Science‘s COVID-19 coverage is supported by the Pulitzer Center.
On 30 April, Valerie McCarthy’s test result confirmed that her grinding fatigue and pummeling headaches were caused by the new coronavirus. She wasn’t hospitalized, but the very next day, a nurse at Stanford University Medical Center gave the 52-year-old marathon runner an injection that contained either a placebo or a natural virus fighter: interferon.
McCarthy was Patient 16 in a clinical trial that, it’s hoped, will help fill a huge void in treatments for COVID-19: Doctors have no drugs that, given early, have been proven to prevent infection or help beat back the virus before it takes hold. So far, the two scientifically validated treatments for COVID-19—remdesivir and dexamethasone—have only been shown to work in hospitalized patients with serious illness.
But a small flurry of recent papers suggests the novel coronavirus does some of its deadly work by disabling interferons, powerful proteins that are the body’s own frontline defenders against viral invasion. If so, synthetic interferons given before or soon after infection may tame the virus before it causes serious disease—a welcome possibility that additional recent studies support.
Several interferons were approved decades ago by the U.S. Food and Drug Administration, their immune-boosting powers deployed against diseases including cancer and hepatitis. And in an early, unrandomized preventive trial in a hospital in China’s Hubei province, none of 2415 medical workers who took daily interferon nose drops got the virus, according to a medRxiv preprint.
The Stanford trial is one of dozens now trying interferons against COVID-19, including in people who aren’t sick but might have been exposed to the virus. First results from a controlled trial at the University of Southampton are expected by August.
“Every study in every species has shown that if you induce interferons before [a] virus comes in, the virus loses,” says Andreas Wack, an immunologist at the Francis Crick Institute. “The earlier you can give it, the better, and the best thing you can do is to give it before the virus is there.”
Timing is crucial, adds Miriam Merad, an immunologist at the Icahn School of Medicine at Mount Sinai. “It’s going to be important to know when to give these drugs.” If given too late in the course of infection, interferons might pour fuel on the out-of-control inflammation that is a hallmark of severe COVID-19, she and others say. “Interferons are strong antivirals,” Merad says. “But they also activate immune cells and can cause immunopathology.”
Interferons are molecular messengers that launch an immediate, intense local response when a virus invades a cell. They trigger production of myriad proteins that attack the virus at every stage of invasion and replication, and they alert uninfected neighboring cells to prepare their own defenses. Interferons also help recruit immune cells to the site of infection and activate them when they arrive.
But SARS-CoV-2, the virus that causes COVID-19, disables this defense by blocking the powerful interferons that lead it, says Benjamin tenOever, a virologist at Mount Sinai. He and his colleagues studied SARS-CoV-2 infection in a range of models: human lung and bronchial cells, ferrets, lung tissue from deceased COVID-19 patients, and blood from living ones. In virtually every system, “interferon is badly suppressed,” tenOever says. As it shuts down interferons, his team reported in Cell in May, the virus also ramps up production of chemokines, a different set of messenger molecules that summon distant immune cells and trigger inflammation.
Findings from a team led by immunologist Benjamin Terrier of the Cochin Hospital in Paris and published as a preprint on medRxiv, echo tenOever’s. Terrier’s team also looked at blood from 50 COVID-19 patients, finding strikingly depressed interferon activity and elevated chemokines in those whose disease became severe and critical—but not in those who ended up with mild or moderate disease. Terrier posits that local viral replication, unchecked by interferons, gins up tissue-damaging inflammation, as do armies of immune cells summoned from afar. The result is the out-of-control inflammatory response that ends many lives (Science, April 24, p. 356).
But not everyone is persuaded that the virus itself is responsible for missing-in-action interferons. Are low interferons “the cause or the consequence of severe disease?” asks Jean-Laurent Casanova, an infectious disease geneticist at the Rockefeller University. Since 2015, he has found three inherited mutations that profoundly inhibit the interferon response, raising the possibility that genetic predisposition plays a role in some cases of severe COVID-19.
And some data challenge the notion that interferons are suppressed at all. One report, published in Cell Host & Microbe by Jianwei Wang of Peking Union Medical College and colleagues last month, found strong expression of numerous interferon-stimulated genes (ISG’s)—often used as a marker for interferon activity—in the lung fluid of eight COVID-19 patients. Similarly, in unpublished data, John Tsang, a systems immunologist at the U.S. National Institute of Allergy and Infectious Diseases, found robust ISG expression in immune cells in the blood of 35 severely ill COVID-19 patients.
All the same, at least five studies since April have found that interferon treatment or pretreatment has a protective effect in cells and in mice infected with SARS-CoV-2. These studies parallel earlier ones that found beneficial effects of early interferon administration in mice infected with the new coronavirus’ cousins, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome. The data support giving interferons as a treatment for COVID-19, especially early in infection, advocates say.
But plenty of caveats remain. For starters, when given as drugs, the powerful type I interferons can have awful side effects, as patients who have taken them for months on end for cancer and other diseases know. Side effects include flulike symptoms, headache, vomiting, and depression. But COVID-19 treatment does not require continuous dosing for months, and one trial in chronic hepatitis showed that a synthetic type III interferon had fewer side effects than a type I interferon. (Type I interferons have receptors on every cell in the body, but type III do not.)
McCarthy’s trial was of a type III interferon. She was warned of “headaches and fatigue,” but was not dissuaded. “I thought: ‘I’m already tired … that’s OK,’” she says.
Two papers published in Science last month suggested type III interferons might be harmful if given late in infection. In one paper, Wack’s group reported that in mice, naturally occurring type III interferon disrupted the lung repair crucial to recovery from influenza; in the other, a team led by immunologist Ivan Zanoni of Boston Children’s Hospital reported similar findings in mice—and also found type III interferons in the lung fluid of severely ill COVID-19 patients. “The take home message for the clinical people,” says Zanoni, is: “If you want to give type III interferons as antivirals, give them early.”
Eleanor Fish, an immunologist at the University of Toronto who is launching, with colleagues, two preventive interferon trials, says data already point to interferons’ safety. She and colleagues published an uncontrolled study of 77 hospitalized patients in Wuhan, China, in Frontiers in Immunology. They reported that patients given a type I interferon (with or without an antiviral medicine) had lower levels of a key inflammatory biomarker than other patients—and also cleared the virus 7 days sooner. Similar promising findings emerged from uncontrolled studies that Fish published years ago, examining the effects of the drugs in patients hospitalized with SARS and Ebola. “This notion of [interferons being] harmful later, I just want to throw it out the window,” Fish says.
Even as scientists debate the underlying biology, they are keenly aware that only controlled clinical trials will answer their questions. As for McCarthy, 8 weeks after first testing negative for the virus, she struggles to slowly run 3 kilometers. She still doesn’t know whether she received placebo or an interferon. Like everyone else, she’ll have to wait for the trial’s results.