Trained immunity as a novel approach against COVID-19 with a focus on Bacillus Calmette-Guérin vaccine: mechanisms, challenges and perspectives

Abstract

COVID-19 is a severe health problem in many countries and has altered day-to-day life in the whole world. This infection is caused by the SARS-CoV-2 virus, and depending on age, sex and health status of the patient, it can present with variety of clinical symptoms such as mild infection, a very severe form or even asymptomatic course of the disease. Similarly to other viruses, innate immune response plays a vital role in protection against COVID-19. However, dysregulation of innate immunity could have a significant influence on the severity of the disease. Despite various efforts, there is no effective vaccine against the disease so far. Recent data have demonstrated that the Bacillus Calmette-Guérin (BCG) vaccine could reduce disease severity and the burden of several infectious diseases in addition to targeting its primary focus tuberculosis. There is growing evidence for the concept of beneficial non-specific boosting of immune responses by BCG or other microbial compounds termed trained immunity, which may protect against COVID-19. In this manuscript, we review data on how the development of innate immune memory due to microbial compounds specifically BCG can result in protection against SARS-CoV-2 infection. We also discuss possible mechanisms, challenges and perspectives of using innate immunity as an approach to reduce COVID-19 severity.

Keywords: BCG; COVID‐19; trained immunity; vaccine.

Figure 1

The molecular basis of trained immunity. The induction of trained immunity by microbial components (β‐glucan) and human vaccines (BCG) involves a complex network of metabolic and epigenetic rewiring of haematopoietic stem and progenitor cells as well as circulating peripheral myeloid cells. (a) The process is initiated by the recognition of the stimulus by its associated pattern recognition receptors (PRRs). (b) Subsequently, the activation of different metabolic routes in the innate immune cells plays a central role by providing enzymes that are crucial co‐factors or inhibitors of epigenetic regulators (histone modifications). (c) Epigenetic rewiring leads to increased gene transcription of mediators that are important for an enhanced immune response against pathogens. (d) The induction of such mechanisms results in increased cytokine production, PRRs expression as well as costimulatory and activation molecules upon re‐stimulation. Altogether, these changes contribute to the non‐specific protection against viral, bacterial and parasitic infections.

Figure 2

Possible impact of BCG vaccination on improvement of host defence against SARS‐CoV‐2. People with a weak immune systems or pre‐existing medical conditions are at higher risk of developing sever symptoms characterised by systemic inflammation, multiple organ dysfunction and massive viral load (a). In contrast, patients with BCG vaccination history develop a strong local immune response against the virus which results in a mild inflammation, less severe symptoms and an effective virus elimination (b). BCG vaccination of people with weakened/ immunocompromised immune system may develop severe adverse reactions. If these patients experience COVID‐19, they may develop a more severe form of the disease (c).

Figure 3

BCG vaccination improves immune response in COVID‐19 patients. Based on current knowledge, we assume that COVID‐19 patients often suffer from super inflammation and high virus load in their lung (a, b) and prior BCG immunisation can reduce systemic inflammation and virus load in the lung (a–c).