NEWS

Organizers also kept Recovery simple, a group receiving a placebo. “We’ll know COVID-19 allowing any NHS hospital to participate. what happened to those patients, but we Inspired by trials of heart-attack treatments won’t know whether they would have been that his Oxford colleague Richard Peto and better off actually, if they hadn’t got the Can interferons others did in the 1980s, Landray says they convalescent plasma.” Convincing clinicians radically cut down on the data health care that therapies still need to be tested can be workers need to collect, with only a few difficult, Henao Restrepo says. “Some are stop COVID-19 questions asked at enrollment and at just convinced they know which drugs work.” one later point: when the patient dies, is She still has high expectations for the discharged, or 28 days after enrollment. Solidarity trial. “The preparatory work is before it Clinical trials have become excessively cum- paying off,” she says. Its recruitment has bersome in recent years, Landray argues. picked up as more countries, many with Solidarity has a similarly straightforward surging cases such as Iran, have joined. So takes hold? design, but its more international nature has far, 39 countries are participating and 60 proved a challenge. The trial, designed to more signing up. “One of the advantages of Biology of infection supports test four treatments—hydroxychloroquine, such a global trial is that you can follow the early treatment with body’s lopinavir/ritonavir, interferon beta plus pandemic as it evolves,” Røttingen says. lopinavir/ritonavir, and remdesivir—was an- With recruitment running at about own viral defenses nounced on 20 March and enrolled its first 500 patients per week now, Solidarity’s two patient in Norway 1 week later. But rolling out remaining treatment arms—it stopped the By Meredith Wadman the trial in dozens of countries hydroxychloroquine and the Downloaded from has meant getting approval lopinavir/ritonavir ones as n 30 April, Valerie McCarthy’s test from dozens of regulatory “The three results emerged—are likely result confirmed that her grinding agencies and ethics boards as to yield answers soon, raising fatigue and pummeling headaches well. “That has taken a surpris- Recovery trials the question of what drugs to were caused by the new coronavi- ingly long time in many juris- are the best trials test afterward. More repur- rus. She wasn’t hospitalized, but the

O http://science.sciencemag.org/ dictions, including in Europe,” posed drugs are being dis- very next day, a nurse at Stanford Røttingen says, and recruit- that have been cussed, but increasingly the University Medical Center gave the 52-year- ment in Europe slowed over attention is turning to mono- old marathon runner an injection that con- time as the epidemic subsided. performed to date.” clonal antibodies targeting tained either a placebo or a natural virus “When countries were ready to Eric Topol, the virus. fighter: interferon. sort of start, the epidemic was Scripps Research Henao Restrepo thinks the McCarthy was Patient 16 in a clinical trial under control in many ways,” Translational Institute international nature of Soli- that, it’s hoped, will help fill a huge void in he notes. darity makes its results more treatments for COVID-19: Doctors have no A European trial called Discovery, coor- generalizable and likely to be accepted. drugs that, given early, have been proven to dinated by the French research institute Herold expects that the Discovery trial con- prevent infection or help beat back the virus INSERM and meant to join with Solidarity tribute as well. Started in part to supple- before it takes hold. So far, the two scientifi- in testing the same drugs, also fell short. ment Solidarity, it collects not only basic cally validated treatments for COVID-19— on July 9, 2020 The goal was to enroll 3200 patients across mortality data, but also information on vi- remdesivir and dexamethasone—have only the continent. The study almost met its ral levels and blood parameters. Those data been shown to work in hospitalized patients goal of 800 participants in France, but it can indicate not just which drugs are effec- with serious illness. barely managed to recruit patients else- tive, but also how they work and at what But a small flurry of recent papers sug- where. Although France funded its part of stage of the disease. gests the novel coronavirus does some of its the trial, it expected partner countries to The Recovery trial continues, with its deadly work by disabling interferons, pow- pick up their own tabs. “One of the issues team scrambling to publish full results. erful proteins that are the body’s own front- was that not all the countries had funding,” Some researchers have criticized its prac- line defenders against viral invasion. If so, says Yazdan Yazdanpanah, head of infec- tice of releasing important results as press synthetic interferons given before or soon tious diseases at INSERM. releases; so far, it has given details for after infection may tame the virus before it Meanwhile dozens of small trials competed only one of the three headline findings, causes serious disease—a welcome possibil- for patients in countries, most of them focus- on dexamethasone, in a preprint posted ity that additional recent studies support. ing on the same drugs, such as hydroxychlo- 6 days after the release. The Recovery team Several interferons were approved de- roquine. “I don’t understand why everyone is still collecting trial data on the antibiotic cades ago by the U.S. Food and Drug Ad- was looking at the same thing,” Yazdanpa- azithromycin, an antibody called tocili- ministration, their immune-boosting powers nah says. “I think we can do better.” Susanne zumab, and the antibody-rich plasma col- deployed against diseases including cancer Herold, an expert on pulmonary infections lected from recovered patients. and hepatitis. And in an early, unrandom- at the University of Giessen, agrees. “There Results on those therapies are likely ized preventive trial in a hospital in ’s needs to be more coordination both within months away, Landray says. But he cautions Hubei province, none of 2415 medical work- countries and across borders,” she says. he has been wrong before. On the morning ers who took daily interferon nose drops got Another problem has been the wide- of 4 June, he had predicted the first results the virus, according to a medRxiv preprint. spread use of treatments outside of ran- from Recovery would likely come in early The Stanford trial is one of dozens now domized trials. Landray notes that tens July. A few hours later, the chairperson of trying interferons against COVID-19, in- of thousands of COVID-19 patients in the the trial’s data monitoring committee called cluding in people who aren’t sick but United States have been given convales- him to say there was enough patient data to might have been exposed to the virus. First cent plasma, for instance, but not alongside declare a verdict on hydroxychloroquine. j results from a controlled trial at the Univer-

