One of the oldest vaccines could protect us against our newest infectious disease, COVID-19. The vaccine has been given to babies to protect them against tuberculosis for almost a century, but has been shown to shield them from other infections too, prompting scientists to investigate whether it can protect against the coronavirus.
This Bacille Calmette-Guérin (BCG) vaccine, named after two French microbiologists, consists of a live weakened strain of Mycobacterium bovis, a cousin of M. tuberculosis, the bacterium that causes tuberculosis. BCG has been given to more than 4 billion individuals, making it the most widely administered vaccine globally.
Because BCG protects babies against some viral infections in addition to TB, researchers decided to compare data from countries with and without mandatory BCG vaccination to see if immunization policies are linked to the number or severity of COVID-19 infections. A handful of preprint publications in the last two months noted that countries with an ongoing BCG vaccination program are experiencing lower death rates from COVID-19 than those without.
These non-specific effects [from BCG] are strongest when we look at respiratory infection outcomes.—Christine Stabell Benn, University of Southern Denmark
One study, for instance, found that mandatory BCG was associated with a significantly slower climb in both confirmed cases and deaths during the first 30-day period of an outbreak. Another modeled mortality in two dozen countries and reported that those without universal BCG vaccination, such as Italy, the US, and the Netherlands, were more severely affected by the pandemic than those with universal vaccination.
A downside with the preprints is that they show a statistical correlation, not cause and effect. “There are many sources of bias inherent in these cross-country comparisons,” warns Zoë McLaren, a professor of public health at the University of Maryland. For example, she says, the types of countries implementing the BCG vaccine may be more likely to also take proactive measures to protect their people against COVID-19, such as “shelter in place” orders. McLaren says she can think of almost 20 sources of bias in these studies. In another example, those who get a BCG vaccine may be more likely to have had a better start in life, putting them on a healthier trajectory. The studies cannot account for all confounding factors.
Epidemiologist Christine Stabell Benn of the University of Southern Denmark has studied BCG vaccine for the last two decades and reported that it reduces overall childhood mortality from infectious diseases. She warns against reading too much into the preprint papers. “This is the weakest kind of evidence that we have in our evidence pyramid,” she says. “It just links prevalence of one thing with the prevalence of another.”
But rather than toss out the idea of BCG’s link to fewer COVID cases or deaths, she says there’s good reason to consider it seriously. She has more direct evidence that BCG vaccination can ready our immune system for viral infections. And a number of clinical trials have now begun to investigate whether a BCG shot given to those most at risk of contracting the infection can protect them from the disease.
Evidence that BCG protects against other infections
Benn’s work is among accumulating evidence, as detailed in a recent review paper, that childhood BCG vaccination protects against other diseases, so-called off target effects. Much of the evidence to support the new clinical studies is based on trials by her group and on work by Mihai Netea of Radboud University Medical Centre in the Netherlands, who came up with a mechanistic explanation as to why BCG—designed to thwart a bacterial infection—could boost immune responses to viruses.
A study in 2000 led by Benn’s spouse and long-time collaborator Peter Aaby at the Bandim Health Project reported a significant reduction in mortality that was far greater than could be explained by preventing tuberculosis in infants who received BCG in Guinea-Bissau. And a 2005 study found a reduction in lower respiratory tract infections in BCG-vaccinated infants in the same country. In later studies, including one published in 2017, Benn and Aaby randomized thousands of low–birth weight children in this west African country to receive BCG right at birth or to be vaccinated at six weeks of age, which is the usual practice there. “There was a one-third reduction in neonatal mortality in those receiving BCG [earlier]” Benn says. The benefits mostly came from reduced rates of respiratory disease and septicemia in the babies, she adds.
In Guinea-Bissau, the researchers also compared children who developed a scar after vaccination with those who received the vaccine but did not develop a scar. The scar signals an appropriate immune response to the vaccine. In 2003, Aaby and colleagues reported significantly lower mortality in children with a vaccine scar. In a subsequent meta-analysis of similar studies, they suggested that the effect of revaccinating scar-negative children should be considered.
“We saw more than 40 percent reduction in overall mortality among those who had a scar, versus those who didn’t have a scar,” says Benn.
Benn says she is hopeful that BCG might offer some benefits against severe COVID-19. She gave herself a booster shot a few weeks back. “These non-specific effects [from BCG] are strongest when we look at respiratory infection outcomes,” says Benn.
A possible mechanism
When Benn and Aaby reported that BCG reduces infectious disease rates more than a decade ago, this was dismissed as biologically implausible at the time, she recalls. Vaccines induce long-lived memory B cells, which tweak their own genes to tailor-make antibodies against a specific microbe. These B cells are then kept in reserve in bone marrow. They quickly proliferate if the host again encounters the pathogen, giving long-lived immunity. B cells do not explain why a vaccine would allow someone to respond better to an unrelated microbe.
Netea proposed in 2012 that BCG works by putting the “innate” arm of the immune system, such as macrophages, on a higher alert status, a phenomenon termed “trained immunity.” The task of macrophages is to identify, engulf, and destroy foreign entities. They can also signal for reinforcements using cytokines. It was assumed that these guards did not remember particular pathogens, but stand as a blunt frontline defense. Twenty years ago, this innate system was viewed by most as crude and non-specific, says immunologist Luke O’Neill of Trinity College Dublin. “Then there was a Copernican revolution in immunology. Suddenly, it was realized how important the innate side was.”
