The tuberculosis vaccine mysteriously protects against many things. Now we know why

When babies in the African countries of Guinea-Bissau and Uganda received the TB vaccine, something remarkable happened.

Instead of the vaccine only protecting against the target bacterium – Myocbacterium tuberculosis – the TB vaccine offered broad protection against a range of unrelated infections, including respiratory infections and serious complications such as sepsis.

Australian researchers have now identified the biological mechanism behind the off-target effects of the TB vaccine.

The team administered the Bacille Calmette-Guérin (BCG) vaccine to 63 infants within ten days of birth and compared their progress to a control group of 67 infants who had not received 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 innate immune system of the human body, which is the first line of defense against pathogens and is not specific to any particular disease.

By examining these monocytes, the researchers found distinct epigenetic differences — changes in how genes are expressed or control which genes are on and which are off — between the vaccinated and unvaccinated group that lasted on average about 14 months after vaccination.

In vaccinated babies, the BCG vaccine reprogrammed or “trained” monocytes to be more reactive to pathogens in general, and this epigenetic signature was passed on to the next generation of monocytes for more than a year after the vaccination.

According to the researchers, this is the mechanism behind the broad protective effect of BCG vaccines observed in African countries.

“For the first time, we have shown how the BCG vaccine can have lasting effects on the immune system of infants,” says Boris Novakovic, lead author and molecular biologist at the Murdoch Children’s Research Institute (MCRI) in Melbourne, Australia.

The researchers also used a in vitro experiment to explore these epigenetic changes in detail.

They isolated monocytes from healthy adults and exposed the cells to two types of BCG vaccine and detected distinct changes in different types of epigenetic modifications.

These included DNA methylation – molecular tags that worship the DNA sequence – and histones – large proteins around which DNA strands are wrapped.

Monocytes respond to pathogens using receptors on the outer surface of the cell.

When these receptors come into contact with a pathogen, it prompts the monocyte cell to “eat” the pathogen (phagocytosis), which also causes a cascade of events inside the cell where one protein activates another protein and so on, until it triggers a change in the gene expression of the cell.

Prior exposure to the BCG vaccine repackages the DNA of monocytes in a way that speeds up this whole process and quickly activates the genes needed to respond to threats, Novakovic told ScienceAlert.

Putting monocytes on high alert makes them more responsive to all infections, not just TB.

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 pathogens it has encountered before).

Over the past decade, scientists have discovered that the innate immune system can actually produce a nonspecific memory, called “trained immunity.”

“That was the breakthrough,” Novakovic told ScienceAlert.

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

Conditions that put stress on the body, such as obesity and high cholesterol, or injury, also make the innate immune system more reactive. That’s not always a good thing.

While Novakovic and his colleagues’ study focused on the underlying biological mechanisms of trained immunity, there are real-world implications.

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

In an Australian setting where babies rarely die from infectious diseases, there is greater interest in the potential use of the BCG vaccine to prevent allergies and eczema in children, Novakovic said.

The idea is that the BCG vaccine can have a beneficial effect on the development of the immune system.

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

The epigenetic study was published in Scientists progress

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