Why a century-old vaccine offers new hope against pathogens

At the start of the Covid-19 pandemic, when prevention seemed light years away, several scientists launched 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 broad effects on the immune system and is still given to infants in developing countries and countries where tuberculosis is prevalent.

Scientists observed many years ago that the vaccine appears to train the immune system to respond to various infectious diseases, including viruses, bacteria and parasites, and reduces infant mortality.

As new threats like monkeypox and poliomyelitis reemerge and the coronavirus continues to evolve, the potential of the old vaccine to provide a universal measure of protection against infectious disease has sparked renewed interest among scientists.

Now the results of 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, are from a trial initiated 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 infections.

In January 2020, at the start of the pandemic, investigators 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 third had received multiple placebo injections.

Scientists are still evaluating the long-term effects of the vaccine on type 1 diabetes itself. But they commissioned an independent group to look at Covid infections among the participants for 15 months, before any of them had received Covid vaccines.

The results were dramatic: Only one – or less than 1% – of the 96 people who received the BCG doses developed Covid, compared to six – or 12.5% ​​– of the 48 participants who received the dummy injections.

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

People with type 1 diabetes are particularly prone to infections. “We saw a significant decrease in bladder infections, less flu and fewer colds, fewer respiratory tract infections and fewer sinus infections that diabetics get a lot,” Dr. Faustman added.

The vaccine “appears to reset the host’s immune response to be more alert, more primed, not as sluggish.”

Another trial of BCG on 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 also reduced rates of other respiratory infections.

Only two individuals who received the vaccine were hospitalized with Covid-19, compared to six who received the placebo injections, according to the study, published in July in Frontiers in Immunology.

“We have seen clear immunological effects of BCG, and it is tempting to wonder if we could use it – or other vaccines that induce immunity training effects – against a new pathogen that is emerging in the future, which is unknown and which we don’t have a vaccine for,” said Dr Mihai Netea, co-lead author of the paper and 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 other trials have had disappointing results. A Dutch study of some 1,500 healthcare workers who were vaccinated with BCG found no reduction in Covid infections, and a South African study by 1,000 healthcare workers found no impact of BCG on Covid incidence or severity.

The results of the largest BCG trial, an international study that followed more than 10,000 healthcare workers in Australia, the Netherlands, the United Kingdom, Spain and Brazil for a year, are still being analyzed and are expected in the coming months. The study also followed healthcare workers after receiving Covid vaccines to see if BCG improved their responses.

“BCG is a controversial area – there are believers and non-believers,” said the trial’s lead researcher, Dr Nigel Curtis, professor of pediatric infectious diseases at the University of Melbourne in Australia and chief from the Infectious Diseases Group of the Murdoch Children’s Research Institute. . (Dr. Curtis calls himself “agnostic.”)

“No one is claiming there are off-target effects, but how deep are they and does this translate into a clinical effect? ​​And is it limited to neonates, whose immune systems are more sensitive? These are very different questions,” Dr. Curtis said.

A number of factors could explain the disparate results. BCG is made up 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 strain from Denmark, which is the easiest to obtain. The number of doses can also affect immunity, as many vaccines require repeated inoculations to maximize protection.

Dr Faustman said his work has shown that it takes time for the vaccine to have its maximum effect. Patients with type 1 diabetes in his study had received multiple BCG injections before the pandemic.

Either way, scientists interested in BCG’s potential to provide universal, broad-spectrum protection against pathogens have redefined their goals. They no longer seek to prevent Covid-19, because the 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 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 could have had a significant protective effect on the population in the first year of the pandemic.”

The Open Source Pharma Foundation, a global nonprofit that seeks to develop affordable new therapies in areas of greatest need, is interested in repurposing off-patent vaccines for use in current pandemics. and future, said its president and co-founder Jaykumar Menon.

“Imagine if we could use existing vaccines to curb pandemics – that would change the history of the world,” Menon said, adding that BCG isn’t the only vaccine with broad effects on the immune system.

“These narrow, very specific vaccines, like the Pfizer or Moderna mRNA vaccines, are very closely tied to the spike protein of the virus that causes Covid-19, but if that protein mutates – which it does – you lose energy. ‘efficiency,’ said Mr. Menon.

The alternative? “A broad, universal vaccine that works on innate immunity sets up this fortified gap that pushes all comers back,” he said.

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