Hypothesis: BCG vaccination as a treatment option for ME/CFS and Long COVID – Patient Led Re... https://patientresearchcovid19.com/hypothesis-bcg-vaccination-as-a-treatment-option-for-me-cfs-an...

HOME ABOUT US WORK NEWS & IMPACT RESOURCES DONATE TO PLRC SITE MAP

Hypothesis: BCG vaccination as a treatment option

for ME/CFS and Long COVID

Herbert Renz-Polster, MD1,2

1
ME/CFS patient
2
Research scientist at University Medicine Mannheim, Heidelberg University, Mannheim
Email: Herbert.Renz-Polster@posteo.de

Cite as: Renz-Polster, H. (2024). BCG vaccination as a treatment option for ME/CFS and
Long COVID. Patient-Generated Hypotheses Journal for Long COVID & Associated
Conditions, Vol. 2, 23-28

Abstract
The Bacillus Calmette-Guérin (BCG) vaccine has notable “trained immunity” effects. It has shown
therapeutic effects in autoimmune diseases such as type 1 diabetes (T1D) and multiple sclerosis
(MS). The BCG vaccine is the most commonly used vaccine worldwide. It may be a treatment option
for Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Hypothesis
COVID-19, like many viral infections, can lead to myalgic encephalomyelitis/chronic fatigue
syndrome (ME/CFS).1 Although many biological abnormalities are described for ME/CFS, it is still
unknown what ultimately drives the disease process. There is evidence that viral reactivation or its
immunological consequences may play a central role.2

During viral reactivation, some of the viruses that all humans harbor within their bodies leave their
latent (dormant) stage and begin to replicate. One of the viruses frequently implicated here is
Epstein-Barr virus (EBV), a member of the family of the human herpesviruses.3–5 In this respect, ME/
CFS shows similarities to other immune-related disorders that have altered immune responses to
EBV. These include systemic lupus erythematosus (SLE), Sjögren’s syndrome, and multiple sclerosis
(MS).6,7 It has proven difficult to stop viral reactivation on a durable basis with classical antiviral
medications.8

Immunomodulatory effects of the BCG vaccine

The BCG vaccine, used since 1921 to prevent tuberculosis, has several non-specific effects which all
relate to its ability to modulate immune functions. These include anti-cancer effects9 and preventive
effects against infectious diseases such as respiratory syncytial virus, human papillomavirus, herpes Privacy - Terms

1 de 5 10/07/2024, 21:20
Hypothesis: BCG vaccination as a treatment option for ME/CFS and Long COVID – Patient Led Re... https://patientresearchcovid19.com/hypothesis-bcg-vaccination-as-a-treatment-option-for-me-cfs-an...

simplex virus,10 and malaria.11

The BCG vaccine also has disease-modifying effects in a range of autoimmune diseases. For
instance, in humans with early-onset type 1 diabetes (T1D), repeated BCG vaccinations (three shots
within 2 years) were shown to induce long-term clinical remission in a double-blind, randomized
controlled trial.12,13 In early stages of MS, a single dose of BCG vaccine was shown to prevent
progression to clinically definite disease when given after the first demyelinating event.14 BCG
vaccination was also shown to have preventive immune effects, including increasing resistance
against childhood leukemia,15 atopic dermatitis,16 juvenile T1D,17 and, in patients with T1D, against
COVID-19.18

Hypothesis

From these clinical observations, it appears plausible that BCG vaccination could also have disease-
modifying effects in ME/CFS and/or in the ME/CFS subtype of Long COVID. It is especially intriguing
that BCG vaccination was shown to be therapeutically effective in other disorders where an aberrant
immune response against reactivated EBV seems to play a central role, such as MS.14

Also notable are the documented antiviral effects of BCG vaccination on human herpesviruses.
These effects suggest that BCG vaccination may be able to prevent reactivation of latent viruses,
including human herpesviruses such as varicella zoster virus, cytomegalovirus, or EBV.10 There is a
considerable body of evidence both from animal research and from human trials that BCG
vaccination may be effective against reactivations of human herpesvirus.19 This has recently been
confirmed in a subgroup analysis from a randomized controlled trial where BCG vaccination was
tested for its ability to prevent COVID.20 However, in the latter trial, benefits were restricted to
males.

