Researchers are testing whether decades-old vaccines for polio and tuberculosis could protect against infection. As the world waits for a coronavirus vaccine, tens of thousands of people could die. But some scientists believe a vaccine might already exist. Surprising new research in a niche area of immunology suggests that certain live vaccines that have been around for decades could, possibly, protect against the coronavirus. The theory is that these vaccines could make people less likely to experience serious symptoms — or even any symptoms — if they catch it. At more than 25 universities and clinical centers around the world, researchers have begun clinical trials, primarily in health care workers, to test whether a live tuberculosis vaccine that has been in use for 99 years called the bacillus Calmette-Guérin, or B.C.G., vaccine, could reduce the risks associated with the coronavirus. Another small but esteemed group of scientists is raising money to test the potential protective effects of a 60-year-old live polio vaccine called O.P.V. It’s counterintuitive to think that old vaccines created to fight very different pathogens could defend against the coronavirus. The idea is controversial in part because it challenges the dogma about how vaccines work. But scientists’ understanding of an arm of immunology known as innate immunity has shifted in recent years. A growing body of research suggests that live vaccines, which are made from living but attenuated pathogens (as opposed to inactivated vaccines, which use dead pathogens) provide broad protection against infections in ways that no one anticipated. “We can’t be certain as to what the outcome will be, but I suspect it’ll have an effect” on the coronavirus, said Jeffrey Cirillo, a microbiologist and immunologist at Texas A&M University who is leading one of the B.C.G. trials. “Question is, how big will it be?” Scientists stress that these vaccines will not be a panacea. They might make symptoms milder, but they probably won’t eliminate them. And the protection, if it occurs, would most likely last only a few years. Still, “these could be a first step,” said Dr. Mihai Netea, an immunologist at Radboud University in the Netherlands who is leading another one of the trials. “They can be the bridge until you have the time to develop a specific vaccine.” The first evidence to suggest that live vaccines could be broadly protective trickled in nearly a century ago, but no one knew what to make of it. In 1927, soon after B.C.G. was rolled out, Carl Naslund of the Swedish Tuberculosis Society observed that children vaccinated with the live tuberculosis vaccine were three times less likely to die of any cause compared with kids who weren’t. “One is tempted to explain this very low mortality among vaccinated children by the idea that B.C.G. vaccine provokes a nonspecific immunity,” he wrote in 1932. Then, in clinical trials conducted in the 1940s and ’50s in the United States and Britain, researchers found that B.C.G. reduced nonaccidental deaths from causes other than tuberculosis by an average of 25 percent. Also in the 1950s, Russian researchers, including Marina Voroshilova of the Academy of Medical Science in Moscow, noticed that people who had been given the live polio vaccine, compared with people who hadn’t, were far less likely to fall ill with the seasonal flu and other respiratory infections. She and other scientists undertook a clinical trial involving 320,000 Russians to more carefully test these mysterious effects. They found that among individuals who had received the live polio vaccine, “the incidence of seasonal influenza was reduced by 75 percent,” said Konstantin Chumakov, Voroshilova’s son, who is now an associate director for research in the U.S. Food and Drug Administration’s Office of Vaccines Research and Review. Recent studies have produced similar findings. In a 2016 review of 68 papers commissioned by the World Health Organization, a team of researchers concluded that B.C.G., along with other live vaccines, “reduce overall mortality by more than would be expected through their effects on the diseases they prevent.” The W.H.O. has long been skeptical about these “nonspecific effects,” in part because much of the research on them has involved observational studies that don’t establish cause and effect. But in a recent report incorporating newer results from some clinical trials, the organization described nonspecific vaccine effects as “plausible and common.” Dr. Stanley Plotkin, a vaccinologist and emeritus professor at the University of Pennsylvania who developed the rubella vaccine but has no involvement in the current research, agreed. “Vaccines can affect the immune system beyond the response to the specific pathogen,” he said. Peter Aaby, a Danish anthropologist who has spent 40 years studying the nonspecific effects of vaccines in Guinea-Bissau, in