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On January 10, as soon as the genetic sequence was posted for the new coronavirus then rampaging through China—it didn’t even have the name SARS-CoV-2 yet—Florian Krammer and his lab went to work. Krammer is a virologist and vaccinologist at the Mount Sinai School of Medicine; he specializes in figuring out the bits and pieces of viruses that can teach the human immune system to recognize and fight off germs.
But this time, Krammer wasn’t looking for the soul of a new coronavirus vaccine—at least, not necessarily. He was looking for the sequence for the gene that makes a protein called a spike. Coronaviruses wave it from their outer shells like a cudgel. It’s part of the machinery they use to attach to and invade cells, turning them into factories for making more viruses (and making people sick along the way). Krammer planned to engineer cells to make that spike protein, so he could drag it through a blood sample to see if any antibodies—the action heroes of the immune system—stuck to it. That is, Krammer was building a blood test for Covid-19.
This kind of “serological assay” might lead to the first real treatment for the disease. The idea is called “convalescent serum” or “convalescent plasma,” a century-old idea that uses the blood of people who’ve recovered from a disease to treat people who still have it. Survivors of a disease keep antibodies to that pathogen in their blood; they’ve “seroconverted,” which is to say their blood and immune system have changed. “There are several initiatives right now to find people who seroconverted and use their serum, their plasma, to treat severe cases. That has been done in China, and China also sent serum to Italy,” Krammer says. But to do it right, you need to know who those seroconverted people are and how many antibodies they’re packing. You need a test.
The nasal-swab snot tests that have been in such short supply can tell if someone is actively infected with the virus. A blood test can’t—at least, not until the infection is far enough along that the immune system has kicked into gear. But a blood test can tell if someone has already been infected and gotten better. (This is why epidemiologists would love to see widespread blood testing too—it’d give them a more accurate idea of the total number of infections out in the world.) And a blood test would work even if that person never displayed any symptoms. “Some people get asymptomatic infections or mild infections and never get detected, but they become, most likely, immune,” Krammer says. “If you have health care workers and can test them to find out they have immunity already, you can strategically use them to deal with Covid-19 patients … You could also think about screening people in the population to see who is immune and can go back to work safely.”
Making the test turned out to be relatively easy. Krammer’s lab published the methods as a preprint—not peer-reviewed, but available for people to try—on March 18. Within three days, 50 labs around the world had requested the fragment of viral RNA he used to make the spike protein and samples of the spike protein itself, which Krammer shipped out. Everyone working on the problem knew that tests were in the pipeline, that Chinese researchers had a serological test but hadn’t released data, and that Singapore was using a test but hadn’t published the recipe. Now that Krammer’s was out there, the hard work could start.
While Krammer was synthesizing his spike protein, a coalition of more than 100 scientists was assembling around the country to start using convalescent plasma against Covid-19. It’s an approach to fighting disease that predates vaccines and antibiotics, and now—with skyrocketing numbers of people infected with a disease against which they have no natural defenses and no drugs—it may be the stopgap that health care workers are hoping for.
On February 27, researchers in China published a short note in the journal Lancet Infectious Diseases citing some evidence of the success of convalescent plasma in treating Ebola and previous respiratory viruses, including SARS, MERS, and influenza H1N1. That same day, Arturo Casadevalsl, an infectious disease expert at Johns Hopkins School of Public Health, published an op-ed in The Wall Street Journal about the use, to treat measles in the 1930s, of what was then called convalescent serum. Take the blood of people who’ve recovered, let the red blood cells clot and remove them, and transfuse what’s left—the “serum”—into people in the early stages of the disease. (You have to match their blood types.) Not only does this process ease symptoms and potentially save lives, it accelerates the path to immunity, like something in between a drug and a vaccine. In addition to measles, it was used against polio, mumps, and even the 1918 influenza pandemic.
“When serum was used way back then, they didn’t have the same understanding of antibodies. Antibodies hadn’t really been purified the same way,” says Liise-anne Pirofski, chief of the infectious disease division at Albert Einstein College of Medicine and Montefiore Medical Center, and one of the first advocates for using plasma on Covid-19. She’s also a longtime colleague of Casadevalsl, a fellow advocate of the approach. “Here we are in this crisis, and something that was used 100 years ago is something that could save us now. I just think that’s very cool,” she continues.
Casadevalsl’s op-ed reawakened the interest of infectious disease experts and other scientists. Colleagues started pinging him saying they wanted to turn the idea into a project. Casadevalsl and Pirofski were already at work on an article to that end for the Journal of Clinical Investigation: “The Convalescent Sera Option for Containing Covid-19.” Since then, that loose group has grown to perhaps as many as 100 researchers. Casadevalsl has since tweeted that the Covid-19 Convalescent Plasma Project even has the support of the National Academies of bet365体育赛事s, Engineering, and Medicine.