It may also be worth considering that a different vaccine—a staphylococcal vaccine no longer on
the market—is among the few interventions that have been shown to be effective against ME/CFS
in the past.21,22

Immune system benefits for patients with ME/CFS and/or Long

COVID
The biological effects observed after BCG vaccination may also explain why the vaccine could be
effective in ME/CFS and Long COVID. For one, BCG vaccination was shown to affect regulatory
immune cells involved in the dampening and balancing of systemic inflammation.23,24 This effect is
thought to be based on the expansion of CD4+ T cells (Tregs). Indeed, BCG vaccination was
associated with gradual demethylation (activation) of signature genes expressed in highly potent
Tregs, including Foxp3, TNFRSF18, CD25, and IL2.25

These changes occur on the epigenetic/transcriptional level and apparently involve bone marrow
stem cells.26 That change process may explain the long latency between BCG vaccination and
clinical effects in the T1D and MS trials.

The biological effects of BCG administration seem to also include metabolic changes in immune
cells, with a shift of glucose metabolism from overactive oxidative phosphorylation toward
accelerated aerobic glycolysis. This shift may explain the BCG vaccine’s effect on blood glucose
levels in the T1D trials27 and its possible benefits in autoimmune and nervous system diseases.28
This metabolic reprogramming may be of benefit in ME/CFS, where CD4+ and CD8+ T cells were
found to have reduced glycolysis at rest (while CD8+ T cells also had reduced glycolysis following
activation).29

2 de 5 10/07/2024, 21:20
Hypothesis: BCG vaccination as a treatment option for ME/CFS and Long COVID – Patient Led Re... https://patientresearchcovid19.com/hypothesis-bcg-vaccination-as-a-treatment-option-for-me-cfs-an...

BCG vaccination was also shown to induce tumor necrosis factor alpha (TNFα) with subsequent
reduction of cytotoxic (including autoreactive) T cells.30 This could explain the effects of BCG
vaccination in MS, with its pathogenetic background of autoreactivity (autoimmunity). A certain
background of autoreactivity has also been found in ME/CFS and Long COVID.31, 32,33

BCG vaccinations as a trained immunity intervention

On a broader and more principal level, the effect of BCG might be in accordance with the “old
friends hypothesis.”34 This hypothesis tries to explain why allergic and autoimmune diseases—such
as T1D, MS, and ME/CFS—are on the rise in modern environments.

According to the “old friends hypothesis,” diverse microbes play a key role in the immune system’s
development. Constant exposure to those microbes, found both in the environment and in the
human body, can strengthen certain immune responses. Without exposure to those microbes, the
immune system fails to develop properly, increasing the risk of autoimmune disease. The set of
microbes living within the human body—the human endogenous microbiome—has included
mycobacteria since the times of the Neanderthals. These mycobacteria may have helped to keep
our endogenous microbiome in a good balance—including the many species of herpesviruses,
which are also part of this internal microbial orchestra, and which were shown to confer health
benefits if kept in a controlled (latent) stage.35 It has long been known, for instance, that
tuberculosis itself protects from both T1D and MS.36

From these considerations, it may be plausible to mimic these “old friends” with interventions now
widely discussed as “trained immunity” interventions.37,38 Here, BCG vaccinations may be the most
powerful option.39, 40, 41

How to test the hypothesis

A feasible way to gather evidence on the effectiveness of BCG vaccination would be a large cohort
study with random selection of Long COVID or ME/CFS patients to receive the BCG vaccine—which
would be much easier and cheaper than a randomized controlled trial (RCT). Also, double-blind
RCTs may be difficult in this context given the fact that BCG vaccine causes a typical skin reaction at
the injection site. Faustman Laboratory at Massachusetts General Hospital has performed rigorous
BCG vaccine studies, and their expertise should be tapped in any study plans with BCG
vaccination.12,18

References
1. Komaroff, A. L. & Lipkin, W. I. ME/CFS and Long COVID share similar symptoms and biological abnormalities: road map to the
literature. Front. Med. 10, 1187163 (2023).