SCIENCE sciencemag.org 10 JULY 2020 • VOL 369 ISSUE 6500 125

Published by AAAS NEWS | IN DEPTH sity of Southampton are expected by August. summoned from afar. The result is the out- patients who have taken them for months “Every study in every species has shown of-control inflammatory response that ends on end for cancer and other diseases know. that if you induce interferons before [a] vi- many lives (Science, April 24, p. 356). Side effects include flulike symptoms, rus comes in, the virus loses,” says Andreas But not everyone is persuaded that the headache, vomiting, and depression. But Wack, an immunologist at the Francis Crick virus itself is responsible for missing-in- COVID-19 treatment does not require con- Institute. “The earlier you can give it, the action interferons. Are low interferons “the tinuous dosing for months, and one trial in better, and the best thing you can do is to cause or the consequence of severe disease?” chronic hepatitis showed that a synthetic give it before the virus is there.” asks Jean-Laurent Casanova, an infectious type III interferon had fewer side effects Timing is crucial, adds Miriam Merad, an disease geneticist at the Rockefeller Univer- than a type I interferon. (Type I interferons immunologist at the Icahn School of Medi- sity. Since 2015, he has found three inher- have receptors on every cell in the body, but cine at Mount Sinai. “It’s going to be im- ited mutations that profoundly inhibit the type III do not.) portant to know when to give these drugs.” interferon response, raising the possibility McCarthy’s trial was of a type III inter- If given too late in the course of infection, that genetic predisposition plays a role in feron. She was warned of “headaches and interferons might pour fuel on the out-of- some cases of severe COVID-19. fatigue,” but was not dissuaded. “I thought: control inflammation that is a hallmark of And some data challenge the notion that ‘I’m already tired … that’s OK,’” she says. severe COVID-19, she and others say. “In- interferons are suppressed at all. One re- Two papers published in Science last terferons are strong antivirals,” Merad says. port, published in Cell Host & Microbe by month suggested type III interferons might “But they also activate immune cells and Jianwei Wang of Peking Union Medical be harmful if given late in infection. In one can cause immunopathology.” College and colleagues last month, found paper, Wack’s group reported that in mice, Interferons are molecular messengers strong expression of numerous interferon- naturally occurring type III interferon dis- that launch an immediate, rupted the lung repair crucial Downloaded from intense local response when to recovery from influenza; a virus invades a cell. They in the other, a team led by trigger production of myriad immunologist Ivan Zanoni of proteins that attack the virus Boston Children’s Hospital at every stage of invasion and reported similar findings in