Their idea is simple: develop, simultaneously, both studies and arguments for “compassionate use” to give serum antibodies to people with early Covid-19 symptoms. Compassionate use, the Food and Drug Administration’s term for special permission to administer experimental treatments, usually gets invoked for people who are at immediate risk of dying, or who have a disease for which no cure or better treatment exists. In this case, they’d give convalescent plasma to Covid-19 patients the same way doctors have used plasma for decades—with the goal of keeping people in the emergency room from ending up in the intensive care unit, breathing with a ventilator.
As a second possibility, researchers will try testing post-exposure prophylaxis, giving the antibodies to people who might be exposed to the virus, like health care workers, to induce immunity for as long as the foreign antibodies last in their bodies. This “passive immunity” wouldn’t be permanent like a vaccination, but it could keep these workers healthy and at work.
“And there’s a third potential use case, which is Hail Mary-ing people who are really sick,” says Michael Joyner, a physiologist at the Mayo Clinic and one of the group’s organizers. Nobody knows yet if that approach will work at all. But Joyner says it’s an option worth testing. “In an emergency situation like this, the enemy of good is better.” Joyner isn’t an infectious diseases specialist; he’s a physiologist who studies how oxygen moves in the body. But he’s a networker, and he wanted to be part of the mobilization of scientists fighting the pandemic.
Spinning all that up won’t be easy. The coalition has grown to include researchers all over the United States—clinicians and bench researchers, all on regular conference calls and email chains—laying out what they’d need. “We’re talking about the top places in the country with a lot of expertise, people with a lot of depth, and a lot of places where we have true content experts who can hopefully adapt these protocols,” Joyner says. “Virology, transfusion medicine, clinical trials design, regulatory support and communications—all built in parallel rather than series.”
A immunology-based blood test is the first step. Sure, a simpler test of how well a person’s blood neutralizes the virus would eventually yield similar data, but those can take more than three days. And you have to use the active virus to do it, which means a biosesafety level 3 lab and permission from the CDC, which is doling out the active virus specimens. On the other hand, pretty much any biochemistry lab can do a blood test based on an enzyme-linked immune system assay, or ELISA, if the lab has the proteins. “It’s relatively high-throughput if you set it up right,” Krammer says. “With one operator you can probably test a few thousand people per week, and you can do that in parallel with more than one operator.”
The test will determine whether a person is a good plasma donor, with a high enough “titer” of antibodies to be helpful. (It’s still not clear how many days after recovering from an infection a person’s blood will reach a high enough titer.) “If you go from the beginning of the illness itself, you start seeing it between seven and 14 days with this virus,” says Jeffrey Henderson, an infectious disease researcher at Washington University School of Medicine and another coalition member. “And then, we’re not sure how long the antibodies last. Sometimes they last a while at high levels. Sometimes they go up and come back down.”
The other complicated part will be setting up approvals to do all this—collecting blood from people, testing it, prepping the plasma, and administering it—while simultaneously studying how well the process works. Once the US has enough people who’ve been sick but recovered from the disease, the researchers will all have to learn the best way to collect their blood and make it into a usable product. That’ll require an unusual level of cooperation among researchers, clinicians, and the people who run blood banks and labs. At a press conference on Monday, Deborah Birx, response coordinator for the White House Coronavirus Task Force, said the FDA was evalsuating serological tests and were a couple weeks from having one ready. “It’s like an old technology encountering modern regulatory burdens in the midst of an urgent need,” Henderson says.
On Tuesday, the FDA came through with an Investigational New Drug approval, the first step in beginning trials for a drug. That allows for the possibility of compassionate-use administration of plasma, and hospitals in New York are going to be starting clinical trials, including giving high-titer, therapeutic plasma to some patients and regular plasma to others, as a control. “We just want to get this whole response coordinated so we can get convalescent serum and give it to patients in a controlled way, the safest possible way, in a way that’s scientifically sound,” Joyner says. Maybe some other ELISA-based test will be better than Krammer’s, or there’ll be more than one. And it’s possible that Chinese researchers already solved some of these procedural questions for getting and giving plasma—the group is working on translating the protocol used by researchers in China too.
