BCG and immunity in the context of COVID-19
Bacille Calmette-Guérin (BCG), the live-attenuated vaccine against tuberculosis (caused by Mycobacterium tuberculosis in humans), is a weakened strain of the related bacterium Mycobacterium bovis, which causes tuberculosis in cattle. The genomes of M. tuberculosis and M. bovis show 98 percent DNA sequence similarity, with several proteins being identical in their amino acid sequences.
Recently, there has been extensive debate on whether BCG could also confer protection against COVID-19. Some studies, which have not been peer-reviewed yet, suggest that countries with universal BCG vaccination may have fewer severe cases and deaths. There is a striking difference in the COVID-19 burden between Denmark ‒ which manufactures the BCG vaccine for the entire world at its Statens Serum Institut and uses it for its own population ‒ and its neighbours such as Belgium and Netherlands ‒ which share similar latitudes and climates, but do not have a universal BCG vaccination policy. Some countries have started clinical trials to test the vaccine’s effectiveness against COVID-19; the Indian Council of Medical Research is also looking into this.
In this context, this article describes how BCG has, in the past, shown efficacy in protecting against diseases other than tuberculosis, and its link to the innate immune system, which plays a frontline role in fighting infections.
BCG and other diseases
After BCG vaccination for children became widespread in the 1940s, it was observed that BCG recipients also benefited from a reduced burden of diseases other than TB, leading to dramatic reductions in childhood mortality. A study in Brazil published in 1992 found an impressive 50 percent reduction in deaths from pneumonia in children who had been given the BCG vaccine. Similar observations were made in West Africa and Burkina Faso. Many studies have reported such non-specific protective effects of BCG vaccination against a host of viral agents, including the human papilloma virus, influenza A virus, herpes simplex virus and yellow fever vaccine virus (these studies were compiled in an excellent review published in 2019).
BCG has also been used as a treatment for invasive bladder cancer since the 1980s, when researchers began to widely recognize its generalized role in stimulating the immune system. Studies have reported that the beneficial effect of BCG required a strong host immune system and that the live BCG organism had to come in contact with the tumour cells.
These protective effects of BCG were also known to be retained by killed BCG organisms, which were used as “adjuvants” – boosting agents – in a formulation referred to as Freund’s Complete Adjuvant (FCA). Immunologists routinely used FCA to boost antibody responses while immunizing rabbits and mice with various proteins for the purpose of generating antibodies. In fact, back in 1967, mice treated with FCA were shown to develop widespread resistance against the virus that causes foot and mouth disease. Interestingly, this type of generalized non-specific resistance was also seen after exposure to certain microbial components in plants and insects, which rely predominantly on innate immune defense, especially involving cells called macrophages.
BCG and innate immunity
Our immune system has two broad arms, called “innate” and “adaptive”. The innate immune system consists of cells arising from the bone marrow or spinal cord, including macrophages, monocytes, neutrophils, eosinophils and natural killer cells. These cells make up the frontline defense against all invading entities. In order to control any invasion quickly and efficiently, this system is relatively non-specific in nature. It treats an inhaled soot particle in much the same way as it would treat an inhaled bacterium or virus, somewhat like the ‘shooting from the hip’ style of the proverbial Wild West cowboy.
The “adaptive” immune system, which one might say makes up the back-end, kicks into play next. Adaptive immune cells called B and T cells specifically recognize components of the invader presented to them by the cells of the innate system, and expand in numbers to mount a strong defense against the invading organism. By definition, therefore, this specific adaptive response is delayed, while the innate immune system holds the fort, and together they bring the invader under control.
Another well-recognized and supposedly unique feature of the adaptive immune system is its “memory”. Once they specifically recognize intruders, B and T cells selectively move into discrete memory compartments and potentially remain there for life, to be recalled when the same intruder appears again. This type of “memory immunity” underpins the principle of vaccination, where the memory-adaptive immune cells are drafted when required later during one’s lifespan.
For a long time, the immunology community never credited cells of the innate immune system with having this property of memory. However, recent studies have shown that mice immunized with dead BCG are eventually able to generate elevated levels of reactive oxygen species and cause intracellular killing of fungal pathogens – functions that are part of the innate immune system, not the adaptive system. This led to the issue of innate immune memory being revisited.
It was against this backdrop that Mihai Netea, an infectious diseases specialist at Radboud University, Netherlands, and his group probed this phenomenon and termed it as “trained immunity” to distinguish it from the “memory immunity” of adaptive immune cells. Netea’s lab revealed through elegant experiments that trained immunity was mediated by changes in the chromatin – the complex inside which our DNA is packed – unrelated to the DNA sequences itself, which are referred to as epigenetic changes. They showed that human blood monocytes, from individuals vaccinated with BCG, underwent epigenetic changes that were retained for months, conferring it some sort of memory. Incidentally, Netea’s group is currently leading clinical trials in the Netherlands to test the effectiveness of BCG against COVID-19.
These observations show how BCG has the potential to offer broad-based immunity against a host of infectious agents. Therefore, the promising benefits of BCG against SARS-CoV-2, which the human immune system has never encountered before, should come as little surprise for those in the immunology community. It would be useful for all countries to adopt routine childhood BCG vaccination to benefit from its broad-based host immune stimulation in times of such pandemics.
S. Vijaya is a Professor at the Department of Microbiology and Cell Biology, Indian Institute of Science (IISc), Bengaluru. Her research focuses on human immunology, cell and molecular biology of Mycobacterium tuberculosis and flaviviral infections including Japanese encephalitis virus and dengue. She has served two terms on the World Health Organization’s TB vaccine steering committee.