The Bacillus Calmette-Guérin (BCG) vaccine has been used as a defence against tuberculosis for some 100 years. Now researchers are studying if it has an effect against Covid-19 too. This is the story of how we got here.

On the first Saturday in April, I woke up to a message from a scientist friend in Japan:

“Do any of you remember whether we had BCG vaccinations as kids? Apparently there’s a decent chance it could boost immunity to Covid-19.”

The message was to a small group of friends born in South Africa in the 1970s. It was some hopeful news amid the unfolding coronavirus pandemic, so I wrote to my older brother in London to see if he could remember whether we’d had the vaccine. His response was definitive:

“Yes, it’s the circular injection that leaves a round scar on your upper arm.”

I pulled up my left sleeve and located the scar, which I’d largely forgotten about since getting the injection some 40 years ago. When I told all this to my girlfriend, who is from Russia, she said she’d also received the vaccine as a child. Her arm bears the same circular scar.

Later that same morning, another message came in on my phone. This time from a friend in Cape Town, forwarding an article about how US researchers had linked the BCG vaccine to fewer coronavirus cases in certain countries.

This seemed to be the subject of the day, so I turned to my computer to find out all I could about this 100-year-old tuberculosis vaccine. I would end up spending much of the April lockdown researching the background for this article.


Some two billion people have latent tuberculosis

The Bacillus Calmette-Guérin vaccine was developed at the Pasteur Institute in France by Albert Calmette (a doctor) and Camille Guérin (a veterinarian). The pair spent 13 years successively sub-culturing mycobacterium tuberculosis – the bacteria that cause the disease – until they produced a strain weak enough to be used as a vaccine. It was first administered to a human being in 1921.

In the early 1900s, tuberculosis was the world’s second-leading cause of death (after influenza and pneumonia), killing at rates comparable to those of cancer and heart disease today. Also known as “consumption” or “the white plague”, tuberculosis (TB) spreads through the air from coughs and sneezes, getting into the lungs, the kidneys and even the central nervous system. The TB bacteria invade white blood cells and destroy tissue, eventually killing through bleeding in the lungs or multiple organ failure. Notable people who have died from tuberculosis include Jane Austen, Frédéric Chopin, Franz Kafka, George Orwell and Eleanor Roosevelt.

Not everybody who inhales the TB bacteria becomes sick though. Hence, there are two defined types of tuberculosis: latent TB infection and active TB disease.

When you have latent TB, mycobacterium tuberculosis is present in the body but you do not feel ill and are not infectious. The World Health Organization estimates that up to a quarter of the global population has latent TB. That’s almost two billion people.

Approximately 5-15% of these latent TB cases will progress to active TB. This means about 10 million people each year, of which 1.5 million will die. While active TB can often be treated with one or a combination of several antibiotics (Rifampicin being the most common), there are drug-resistant strains of the disease too. So the traditional first line of defence against tuberculosis has been to vaccinate children with the Bacillus Calmette-Guérin vaccine.


Different approaches from country to country

As with any vaccine, BCG is not without controversy. And it got off to a rocky start.

In 1930, the Pasteur Institute supplied the new vaccine to health authorities in the German city of Lübeck for an inoculation program there. But the lab in Germany mistakenly stored the vaccine next to a virulent strain of TB and contaminated the doses. These were then administered to 251 new-born babies, 72 of whom died of tuberculosis before their first birthday. Two German lab technicians were subsequently sent to prison for gross negligence in what became known as the “Lübeck Disaster”.

It wasn’t until after the second world war that the vaccine was put into wider use. Rates of tuberculosis infection had skyrocketed in Europe during the war years, with many soldiers bringing the disease back home too. In 1947, the Danish Red Cross began immunizing children in Poland, where tuberculosis was rampant. The Danes were soon joined by Norwegian and Swedish relief organizations to form the so-called Joint Enterprise – later renamed the International Tuberculosis Campaign – which together with the support of UNICEF and the fledgling World Health Organization vaccinated some eight million children in war-torn areas of Eastern Europe. The program eventually covered 22 countries, with up to 14 million children receiving the BCG vaccine by 1951.