Their urgency is obvious. Most US health workers and disease researchers think the wave of Covid-19 patients now threatening to overwhelm New York City hospitals is a portent of what’s coming to every city. Social distancing and shelter-in-place measures are designed to reduce contact among people and slow down the spread of Covid-19, but those tools don’t start to work until something like two weeks after people start sheltering. Once patients are in the hospital, physicians and nurses worry they won’t have anything to offer them other than ventilators, which are already in short supply. Any therapeutic approach will look like a lifesaver. That’s part of the reason for all the excitement over chloroquine, the antimalarial drug that has shown activity against the new coronavirus in a petri dish and in a small, underpowered study.
If plasma helps? “The case fatality rate will go down and hopefully we will be in a situation where we can reduce the number of cases. And then a vaccine or some other product will come in and get us some herd immunity,” Joyner says. “We’re just trying to hold the line until the biotech cavalry arrives.”
That biotech cavalry is a whole other audience for a Covid-19 blood test.
The specific antibodies that respond to the spike protein might teach immunologists about how the disease penetrates the body’s defenses. That’s good for basic science. It’s also good for research into a different kind of treatment—one that would take the immunological shotgun approach of convalescent plasma and instead turn it into a laser gun.
Using plasma is a scattershot approach. The plasma cocktail would contain antibodies to every pathogen that person ever encountered, a reverse impression of its donor’s journey through earth’s microbiome. In the language of immunology, that mixture is polyclonal—a sea full of disease-fighting fish, each with a slightly different job. Some of them might attack a pathogen directly, targeting different proteins on its surface. Some of them might talk to other immune cells, and work out strategies for destroying not only the virus but also cells that it has infected and assimilated into its Borg-y virus collective. Transfused into a sick person, that plasma would have a diluted generality—in fighting everything, it might not wage as intense an attack on the specific disease you’re after.
Instead, it would be great to have a therapy that locked onto one illness—ideally a therapy that didn’t require an unending line of blood donors, and didn’t have the risks that come with giving a blood product to a person. For that, you want a monoclonal antibody. That’s a synthetic version of an antibody, targeted at a specific disease.
Monoclonal antibodies aren’t easy to make, but when they work, they’re aces. It’s a hot field in infectious disease and cancer right now; the front-line treatments for Ebola, like Zmapp, are based on antibodies derived either from animal models or from previously infected humans. The FDA has approved more than 80 monoclonal antibody drugs for lupus, Crohn’s disease, asthma, cancers, and a handful of other diseases.
The process for developing those drugs begins with a serological test. “In a serological test, you just want to make sure you are detecting antibodies to the disease of interest,” says Kartik Chandran, a virologist at Albert Einstein College of Medicine who’s working on a monoclonal antibody for SARS-CoV-2. “When you want to make antibodies for therapeutics, you’re starting with the same library, but you want those antibodies that are going to be useful to treat somebody with that infection … We used to call them ‘magic unicorn antibodies.’”
In the case of SARS-CoV-2, though, it seems likely that the antibodies that attack the spike protein, the one that Krammer’s test identifies, will also be candidates to become part of a monoclonal therapy. Chandran’s group is looking to capture the immune cells that make those spike hunters, called Memory B cells.
Once that basic immunology gets done, researchers like Chandran will race to get the genetic sequence for the candidate antibodies. They can actually optimize those sequences, improve them to work better in people, and then engineer the sequence into other cells—usually yeast—that’ll manufacture those antibodies in giant vats called bioreactors. This is the biotechnology that the plasma coalition is trying to hold the line for. “Making a clonal cell line, identifying a single cell that is producing the antibody, that is the right antibody and is suitable for scaling up to large production, takes time and has to be done in a specific way for human use,” Chandran says. “Then you have to purify the antibody, and do it at scale. That has a whole bunch of process implications.”
It’s not as hard as it was 20 years ago. Decades of experience with monoclonal antibodies against other diseases mean that scientists at least know what they don’t know. The pipeline for various approaches is only starting, but it’s full—it even includes ideas from a bunch of different labs to use raw genetic material injected into muscle cells, to turn the patient’s own body into the bioreactor. It’s tough to get genes into cells and make them work, but this approach could make monoclonal antibody development cheaper and the drugs easier to deliver. It seems to have worked against Ebola in mice.
The search for a monoclonal treatment doesn’t preclude the use of plasma in the meantime. “The advantage of the plasma transfusion approach is it’s much faster. You can go from plasma collected from a patient to transfusing it to another patient in a matter of weeks,” Chandran says. “It takes months to do the selection process of monoclonal antibodies and manufacture them at scale. So it’s not an either/or thing. They’re complimentary. We need a short-term stopgap.”
That stopgap starts with a blood test—seemingly simple, but the core of the unfolding response to the Covid-19 pandemic.
Updated 3/24/20 6:00 PM PT to reflect the FDA approval of trials and New York's announcement of their initiation.
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