Old tuberculosis vaccine finds new life in coronavirus test

Research is ongoing to test whether vaccination with BCG can protect doctors and nurses COVID-19 (New Coronavirus Infection) (# If there is no character limit, add parentheses when first appearing.

One of the oldest vaccines was able to protect us from the latest infectious disease, COVID-19. Vaccines have been given to babies to protect against tuberculosis for almost a century, but they have been shown to protect babies from other infections, and scientists should investigate whether they can protect against coronaviruses. Are urged to.

Named after two French microbiologists, the Bacille Calmette-Guérin (BCG) vaccine is the tuberculosis-causing bacterium M. BCG, which has been administered to more than 4 billion people and is the most widely administered in the world. It is a vaccine.

Because BCG protects babies from some viral infections in addition to TB, researchers compared data from countries with and without the essential BCG vaccination, and vaccination policies show that the number of COVID-19 infections Or check if it is related to severity. Several preprint publications in the last two months point out that COVID-19 mortality rates are lower in countries with ongoing BCG vaccination programs than in countries that do not.

For example, one study found that compulsory BCG was associated with a marked slow rise in both confirmed cases and deaths during the first 30 days of development. Another model models mortality in 24 countries, where people without the BCG universal vaccination, such as Italy, the United States, and the Netherlands, were more affected by pandemics than those with universal vaccination. I am reporting.

The disadvantage of preprints is that they show statistical correlation, not cause and effect. “There are many underlying causes of bias in these cross-country comparisons,” said Zoku McLaren, a professor of public health at the University of Maryland. For example, the types of countries that have BCG vaccines are likely to place precautions to protect people from COVID-19, such as ordering “shelter-in-place.” McLaren says nearly 20 of the causes of bias can be considered in these studies. In another example, people who have been vaccinated with the BCG vaccine are more likely to start a better life and get on a healthier path. Research cannot account for all confounders.

Christine Stabbel Ben, an epidemiologist at a university in Southern Denmark, has been studying the BCG vaccine for the past 20 years and reports that it reduces overall childhood mortality from infectious diseases. She warns against reading too much preprinted paper. “This is the weakest kind of evidence in our evidence pyramid,” she says. “It only associates one prevalence with another.”

But she says there are good reasons to seriously consider rather than abandon the idea that BCG leads to less COVID cases and deaths. She has more direct evidence that she can get a BCG vaccination Prepare our immune system Viral infections. And now, many clinical trials have begun to investigate whether BCG shots given to those at highest risk of infection can protect them from disease.

Evidence that BCG protects against other infections

Ben’s study is one of a growing body of evidence that childhood BCG vaccination protects against other diseases, the so-called off-target effects, as detailed in a recent review paper. Much of the evidence supporting new clinical research is based on studies by her group and by Mihai Netea at the Medical Center of the University of Radobud, The Netherlands. A medical center at Radboud University in the Netherlands explained the mechanism of BCG designed to prevent bacterial infections. -It can enhance the immune response to the virus.

A 2000 study led by Benn’s spouse and longtime collaborator Peter Aaby of the Bandim Health Project showed a significant reduction in mortality far more than could be explained by preventing tuberculosis in infants with BCG in Guinea-Bissau. Was reported. A 2005 study also found a reduction in lower respiratory tract infections in infants vaccinated with the BCG vaccine from the same country. In later studies, including those published in 2017, Ben and Urby randomly randomized thousands of low-birth-weight babies in this West African country to receive BCG at birth or vaccine at 6 weeks of age. I received an inoculation. “Newborn mortality among people who have had BCG has been reduced by a third [earlier]Ben says. She added that the benefits were primarily due to a lower incidence of respiratory disease and sepsis in babies.

In Guinea-Bissau, researchers also compared children who developed scars after vaccination with children who received the vaccine but did not. Scars show a proper immune response to the vaccine. In 2003, Aaby and colleagues reported significantly lower mortality in children with vaccine scars. Subsequent meta-analyses of similar studies suggested that they should consider the impact of revaccination on scar-negative children.

“In people with and without scars, overall mortality was reduced by more than 40%,” said Benn.

Ben hopes BCG could bring some benefits to severe COVID-19. She gave her a booster shot a few weeks ago. “These unspecified effects [from BCG] It’s the strongest looking at the results of respiratory infections, “says Ben.

Possible mechanism

She recalled that when Ben and Arby reported that BCG reduced the incidence of infections more than a decade ago, it was rejected as biologically incredible at the time. Vaccines induce long-lived memory B cells and direct antibodies against specific microbes to unique genes. These B cells are then stored in the bone marrow. When the host encounters the pathogen again, they multiply rapidly and confer long-lived immunity. B cells do not explain why vaccines allow them to respond better to unrelated organisms.

Netea proposed in 2012 that BCG works by putting the “natural” arms of the immune system, such as macrophages, at a higher level of vigilance. This is a phenomenon called “trained immunity”. The role of macrophages is to identify, swallow, and destroy foreign bodies. They can also use cytokines to signal enhancement. It was assumed that these guards did not remember the particular pathogen, but stood as a dull front line defense. Twenty years ago, this innate system was considered largely crude and nonspecific, says Luke O’Neill, an immunologist at Trinity College Dublin. “Then there was the Copernicus revolution in immunology. Suddenly I realized how important the congenital dimension was.”

