In 2010, Aaby and Benn were prolifically publishing observations from Guinea Bissau when Netea’s lab stumbled into this turf by accident. Netea’s graduate student Johanneke Kleinnijenhuis, then at Radboud University Medical Centre, was running a routine experiment. She had some blood from graduate students who’d gotten BCG shots before heading to TB-endemic countries for coursework, and was testing the cells against the TB bacterium to see if an immune response was triggered. For the sake of comparison, she also tested the cells against the fungus Candida albicans. To her surprise, she found that the cells also had an immune response to the fungus. “Initially we thought, ‘This is a mistake,’” Netea says. “And then we repeated it. And we saw the same thing.”
He felt disbelief because vaccines aren’t supposed to work this way. The US Centers for Disease Control defines a vaccine as a product that generates immunity to a specific disease, and protects a person from that disease. But the grad student’s petri dish suggested the BCG vaccine could react to more than just TB.
This is how the immune system has been thought to work: When a bug enters us, it aims to invade our cells, take control and replicate. Our bodies mount a forceful attack and trigger inflammation, which kills the invaders quickly and non-specifically. This is the “innate” immune response.
If the invaders escape, the “adaptive” immune response kicks in after a few days. Our bodies assemble killer cells that are highly selective, and target the trespassers and the infected cells. After the war ends, the body stores a copy of the killer cells, so the next time there’s an invasion, the adaptive immune system quickly eliminates the threat. So, a person who has been exposed to, say, a weakened tuberculosis bacterium through a BCG vaccine is theoretically protected against TB for life due to this adaptive memory.
The work of scientists like Netea suggests there’s a third kind of immune response—a “trained” innate immune response. He says that a BCG vaccine not only creates an adaptive memory against TB, it also rewires the innate immune system—that first line of defense. Genes that encode the frontline inflammation defenders remain at the ready for some time, so when any infection happens, the innate immune system reacts instantaneously. He thinks that trained immunity may especially repel respiratory viruses, which come face-to-face with immune cells almost immediately upon invading the lungs. The broad antimicrobial effect, Netea speculates, may last a year, if not more.
But research into vaccine non-specific effects—and to figure out both how and if they might work—is still novel scientific turf. And after Covid-19, some 20 scientific teams began testing BCG to see if they can make a connection between the vaccine and protection against the disease. “What is happening is not in textbooks yet,” says Andrew DiNardo, an infectious disease specialist at the Baylor College of Medicine, who is part of a team running a BCG Covid-19 study in the US. The team is giving either BCG or a placebo to 1,800 health workers, and will track whether the vaccinated group is less likely to contract Covid-19 over six months.