When children in the African countries of Guinea-Bissau and Uganda were vaccinated against tuberculosis, something extraordinary happened.
Instead of a vaccine that protects against only the target bacteria – Myocbacterium tuberculosis – the tuberculosis vaccine provided extensive 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 unforeseen effects of the tuberculosis vaccine.
The team administered Bacille Calmette-Guérin (BCG) vaccine to 63 infants within ten days of their birth and compared their progress with a control group of 67 infants who did not receive the BCG vaccine.
The researchers took blood samples from the babies and examined the 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 disease.
By looking at these monocytes, scientists found clear epigenetic differences – changes in the way genes are expressed or controlled which genes are active and which genes are turned off – between the vaccinated and unvaccinated groups that lasted an average of around 14 months after vaccination.
In vaccinated infants, the BCG vaccine has reprogrammed or “trained” monocytes to generally better respond to pathogens, and this epigenetic signature was passed on to the next generation of monocytes for more than one year after vaccination.
According to the researchers, this is the mechanism behind the broad protective effect of BCG vaccines observed in African countries.
“We showed for the first time how the BCG vaccine can have long-term effects on the immune system of babies,” says Boris Novakovic, senior author and molecular biologist at the Murdoch Children’s Research Institute (MCRI) in Melbourne, Australia.
Scientists also used in vitro experiment to study these epigenetic changes in detail.
They isolated monocytes from healthy adults and exposed the cells to two types of BCG vaccine and found clear changes in different types of epigenetic modifications.
These included DNA methylation – molecular markers that adore the DNA sequence – and histones – bulky proteins around which strands of DNA are wrapped.
Monocytes respond to pathogens with receptors on the outer surface of the cell.
When these receptors come into contact with a pathogen, this causes the monocyte cell to “eat” the pathogen (phagocytosis), which also causes a cascade of events inside the cell where one protein switches to another protein, and so on until expression changes. cell genes.
Prior exposure to the BCG vaccine repackages monocyte DNA in a way that speeds up the process and quickly turns on the genes required to respond to threats, Novakovic told ScienceAlert.
Putting monocytes on high alert makes them more vulnerable to all infections, not just tuberculosis.
Previously, it was 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 dealt with before).
Over the past decade, scientists have discovered that the innate immune system can actually produce a non-specific memory, called “trained immunity.”
“It was a breakthrough,” Novakovic told ScienceAlert.
It is not only the BCG vaccine that causes the innate immune system to become oversensitive. Other live attenuated vaccines have a similar effect, which use a weakened form of the virus to protect against diseases such as polio, measles and smallpox.
Conditions that weigh on the body, such as obesity and high cholesterol or injuries, also make the innate immune system more vulnerable. This is not always good.
While the study by Novakovic and colleagues focused on the basic biological mechanisms of trained immunity, there are some real-world implications.
In countries where infant mortality is high, vaccination against tuberculosis, measles or smallpox may have a beneficial effect in protecting infants against a range of other infections.
In an Australian context where children rarely die from infectious diseases, there is more interest in the potential use of the BCG vaccine to prevent allergies and eczema in children, Novakovic said.
It is believed that the BCG vaccine may have a beneficial effect on the developing immune system.
A study by MCRI researchers published in Allergy Last year, BCG vaccination was found to have had a moderate benefit in preventing eczema in infants predisposed to developing common skin disease.
The epigenetic study was published in Progress in science