2. Davis, H. E., McCorkell, L., Vogel, J. M. & Topol, E. J. Long COVID: major findings, mechanisms and recommendations. Nat. Rev.
Microbiol. 21, 133–146 (2023).

3. Ariza, M. E. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back! Biomolecules 11, 185
(2021).

4. Loebel, M. et al. Deficient EBV-Specific B- and T-Cell Response in Patients with Chronic Fatigue Syndrome. PLOS ONE 9, e85387
(2014).

5. Ruiz-Pablos, M., Paiva, B. & Zabaleta, A. Epstein–Barr virus-acquired immunodeficiency in myalgic encephalomyelitis—Is it
present in long COVID? J. Transl. Med. 21, 633 (2023).

6. Bjornevik, K., Münz, C., Cohen, J. I. & Ascherio, A. Epstein–Barr virus as a leading cause of multiple sclerosis: mechanisms and
implications. Nat. Rev. Neurol. 19, 160–171 (2023).

3 de 5 10/07/2024, 21:20
Hypothesis: BCG vaccination as a treatment option for ME/CFS and Long COVID – Patient Led Re... https://patientresearchcovid19.com/hypothesis-bcg-vaccination-as-a-treatment-option-for-me-cfs-an...

7. Jog, N. R. & James, J. A. Epstein Barr Virus and Autoimmune Responses in Systemic Lupus Erythematosus. Front. Immunol. 11,
(2021).

8. Kerr, J. R. Epstein-Barr virus (EBV) reactivation and therapeutic inhibitors. J. Clin. Pathol. 72, 651–658 (2019).

9. Redelman-Sidi, G., Glickman, M. S. & Bochner, B. H. The mechanism of action of BCG therapy for bladder cancer–a current
perspective. Nat. Rev. Urol. 11, 153–162 (2014).

10. Moorlag, S. J. C. F. M., Arts, R. J. W., van Crevel, R. & Netea, M. G. Non-specific effects of BCG vaccine on viral infections. Clin.
Microbiol. Infect. Off. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis. 25, 1473–1478 (2019).

11. Walk, J. et al. Outcomes of controlled human malaria infection after BCG vaccination. Nat. Commun. 10, 874 (2019).

12. Karaci, M. Chapter 4 – The Protective Effect of the BCG Vaccine on the Development of Type 1 Diabetes in Humans. in The Value
of BCG and TNF in Autoimmunity (ed. Faustman, D. L.) 52–62 (Academic Press, 2014). doi:10.1016/B978-0-12-799964-7.00004-1.

13. Kühtreiber, W. M. et al. Long-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic
glycolysis with BCG vaccinations. NPJ Vaccines 3, 23 (2018).

14. Ristori, G. et al. Effects of Bacille Calmette-Guerin after the first demyelinating event in the CNS. Neurology 82, 41–48 (2014).

15. Morra, M. E. et al. Early vaccination protects against childhood leukemia: A systematic review and meta-analysis. Sci. Rep. 7,
15986 (2017).

16. Thøstesen, L. M. et al. Neonatal BCG vaccination and atopic dermatitis before 13 months of age: A randomized clinical trial.
Allergy 73, 498–504 (2018).

17. Doupis, J. et al. The Role of Pediatric BCG Vaccine in Type 1 Diabetes Onset. Diabetes Ther. 12, 2971–2976 (2021).

18. Faustman, D. L. et al. Multiple BCG vaccinations for prevention of COVID-19 and other infectious diseases in Type 1 diabetes.
Cell Rep. Med. 0, (2022).

19. Pittet, L. F., & Curtis, N. (2021). Does bacillus Calmette-Guérin vaccine prevent herpes simplex virus recurrences? A systematic
review. Reviews in Medical Virology, 31(1), 1–9. https://doi.org/10.1002/rmv.2151.

20. Pittet, L. F., Moore, C. L., McDonald, E., Barry, S., Bonten, M., Campbell, J., Croda, J., Dalcolmo, M., Davidson, A., Douglas, M. W.,
Gardiner, K., Gwee, A., Jardim, B., Lacerda, M. V. G., Lucas, M., Lynn, D. J., Manning, L., Oliveira, R. D. de, Perrett, K. P., … Venton, T.
(2023). Bacillus Calmette-Guérin vaccination for protection against recurrent herpes labialis: A nested randomised controlled trial.
eClinicalMedicine, 64. https://doi.org/10.1016/j.eclinm.2023.102203.

