Why a century-old vaccine offers new hope against pathogens

In the early days of the Covid-19 pandemic, when prevention seemed light years away, many 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 broad effects on the immune system, and is still given to children in developing countries and countries where tuberculosis is endemic.

Scientists observed years ago that vaccination trains 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, an old vaccine’s ability to provide universal protection against infectious diseases has received renewed interest among scientists.

Now the results of clinical trials conducted during the pandemic are coming in, and the findings, though mixed, are encouraging.

The latest results, published Monday in Cell Medical Reports, come from a trial that began before the outbreak of Covid-19. It was Designed to see if there are multiple BCG injections It can benefit people with type 1 diabetes who are more susceptible to infection.

In January 2020, soon after the pandemic began, they began tracking Covid infections among 144 participants in the trial. All of them had type 1 diabetes; Two-thirds had received at least three BCG doses before infection. 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 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 in 96 people who received the BCG dose — or less than 1 percent — developed 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 the Moderna and Pfizer mRNA vaccines,” said Dr. Denise Fastman, lead author of the study and director of immunobiology at Massachusetts General Hospital.

People with type 1 diabetes are especially prone to infections. “We found that people with diabetes had more bladder infections, fewer fevers and colds, fewer respiratory tract infections, and fewer sinus infections,” Dr. Fastman added.

The vaccine appears to “make the host’s immune response more alert, more primed, not blunted.”

Another trial of BCG involved 300-year-old Greek adults with underlying health problems such as heart or lung disease. BCG vaccine reduced covid-19 infections Two-thirds and reduced rates 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.

“We have seen clear immunological effects of BCG, and it is tempting to ask whether we can use other vaccines that induce training effects on the immune system – or against a new pathogen that emerges in the future, unknown and that we do not. Vaccinate,” said the paper’s co-lead author and Radbot University Medical Center in the Netherlands. Professor Dr. Mihai Netia said.

He called the results of the type 1 diabetes trial “very strong” but urged caution, noting that other trials have had disappointing results. A A Dutch study of about 1,500 healthcare workers A South African study found no reduction in covid infections in people vaccinated with BCG 1,000 health workers BCG has no effect on the incidence or severity of covid.

The results of BCG’s largest trial, An international study followed more than 10,000 healthcare workers Australia, the Netherlands, the UK, Spain and Brazil for a year, which is still being analyzed and is expected in the next few months. The study followed healthcare workers after they received their 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 chair of the Murdoch Children’s Research Institute’s infectious diseases group. . (Dr. Curtis calls himself “an agnostic”.)

“No one is arguing that there are off-target effects, but how deep is it, does it translate to a clinical effect? ​​And is it just with newborns, whose immune systems are more susceptible? Those are very different questions,” said Dr. Curtis.

Several factors may explain the divergent findings. BCG is made of a live attenuated bacterium that has been cultivated in laboratories around the world for decades, introducing mutations that create different strains.

Dr. Fastman’s lab uses the Tokyo strain, which is considered particularly potent, Dr. Curtis said. His own studies used the Denmark strain, which is easier to obtain. Because many vaccines require repeated vaccinations to increase protection, the number of doses can also affect immunity.

Dr. Fastman says his work shows that it takes time for a vaccine to have its maximum effect. In his study, patients with type 1 diabetes received multiple BCG shots before the infection.

However, scientists interested in BCG’s potential to provide universal, broad-spectrum protection against pathogens have reconsidered their objectives. Because current vaccines are so effective, they are no longer seen to prevent Covid-19.

Instead, they want to develop tools for the next pandemic, which could be another coronavirus, a deadly new flu, or an unknown pathogen.

“This is more for the future,” said Dr. Netia, who has called for larger clinical trials of BCG and other vaccines that have demonstrated broad protective effects.

“If we had known this early in the Covid-19 pandemic, we could have had a huge protective effect on the population in the first year of the pandemic.”

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

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

“These shorter, more specific vaccines, like the Pfizer or Moderna mRNA vaccines, are placed very tightly on the spike protein of the virus that causes Covid-19, but if that protein mutates — and it does — you lose effectiveness,” Mr. Menon said.

Alternative? “A broad universal vaccine that works on innate immunity puts in place this fortified moat that repels intruders,” he said.

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