When babies in the African countries of Guinea Bissau and Uganda were given the tuberculosis vaccine, something remarkable happened.

Instead of the vaccine only protecting against the target bacteria – Mycobacterium tuberculosis – the tuberculosis vaccine offered broad protection against a range of unrelated infections, including respiratory infections and serious complications such as sepsis. Australian researchers have now pinpointed the biological mechanism behind the off-target effects of the tuberculosis vaccine.

The team administered the Bacille Calmette-Guérin (BCG) vaccine to 63 infants within ten days of their birth and compared their progress to a control group of 67 infants who did not receive the BCG vaccine. The researchers took blood samples from the infants and examined circulating white blood cells called monocytes in both groups.

Monocytes are part of the human body's innate immune system, which provides the first line of defence against pathogens and is not specific to any one disease.

Looking at these monocytes, researchers found distinct epigenetic differences – changes to the way genes are expressed or control which genes are active and which are switched off – between the vaccinated group and the unvaccinated group that lasted on average around 14 months after vaccination. 

In vaccinated babies, the BCG vaccine reprogrammed or 'trained' monocytes to be more responsive to pathogens in general, and this epigenetic signature was passed down to the next generation of monocytes for more than a year after vaccination. According to the researchers, this is the mechanism behind the broad, protective effect of BCG vaccines seen in African countries.

"For the first time, we have shown how the BCG vaccine can have long-lasting effects on the immune system of infants," says Boris Novakovic, senior author and molecular biologist at the Murdoch Children's Research Institute (MCRI) in Melbourne, Australia. The researchers also used an in vitro experiment to explore these epigenetic changes in detail.

They isolated monocytes from healthy adults and exposed the cells to two types of the BCG vaccine and detected distinct changes in different types of epigenetic modifications. These included DNA methylation – molecular tags adoring the DNA sequence – and histones – bulky proteins around which DNA strands are wound.

Monocytes respond to pathogens using receptors on the cell's outside surface. When these receptors contact a pathogen, it triggers the monocyte cell to 'eat' the pathogen (phagocytosis), which also causes a cascade of events inside the cell where one protein switches on another protein and so on, until this triggers a change in the gene expression of the cell. 

Prior exposure to the BCG vaccine repackages the monocyte DNA in a way that speeds this whole process up and gets the genes required to respond to threats switched on quickly, Novakovic told ScienceAlert. Putting monocytes on high alert makes them more responsive to all infections, not just tuberculosis.

It was previously thought that the innate immune system had no way of remembering previous infections, unlike the adaptive immune system (which uses T cells and specific antibodies to remember the pathogens it has encountered before). 

Over the last decade, scientists have discovered that the innate immune system can actually produce a non-specific memory, called 'trained immunity.

"That's been the breakthrough," Novakovic told ScienceAlert. 

It's not just the BCG vaccine that makes the innate immune system hyperresponsive. Other live attenuated vaccines that use a weakened form of the virus to protect against diseases such as polio, measles, and smallpox have a similar effect.

Conditions that put stress on the body, such as obesity and high cholesterol, or injuries, also make the innate immune system more responsive. That's not always a good thing. While the study by Novakovic and colleagues focused on the underlying biological mechanisms of trained immunity, there are some real-world implications.

In countries where infant mortality is high, vaccinating against tuberculosis, measles, or smallpox may have a beneficial effect in protecting infants against a range of other infections.

In an Australian context where babies rarely die of infectious diseases, there is greater interest in the potential use of the BCG vaccine to prevent allergies and eczema in kids, Novakovic said. The thinking is that the BCG vaccine may have a beneficial effect on the developing immune system. 

A study from MCRI researchers published in Allergy last year found that BCG vaccination had a modest beneficial effect in preventing eczema in infants predisposed to developing the common skin condition.

The epigenetics study was published in Science Advances