21. Zachrisson, O. et al. Treatment with staphylococcus toxoid in fibromyalgia/chronic fatigue syndrome—a randomised controlled
trial. Eur. J. Pain 6, 455–466 (2002).

22. Zachrisson, O., Colque-Navarro, P., Gottfries, C. G., Regland, B. & Möllby, R. Immune Modulation with a Staphylococcal
Preparation in Fibromyalgia/Chronic Fatigue Syndrome: Relation Between Antibody Levels and Clinical Improvement. Eur. J. Clin.
Microbiol. Infect. Dis. 23, 98–105 (2004).

23. Keefe, R. C. et al. BCG therapy is associated with long-term, durable induction of Treg signature genes by epigenetic
modulation. Sci. Rep. 11, 14933 (2021).

24. Koeken, V. A. et al. BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner. J. Clin. Invest. 130,
5591–5602 (2020).

25. Singhania, A. et al. CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature. EBioMedicine 74, 103746 (2021).

26. Cirovic, B. et al. BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment. Cell Host
Microbe 28, 322-334.e5 (2020).

27. Dias, H. F. et al. Epigenetic changes related to glucose metabolism in type 1 diabetes after BCG vaccinations: A vital role for
KDM2B. Vaccine 40, 1540–1554 (2022).

28. Faustman, D. L. Benefits of BCG-induced metabolic switch from oxidative phosphorylation to aerobic glycolysis in autoimmune
and nervous system diseases. J. Intern. Med. 288, 641–650 (2020).

29. Mandarano, A. H. et al. Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and
cytokine associations. J. Clin. Invest. 130, 1491–1505 (2020).

30. Ban, L. et al. Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism. Proc. Natl. Acad. Sci.
U. S. A. 105, 13644–13649 (2008).

31. Wirth, K. & Scheibenbogen, C. A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue

4 de 5 10/07/2024, 21:20
Hypothesis: BCG vaccination as a treatment option for ME/CFS and Long COVID – Patient Led Re... https://patientresearchcovid19.com/hypothesis-bcg-vaccination-as-a-treatment-option-for-me-cfs-an...

Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors. Autoimmun. Rev. 19, 102527
(2020).

32. Bynke, A. et al. Autoantibodies to beta-adrenergic and muscarinic cholinergic receptors in Myalgic Encephalomyelitis (ME)
patients – A validation study in plasma and cerebrospinal fluid from two Swedish cohorts. Brain Behav. Immun. – Health 7, 100107
(2020).

33. Wallukat, G. et al. Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19
symptoms. J. Transl. Autoimmun. 4, 100100 (2021).

34. Rook, G. A. W. The old friends hypothesis: evolution, immunoregulation and essential microbial inputs. Front. Allergy 4, (2023).

35. Barton, E. S. et al. Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447, 326–329 (2007).

36. Airaghi, L. & Tedeschi, A. Negative association between occurrence of type 1 diabetes and tuberculosis incidence at population
level. Acta Diabetol. 43, 43–45 (2006).

37. Hu, Z., Lu, S.-H., Lowrie, D. B. & Fan, X.-Y. Trained immunity: A Yin-Yang balance. MedComm 3, e121 (2022).

38. Netea, M. G. et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. 20, 375–388 (2020).

39. Covián, C. et al. BCG-Induced Cross-Protection and Development of Trained Immunity: Implication for Vaccine Design. Front.
Immunol. 10, (2019).

40. Hu, S. et al. The mechanisms and cross-protection of trained innate immunity. Virol. J. 19, 210 (2022).

41. Chen, J. et al. BCG-induced trained immunity: history, mechanisms and potential applications. J. Transl. Med. 21, 106 (2023).

Contact Us

For questions, media inquiries and collaborations, email

us at: team@patientledresearch.com

Follow us on Twitter @patientled

Donate

Support our work

Copyright © 2024 Patient Led Research Collaborative

5 de 5 10/07/2024, 21:20