As we await a coronavirus vaccine, the spotlight in COVID-19 treatments is returning to antibodies, the body’s natural defenses against viruses.
On Monday, federal health officials kicked off two large clinical trials of synthetic antibodies to treat mild, moderate, and hospitalized coronavirus cases. A biotech firm is starting a related trial in nursing homes. And the FDA is expected to soon give emergency authorization to treating patients with the “convalescent plasma” of COVID-19 survivors — the part of blood that is rich in antibodies.
While almost no US hospitals were using convalescent plasma treatment before April, it is now administered to an estimated 1,500 patients a day in around 2,000 hospitals nationwide. And antibodies look only more likely to expand in use until a vaccine arrives. A 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 COVID-19 patients given plasma with higher concentrations of antibodies compared to those given lower dose ones.
But since 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 manufacturing them from scratch, could hold longer-term promise.
“Convalescent plasma was never intended to be the final treatment for a disease,” infectious disease expert Nicole Bouvier of the Icahn School of Medicine at Mount Sinai told BuzzFeed News. “It gives us more time to work on making other therapeutics.”
Antibodies are made in dizzying varieties by patients with a SARS-CoV-2 infection, with studies showing that people with more severe illness may produce higher levels of the protective proteins. They work by glomming onto the outside of viruses, blocking their reproduction and marking them for disposal 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 tell 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 only able to check how high of a dose of antibodies patients got in retrospect, allowing them to see how those doses may have affected their outcomes.
“Nature is the manufacturer,” said Bouvier. “That’s why it is both the quickest therapy we will have for a virus, and also why it will never be more than a stopgap.”
In April, the FDA had first promoted antibodies for that stopgap role as US cases started to surge in New York, calling for the Mayo Clinic and blood banks nationwide to deliver convalescent plasma to patients under nationwide emergency use guidelines. At least 85,000 patients have received convalescent plasma under the program, so far, Mayo Clinic cardiologist Scott Wright told BuzzFeed News. “The machinery to do this is running. We’ve made extraordinary strides.”
Convalescent plasma has been employed against viruses for more than a century, including in the 1918 flu pandemic and as far back 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 enter sick patients into trials since they face a chance of receiving a placebo instead of the antibodies, as the New York Times reported this week.
And as case numbers have dropped in the cities like New York City where the trials were first launched, the clinical trials “have run out of patients,” immunologist Arturo Casadevall of the Johns Hopkins Bloomberg School of Public Health told BuzzFeed News. A trial in Wuhan, China, was also halted after only enrolling 103 volunteers, half the number it needed, when the outbreak ended there. The published results of that trial didn’t find a statistical benefit to the treatment, but did point to better recoveries in patients who received plasma with higher concentrations of antibodies.
“Asking doctors to organize the protocols and get permissions for a clinical trial — which are vital to protecting patient safety, and just take time — in the middle of them treating crushing numbers of people isn’t going to happen,” said Bouvier.
Nevertheless, the data are very encouraging from less rigorous studies where patients who received plasma are matched retrospectively against those who didn’t, said Bouvier. In particular, these early studies show that high-antibody doses of convalescent plasma don’t trigger the immune system overreactions, called cytokine storms, that cause many of the most severe COVID-19 patients to die. A related effort is underway to pool the data from half-completed randomized clinical trials to complete a study as well.
Both Wright and Casadevall attributed a lower death rate among hospitalized COVID-19 patients partly to improved therapies, including convalescent plasma. “We are getting better at treatment,” said Wright. “But this is still a terrible disease. It’s not the flu or a cold — it’s a lot worse.”
If convalescent plasma receives an emergency use authorization designation from the FDA, as the Wall Street Journal has reported is under consideration, it will join the antiviral drug remdesivir and the steroid drug dexamethasone as the only clearly useful treatments for COVID-19. “What’s important is we now understand that convalescent plasma is better early in an infection,” said Casadevall. Remdesivir is prioritized later in an infection for hospitalized patients on oxygen, and dexamethasone is most helpful for the worst cases, where patients are on a ventilator.
Along these lines, the early Mayo Clinic results only found a reduction in deaths among patients given the plasma within three days of hospitalization, said Wright. They found convalescent plasma rich in a kind of antibody called immunoglobulin G, typically produced later in an infection, was a better indicator of survival than a broader measure of “neutralizing” antibodies.
It makes sense that antibody transfusions would be most effective early in the infection, when virus levels are highest in COVID-19 patients, said Casadevall. Patients on ventilators later in the course of the disease appear often to be dying from their immune system overreacting and tracking their own organs, when more antibodies could be harmful. That explains why drugs like dexamethasone, which tamps down immune system responses, are helpful later on in an infection.
“This is important now because we're talking about people who don't require hospitalization and those who are in the hospital but don't require the kinds of intervention that we see in late-stage disease,” said National Institute of Allergy and Infectious Diseases chief Anthony Fauci, in a Monday briefing on testing synthetic antibodies 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 that each patient produces and the limited number of antibodies any one person can make.
Monoclonal antibodies are manufactured versions of the human-made ones found in convalescent plasma, picked to mimic the ones that show the best “neutralizing” effect — blocking reproduction of the virus. They are difficult to make, requiring industrial scale-ups of cells from “humanized” mice. The breast cancer drug Herceptin is one of the best-known examples and is one of the most expensive treatments around.
In one of the trials announced by Fauci and other federal officials on Monday, called ACTIV-2, half of around 220 outpatients with COVID-19 will receive a shot of a particularly potent neutralizing antibody copied from a recovered patient. In a second trial called ACTIV-3, 300 people hospitalized with mild to moderate COVID-19 will be given either the antibodies or a placebo infusion and watched for five days. If it proves safe, another 700 patients will be enrolled in the trial, converting it to a larger Phase 3 trial that will include people with more severe illness.
Janet Woodcock, the FDA official assigned to oversee therapeutics on the White House's Operation Warp Speed effort, hinted that an announcement of increased funding for manufacturing monoclonal antibodies would be forthcoming from the Trump administration, after an Eli Lilly representative acknowledged the firm expected to have only 100,000 monoclonal antibody doses ready by November, when the trials will hopefully be completed.
Flexible clinical trials like the ACTIV ones, with multiple locations to take advantage of outbreaks surging and then receding, are a new lesson learned from the coronavirus pandemic.
“If, God forbid, we have another pandemic on top of this one, of bird flu or anything else, we have to move rapidly to set up these clinical trials before anyone gets ill,” said Casadevall. “You really have to have them almost ready on tap.” ●