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Nobel prizes went in 2011 to scientists who discovered innate receptors as gatekeepers of the immune system. Their research had kindled greater research interest in innate immune cells. Netea subsequently proposed that BCG primes frontline immune cells through epigenetic changes and metabolic rewiring. This is what allows them not to be placed on higher alert.
Priming the innate immune system matters for vaccines and for future infections. “If you vaccinate first with BCG and then give an influenza vaccine, the influenza vaccine works better,” says Netea. He reported this in 2015 in a randomized, placebo-controlled study of a vaccine against the 2009 pandemic strain. The experiment involved 40 men. Benn will this autumn test whether BCG administration 14 days prior to a seasonal flu vaccine could elicit a better response in those over 65.
To get a sense of how BCG might protect against a future pathogen, Netea infected healthy human volunteers with attenuated yellow fever virus in a randomized, placebo-controlled trial. Subjects who had been BCG vaccinated one month prior to the exposure showed significantly lower amounts of circulating yellow fever virus than those injected with placebo instead. The study, published last year, concluded that BCG induced epigenetic reprogramming of human monocytes and led to a more robust response against yellow fever virus.
After BCG administration, “there is more production of pro-inflammatory cytokines. They recruit immune cells easier to the site of infection, and those cells are better at killing and eliminating the virus,” says Netea.
According to Netea’s hypothesis, BCG could prep macrophages in a way that results in a locally stronger cytokine response directed against SARS-CoV-2, focused at the site of infection. “This would prevent inefficient systemic response later, which can harm the patient,” he explains, the so-called cytokine storm. Macrophages call to arms B and T cells, which would mean that those primed with BCG should be more efficient at killing off a SARS-CoV-2 infection.
Innate immune priming after BCG is probably optimal for two or three years, says Netea, an estimate based on epidemiological data in children. In his view, “the fact that somebody has been vaccinated 50 or 60 years ago is probably non-protective.” This runs counter to the links in epidemiological data suggesting that BCG is now assisting adults in responding to COVID-19. McLaren says even the vaccine’s protection against TB probably lasts just two decades. O’Neill too is skeptical about innate priming lasting this long. He says he wonders if countries with high childhood BCG vaccination rates, such as Japan, may protect elderly people indirectly from COVID-19, because vaccinated kids don’t spread it as much to them.
Benn says she thinks innate memory may yet surprise us. “We know for sure that the [BCG] effect lasts for at least one year in children. We also have indications it can last much longer,” she says, “in principle up to forty years.” One Danish study by Aaby and Benn indicated that people who had received smallpox and/or BCG vaccine at school entry had a more than 40 percent reduced risk of dying up to the age of 45. “This was seen in infectious disease, but also cardiovascular disease and neurological disease,” Benn explains.
BCG clinical trials begin
Netea, who collaborates with Benn, is wary about suggesting that a BCG shot from decades ago protects against COVID-19 but remains open-minded about the efficacy of more recent BCG shots. “We need randomized clinical trials to be able to draw conclusions,” he says. Trials are kicking off in the Netherlands, Greece, Australia, Denmark, France, Germany, and the US, says Netea, mostly to test BCG in medical staff.
This vaccine protects babies against TB. If we start using it for something unproven, there is a danger a price will be paid by young children.—Nigel Curtis, Murdock Children’s Research Institute and the University of Melbourne
In an Australian trial among 4,000 healthcare workers, “we will measure whether those who get the vaccine get less COVID-19, and if they do get it, if they are unwell for less time or have less severe symptoms,” says Nigel Curtis, a clinician and researcher at the Murdock Children’s Research Institute and the University of Melbourne.
In the Netherlands, Netea is recruiting 1,500 volunteer healthcare providers, half of whom will be randomly selected to receive BCG. He is also starting a trial soon on 1,600 volunteers over the age of 60, half of whom will receive a placebo injection, the other half BCG. Netea advocates BCG as a possible preventive measure only for at-risk groups to avoid shortages. “It could be a bridge to a vaccine,” says O’Neill, who notes that tuberculosis bacteria live in the lungs, so BCG could perhaps boost immunity there. “I am waiting for the trials of course.”
Benn is planning a trial in Denmark to look at 1,500 healthcare workers randomized to receive BCG or placebo and then followed for COVID-19 and other infectious diseases. Denmark used BCG up until the 1980s, so there will be a subgroup among the newly vaccinated who received BCG once before, at school. Benn hypothesizes that BCG benefits will be more pronounced amongst this subset of healthcare workers than those who did not get a BCG jab as children.
A risk for BCG shortages
In the absence of clinical trial data, the World Health Organization does not recommend BCG for the prevention of COVID-19. There is concern that people might jump the gun and decide BCG is effective before the trial results come out. McLaren says she worries that the rash of preprint comparison studies could inflict harm. “If people interpret these correlation studies as high-quality evidence or jump on the bandwagon of BCG, then we might invest in polices that are ineffective and take resources away from infants and children who need BCG vaccines,” she says.
Curtis too is concerned. He says he has heard about vaccine supplies in parts of Africa meant for children being diverted to healthcare workers. “That is a tragedy,” says Curtis. “This vaccine protects babies against TB. If we start using it for something unproven, there is a danger a price will be paid by young children.”