Repurposing an old tuberculosis vaccine against diabetes

By Madeline Eaton

Type 1 diabetes is a serious autoimmune condition in which patient’s own immune system destroys insulin production beta cells in their pancreas, meaning the patient is unable to control blood sugar levels, over time leading to nerve and blood vessel damage vision problems, and more.1 In the UK, 400,000 people are diagnosed with type 1 diabetes and the number of new diagnoses is rising each year.2 The current treatment for type 1 diabetes is injecting insulin aimed at controlling blood sugar levels, however in some countries this treatment this can be expensive or cumbersome. In 2018, Alex Smith died in Michigan at the age of 26 from diabetic ketoacidosis, a serious complication of type 1 diabetes. He had started rationing his insulin because it was $1,300 a month and he couldn’t afford either health insurance or his monthly insulin treatment.3 This demonstrates the need for new treatments for type 1 diabetes that are potentially preventative or do not require constant monitoring and injections by the patient, but most importantly are not cheap and easy to produce. Surprisingly, an old tuberculosis vaccine may hold promise in this area.

BCG (Bacillus Calmette-Guerin) is a shot originally designed against TB implemented in the 1920s. It contains a weakened strain of M. Bovis, which is a relative of M. tuberculosis (the infectious agent causing TB).4 However, researchers noticed a surprising drop in infant deaths in some areas after its introduction. Around 70 years after, this effect was studied more closely and Peter Aaby et al in West Africa reported that the BCG vaccine had a non-specific beneficial effect causing a 45% reduction in mortality.5 On further research, it seems that while the vaccine boosts immunity (against TB for example), it can also calm the immune system and/or inflammation.4 This property is what makes it so promising for treating autoimmune diseases like type 1 diabetes. A report in Cell showed one dose of the BCG vaccine reduced the risk of respiratory infection compared to a placebo vaccine in older patients.6 Additionally, a team at Harvard Medical School working on using the BCG vaccine for diabetes treatment showed in 2018 that the vaccine improves blood glucose control in type 1 diabetes patients taking insulin.7 There is hope that early intervention with this treatment may be able to help reset the immune system and fix blood sugar levels.

But why exactly does this vaccine designed for tuberculosis, a bacterial pathogen, work against an autoimmune disease like diabetes? The answer lies in T cells. In type 1 diabetic patients, the insulin producing beta cells in pancreatic islets are destroyed by T cells, and the body is no longer able to produce insulin to regulate blood sugar.2 Since the 1990s, it has been known that some immune cells produce a molecule called TNF alpha (tumor necrosis factor) that help kill these autoreactive T cells destroying insulin producing cells.4 TNF alpha helps produce T regulatory cells, which prevent damage during an immune response, and are defective in type 1 diabetes patients.4 However, administering TNF alpha directly isn’t a viable option, so researchers have been looking for something else to administer that can trigger its production, and they eventually landed on BCG.4 A team at the Massachusetts General Hospital showed that BCG administration helps restore T-reg cell expression. After conducting a clinical trial in 143 diabetes patients, patients who received two doses of BCG showed T-reg gene expression comparable to non-diabetic patients after 3 years of treatment.8 They purported that BCG fixed the hypermethylation of the Foxp3 T-reg gene which is found in type 1 diabetic patients.8 In addition to resetting the immune response via modulation of gene expression, their findings showed that BCG resets the body’s metabolism to increase glucose consumption and eliminate the high sugar levels found in type 1 diabetes patients. White blood cells from diabetes patients consume less glucose than those in healthy patients, but BCG corrected this when exposed to these white blood cells.4 BCG also increased expression of genes increasing glucose breakdown by inducing a shift to aerobic glycolysis via activation of Myc, a key transcription factor in metabolic pathways.9 This further helps regulate the high glucose levels found in diabetics.

