID with boosters.
The BNT162b2 booster could have a beneficial effect in reducing the risk and burden of long COVID. Boosted participants reported fewer and less durable symptoms, which contributed to improve HRQoL and maintain WPAI levels. Limitations included self-reported data and small sample size for WPAI.

One-dose post-COVID vaccination was associated with a 15% reduced odds of long COVID (number of studies = 5, summary OR = 0.85, 95% CI = 0.73-0.98, p-value = 0.024). The OR of two-dose post-COVID vaccination against long COVID was statistically insignificant but was far away from 1 (number of studies = 3, summary OR = 0.63, 95% CI = 0.38-1.03, p-value = 0.066).
 
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There was some historic (mostly fringe) interest in the use of vaccinations as a treatment for ME/CFS; in particular I remember there was a Swedish psychiatrist, many years ago, who trialled a staph vaccine (one paper: "Immunotherapy of Fibromyalgia and Chronic Fatigue Syndrome by a Staphylococcus Toxoid Vaccine", Bulletin of the IACFS/ME 2009-10;17(4):168-183). If I recall correctly trials in this area were not particularly robust.

Thanks, I made a thread for that: Long-Term Treatment with a Staphylococcus Toxoid Vaccine in Patients with Fibromyalgia and Chronic Fatigue Syndrome, 2004, Gottfries et al

I was thinking it'd need to be a vaccine to whatever is persistent, but I suppose it might work to just give a vaccine containing some other random pathogen to ramp up a general immune response that might kick out the persistent virus (assuming there is one).
 
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Really feels like we're finally on the precipice of a huge change in understanding of and attitude toward long COVID, and hopefully related diseases, if "long infection" pans out.

'Long infection' is something we have been well aware of for at least fifty years. But it is a very organism specific thing. Nor virus persists, EBV persists, Varicella-zoster persists, but most viruses do not as far as we know. If long infection is relevant to Long Covid it probably means that Long Covid is not very relevant to ME/CFS - or at least all cases before Covid.

For EBV we know about the viral persistence but it probably has nothing to do with the post-viral fatigue commonly seen with EBV because persistence carries on long after the fatigue has gone.
 
If long infection is relevant to Long Covid it probably means that Long Covid is not very relevant to ME/CFS - or at least all cases before Covid.

Maybe - and I definitely could be wrong, I might just be seeing what I want to see - but I think there's a good chance in people with pre-COVID ME/CFS there was a first infection, the analogue virus to SARS-CoV-2. Maybe a coronavirus, enterovirus, maybe even somehow EBV. Maybe different ones.

It gets in the body and persists somewhere. Maybe the acute infection is even asymptomatic. Like in long COVID, the ME/CFS can start immediately after the virus gets in. But there's also the possibility that initially the persistence does not produce any apparent symptoms for some time, until some other trigger, be it another infection of an unrelated virus, a trauma, or whatever, allows the persisting virus to quickly replicate to levels where it now causes symptoms indefinitely, like in long COVID.

Maybe if the persisting virus happens to be EBV, the reason it does not produce symptoms in everyone is that the reservoir location is unusual in ME/CFS. So almost everyone has EBV, but maybe not everyone has it in like the brain stem or megakaryocytes or something. If it gets there it causes ME/CFS symptoms.
 
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The conversation article said:
However, formal proof that virus capable of replicating can last for years in the body remains elusive. This is because isolating the live virus from reservoirs inside the body where the virus “hides” is technically challenging.

The December 2024 study focused on antigens, not RNA:

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(24)00432-4/abstract



Persistent antigen fragments is not evidence of persistent viral infection, as follicular dendritic cells are know to capture such fragments and preserve them for years (for stimulating B-cells), this is part of the reason why we can have a sustained level of anti-pathogen IgG long after an acute infection.

The Feb 2024 found that in over 90,000 samples, they only found 54 cases where infection persisted over 56 days and there was no evidence of a difference for long COVID at 26 weeks or more post-infection.

https://www.nature.com/articles/s41586-024-07029-4

The following study found a weak odds ratio (1.23) of detection of anti-sense SARS-CoV-2 RNA predicting LongCOVID (~24 months):
https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(24)00055-7/fulltext#app-1

Put together, this suggests that persistent infection itself cannot be the cause of a majority of LongCOVID pathology.

However it is possible that prolonged infection during the initial acute infection phase itself may increase the risk of developing LongCOVID.
 
Put together, this suggests that persistent infection itself cannot be the cause of a majority of LongCOVID pathology.

I think it could be a case of it being difficult to find the reservoir. In this situation, I think not finding antisense in a given study is weak evidence of there not being any antisense anywhere. Just evidence of no antisense where they looked.


The blood transcriptomics study you linked found it in a pretty large portion of people at an average of 2 years:
For antisense RNA (indicates replication) 65% of LC positive vs 25% of controls.
Yes, controls have it too, but I don't think that's evidence it doesn't cause long COVID in some.

Although another group was unable to replicate their results:
Correspondence to the journal: "Blood transcriptomic analyses do not support SARS-CoV-2 persistence in patients with post-COVID-19 condition with chronic fatigue syndrome" (25 October 2024):


Another group presented unpublished data on high prevalence of antisense at median 16 months after infection:
In about 2/3 of people with LC, their CD41+ megakaryocytes contained spike and viral positive RNA. None of the COVID recovered participants' megakaryocytes had these viral components. Double stranded viral RNA was also found in LC megakaryocytes, but not recovered controls, indicating ongoing replication.

Found that platelets in most people with LC also had spike, positive RNA and negative RNA, indicating replication. Tested infectious ability of these platelets, and they were able to cause infection of other cells, again from about 2/3 of people with long COVID.

I'm looking forward to seeing whether the above gets peer reviewed and published.

Edit: I was reading too fast and misread the part of yours I quoted as meaning persistent infection is not involved at all. I agree there are likely other factors involved; I just think there's a good chance persisting virus is one necessary factor, at least in many people with LC.
 
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For the vaccine as treatment for LC discussion, new study didn't find much difference in numbers who improved or worsened after vaccination:

Post-COVID-19 Vaccination and Long COVID: Insights from Patient-Reported Data, 2024, Quach et al
Within the PASC Clinic patient cohort (n = 128) [...] A total of 60.2% (n = 77) of PASC Clinic patients reported no change in their PASC symptoms after vaccination, 17.2% (n = 22) reported improved symptoms, and 22.7% (n = 29) reported worsened symptoms.

In the multinational survey cohort (n = 484) [...] vaccine effects on PASC symptoms was 20.2% worsened (n = 98), 60.5% no effect (n = 293), and 19.2% improved (n = 93).

But maybe some predictors for improvement:
BMI was significant for symptom improvement (p = 0.026) in the PASC Clinic cohort, while a history of booster doses was significant for symptom improvement (p < 0.001) in the survey cohort.
 
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