A vaccine that was developed 100 years ago to fight the tuberculosis scourge in Europe is now being tested against the coronavirus by scientists eager to find a quick way to protect health care workers, among others.
The Bacillus Calmette-Guerin vaccine is still widely used in the developing world, where scientists have found that it does more than prevent TB. The vaccine prevents infant deaths from a variety of causes, and sharply reduces the incidence of respiratory infections.
The vaccine seems to "train" the immune system to recognize and respond to a variety of infections, including viruses, bacteria and parasites, experts say. There is little evidence yet that the vaccine will blunt infection with the coronavirus, but a series of clinical trials may answer the question in just months.
On Monday, scientists in Melbourne, Australia, started administering the BCG vaccine or a placebo to thousands of physicians, nurses, respiratory therapists and other health care workers - the first of several randomised controlled trials intended to test the vaccine's effectiveness against the coronavirus.
"Nobody is saying this is a panacea," said Dr Nigel Curtis, head of infectious diseases at Royal Children's Hospital in Melbourne, who planned the trial. "What we want to do is reduce the time an infected health care worker is unwell, so they recover and can come back to work faster."
A clinical trial of 1,000 health care workers began 10 days ago in the Netherlands, said Dr Mihai Netea, an infectious disease specialist at Radboud University Medical Center in Nijmegen. Eight hundred health care workers have already signed up. (As in Australia, half of the participants will receive a placebo.)
Nobody is saying this is a panacea. What we want to do is reduce the time an infected health care worker is unwell, so they recover and can come back to work faster.
Dr Denise Faustman, director of immunobiology at Massachusetts General Hospital, is seeking funding to start a clinical trial of the vaccine in health care workers in Boston as well. Preliminary results could be available in as little as four months.
"We have really strong data from clinical trials with humans - not mice - that this vaccine protects you from viral and parasitic infections," said Faustman. "I'd like to start today."
History of the vaccine
The BCG vaccine has an unusual history. It was inspired in the 1800s by the observation that milkmaids did not develop tuberculosis. The vaccine is named after its inventors, Dr Albert Calmette and Dr. Camille Guerin, who developed it in the early 1900s from mycobacterium bovis, a form of tuberculosis that infects cattle.
The scientists cultured bacterial scrapings from cow udders, and continued to culture bovine TB for over a decade until it was weak enough that it no longer caused virulent disease when given to lab animals.
The weakened virus was first used in humans in 1921 and was widely adopted after the Second World War. Now BCG is primarily used in the developing world and in countries where TB is still prevalent, where it is given to over 100 million babies a year.
Like other vaccines, BCG has a specific target: TB. But evidence accumulating over the past decade suggests the vaccine also has so-called off-target effects, reducing viral illnesses, respiratory infections and sepsis, and appears to bolster the body's immune system.
The idea is an offshoot of the "hygiene hypothesis," which suggests that the modern emphasis on cleanliness has deprived children of exposure to germs. The lack of "training" has resulted in weakened immune systems, less able to resist disease.
One of the earliest studies hinting at the broad benefits of BCG vaccination was a randomised trial of 2,320 babies in Guinea-Bissau in West Africa, published in 2011, that reported that death rates among low-birth-weight babies were dramatically reduced after vaccination. A follow-up trial reported that infectious-disease mortality rates in low-birth-weight babies who were vaccinated were cut by more than 40 per cent.
Other epidemiological studies - including a 25-year study of over 150,000 children in 33 countries - have reported a 40 per cent lower risk of acute lower respiratory tract infections in children who received a BCG vaccine. A study in the elderly found that consecutive BCG vaccinations reduced the incidence of acute upper respiratory tract infections.
A recent review by the World Health Organisation (WHO) concluded that BCG had beneficial "off-target effects," and recommended doing more trials of the vaccine against a wider range of infections.
"This vaccine has saved as many lives as the polio vaccine - it's an amazing story," said Curtis, who designed and launched the BCG trial in Melbourne in less than a month, hoping to stay one step ahead of the coronavirus' spread in Australia.
What you need to know
While he described the BCG vaccine as underappreciated, he emphasized that it was "not a specific COVID-19 vaccine." BCG also cannot be administered to anyone who has a compromised immune system, because it is a live-attenuated vaccine - meaning it contains live but weakened TB.
Faustman said it should not be used in hospitalized patients with active disease, because it may not work fast enough and could interact poorly with other treatments.
Not everyone is convinced BCG holds much promise. Dr Domenico Accili, an endocrinologist at Columbia University, said he thought efforts to use the vaccine against the coronavirus sound "a bit like magical thinking."
While acknowledging that BCG is "a non-specific booster of the immune system," he said, "we should be able to deploy a more tailored approach."
One question is what effect the vaccine may have in patients whose immune systems overreact to the coronavirus, resulting in what are called cytokine storms. Dr Randy Cron, an expert on cytokine storms at the University of Alabama at Birmingham, said it was impossible to know.
A recent analysis of the disparate toll the new coronavirus has taken on middle- and high-income countries found a correlation with BCG policies, concluding that countries that did not implement or had abandoned universal BCG vaccination have had more coronavirus infections per capita and higher death rates. (Low-income countries were excluded from the analysis because of unreliable COVID-19 reporting data and generally poor medical systems.)
"You can make a new vaccine," Faustman said. "We're really smart, and we can do that. But it's two years off, and two years is going to be two years too late."
"If we've got something generic globally at hand that we can use to make the human host stronger, this is a win-win for the public right away."