Why does a century-old vaccine offer new hope against pathogens?

In the early days of the Covid-19 pandemic, when prevention seemed like easy years, 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 it is still given to infants in developing countries and countries where tuberculosis is common.

Scientists discovered years ago that vaccines reduce infant mortality by training the immune system to fight a variety of infectious diseases, including viruses, bacteria and parasites.

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 sparked renewed interest among scientists.

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

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

In January 2020, when the pandemic began, investigators began monitoring 144 trial participants for Covid infections. All of them had type 1 diabetes; two-thirds received at least three BCG doses before the pandemic. The other third received multiple placebo injections.

Researchers 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 infection among the participants over a 15-month period, before any of them received Covid vaccines.

The results were striking: Only one of the 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 shot.

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

People with type 1 diabetes are especially prone to infections. “We’ve seen a reduction in bladder infections, colds and flu, respiratory infections and sinus infections in people with diabetes,” said Dr. Faustman added.

The vaccine “appears to be designed more to restore the host’s immune response and keep it alert, rather than lazy.”

Another trial of BCG in 300 elderly Greek men, all of whom had underlying 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.

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

“We’ve seen clear immunological effects of BCG, and it’s tempting to ask whether we can use it or other vaccines that have an immune-enhancing effect—against a new pathogen that may appear in the future, unknown and unknown to us. there is a vaccine,” said Dr. Mihai Netea, the paper’s lead author 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 other trials have had disappointing results. A Dutch study of nearly 1,500 healthcare workers vaccinated with BCG found no reduction in Covid infections, while a South African study of 1,000 healthcare workers found no effect of BCG on the incidence or severity of Covid.

The results of the largest trial of BCG, an international study involving more than 10,000 healthcare workers for a year in Australia, the Netherlands, Great Britain, Spain and Brazil, are still being analyzed and are expected in the next few 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 investigator, Dr. Nigel Curtis, Professor of Pediatric Infectious Diseases at the University of Melbourne in Australia and Group Leader of Infectious Diseases at the Murdoch Children’s Research Institute. (Dr. Curtis calls himself “agnostic.”)

“No one disputes that there are off-target effects, but how deep is it and does it translate into a clinical effect? And does it only apply to newborns, whose immune systems are more sensitive? These are completely different questions,” said the doctor. said Curtis.

Several factors may explain the different results. BCG consists of a live attenuated virus that has been grown in laboratories around the world for decades and introduced mutations to form different strains.

Dr. Faustman’s laboratory uses the Tokyo strain, which is believed to be particularly potent, Dr. said Curtis. His own research used the Danish strain, which is easy to obtain. The number of doses can also affect immunity, as many vaccines require repeated vaccinations to maximize protection.

Dr. Faustman said his work showed that it takes time for the vaccine to have its maximum effect. In his study, patients with type 1 diabetes had received multiple BCG injections before the pandemic.

In any case, scientists interested in BCG’s ability to provide universal, broad-spectrum protection against pathogens have shifted their focus. They no longer aim to prevent Covid-19 because current vaccines are very effective.

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

“This is for the future,” said the doctor. Netea called for large-scale clinical trials of BCG and other vaccines that show broad protective effects.

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

The Open Source Pharma Foundation, a global nonprofit that seeks to develop the most cost-effective new therapies in areas of need, is interested in repurposing off-patent vaccines for use in current and future pandemics, said its chairman and founder Jaikumar Menon.

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

“These narrow, highly specific vaccines, such as Pfizer’s or Moderna’s mRNA vaccines, are anchored on the protein of the virus that causes Covid-19, but if that protein mutates, you lose effectiveness.” Menon said.

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

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