West Africa, and whose findings have been criticized as implausible, is hopeful that these trials will be a tipping point for research in the field. “It’s kind of a golden moment in terms of actually having this taken seriously,” he said. The possibility that vaccines could have nonspecific effects is brow-furrowing in part because scientists have long believed that vaccines work by stimulating the body’s highly specific adaptive immune system. After receiving a vaccine against, say, polio, a person’s body creates an army of polio-specific antibodies that recognize and attack the virus before it has a chance to take hold. Antibodies against polio can’t fight off infections caused by other pathogens, though — so, based on this framework, polio vaccines should not be able to reduce the risk associated with other viruses, such as the coronavirus. But over the past decade, immunologists have discovered that live vaccines also stimulate the innate immune system, which is less specific but much faster. They have found that the innate immune system can be trained by live vaccines to better fight off various kinds of pathogens. For instance, in a 2018 study, Dr. Netea and his colleagues vaccinated volunteers with either B.C.G. or a placebo and then infected them all with a harmless version of the yellow fever virus. Those who had been given B.C.G. were better able to fight off yellow fever. Research by Dr. Netea and others shows that live vaccines train the body’s immune system by initiating changes in some stem cells. Among other things, the vaccines initiate the creation of tiny marks that help cells turn on genes involved in immune protection against multiple pathogens. This area of innate immunity “is one of the hottest areas in fundamental immunology today,” said Dr. Robert Gallo, the director of the Institute of Human Virology at the University of Maryland School of Medicine and co-founder of the Global Virus Network, a coalition of virologists from more than 30 countries. In the 1980s, Dr. Gallo helped to identify H.I.V. as the cause of AIDS. Dr. Gallo is leading the charge to test the O.P.V. live polio vaccine as a treatment for coronavirus. He and his colleagues hope to start a clinical trial on health care workers in New York City and Maryland within six weeks. O.P.V. is routinely used in 143 countries, but no longer in the United States. An inactivated polio vaccine was reintroduced here in 1997, in part because one out of every 2.7 million people who receive the live vaccine can actually develop polio from it. But O.P.V. does not pose this risk to Americans who have received a polio vaccine in the past. “We believe this is very, very, very safe,” Dr. Gallo said. It’s also inexpensive at 12 cents a dose, and is administered orally, so it doesn’t require needles. Some scientists have raised concerns over whether these vaccines could increase the risk for “cytokine storms” — deadly inflammatory reactions that have been observed in some people weeks after they have been infected with the coronavirus. Dr. Netea and others said that they were taking these concerns seriously but did not anticipate problems. For one thing, the vaccines will be given only to healthy people — not to people who are already infected. Also, B.C.G. may actually be able to ramp up the body’s initial immune response in ways that reduce the amount of virus in the body, such that an inflammatory response never occurs. It may “lead to less infection to start with,” said Dr. Moshe Arditi, the director of the Infectious and Immunological Diseases Research Center at Cedars-Sinai Medical Center in Los Angeles, who is leading one of the trial arms. The science on this is still early days. Several pre-prints — scientific papers that have not yet been peer-reviewed — published over the past few months support the idea that B.C.G. could protect against the coronavirus. They have reported, for instance, that death rates are lower in countries that routinely vaccinate children with B.C.G. But these studies can be fraught with bias and difficult to interpret; it’s impossible to know whether the vaccinations, or something else, provided the protection. Such studies are “at the very bottom of the evidence hierarchy,” said Dr. Christine Stabell Benn, who is raising funds for a Danish B.C.G trial. She added that the protective effects of a dose of B.C.G given to adults decades ago, when they were infants, may well differ from the protective effects the vaccine could provide when given to adults during an outbreak. “In the end,” said Dr. Netea, “only the clinical trials will give the answer.” Thankfully, that answer will come very soon. Initial results from the trials that are underway may be available within a few months. If these researchers are right, these old vaccines could buy us time — and save thousands of lives — while we work to develop a new one. Source
