Blood of coronavirus survivors saves lives

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While waiting for a vaccine against the coronavirus, the spotlight of COVID-19 treatments is returning to antibodies, the body’s natural defenses against viruses.

Federal health officials launched two large clinical trials of synthetic antibodies to treat mild, moderate, and hospitalized coronavirus cases on Monday. Biotech company launches related trial in nursing homes. And the FDA is expected to give emergency clearance soon to treat patients with the “convalescent plasma” of COVID-19 survivors – the part of the blood that is rich in antibodies.

While almost no US hospital used convalescent plasma treatment before April, it is now being administered to about 1,500 patients per day in about 2,000 hospitals nationwide. And antibodies only seem more likely to develop until a vaccine comes along. Preliminary analysis of data from about 50,000 patients presented to the FDA on Saturday at a Mayo Clinic symposium found a 10% drop in deaths among critically ill hospitalized patients with COVID-19 receiving plasma with higher concentrations of antibodies compared to those receiving lower doses.

But because plasma treatment relies on people continuing to get sick and recover from COVID-19, it’s not a permanent solution. Other treatment options involving antibodies, including making them from scratch, may hold promise in the longer term.

“Convalescent plasma was never intended to be the end treatment for disease,” infectious disease expert Nicole Bouvier from Icahn School of Medicine at Mount Sinai told BuzzFeed News. “It gives us more time to work on creating other therapies.”

The antibodies are made in dizzying varieties by patients with SARS-CoV-2 infection, with studies showing that people with more severe disease can produce higher levels of protective proteins. They work by glumming on the outside of viruses, blocking their reproduction and marking them for elimination by other cells. Their signature in the bloodstream is a sign of a past infection.

Convalescent plasma, the yellowish fluid transfused into patients, is essentially blood stripped of red and white blood cells, leaving behind antibodies, water, salt, and enzymes. In the coronavirus pandemic, tests to distinguish convalescent plasma doses with high amounts of antibodies from those with low doses have only been validated in recent months. In the Mayo Clinic analysis, scientists were in many cases unable to retrospectively verify what dose of antibody patients had received, allowing them to see how those doses might have affected their results.

“Nature is the maker,” said Bouvier. “This is why this is both the fastest therapy we will have for a virus, and also why it will never be more than a stopgap.”

In April, the FDA first promoted antibodies for this stopping role as US cases began to rise in New York City, calling on the Mayo Clinic and blood banks nationwide to provide convalescent plasma for patients. in accordance with national guidelines for emergency use. At least 85,000 patients have received convalescent plasma as part of the program, so far, Mayo Clinic cardiologist Scott Wright told BuzzFeed News. “The machines to do this work. We have made extraordinary progress.

Convalescent plasma has been used against viruses for over a century, including during the 1918 influenza pandemic and as early as 1907 against polio, as well as more recently in the SARS and MERS coronavirus outbreaks.

Ironically, the popularity of convalescent plasma has undermined attempts to verify its effectiveness in fully randomized clinical trials for at least two reasons. First, doctors are reluctant to subject sick patients to trials because they are at risk of receiving a placebo instead of the antibodies, as The New York Times reported this week.

And as the number of cases has plummeted in cities like New York, where trials were first launched, clinical trials “are running out of patients,” Johns Hopkins Bloomberg immunologist Arturo Casadevall said. School of Public Health at BuzzFeed News. A trial in Wuhan, China, was also halted after recruiting just 103 volunteers, half the number needed, when the outbreak ended there. The published results of this trial did not find a statistical benefit for the treatment, but indicated better recovery in patients who received plasma with higher concentrations of antibodies.

“Asking doctors to organize protocols and get clearances for a clinical trial – which are vital to protecting patient safety, and only take time – in the midst of them, treating an overwhelming number of people failing to will not happen, ”Bouvier said.

Nonetheless, the data is very encouraging from less rigorous studies where patients who received plasma are compared retrospectively with those who did not, Bouvier said. In particular, these early studies show that high doses of antibodies in convalescent plasma do not trigger overreactions of the immune system, known as cytokine storms, which kill many patients with the most severe COVID-19. A related effort is underway to pool data from half-completed randomized clinical trials to also complete a study.

Wright and Casadevall both attributed a lower death rate in hospitalized COVID-19 patients in part to improved therapies, including convalescent plasma. “We are improving in the treatment,” said Wright. “But it’s still a terrible disease. It’s not the flu or the common cold – it’s much worse.

If convalescent plasma receives emergency use clearance from the FDA, as reported by the Wall Street Journal, it will join the antiviral drug remdesivir and the steroid drug dexamethasone as the only clearly helpful treatments for COVID-19. “What’s important is that we now understand that convalescent plasma is better at the onset of an infection,” said Casadevall. Remdesivir is prioritized later in infection in hospital patients on oxygen, and dexamethasone is more helpful in the worst cases, when patients are on a ventilator.

In that sense, the first results from the Mayo Clinic only revealed a reduction in deaths among patients receiving the plasma only within three days of hospitalization, Wright said. They found that convalescent plasma rich in a kind of antibody called immunoglobulin G, usually produced later in an infection, was a better indicator of survival than a larger measure of “neutralizing” antibodies.

It makes sense that antibody transfusions are more effective early in infection, when virus levels are highest in COVID-19 patients, Casadevall said. Patients on ventilators later in the illness often seem to die from the overreacting of their immune system and the tracking of their own organs, when more antibodies could be harmful. This explains why drugs like dexamethasone, which suppress immune system responses, are useful later in an infection.

“It’s important now because we’re talking about people who don’t require hospitalization and those who are in hospital but don’t require the types of interventions that we see in advanced disease,” said the National Allergy Institute and Anthony Fauci, head of infectious diseases, during a briefing Monday on synthetic antibody testing in patients.

These tests will be important because relying on COVID-19 survivors to produce convalescent plasma is too limited an approach in a pandemic, both because of the totally random batch of antibodies each patient produces and the limited number. of antibodies that a person can make.

Monoclonal antibodies are fabricated versions of those of human origin found in convalescent plasma, chosen to mimic those that show the best “neutralizing” effect – blocking reproduction of the virus. They are difficult to manufacture, requiring industrial scale-up of “humanized” mouse cells. The breast cancer drug Herceptin is one of the best known examples and one of the most expensive treatments.

In one of the trials announced Monday by Fauci and other federal officials, called ACTIV-2, half of 220 outpatients with COVID-19 will receive an injection of a particularly potent neutralizing antibody copied from a patient healed. In a second trial called ACTIV-3, 300 people hospitalized with mild to moderate COVID-19 will either receive the antibodies or a placebo infusion and follow for five days. If it turns out to be safe, another 700 patients will be enrolled in the trial, converting it to a larger Phase 3 trial that will include people with more serious illness.

Janet Woodcock, the FDA official overseeing therapeutics for the White House’s Operation Warp Speed, has hinted that an announcement to increase funding for the manufacture of monoclonal antibodies would be from the Trump administration, after an Eli Lilly representative acknowledged that the company should only have 100,000 doses of monoclonal antibodies ready by November, when trials will hopefully be completed.

Flexible clinical trials like ACTIV’s, with multiple sites to take advantage of the surge in outbreaks and then their decline, is a new lesson learned from the coronavirus pandemic.

“If, God forbid, we have another pandemic besides this one, bird flu or whatever, we need to act quickly to get these clinical trials in place before anyone gets sick,” Casadevall said. “You really must have them almost ready on tap.” ●

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