Why a decades-old TB vaccine is getting attention in the fight against Covid-19

In the desperate search for ammunition to fend off the Covid-19 pandemic, a decades-old tuberculosis vaccine, given in huge numbers around the world, is gaining newfound attention.

Researchers in Australia and the Netherlands are testing the idea that the vaccine, known as BCG — short for bacille Calmette-Guérin — could have broad power to boost the immune system against the novel coronavirus. In the United States, a research group in Boston hopes to test the vaccine in frontline health workers for the same purpose.

The interest stems from multiple studies over a number of years that point to the vaccine as having what are known as “off-target” benefits.

While the vaccine, used in many low- and middle-income countries, isn’t considered to be highly effective against its primary goal, TB, it seems to help the immune system fend off various pathogens, including one that causes leprosy. The question is whether the virus known as SARS-CoV-2 is among them.

Not everyone is convinced.

A leading TB researcher, Madhukar Pai, has warned that the BCG vaccine is unlikely to be the magic bullet some people seem to think it may be. Pai, director of McGill University’s International TB Center, wrote a blog post over the weekend arguing that people may be ascribing almost magical powers to the vaccine.

“I think the idea is 100% worth investigating,” Pai said in an interview with STAT. “That’s why my piece was not against further research. My piece was saying: Right now we’re nowhere close to anything for a policy based on ecological studies that are full of holes.”

The World Health Organization seems to agree. On Sunday it published a scientific brief examining the evidence surrounding BCG. It concludes that there currently is no proof the vaccine protects against the new coronavirus. “In the absence of evidence, WHO does not recommend BCG vaccination for the prevention of COVID-19,” it stated.

Still, some researchers are hopeful.

Denise Faustman, director of immunobiology at Massachusetts General Hospital, has been studying BCG for years as a therapy for type 1 diabetes. She has a stash of the vaccine — which is not used in the United States for tuberculosis prevention — and wants to see if it could benefit frontline health workers. She is seeking institutional permission to quickly mount a trial at Boston’s Brigham and Women’s Hospital.

“The goal is to enroll rapidly over a two-month period, about 4,000 high-risk health care workers. And then the goal will be to watch them … to see if we can get a signal,” Faustman said.

The word has gotten around among health workers in Boston. Faustman’s phone is ringing off the hook. “Certainly the people who want in the trial are calling every five minutes [to ask], ‘How do I get in this trial?’” she said. “We have hundreds of phone calls right now of ‘Why can’t I get this?’”

In some respects, the notion of using a vaccine designed to prevent infection with one pathogen to protect people from another, unrelated bug seems counterintuitive. You wouldn’t expect a flu shot to offer any protection against Covid-19, for instance.

But years of research has suggested the immune system boost that BCG confers applies far more broadly than to just Mycobacterium tuberculosis, which causes TB. Children vaccinated with it in low- and middle-income countries around the world have been seen to have lower death rates from other respiratory infections, for instance.

Faustman is enthusiastic about the vaccine, hoping it will be shown to offer protection and could be used as a tool to safeguard critical health workers until a vaccine specifically developed to ward off Covid-19 infection is available. “That’s our goal.”

Pai agrees the study is worth doing. “Is there a signal to do additional research? I think the answer is yes. We’ve known that BCG has these non-specific effects against multiple [diseases],” he said.

But he also argues that proponents of using the vaccine to protect against Covid-19 are wrongly trying to ascribe differing death rates around the globe to a country’s use or non-use of BCG.

Pai and his group at McGill compiled the data everyone is making these inferences from, an online resource called the BCG World Atlas. It lists whether a country uses BCG, when the program was introduced or discontinued, and when it is given, among other things.

A number of studies, most of which have not yet gone through peer review, have suggested lower Covid-19 case numbers or death rates in some countries can be attributed to their use of BCG — drawing from the BCG Atlas.

“Suddenly everybody and their brother has found the atlas and then taken their Covid data from the WHO or from Johns Hopkins University or wherever, overlaid the two and run regression models and [said] ‘Oh, look here. BCG works,’” Pai said.

That kind of approach is flawed, he said, and doesn’t factor in that different outbreaks around the world are at different stages. That’s important because countries that have seen transmission more recently haven’t experienced the explosion of deaths seen in countries like Italy, Spain and the United States. Likewise, many low- and middle-income countries are not testing for Covid-19 in large numbers; their low case and death rates are more likely the result of under-reporting than of the BCG vaccine, Pai said.

The WHO’s statement also challenged the studies attempting to draw conclusions based on countries where BCG had been used. And it, too, pointed out that a run on the vaccine could create real damage. “BCG vaccination prevents severe forms of tuberculosis in children and diversion of local supplies may result in neonates not being vaccinated, resulting in an increase of disease and deaths from tuberculosis,” the global health agency said.

Pai worries that low- and middle-income countries that use BCG may buy into the untested hype around the vaccine and assume their populations have protection that they may not have. Only clinical trials can answer this question, he said.

“It would be dangerous for policymakers to assume protection from BCG and not act,” Pai said in his blog post in Forbes. “Researchers and journalists need to be responsible as well, and not raise false hopes based on weak evidence. And countries should not hoard BCG vaccines for Covid-19, since the BCG supply chain is weak, and really necessary to protect children in [low- and middle-income countries] from childhood TB.”