This work has provided great hope for many suffering from type 1 diabetes. The possibility of a cheap, cost-effective, and clinically tested treatment that could improve the lives of diabetic patients better than expensive insulin shots excites many in the field. The fact that BCG has its positive effects even on patients who have lived with diabetes for many years is also promising. Additionally, due to BCG’s anti-inflammatory effects it is being looked into for treatment of other autoimmune diseases like multiple sclerosis. A study of 73 patients who had previously experienced MS symptoms but not developed the condition itself by Marco Salvetti & Giovanni Ristori of the Sapienza University of Rome found that BCG vaccination reduced chances of new brain damage versus placebo patients. Furthermore, only 42% of those who had received the vaccine were diagnosed with MS compared to 70% of the placebos.10 However, not everyone is convinced by the results. There has been criticism of the studies on BCG administered to diabetes patients, specifically about the small sample size and the fact that all patients continued taking insulin during the study.4

With all these elements in mind, it is evident that BCG vaccination carries several beneficial effects not only against tuberculosis but more non-specifically. It holds great promise as a treatment of different autoimmune diseases and other conditions, but more rigorous data is needed to confirm the vaccine’s effect. However, it represents a promising hope in the field of type 1 diabetes research, one that could change the lives of 400,000 people in the UK alone.

References:

  1. Symptoms & Causes of Diabetes [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases. 2016 [cited 20 February 2022]. Available from: https://www.niddk.nih.gov/health-information/diabetes/overview/symptoms-

causes#:~:text=or%20heart%20trouble.-

,What%20causes%20type%201%20diabetes%3F,that%20might%20trigger%20the%20diseas e.

figures/

  • Dodds I. How a Minnesota man who died due to insulin prices could change US healthcare forever [Internet]. The Independent. 2021 [cited 20 February 2022]. Available from:

https://www.independent.co.uk/news/world/americas/us-politics/insuluin-prices-diabetes- alec-smith-b1972475.html

  • Keener A. A repurposed TB vaccine shows early promise against diseases like diabetes and MS [Internet]. Science News. 2021 [cited 20 February 2022]. Available from:
  • Gonzalez-Perez M, Sanchez-Tarjuelo R, Shor B, Nistal-Villan E, Ochando J. The BCG Vaccine for COVID-19: First Verdict and Future Directions. Frontiers in Immunology [Internet]. 2021 [cited 20 February 2022];12. Available from:

https://www.frontiersin.org/articles/10.3389/fimmu.2021.632478/full

  • Giamarellos-Bourboulis E, Tsilika M, Moorlag S, Antonakos N, Kotsaki A, Domínguez-Andrés J et al. Activate: Randomized Clinical Trial of BCG Vaccination against Infection in the Elderly.

Cell [Internet]. 2020 [cited 20 February 2022];183(2):315-323.e9. Available from: https://www.cell.com/cell/fulltext/S0092-8674(20)31139- 9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS009286742 0311399%3Fshowall%3Dtrue

  • KUHTREIBER W, TRAN L, NGUYEN B, JANES S, DEFUSCO A, FAUSTMAN D. Long-Term Reduction in Hyperglycemia in Advanced Type 1 Diabetes—The Value of Induced Aerobic

Glycolysis by BCG Vaccinations. Nature [Internet]. 2018 [cited 20 February 2022];23. Available from: https://www.nature.com/articles/s41541-018-0062-8

restores-gene-expression-key-immune- cells#:~:text=The%20ability%20of%20BCG%20to,restores%20the%20key%20immune%20cell s.

  • Kuhtreiber W, Takahashi H, Keefe R. BCG Vaccinations Upregulate Myc, a Central Switch for Improved Glucose Metabolism in Diabetes. iScience [Internet]. 2020 [cited 20 February

2022];23(5). Available from: https://www.sciencedirect.com/science/article/pii/S2589004220302704

  1. Ristori G, Romano S. Effects of Bacille Calmette-Guérin after the first demyelinating event in the CNS. Neurology [Internet]. 2014 [cited 20 February 2022];82(1). Available from:

https://n.neurology.org/content/82/1/41

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