replication, and they alert un- mice—and also found type III http://science.sciencemag.org/ infected neighboring cells to interferons in the lung fluid of prepare their own defenses. severely ill COVID-19 patients. Interferons also help recruit “The take home message immune cells to the site of for the clinical people,” says infection and activate them Zanoni, is: “If you want to give when they arrive. type III interferons as antivi- But SARS-CoV-2, the virus rals, give them early.” that causes COVID-19, disables Eleanor Fish, an immuno- this defense by blocking the logist at the University of To- powerful interferons that lead ronto who is launching, with it, says Benjamin tenOever, colleagues, two preventive on July 9, 2020 a virologist at Mount Sinai. interferon trials, says data He and his colleagues stud- Valerie McCarthy received an injection that contained either placebo or an interferon. already point to interferons’ ied SARS-CoV-2 infection in safety. She and colleagues pub- a range of models: human lung and bron- stimulated genes (ISG’s)—often used as a lished an uncontrolled study of 77 hospital- chial cells, ferrets, lung tissue from deceased marker for interferon activity—in the lung ized patients in Wuhan, China, in Frontiers COVID-19 patients, and blood from living fluid of eight COVID-19 patients. Similarly, in . They reported that patients ones. In virtually every system, “interferon is in unpublished data, John Tsang, a systems given a type I interferon (with or without badly suppressed,” tenOever says. As it shuts immunologist at the U.S. National Institute an antiviral medicine) had lower levels of down interferons, his team reported in Cell of Allergy and Infectious Diseases, found ro- a key inflammatory biomarker than other in May, the virus also ramps up production bust ISG expression in immune cells in the patients—and also cleared the virus 7 days of , a different set of messenger blood of 35 severely ill COVID-19 patients. sooner. Similar promising findings emerged molecules that summon distant immune All the same, at least five studies since from uncontrolled studies that Fish pub- cells and trigger inflammation. April have found that interferon treatment lished years ago, examining the effects of Findings from a team led by immuno- or pretreatment has a protective effect in the drugs in patients hospitalized with SARS logist Benjamin Terrier of the Cochin Hos- cells and in mice infected with SARS-CoV-2. and . “This notion of [interferons be- pital in Paris and published as a preprint These studies parallel earlier ones that found ing] harmful later, I just want to throw it out on medRxiv, echo tenOever’s. Terrier’s team beneficial effects of early interferon adminis- the window,” Fish says. also looked at blood from 50 COVID-19 tration in mice infected with the new coro- Even as scientists debate the underlying patients, finding strikingly depressed in- navirus’ cousins, severe acute respiratory biology, they are keenly aware that only con- terferon activity and elevated chemokines syndrome (SARS) and Middle East respi- trolled clinical trials will answer their ques- in those whose disease became severe and ratory syndrome. The data support giving tions. As for McCarthy, 8 weeks after first critical—but not in those who ended up interferons as a treatment for COVID-19, es- testing negative for the virus, she struggles with mild or moderate disease. Terrier pos- pecially early in infection, advocates say. to slowly run 3 kilometers. She still doesn’t its that local viral replication, unchecked But plenty of caveats remain. For start- know whether she received placebo or an by interferons, gins up tissue-damaging in- ers, when given as drugs, the powerful type interferon. Like everyone else, she’ll have to j flammation, as do armies of immune cells I interferons can have awful side effects, as wait for the trial’s results. FISCH STEVE PHOTO:

126 10 JULY 2020 • VOL 369 ISSUE 6500 sciencemag.org SCIENCE

Published by AAAS Can interferons stop COVID-19 before it takes hold? Meredith Wadman

Science 369 (6500), 125-126. DOI: 10.1126/science.369.6500.125 Downloaded from

ARTICLE TOOLS http://science.sciencemag.org/content/369/6500/125

PERMISSIONS http://www.sciencemag.org/help/reprints-and-permissions http://science.sciencemag.org/

on July 9, 2020

Use of this article is subject to the Terms of Service

Science (print ISSN 0036-8075; online ISSN 1095-9203) is published by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. The title Science is a registered trademark of AAAS. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works