Three years ago, doctors in Greece began recruiting 198 older people for a unique experiment. They injected half of them with a century-old tuberculosis vaccine typically given to newborns in the developing world. They gave the other half a placebo. They wanted to find out if the vaccine, called Bacillus Calmette–Guérin, or BCG, would protect older people—not against TB, but more broadly against viral infections.
Results are now in: During the year after receiving the shot, the BCG group had 80 percent fewer serious respiratory viral infections than the unvaccinated group. The results were published in Cell at the end of August by doctors at the University of Athens Medical School in Greece, and Radboud University Medical Centre in Nijmegen, Netherlands.
That’s a big deal for a few reasons. People 65 years and older are more likely than any other age group to be hospitalized due to respiratory infections such as influenza, and this study is a preliminary signal that some vaccines could have broad beneficial effects beyond protection from a particular disease. And Covid-19, too, is a respiratory viral illness that disproportionately leads to the hospitalization of older people.
“The chances are increased that BCG would have the same effect on Covid-19 as on other viral respiratory infections like the flu,” says Mihai Netea, the senior author of the study and experimental internal medicine chair at Radboud University. Tests of whether BCG specifically protects against Covid-19 are ongoing; there are now at least 20 randomized clinical trials around the world to see whether it can indeed protect health workers and the elderly.
Many scientists now believe that BCG and some vaccines like it that contain a live, weakened virus may act against non-target diseases. A 2016 review commissioned by the World Health Organization found that BCG and the measles vaccines reduce overall mortality by “more than would be expected through their effects on the diseases they prevent.”
“I think that we have to acknowledge that vaccines have effects much broader than the target disease and the effects can be used,” Netea says.
The research that became the Cell study began in 2017, when Netea’s team recruited patients who were visiting the hospital at the University of Athens Medical School. Most were around 80 years old. They were assigned randomly by computer to either the BCG vaccine or placebo group—the scientists were not aware of the assignments as a nurse injected each patient just before their discharge. This process, called “double-blinding,” is meant to reduce bias. The researchers then rang the patients up every month for a year to check on their health. If a doctor had diagnosed them with an illness, the scientists noted this down.
Netea was nervous about patients having an adverse reaction to the vaccination, itself. In aging patients, there’s always a risk that an immune response can overfire, and BCG has traditionally been given to newborns, not the aged.
Then, Covid-19 hit, and observational studies done by scientists such as Luis Escobar, a disease ecologist at Virginia Tech in Blacksburg, Virginia, hinted that nations where newborns get BCG shots are associated with lower Covid-19 mortality. Netea and his colleagues decided to fast track their analysis. In mid-May, they learned that the vaccinated patients had 80 percent fewer moderate-to-severe respiratory infections.
“That is pretty damn good,” says Kim Mulholland, a vaccinologist at the Murdoch Children’s Research Institute in Melbourne, who was more skeptical of broad beneficial effects of vaccines before this study. “This study left me with the feeling that I should go out and get a BCG vaccine.”
Netea’s clinical trial is the first to show the potential of vaccine non-specific effects in the developed world and in older people. But the idea builds upon ongoing observational research in Guinea Bissau, a tiny West African nation, where Peter Aaby, a Danish anthropologist, and his team have tracked almost 200,000 infants since the 1990s. BCG was first introduced in Guinea Bissau in the late 1980s, and the Danish scientists subsequently saw that children who received the vaccine did better in terms of overall survival than ones who did not. They eventually attributed this to the vaccine protecting the children against a variety of other diseases, although they were not able to elucidate a mechanism by which this might be happening. For example, the results of a study they published in 2005 concluded that BCG may protect children against lung infections caused by the respiratory syncytial virus (RSV). They have since published other papers concluding that the measles and the oral polio vaccines may also be broadly beneficial.
Aaby calls vaccine non-specific effects he has seen “enormous.” “They are actually more important for child mortality than the specific effects,” he says.
But some public health researchers are unconvinced by the Guinea Bissau data. Many of the studies are from a single population in the developing world, and are observational, says Paul Fine, a communicable disease specialist at the London School of Hygiene and Tropical Medicine in London, who is critical of some of Aaby’s research. The scientists observed the effects of vaccination on the overall wellbeing of the child, but these weren’t double-blind randomized clinical trials, which are the gold standard for research. The scientists and the parents both knew whether or not a kid had received a vaccine, and the scientists could not ethically choose to give a kid a placebo for the sake of comparison. Fine says that on the topic of vaccine non-specific effects, Aaby “has pushed it very hard, and sometimes it's beyond the boundaries of the data.”
Christine Benn, an epidemiologist at the University of Southern Denmark who is married to Aaby and works with him, says the public health community ignored their work because they couldn’t explain what was happening biologically when vaccine use correlates with improved survival. “It is quite incomprehensible to me, because the basis for medicine today is really epidemiological observation, and not always having the immunological or biological mechanism to explain it,” Benn says.
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.
“For the last 30 or 40 years, the typical paradigm is you identify a specific vaccine for a specific problem,” he continues. “People are quicker to overlook something that doesn't fit into the typical paradigm.”
DiNardo calls the Greece study a “fantastic first step,” especially because it shows that people around 80 years old—the most vulnerable age groups for both respiratory infections and Covid-19—can tolerate the inoculation without adverse effects.
But there are caveats, of course. DiNardo says a second trial in a larger pool of patients will show decisively if Netea’s results can be replicated and if the effect is as large as in the original study. Mulholland of MCRI says the BCG vaccine leaves a prominent scar, so clinical participants with some medical expertise might be able to figure out if they’ve received a vaccine or placebo—thereby ruining the double blind. (Netea says in his experience, the majority of patients do not think about it.) Finally, the strain of BCG administered in the vaccine varies among countries, so its effects may differ by population. That’s why the multi-country BCG Covid-19 trials are so important to hammer down effects, DiNardo says.
Netea agrees this is a first step. He and his colleagues have begun the next step—an 8.5 million Euro clinical trial funded by the Danish government in the Netherlands to re-do their study on a larger scale. The scientists began recruiting more than 5,200 older adults last month. They will follow the patients for three months to see if they contract any serious respiratory illness, including Covid-19, and hope to have results in early 2021.
For Netea, the importance of these trials goes beyond Covid-19. If BCG proves broadly useful, similar trials using live, attenuated, existing vaccines could be quickly started when the next pandemic hits. And if they protect, this could buy society valuable time for the production of a new vaccine, Netea says. “This is important because you don’t have to stop the entire economy. You don’t have to have all this collateral damage of the pandemic,” he says.