The BCG vaccine might assist in preventing a range of major disease

The bacillus Calmette-Guérin vaccine against tuberculosis—or simply BCG—is the oldest vaccine in the world that is still currently in use. Millions of infants in Africa and Asia receive the inoculation each year.

The vaccine provides effective protection against tuberculosis (TB), a leading cause of infectious disease deaths worldwide, second only to COVID. Its development began in Lille, France in 1900, when Albert Calmette, an army physician, was working with Camille Guérin, a veterinarian, to understand how TB was transmitted. The team cultured TB bacteria on potato slices and found that after several passages of the microbes from one slice to a fresh one, they became less virulent over time. The researchers started to vaccinate calves with this live, weakened form of TB to protect cattle. By 1921, after 231 passages, the TB strain was stable and nonvirulent for all animals they tested it on.

At the time, French children born in a family in which someone had TB faced a 25 percent chance of dying from the disease within their first year of life. So in 1921 Calmette and Guérin gave the first dose of BCG to a child born into a family with TB, and the child survived. In 1924 a large clinical trial of more than 5,000 French children showed that the BCG vaccine had 93 percent efficacy in preventing death in the first year of life. As a result, it was widely adopted in France and around the world. Different countries developed different strains of the vaccine over time.

In the midst of this progress against TB, something unexpected happened. It was discovered that BCG seemed to furnish benefits beyond protection against TB deaths. A 1927 trial in very young Swedish children showed that BCG reduced early-life mortality by 1931, and the benefit could not be explained by just the reduction in TB deaths. The researcher who reported these results, Carl Naeslund, suggested that BCG might trigger some “nonspecific” immunity—meaning that it protected against other causes of death, too, through unknown means.

In the ensuing century since the vaccine was first developed, laboratory-based immunological studies, epidemiological surveys and clinical trials have documented that these nonspecific effects appear to be real and robust. Other live vaccines, such as the measles vaccine, also show nonspecific effects, though the best-studied ones are for BCG.

Beyond protecting against various infections, researchers are starting to find that the BCG vaccine can also modulate the risk of other diseases in which the immune system goes awry, including type 1 diabetes, cancer, multiple sclerosis and Alzheimer’s disease. Claims about such broad-ranging effects have been controversial but have grown less so in recent years. Open questions still linger, however, as to which patient groups, and for which conditions, the nonspecific effects of BCG might produce a meaningful clinical benefit.

More clinical trials are needed to address these questions, although there has been limited funding and little to no pharmaceutical interest because the vaccine’s patent expired long ago. From a basic science perspective, researchers are also striving to elucidate the mechanisms by which the BCG vaccine works with an eye to using this knowledge to build better vaccines that could confer broad-based immunity.

In October and November 2022, two conferences brought together researchers and policy makers to explore how to better harness BCG’s nonspecific effects for clinical benefit—and to evaluate whether there is sufficient evidence to recommend policy changes to the schedules of vaccinations for children.

One piece of evidence that spurred the current enthusiasm for BCG’s nonspecific effects came from three clinical trials of the BCG vaccine—in 2011, 2012 and 2017—that were conducted by Danish physician-epidemiologist Christine Stabell Benn, anthropologist Peter Aaby and their colleagues. They found that BCG given at birth to children from Guinea-Bissau with low birth weight reduced all-cause mortality in these children by about 40 percent in the first year of life. The reduction in mortality was the result of fewer cases of non-TB infections, which the vaccine protected against in an undetermined way.

In the past two decades, evidence has surfaced that BCG’s nonspecific effects could modulate the risk of a variety conditions that involve the immune system, including type 1 diabetes, cancer, Alzheimer’s and multiple sclerosis. For example, clinician-scientist Denise Faustman and her colleagues performed a clinical trial at Massachusetts General Hospital demonstrating that three doses of BCG can improve blood sugar control in patients with type 1 diabetes, although the effect takes a couple of years to become manifest. Now she is working to understand how BCG affects the immune cells in these patients.

Some compelling longterm data about BCG’s impact on diabetes risk comes from a 2022 epidemiological study by Marie-Claude Rousseau of the National Institute of Scientific Research in Quebec and her colleagues. The researchers used records from Canada’s national health registry to track people who had received the BCG vaccine as children in the 1970s. They found that early-life BCG vaccination did not reduce the risk of diabetes in adolescence, but by the time those children were adults older than age 30, their risk of type 1 diabetes was 35 percent lower than that of people who had not received BCG in early life.

