In the early years of the last century, the director of a newly-established branch of the famed Institut Pasteur in the northern French city of Lille, Albert Calmette, and his colleague, Camille Guérin, set out to create a vaccine against tuberculosis. In humans, the disease is caused by the bacterium, Mycobacterium tuberculosis. In their quest for a vaccine, Calmette and Guérin worked tirelessly to weaken a related strain found in cattle, Mycobacterium bovis. The idea was that the live but thoroughly weakened microbe would, when administered to people, produce immunity against the TB-causing germ.
The vaccine strain they created, 'bacille Calmette-Guérin' (BCG), was first given to a newborn infant in July 1921. Even today, it is the only vaccine available against TB. The BCG vaccine is no longer routinely given to children in rich countries where chances of catching the disease are low. However, the vaccine is still widely used in developing countries where the disease is rampant. The World Health Organisation estimates that 100 million children receive it each year.
The vaccine provides limited protection against tuberculosis. It does not stop the disease-causing bacterium from establishing an infection, but can help prevent severe forms of TB in infants and young children. It does not, however, provide cover against the disease becoming active in adolescents and adults.
Curiously, the protective effects of the vaccine appear to go beyond tuberculosis. When, for instance, the vaccine was introduced in a northern Swedish province in 1927, a physician noticed that those who received it at birth had a death rate only about one-third of that among unvaccinated children.
Controlled trials among children and teenagers in the U.S. and U.K. during the 1940s and 1950s too found that BCG reduced non-accidental deaths from causes other than TB by 25 per cent, noted Peter Aaby and Christine Stabell Benn of the Statens Serum Institut in Denmark in a commentary published in the journal Proceedings of the National Academy of Sciences (PNAS).
Trials carried out in West Africa a few years back found that the BCG vaccine reduced deaths among low-birth-weight newborns by more than 40 per cent, mainly by preventing sepsis and respiratory infections, they pointed out.
Research carried out by a team of Dutch scientists and published recently in PNAS explains why BCG could be having such a broad protective effect.
Vaccines are known to stimulate the adaptive arm of the immune system, thereby establishing a 'memory' of a specific invader to be recognised and repulsed. BCG, on the other hand, was working on the evolutionarily more ancient innate immune system that is triggered by molecules that commonly marked out a pathogen, such as components of their cell wall.
“The general perception in immunology is that innate immunity, as opposed to adaptive immunity, is static and does not adapt to an enhanced functional state,” observed Mihai Netea of Radboud University Nijmegen Medical Centre and his colleagues in their PNAS paper. BCG was inducing “trained immunity” by reprogramming cells known as monocytes that formed part of innate immune system.
When BCG was administered, the live bacteria in the vaccine would be devoured by the monocytes. Inside the monocytes, muramyl dipeptide, a constituent of the bacterial cell wall, was then able to latch on to a receptor known as NOD2. That, in turn, set off a chain of events that led to molecular tags being attached to a protein, called a histone, around which DNA is wrapped. Such reprogramming allowed certain genes to be more active and thereby produce more protein.
Those monocytes were then capable of an enhanced response when confronted with a range of different pathogens, churning out chemicals known as cytokines that mobilised the immune system to fight off an invading microbe.
The Dutch scientists showed that monocytes taken from volunteers who received BCG showed a considerably increased cytokine response to unrelated pathogens, such as the bacteria Staphylococcus aureus and the yeast Candida albicans. BCG also ensured significantly better survival when mice from a strain that lacked cells of the adaptive immune system were exposed to lethal doses of C. albicans.
The work of these scientists very likely explained why BCG has been consistently observed to reduce death and sickness to a far greater extent than could be explained by the prevention of TB, remarked Dr. Aaby and Dr. Benn in their commentary. Randomised trials had shown that after BCG and measles vaccination, the contribution of nonspecific effects to overall health far outweighed the importance of the specific protection provided by these vaccines. With two trials of early BCG vaccination planned in Denmark and Australia, perhaps the vaccine would be reintroduced in high-income countries for its training effects rather than for protection against TB.
“Disentangling the mechanisms of the nonspecific effects may establish a new paradigm in immunity with a stronger emphasis on training and innate immunity,” they said.
Could the elderly too, with waning immune function that makes them vulnerable to a variety of infectious diseases, benefit from BCG boosting their innate immunity? “Absolutely yes, I think that this could be a major potential treatment and we are working on that,” said Dr. Netea in an email.