The Kids Research Institute Australia researchers working with a global team have identified the mechanism behind one of science’s most enduring mysteries: what makes the 100-year-old tuberculosis (TB) vaccine, BCG, so effective at preventing newborn deaths from diseases other than TB.
The ability of Bacillus Calmette-Guérin (BCG) – one of the oldest, safest and cheapest vaccines available – to provide protection to newborns beyond its intended purpose of fighting off TB has been known since at least the 1940s, but until now no one has been able to explain why or show how this added protection is conferred.
In a study published in Science Translational Medicine, The Kids researchers Professor Tobias Kollmann and Dr Nelly Amenyogbe reveal how they identified a dramatic and rapid increase in neutrophils – white blood cells which patrol the body and destroy invading bacterial pathogens – in mice and babies within three days of BCG vaccination.
They first witnessed the phenomenon – known as emergency granulopoiesis (EG) – in mice, with their global team later validating it in blood samples from newborn babies in West Africa and Papua New Guinea.
“It’s been known for a very long time that neutrophils play a very important role in managing sepsis, but until now nobody understood the role of BCG in initiating this critical process,” Dr Amenyogbe said.
“It was actually thought to be biologically implausible, however we’ve not only shown how BCG is involved, but that it kicks off this process almost instantly following vaccination – far more quickly than anticipated.”
Co-funded by the Perth Children’s Hospital Foundation, Professor Kollmann heads the Systems Vaccinology team at The Kids.
Professor Kollmann said the findings reinforced how critical it was for newborns in low resource settingstoreceive BCG immediately after birth.
“Less than half the babies who should get this vaccine right after birth actually get it then, partly because of logistics and partly because TB is not seen as a huge risk in those first few weeks. Administration is often delayed to 4-6 weeks, but by then it’s too late for many newborns,” Professor Kollmann said.
“Around half of all newborn deaths from infection happen in the first week of life, with about 75 per cent of those deaths caused by sepsis. Given BCG’s clear role in helping newborns to fight off sepsis, we could save the lives of close to a million newborns every year if they were given this vaccine within days of birth instead of weeks later.”
The five-year study, involving researchers from Australia, Canada, the United States, the United Kingdom, Denmark, Papua New Guinea, The Gambia and Guinea Bissau, is the first to demonstrate the beneficial mechanism triggered by administration of BCG in newborns.
“In the initial phase of our project, we found that after giving newborn mice BCG, they ramped up their production of neutrophils, especially in the spleen and the bone marrow,” Dr Amenyogbe said.
“Those neutrophils then just waited, ready to respond. Then, when we challenged the newborn mice with sepsis three days later, the neutrophils deployed as they normally would and much more efficiently cleared the infections, allowing the mice that received BCG to recover very quickly.
“It was a very simple mechanism in the end – one of those things where in retrospect it’s really not shocking, yet it was not previously considered plausible.
“When we later analysed large studies of newborns being undertaken in Guinea Bissau, The Gambia, and Papua New Guinea, we found the same effect happened in human babies given BCG shortly after birth.”
Professor Kollmann and Dr Amenyogbe – who are also involved in the Melbourne, Adelaide and Perth-based BRACE trial, which is testing BCG’s potential to fight off COVID-19 – cautioned that while the effect was rapid and offered robust protection against newborn sepsis, it was relatively short-lived and did not occur in adult mice.
“Everybody’s attention is focused at the moment on whether BCG can help adults, particularly whether it can offer protection against COVID-19,” Dr Amenyogbe said.
“Our study only looked at BCG in the context of newborn sepsis. We narrowed in on sepsis because it’s one of the top causes of infectious death in newborns in low resource settings.
“The potential for BCG to play a protective role for other types of infections, such as COVID-19, remains entirely reasonable and worth looking at, but at the moment, we simply do not know.”
Professor Kollmann said whether BCG may or may not be protective against COVID-19 remained to be seen, but in the meantime, its real and proven potential to save the lives of vulnerable newborns had to be maximised.
“BCG is very, very safe, costs only a few cents per dose, and reduces infectious causes of mortality – not just tuberculosis – in newborns by almost 50 per cent,” he said.
“There’s nothing that we have in our entire current medical arsenal, that is as effective, cheap, safe, feasible and affordable as this vaccine. All we have to do is ensure all newborns at risk get it right away at birth.”