Since then, countries have either introduced BCG-vaccination programs, discontinued them, or never introduced them at all. The BCG World Atlas – maintained by several Canadian universities and institutions – provides a detailed picture that was last updated in 2017. Below is a summary of the information in the atlas:

Europe:

  • Greece, Ireland, Portugal, Russia, the Baltic states, the former-Eastern Bloc countries and the CIS countries still have mandatory BCG vaccination policies
  • Denmark, Finland, Norway and Sweden have all discontinued their BCG vaccination programs
  • Austria, Czech Republic, France, Germany, Slovakia, Slovenia, Spain, Switzerland, and the United Kingdom have all discontinued their programs
  • Italy, Belgium and the Netherlands have never had mandatory BCG vaccination policies

Asia-Pacific:

  • All of Asia is covered by national BCG vaccination policies (although no information is available for North Korea)
  • Australia and New Zealand have both discontinued their mandatory BCG vaccination programs

Africa and the Middle East:

  • With three exceptions, all countries in Africa and the Middle East have mandatory BCG vaccination policies. The exceptions are Israel (which has discontinued its BCG vaccination program) and South Sudan and Western Sahara (for which information is not available)

Americas:

  • Ecuador used to have a BCG vaccination policy for all, but discontinued it
  • The rest of Latin America is covered by national BCG vaccination policies (although no data is available for Suriname or French Guiana)
  • Canada and the United States only give BCG-vaccinations to specific groups. These include healthcare workers, lab technicians, prison guards, and certain communities at risk of TB


A vaccine with variable efficacy

The most obvious reason for a country to have dropped its BCG program is because it no longer considers tuberculosis to represent a significant threat in that geography. But another reason – and a much more controversial one – is that there are wide variations in the efficacy of the BCG vaccine. Reported rates of protection against pulmonary tuberculosis vary from between 0% and 80%.

The efficacy of BCG is discussed at length in a WHO paper from 1999 and again in a 2017 paper from the London School of Tropical Medicine, with several theories proposed for the observed variations.

One theory is that the different strains of the vaccine have variable effects. Some 90% of BCG vaccines are produced from five strains: the Pasteur strain, the Danish strain, the Tokyo strain, the Russian strain, and the Moreau strain. Each varies in its characteristics and together they produce a conflicting picture on efficacy. To this day, there is still no clear understanding or broad agreement on the efficacy of the different strains of BCG.

Another theory argues that prior exposure to environmental bacteria affects efficacy. The WHO paper observes that BCG efficacy is lower in rural regions closer to the equator, where exposure to mycobacteria is greater than in temperate regions. This corresponds with an observation in the London School of Medicine paper that the BCG vaccination is more protective in people who live at higher latitudes. Simply put, if you’ve already been exposed to a lot of bacteria, you may not benefit from the protection afforded by BCG.

Other theories for the variable efficacy of BCG focus on differences in human genetics, variations in the tuberculosis mycobacterium, or the way in which the vaccine is administered (either orally or by injection).

In 1994, researchers from several universities in the United States studied 1,264 articles or abstracts about BCG vaccination and its outcomes. The widely republished study concluded that, on average, the BCG vaccination reduces the risk of tuberculosis by 50%.

Significantly though, BCG is not just a defence against tuberculosis. The efficacy of the vaccine is proven in the treatment of at least two other diseases: leprosy and bladder cancer. There is also a controversial type 1 diabetes study underway at Harvard Medical School, where researchers are looking at BCG’s effect on controlling blood sugar levels.

Amid the coronavirus pandemic, the fact that BCG boosts the body’s defences against conditions other than tuberculosis is now renewing interest in the vaccine.


Testing BCG against Covid-19

It was late March 2020 when US researchers published the paper that has now been widely covered in the international media. The team was proposing that countries without universal BCG vaccination policies had been more severely affected by the novel coronavirus than those with BCG policies.

Although the paper has yet to be peer reviewed, several new BCG vaccine studies have since kicked off around the world. A university in the Netherlands is conducting two placebo-controlled trials; one involving 1,500 medical workers and the other 1,600 people over the age of 60. Researchers in Australia are also conducting a trial focused on thousands of healthcare workers. Both studies aim to evaluate whether the vaccine can provide frontline workers with a barrier of defence against coronavirus. Preliminary results are expected later in 2020.

While correlation does not imply causality, the data in the BCG World Atlas referenced earlier in this article does tempt one to draw inferences about BCG’s efficacy against Covid-19.

For instance, it’s been widely reported that Ecuador – the only country in Latin America without a BCG program – is being ravaged by the novel coronavirus. In Europe, mandatory BCG countries like Greece, Ireland, Portugal and the former Eastern Bloc have fared far better against coronavirus than neighbouring countries that have discontinued their BCG programs. Researchers have also been puzzled by the relatively low rates of coronavirus infection (and mortality) in Southeast Asia and Africa – all regions with universal BCG-vaccination policies.

There’s now so much interest in the topic that the World Health Organization has been forced to put out a precautionary message against drawing premature conclusions. Indeed, it may well be that other factors are causing the US researchers behind the initial report to draw a false positive about the BCG vaccination. The average age of a country’s citizens, its handling of the coronavirus pandemic, population density – all these and more are factors that could influence coronavirus infection and mortality rates.

Whether BCG’s effect against Covid-19 is proven or disproven, the latest round of research is writing yet another chapter into the 100-year-old story of a vaccine that seems to raise as many questions as it answers.