The mysterious ability of the veteran tuberculosis vaccine, BCG, to solve health problems way beyond its remit has puzzled scientists for decades. Now, Telethon Kids researchers have not only unlocked part of the secret to its success in saving the lives of newborns, but they’re at the forefront of global efforts to test its ability to fight COVID-19.
It was close to midnight on a wintry Vancouver night in 2013 when Dr Nelly Amenyogbe hit the biology jackpot. Trudging through the cold rain for the latest in a round of regular checks on newborn mice recently given the tuberculosis vaccine, BCG, she wasn’t expecting good news.
The idea had been to try to replicate findings out of Guinea Bissau in Africa a year earlier which suggested that giving BCG to underweight human babies at birth – instead of a month later, as is often the case – reduced their risk of dying by a staggering 50 per cent. The observational study also suggested this positive effect happened within days of BCG administration – much faster than most vaccines kick in.
The findings had been written off by vaccine experts at the highest level as ‘biologically implausible’. It was simply not possible, they suggested, for BCG to work so quickly and to such dramatic effect.
Unwilling to dismiss the idea so readily, Dr Amenyogbe and her colleague, Professor Tobias Kollmann, set up a small study featuring mice vaccinated with BCG shortly after birth and then challenged with sepsis – one of the top causes of early death in newborns in low and middle income countries. They wanted to see whether it was indeed plausible that BCG could rapidly increase newborns’ survival odds.
The night it all came together, Dr Amenyogbe was expecting to make a quick check and then leave. She had peeked in on the sepsis-challenged mice the day before, and all of them – BCG-vaccinated and non-BCG-vaccinated – had looked much the same: sickly and weak.
“I already kind of felt that no, this is not going to work, it’s just not. I was just going to go in there, tick the box, and go home,” she said.
But when she lifted the cage lid this time, she was stunned. Around 70 per cent of the newborn mice that had been vaccinated were now well on their way to recovery. Only about 30 per cent of those which had not received BCG had recovered: the rest remained sickly and weak.
The results – especially the speed with which so many mice recovered – lent weight to the Guinea Bissau findings and paved the way for an eight-year study which has now not only replicated the findings in mice and human babies, but for the first time revealed the biological mechanism triggered by BCG vaccination.
In a study which spanned Canada, the United States, England, Denmark, Africa, Australia and Papua New Guinea, Dr Amenyogbe, Professor Kollmann, and colleagues identified a dramatic and rapid increase in neutrophils – often overlooked white blood cells which patrol the body and destroy invading bacterial pathogens – within three days of BCG vaccination.
Colleague Byron Brook, from the University of British Columbia, performed experiments confirming the neutrophils were responsible for the rapid protection afforded by BCG.
“Those neutrophils just waited, ready to respond,” Dr Amenyogbe said. “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.”
The team later validated the effect in blood samples from three different cohorts of newborn babies in West Africa and Papua New Guinea.
The Bacillus Calmette-Guérin (BCG) vaccine, first used in humans to protect against tuberculosis in 1921, is one of the oldest, cheapest and safest vaccines in the immunisation arsenal.
Although not widely used until after World War II, countries which began using the vaccine noticed that within a year of use, newborn mortality rates plummeted by up to 50 per cent compared to previous years.
From the 1940s onwards, scientists began to document some of the ‘off-target’ effects of BCG, noting the survival advantages it offered beyond its immediate effect on tuberculosis. Since then, these off-target effects have been documented in relation to an ever-expanding list of health issues, including infectious disease, allergies, multiple sclerosis, auto-immunity, type 1 diabetes, and respiratory tract infections.
It is this broader impact which has led BCG to be investigated for its potential to fight off COVID-19.