The Bacillus-Calmette-Guerin vaccine has long been known to have broad effects on the immune system and is still administered to infants in the developing world and countries where tuberculosis is prevalent. Scientists noticed many years ago that the vaccine appears to train the immune system to respond to a variety of infectious diseases, including viruses, bacteria and parasites, and reduces infant mortality. As new threats such as monkeypox and polio re-emerge and the coronavirus continues to evolve, the old vaccine’s potential to provide a measure of universal protection against infectious disease has gained renewed interest among scientists. Now the results of clinical trials conducted during the pandemic are coming in, and the findings, while mixed, are encouraging. The latest results, published Monday in Cell Medicine Reports, come from a trial that began before the emergence of Covid-19. It was designed to see if multiple BCG injections could benefit people with Type 1 diabetes, who are very susceptible to the infection. In January 2020, as the pandemic began, researchers began tracking Covid infections among the 144 trial participants. All had type 1 diabetes. Two-thirds had received at least three doses of BCG before the pandemic. The remaining one-third had received multiple placebo injections. The scientists are still evaluating the long-term effects of the vaccine on type 1 diabetes itself. But they commissioned an independent team to look at Covid infections among the participants for 15 months, before any of them received Covid vaccines. The results were dramatic: only one – or less than 1 percent – of the 96 people who had received the BCG doses developed Covid, compared to six – or 12.5 percent – of the 48 participants who received sham shots. Although the trial was relatively small, “the results are as dramatic as those for the Moderna and Pfizer mRNA vaccines,” said Dr. Denise Faustman, the study’s lead author and director of immunobiology at Massachusetts General Hospital.
Read more about the coronavirus pandemic
People with type 1 diabetes are particularly prone to infections. “We saw a significant reduction in bladder infections, fewer flus and fewer colds, fewer respiratory tract infections and fewer sinus infections that diabetics get a lot,” added Dr. Faustman. The vaccine “seems to reset the host’s immune response to be more alert, to be more prepared, not so lethargic.” Another trial of BCG in 300 older Greek adults, all of whom had health problems such as heart or lung disease, found that the BCG vaccine reduced Covid-19 infections by two-thirds and reduced rates of other respiratory infections. Only two people who received the vaccine were hospitalized with Covid-19, compared with six who received the placebo vaccines, according to the study published in July in Frontiers in Immunology. “We have seen clear immunological effects of BCG, and it is tempting to ask whether we could use it – or other vaccines that induce immune training effects – against a new pathogen that appears in the future, that is unknown and that we do not have a vaccine for it,” said Dr. Mihai Netea, co-lead author of the paper and a professor at Radboud University Medical Center in the Netherlands. He called the type 1 diabetes trial results “very strong” but urged caution, noting that other trials have had disappointing results. A Dutch study of about 1,500 healthcare workers vaccinated with BCG found no reduction in Covid infections, and a South African study of 1,000 healthcare workers found no effect of BCG on the incidence or severity of Covid. The results of BCG’s largest trial, an international study that followed more than 10,000 healthcare workers in Australia, the Netherlands, the UK, Spain and Brazil for a year, are still being analyzed and are expected in the coming months. The study also followed healthcare workers after they received Covid vaccines to see if BCG improved their responses. “BCG is a controversial area — there are believers and nonbelievers,” said the trial’s lead investigator, Dr. Nigel Curtis, professor of pediatric infectious diseases at the University of Melbourne in Australia and head of the Infectious Diseases Group at the Murdoch Institute for Children’s Research. . (Dr. Curtis calls himself an “agnostic.”) “No one is arguing that there are off-target effects, but how profound is that and does it translate into a clinical outcome? And is it limited to newborns, whose immune systems are more sensitive? Those are very different questions,” Dr. Curtis said. A number of factors could explain the different findings. BCG consists of a live attenuated bacterium that has been cultivated in laboratories around the world for decades, introducing mutations that create different strains. Dr. Faustman’s lab uses the Tokyo strain, which is considered particularly potent, Dr. Curtis said. His own studies used the Danish strain, which is easier to obtain. The number of doses may also have an effect on immunity, as many vaccines require repeated vaccinations to maximize protection. Dr. Faustman said her work has shown that it takes time for the vaccine to have its maximum effect. The patients with type 1 diabetes in her study had received multiple BCG vaccines before the pandemic. In any case, scientists interested in BCG’s potential to provide universal, broad-spectrum protection against pathogens have reformulated their goals. They are no longer looking at preventing Covid-19, as current vaccines are very effective. Instead, they want to develop tools for use in the next pandemic, which could be another coronavirus, a deadly new strain of flu, or an unknown pathogen. “It’s more about the future,” said Dr. Netea, who called for large clinical trials of BCG and other vaccines that have shown broad protective effects. “If we knew this at the beginning of the Covid-19 pandemic, we could have a large protective effect on the population during the first year of the pandemic.” The Open Source Pharma Foundation, a global nonprofit that seeks to develop affordable new treatments in areas of greatest need, is interested in repurposing off-patent vaccines for use in current and future pandemics, said its president and co-founder Jaykumar Menon. “Imagine if we could use existing vaccines to contain pandemics – that would change world history,” said Mr Menon, adding that BCG is not the only vaccine with major effects on the immune system. “These narrow, very specific vaccines, like the Pfizer or Moderna mRNA vaccines, are very closely guarded against the spike protein of the virus that causes Covid-19, but if that protein mutates – which it does – you lose your effectiveness,” he said. Mr. Menon said. The alternative? “A broad universal vaccine that acts on innate immunity creates this reinforced moat that repels all comers,” he said.