See “Thank you for your memories”

The Nobel Prize was awarded in 2011 to scientists who discovered the innate receptor as a gatekeeper for the immune system. Their work sparked a greater research interest in innate immune cells. Later, Netea proposed that BCG stimulates front-line immune cells through epigenetic alterations and metabolic rewiring. This is to prevent them from being put on higher alert.

Priming the innate immune system is important for vaccines and for future infections. “If you get the BCG first and then the flu vaccine, the flu vaccine works better,” says Netea. He reported this in 2015 in a randomized, placebo-controlled trial of the vaccine against a pandemic strain in 2009. Forty men participated in the experiment. In this fall test, Ben will test if BCG 14 days before the seasonal flu vaccine gives better response in patients age 65 and older.

To understand how BCG protects against future pathogens, Netea infected healthy human volunteers with attenuated yellow fever virus in a randomized, placebo-controlled trial. Subjects who were vaccinated with BCG one month prior to exposure showed significantly lower levels of circulating yellow fever virus than subjects who received placebo instead. This study, published last year, concluded that BCG induced epigenetic reprogramming of human monocytes, resulting in a stronger response to the yellow fever virus.

After BCG administration, “increased production of pro-inflammatory cytokines. They easily recruit immune cells to the site of infection, and those cells are better at killing and eliminating the virus,” says Netea. ..

According to Netea’s hypothesis, BCG can prepare macrophages in such a way as to produce a strong cytokine response locally to SARS-CoV-2 focusing on the site of infection. “This prevents inefficient systemic reactions that can later harm the patient,” he explains, the so-called cytokine storm. Macrophages call B cells and T cells. This means that BCG primed is more efficient at killing SARS-CoV-2 infections.

Innate immunity priming after BCG is probably optimal for 2-3 years, says Netea, an estimate based on epidemiologic data in children. In his view, “the fact that someone was vaccinated 50 or 60 years ago is probably unprotected.” This helps BCG help adults in responding to COVID-19. It goes against the epidemiological data link that suggests that McLaren says even vaccine protection against tuberculosis probably lasts only 20 years. O’Neill is also skeptical of this long-lasting natural priming. He believes that countries such as Japan with high rates of childhood BCG vaccination may indirectly protect older people from COVID-19.

Ben says she thinks innate memory may still surprise us. “We are sure [BCG] The effect lasts at least a year in children. It also shows that it can last much longer, “she says. One Danish study by Aaby and Benn shows that those who received the smallpox or BCG vaccine at school had a 40% or greater reduction in the risk of dying by age 45. “This was not just an infection, but a cardiovascular disease and a neurological disorder,” Ben explains.

BCG clinical trial begins

Netea, working with Ben, has suggested that BCG shots decades ago may protect against COVID-19, but warns that the effectiveness of recent BCG shots remains open-minded. I will. “We need randomized clinical trials to draw conclusions,” he says. Netea says the trials have started in the Netherlands, Greece, Australia, Denmark, France, Germany and the United States, primarily to test BCG in medical staff.

An Australian trial of 4,000 health workers found, “Whether vaccinees reduce COVID-19 and, if they do, they are not upset or ill in the short term. It measures, “says Nigel Curtis. Clinician and researcher at Murdoch Children’s Institute and University of Melbourne.

In the Netherlands, Netea is recruiting 1,500 volunteer healthcare providers, half of which will be randomly selected for BCG. He is also about to begin testing 1,600 volunteers over the age of 60, half of whom received placebo injections and the other half of which are BCG. Netea advocates BCG as a possible precaution to avoid shortages only for at-risk groups. “It could be a bridge to the vaccine,” O’Neill said, because B. tuberculosis lives in the lungs, BCG could probably boost immunity there. “Of course I am waiting for a trial.”

Benn plans a study in Denmark of 1,500 healthcare workers randomized to administer BCG or placebo in Denmark, following up on COVID-19 and other infectious diseases .. Denmark used BCG until the 1980s, so there is a subgroup among newly vaccinated people who once had BCG once at school. Ben assumes that the benefits of BCG will be more pronounced in this subset of healthcare workers than those who did not receive the BCG jab as a child.

BCG shortage risk

The World Health Organization does not recommend BCG for the prevention of COVID-19 due to lack of clinical trial data. There is concern that people may jump guns and determine that BCG is valid before the outcome of the trial. McLaren says he is worried that the proliferation of preprint comparative studies could be harmful. “ If people interpret these correlation studies as high-quality evidence or jump into the BCG epidemic, they may be ineffective and invest in policies that deprive infants and children of the BCG vaccine of their need. There is, ”she says.

Curtis is also worried. He says he heard about a vaccine supply for children being diverted to health workers in parts of Africa. “It’s a tragedy,” Curtis says. “This vaccine protects babies from tuberculosis. If you start using something that hasn’t been proven, you risk paying for young children.”

* Originally created by Anthony King for scientists