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 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

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

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