COVID-19 Antibody Study: A stunning observation and a game-changer?

An American COVID-19 Immunity Study is a Game Changer and comes from HHMI Virginia
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If you catch COVID-19, what are the chances you will die or get severely ill? This is an important question, and if a simple test can predict this even before you get the virus, it would create a priority list for people that should be more careful or get the vaccine earlier. If this knowledge could also offer treatment, this would be a true game-changer.

It would certainly be a game-changer, and we may already be at this point according to two new studies by HHMI in Virginia, USA that offers an explanation for why COVID-19 cases can be so variable.

A subset of patients has mutations in key immunity genes; other patients have autoantibodies that target the same components of the immune system. Both circumstances could contribute to severe forms of the disease.

HHMI scientists are joining many of their colleagues worldwide in working to combat the new coronavirus. Theyโ€™re developing diagnostic testing, understanding the virusโ€™s basic biology, modeling the epidemiology, and developing potential therapies or vaccines. Over the next several weeks, we will beย sharing stories of some of this work.

People infected by the novel coronavirus can have symptoms that range from mild to deadly. Now, two new analyses suggest that some life-threatening cases can be traced to weak spots in patientsโ€™ immune systems.

At least 3.5 percent of study patients with severe COVID-19, the disease caused by the novel coronavirus, have mutations in genes involved in antiviral defense. And at least 10 percent of patients with severe disease create โ€œauto-antibodiesโ€ that attack the immune system, instead of fighting the virus. The results, reported in two papers in the journal Science on September 24, 2020, identify some root causes of life-threatening COVID-19, says study leader Jean-Laurent Casanova, a Howard Hughes Medical Institute Investigator at The Rockefeller University.

Seeing these harmful antibodies in so many patients โ€“ 101 out of 987 โ€“ was โ€œa stunning observation,โ€ he says. โ€œThese two papers provide the first explanation for why COVID-19 can be so severe in some people, while most others infected by the same virus are okay.โ€

The work has immediate implications for diagnostics and treatment, Casanova says. If someone tests positive for the virus, they should โ€œabsolutelyโ€ be tested for the auto-antibodies, too, he adds, โ€œwith medical follow-up if those tests are positive.โ€ Itโ€™s possible that removing such antibodies from the blood could ease symptoms of the disease.

A global effort

Casanovaโ€™s team, in collaboration with clinicians around the world, first began enrolling COVID-19 patients in their study in February. At the time, they were seeking young people with severe forms of the disease to investigate whether these patients might have underlying weaknesses in their immune systems that made them especially vulnerable to the virus.

The plan was to scan patientsโ€™ genomes โ€“ in particular, a set of 13 genes involved in interferon immunity against influenza. In healthy people, interferon molecules act as the bodyโ€™s security system. They detect invading viruses and bacteria and sound the alarm, which brings other immune defenders to the scene.

Casanovaโ€™s team has previously discovered genetic mutations that hinder interferon production and function. People with these mutations are more vulnerable to certain pathogens, including those that cause influenza. Finding similar mutations in people with COVID-19, the team thought, could help doctors identify patients at risk of developing severe forms of the disease. It could also point to new directions for treatment, he says.

In March, Casanovaโ€™s team was aiming to enroll 500 patients with severe COVID-19 worldwide in their study. By August, they had more than 1,500, and they now have over 3,000. As the researchers began analyzing patient samples, they started to uncover harmful mutations, in people young and old. The team found that 23 out of 659 patients studied carried errors in genes involved in producing antiviral interferons, the team found.

Without a full complement of these antiviral defenders, COVID-19 patients wouldnโ€™t be able to fend off the virus, the researchers suspected. That thought sparked a new idea. Maybe other patients with severe COVID-19 also lacked interferons โ€“ but for a different reason. Maybe some patientsโ€™ bodies were harming these molecules themselves. As in autoimmune disorders such as type 1 diabetes and rheumatoid arthritis, some patients might be making antibodies that target the body. โ€œThat was the eureka moment for us,โ€ Casanova says.

The teamโ€™s analysis of 987 patients with life-threatening COVID-19 revealed just that. At least 101 of the patients had auto-antibodies against an assortment of interferon proteins. โ€œWe said, โ€˜bingoโ€™!โ€ Casanova remembers. These antibodies blocked interferon action and were not present in patients with mild COVID-19 cases, the researchers discovered.

โ€œItโ€™s an unprecedented finding,โ€ says study co-author Isabelle Meyts, a pediatrician at the University Hospitals KU Leuven, in Belgium, who earlier this year helped enroll patients in the study, gather samples, and perform experiments. By testing for the presence of these antibodies, she says, โ€œyou can almost predict who will become severely ill.โ€

The vast majority โ€“ 94 percent โ€“ of patients with the harmful antibodies were men, the team found. Men are more likely to develop severe forms of COVID-19, and this work offers one explanation for that gender variability, Meyts says.

Casanovaโ€™s lab is now looking for the genetic driver behind those auto-antibodies. They could be linked to mutations on the X chromosome, he says. Such mutations might not affect women, because they have a second X chromosome to compensate for any defects in the first. But for men, who carry only a single X, even small genetic errors can be consequential.

Looking ahead

Clinically, the teamโ€™s new work could change how doctors and health officials think about vaccination distribution strategies, and even potential treatments. A clinical trial could examine, for instance, whether infected people who have the auto-antibodies benefit from treatment with one of the 17 interferons not neutralized by the auto-antibodies, or with plasmapheresis, a medical procedure that strips the antibodies from patientsโ€™ blood. Either method could potentially counteract the effect of these harmful antibodies, Meyts says.

In addition to the current work, Meyts, Casanova, and hundreds of other scientists involved with an international consortium called the COVID Human Genetic Effort are working to understand a second piece of the coronavirus puzzle. Instead of hunting for factors that make patients especially vulnerable to COVID-19, theyโ€™re looking for the opposite โ€“ genetic factors that might be protective. Theyโ€™re now recruiting people from the households of patients with severe COVID-19 โ€“ people who were exposed to the virus but did not develop the disease. โ€œOur lab is currently running at full speed,โ€ Casanova says.


About the author

Avatar of Juergen T Steinmetz

Juergen T Steinmetz

Juergen Thomas Steinmetz has continuously worked in the travel and tourism industry since he was a teenager in Germany (1977).
He founded eTurboNews in 1999 as the first online newsletter for the global travel tourism industry.

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