Why an age-old vaccine could be the next weapon against viruses

In the early days of the Covid-19 pandemic, when prevention seemed light years away, several scientists began trials to see if a tuberculosis vaccine developed in the early 1900s could protect people by boosting the immune system.

The Bacillus-Calmette-Guerin vaccine has long been known to have a wide-ranging effect on the immune system and is still administered to infants in developing countries and countries where tuberculosis is endemic.

Years ago, scientists noticed that the vaccine seemed to train the immune system to respond to a variety of infectious diseases, including viruses, bacteria and parasites, and reduced infant mortality.

As new threats such as monkeypox and polio re-emerge and the coronavirus continues to evolve, the potential of an old vaccine to provide universal protection against infectious diseases has rekindled interest among scientists.

Now, results from clinical trials conducted during the pandemic are coming in, and the results, while mixed, are encouraging.

The latest results, published Monday in Cell Medicine Reports, come from trials that began before the emergence of Covid-19. It was designed to see if multiple injections of BCG could benefit people with type 1 diabetes, who are highly susceptible to infections.

In January 2020, when the pandemic began, researchers began tracking Covid infection among 144 trial participants. They all had type 1 diabetes; two-thirds received at least three doses of BCG before the pandemic. The remaining third received multiple placebo injections.

Scientists are still evaluating the long-term effects of the vaccine on type 1 diabetes. But they commissioned an independent group to monitor Covid infections among 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 received the BCG doses got Covid, compared with six — or 12.5 percent — of the 48 participants who received the sham shots.

Although the trial was relatively small, “the results are as dramatic as those for Moderna’s and Pfizer’s mRNA vaccines,” said Dr. Denise Faustman, the study’s lead author and director of immunobiology at Massachusetts General Hospital.

People with type 1 diabetes are especially prone to infections. “We’ve seen a significant reduction in bladder infections, fewer flus and fewer colds, fewer respiratory infections and fewer sinus infections that diabetics often get,” added Dr. Faustman.

The vaccine “seems to reset the host’s immune response so that it is more alert, more prepared, and not so lethargic.”

Another trial of BCG in 300 elderly Greeks, all of whom had underlying health problems such as heart or lung disease, found that the BCG vaccine reduced the number of Covid-19 infections by two-thirds and also reduced the rate of other respiratory infections.

According to a study published in July in Frontiers in Immunology, only two people who received the vaccine were hospitalized with Covid-19, compared to six who received placebo shots.

“We’ve seen clear immunological effects of BCG, and it’s tempting to ask whether we can use it—or other vaccines that induce an immune learning effect—against a new pathogen that will appear in the future that is unknown and that we don’t know. there is a vaccine,” said Dr. Mihai Netea, co-author of the paper and a professor at Radboud University Medical Center in the Netherlands.

He called the results of the type 1 diabetes trial “very strong” but urged caution, noting that results from other trials were disappointing. A Dutch study of about 1,500 healthcare workers who were 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 disease.

The results of the largest BCG trial, an international study that followed more than 10,000 health professionals in Australia, the Netherlands, Great Britain, Spain and Brazil for a year, are still being analyzed and are expected in the next few months. The study also followed healthcare workers after they received the Covid vaccines to see if BCG improved their response.

“BCG is a controversial area – there are believers and non-believers,” 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 Children’s Research Institute. . (Dr. Curtis calls himself an “agnostic.”)

“No one disputes that there are adverse effects, but how deep is it and does it translate into a clinical effect? And is it only newborns whose immune system is more susceptible? These are very different questions,” said Dr. Curtis.

A number of factors may explain the different findings. BCG consists of a live, weakened virus that has been cultivated for decades in laboratories around the world, introducing mutations that create different strains.

Dr. Faustman’s lab uses a Tokyo strain that is considered particularly potent, Dr. Curtis said. His own research used the Denmark strain, which is the easiest to obtain. The number of doses can also affect immunity, as many vaccines require repeated vaccinations for maximum protection.

Dr. Faustman said her work showed that it takes time for a vaccine to have its maximum effect. Patients with type 1 diabetes in her study received multiple injections of BCG before the pandemic.

In any case, scientists interested in BCG’s ability to provide universal, broad-spectrum protection against pathogens have reconsidered their goals. They no longer seek to prevent 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 new deadly strain of flu, or an unknown pathogen.

“It’s more for the future,” said Dr. Netea, who called for large clinical trials of BCG and other vaccines that have shown broad protective effects.

“If we had known this at the very beginning of the Covid-19 pandemic, we would have been able to obtain a large protective effect for 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-label vaccines for use in current and future pandemics, said its chairman and co-founder Jaykumar Menon.

“Imagine if we could use existing vaccines to contain a pandemic – that would change world history,” Mr Menon said, adding that BCG is not the only vaccine with broad effects on the immune system.

“These narrow, very specific vaccines, like Pfizer’s or Moderna’s mRNA vaccines, are anchored very tightly to the spike protein of the virus that causes Covid-19, but if that protein mutates — which it does — you lose effectiveness,” said Mr. n Said Menon.

The alternative? “A broad, universal vaccine that works on innate immunity creates this fortified moat that repels all comers,” he said.