BCG also seems to diminish the risk of cancer. A 60-year follow-up of a clinical trial that began in 1935 among Native American and Alaska Native school-aged children showed that the group that had received BCG in childhood had not only a reduced risk of TB in the ensuing 60 years but also a 2.5-fold lower incidence of lung cancer at the end of the follow-up period. (The original trial, whose first results were published in 1952, was conducted by U.S. Army physician Joseph Aronson. The retrospective record review, from 1992 to 1998, was conducted by his granddaughter Naomi Aronson, director of infectious diseases at the Uniformed Services University in Bethesda, Md. The follow-up study was published in 2019.)

Adding to the growing body of research, an intriguing 2019 study by Hervé Bercovier of the Hebrew University of Jerusalem and his colleagues showed that bladder cancer patients who were treated with  BCG in the bladder—a Food and Drug Administration–approved immunotherapy for this type of cancer—had a more than fourfold lower risk of developing Alzheimer’s than those who did not receive the vaccine during a follow-up period of about eight years. Alzheimer’s is challenging to study because of the long time course over which the disease progresses. Still, Jeff Cirillo, an immunologistat Texas A&M University, is conducting a two-year trial to see if BCG vaccination can alter the “cognitive trajectory” of patients with very early-stage Alzheimer’s.

BCG also came into the public eye during the COVID pandemic. Researchers worldwide investigated whether BCG’s nonspecific effects might be harnessed to protect against the disease as a stopgap measure before COVID vaccines became available. The results were mixed, in part, because the trials were done with different strains of the vaccine and in different populations. The trials that showed some efficacy were mostly done in vulnerable populations, such as people with type 1 diabetes or hospitalized elderly patients, whereas the trials that didn’t demonstrate any effect were done in healthy populations, such as health care workers, Faustman explains, who pivoted her trial of BCG’s effects on type 1 diabetes during the pandemic to study the vaccine’s possible protective effects against COVID.

“The way I see the evidence, BCG reduces the risk of new infections in vulnerable groups,” Stabell Benn says. For those with a well-functioning immune system, there is likely little benefit from BCG, but for vulnerable groups, the vaccine can make a difference. It also seems that several doses are needed, she adds.

Mihai Netea, an immunologist and infectious disease clinician who heads the division of experimental medicine at the department of internal medicine at Radboud University Medical Center in the Netherlands, says that BCG hasn’t helped reduce the number of COVID infections, but the evidence suggests that it could reduce disease severity. In a meta-analysis that he, Stabell Benn and Aaby published in Lancet Infectious Diseaseson the effects of live vaccines against COVID, they found that across five trials, there was a 40 percent reduction in overall mortality in those who received BCG, compared with those who did not.

Netea envisions that by deconstructing how BCG actually works, the scientific community could design vaccines that provide better protection than BCG for emerging infectious diseases and a whole host of other conditions, including cancer. “What we should do now is actually build new vaccines in which the nonspecific … protection can reach not 30 or 40 percent but 60 or 70 percent,” he says. “Then, at the next pandemic, we will have something which is on the shelf that can already protect 60 to 70 percent of the population against mortality,” he says, emphasizing the importance of figuring out how BCG actually changes the immune system.

“To me, it is very important to understand, ‘How does it work?’” concurs Maziar Divangahi, a pulmonary immunologist at the McGill International TB Center. Without the mechanism, these nonspecific effects are a “magical” phenomenon. But by figuring out the mechanism, “we could harness the power of that mechanism to advance health in general,” he says.

Broadly speaking, the immune system has two branches: the innate immune system, which provides a first response against infection, and the adaptive immune system, which takes longer to activate and is aimed at specific targets, or antigens. Vaccines typically work by activating the adaptive immune system’s T and B cells and triggering, in the latter, the production of antibodies to a specific antigen such as the spike protein of the coronavirus that causes COVID.

Previously, researchers thought that the generalized response of the innate immune system was optimized for a rapid defense against infection and kept no persistent memory of an invading pathogen. But what Netea and others have shown over the past decade is that the innate immune system is capable of remembering previous encounters and if this system has prior exposure to the BCG vaccines, the next meeting with an invasive pathogen will trigger an enhanced response, such as the production of more signaling molecules called cytokines that attack microbial invaders.

Netea and his colleagues have worked over the past decade to understand this phenomenon, which they call “trained immunity.” They have shown that BCG vaccination causes metabolic changes in immune cells such as monocytes and macrophages, which in turn alter either the placement or removal of chemical, or “epigenetic,” marks on DNA through processes known as methylation and acetylation. These marks serve as bookmarks for immune-related genes in the innate immune system and enhance the monocytes’ production of cytokines when challenged with an infection. “What BCG is doing is putting an epigenetic bookmark in your DNA. So when you need to read it, you already have the bookmark, and the book opens automatically at the right page,” Netea says.

