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

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:

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.

 

Oh here's something:

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

See last two sections here:


Here are the outcomes used in the above plot:

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.

 

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)

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

And it lists more studies that have been done:

 

Nice, thanks. I've made threads for those.

• Impact of COVID-19 and effects of booster vaccination with BNT162b2 on six-month long COVID symptoms [...], 2023, Fusco et al

This one seems to just be for preventing long COVID with boosters.

• The effect of pre-COVID and post-COVID vaccination on long COVID: a systematic review and meta-analysis, 2024, Chow et al

 

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).

 

https://theconversation.com/long-co...-infection-heres-what-the-science-says-244635

 

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.

 

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.

 

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.

 

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:

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:

Another group presented unpublished data on high prevalence of antisense at median 16 months after infection:

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.