The researchers found that the BCG vaccine does not only affect the epigenetic marks in circulating innate immune cells such as relatively short-lived macrophages, which provide protection by consuming viruses or other invaders. It also alters marks on the DNA in stem cells in the bone marrow that produce new immune cells, which could explain how the effect of the vaccine can persist for many years.

The body of evidence on BCG’s off-target effects is substantial enough now that researchers and policy makers recently convened a workshop in Alexandria, Va., on October 15, 2022, and a meeting in Denmark on November 9–11, 2022, to discuss how to bring this science to bear on public health policy and to optimize the use of the vaccine in public health settings. “If we wanted to be sure that we have the perfect information,” Stabell Benn says, “we will never get going. So this is about finding that cutoff, where you can start and say, ‘We know enough now to move to policy and be reasonably sure that this policy will really truly benefit most of the recipients.’”

Still, the idea of using BCG’s nonspecific effects to treat or prevent a whole host of diseases is not universally accepted. “I’ve never come across a topic that is more polarizing,” says Nigel Curtis, a pediatric infectious diseases physician and BCG researcher at the University of Melbourne and Murdoch Children’s Research Institute in Australia, who calls himself an “agnostic” on the issue of off-target effects. Although there is no question that live vaccines—in particular, BCG—have immune effects beyond their main target, “the bit that remains controversial is to what extent those changes in the immune system are translated to clinically apparent effects,” he explains. In other words, in which populations, and for which conditions, can these off-target effects meaningfully help patients?

In Stabell Benn’s view, sufficient evidence has accumulated for life-saving policy changes to be implemented for some uses. First, in low-income countries where neo-natal mortality is high, BCG should be given at birth rather than months later. Many African countries already vaccinate children with BCG. But only 50 percent of those children receive the vaccine within the first month of life, when they are extremely vulnerable to other infections. Because BCG is given for TB, and children rarely die of TB in the first few months of life, “there’s no incentive for vaccination programs to improve the coverage early on in life,” Stabell Benn explains. But her clinical trials in Guinea-Bissau have shown that receiving the vaccine at birth, rather than months later, can reduce neonatal mortality by about a third. “So you can see that [if you are] coming too late with the vaccine after the neonatal period, the first month of life, you lose a lot of potential for doing a lot of good,” she says.

“My dream would be that we repurpose BCG as a vaccine against neonatal mortality [rather than specifically TB] because that would be a policy change that would really change how it is being used,” she says. Neonatal mortality remains high in Africa, even as child mortality has declined. “So if you can intervene there [in the first month of life], it means many more lives saved in absolute numbers.”

In North America, Europe and Australia, TB is less of a concern, but the vaccine could still be of interest because of its potential to reduce the risk of diabetes, cancer, Alzheimer’s, allergic diseases and other conditions. Both Stabell Benn and Curtis have conducted clinical trials in Denmark and Australia, respectively, showing that BCG vaccination at birth reduces the risk of eczema—especially in babies who are predisposed to the condition because one or both of their parents had it. But before BCG could be recommended as a way to reduce the risk of eczema in babies, regulatory and practical obstacles would have to be overcome. Regulatory agencies would have to review the evidence and approve BCG for a new condition. Also, the vaccine would have to become broadly available, which is not the case in North America, Europe or Australia.

Because BCG is not protected by a patent—a dose would cost about six cents—pharmaceutical companies are not gearing up to conduct the necessary trials to obtain regulatory approval for such use of the vaccine. “The challenges that we face are not really scientific,” says Jaykumar Menon, chair and co-founder of the Open Source Pharma Foundation, a nonprofit attempting to develop affordable therapeutics. “It’s a story of market failure.”

A solution might begin by gaining better insight into the mechanisms of BCG’s off-target effects. Then pharmaceutical companies could improve on the existing vaccine to create a new one for which they would then be able seek patents, Netea says. His group has identified some of the chemical components on the cell wall of BCG that induces trained immunity and developed a nanoparticle on whose surface the BCG-derived components could be placed. The researchers have already shown that the nanoparticle could stimulate trained immunity in animal experiments. Netea envisions that the patentable nanoparticle technology could be the basis for a wholly new vaccine for treating cancer patients—a population in which using the BCG vaccine is usually too risky because such patients are immunosuppressed and might be put at risk by receiving a vaccine made from weakened tuberculosis bacteria. (Bladder cancer is an exception. To treat this type of cancer, BCG is injected into the bladder rather than the bloodstream, and it is evacuated with the urine, so it poses a low risk of infections.)

The “holy grail” of the research that scientists in this area are conducting is not just to understand how vaccines have these effects, Curtis says, but also to use that understanding to design better vaccines and compounds that would target specific conditions, from diabetes to cancer.