Title:
The Resistance
From: https://www.wired.com/story/covid-immunity-antibodies/
Keywords: active-immunity, passive immunity, broadly-neutralizing-antibody,
Author: Roxanne Khamsi
ILLUSTRATION by
NAJEEBAH AL-GHADBAN; GETTY IMAGES
A YEAR AGO, in January, when John Mascola heard that a new coronavirus had been detected in an animal market in Wuhan, China, he left everything at his desk on the fourth floor of the US government’s Vaccine Research Center and walked up one flight of stairs to the office of a longtime colleague, Nicole Doria-Rose. Felicitously, Mascola, who is the center’s director, had been working on ways to immunize people against coronaviruses. A vaccine against this new bug, soon to be known as SARS-CoV-2, was the first priority, the only surefire way of halting the growing pandemic. Mascola and Doria-Rose, an immunologist, go way back. And they hoped there was another approach that might also contribute to the cause, one they’d been chasing for more than a decade. They wanted to find a monoclonal antibody.
This article appears in the March 2021 issue. Subscribe to WIRED.
ILLUSTRATION: RESHIDEV RK
Everybody knows about vaccines, which train the immune system to fight invaders, but monoclonal antibody drugs are less familiar. To develop them, scientists must generally
find a person whose body has done better than most at fighting a disease;
scour their immune system, needle-in-a-haystack style, to locate the most effective antibody; and
use it as a blueprint to fashion a drug for people who are sick.
When former New Jersey governor Chris Christie came down with Covid-19 in early October, he was given an experimental monoclonal antibody drug made by Eli Lilly. That treatment—with the exceedingly unpronounceable name bamlanivimab—can be traced directly back to the conversation Mascola had with Doria-Rose at the start of the pandemic. The Food and Drug Administration approved it for emergency use on November 9. Similarly, a combination of two other antibody drugs, made by the company Regeneron, was given to then-president Donald Trump when he contracted the virus. Like the vaccines made by Pfizer and Moderna, these monoclonals were deployed in record time.
Mascola became interested in monoclonal antibody treatments in the early 2000s, not long after he joined the Vaccine Research Center in Bethesda, Maryland. Back then, if you studied infectious diseases, as Mascola did, you were probably trying to understand HIV. It had killed an estimated 22 million people and seemed unstoppable. HIV wasn’t as easy to contract as a respiratory illness—bodily fluids such as blood or semen, not the air you breathe, are the media for transmission—but once the virus took hold, its passage through the body was relentless. Patients suffered an array of painful symptoms, including mouth ulcers, skin sores, and pneumonia, before succumbing to a total collapse of the body’s defenses. But there was a small percentage of people who held out longer; they made stronger antibodies against the virus.
Other researchers had shown it was possible to isolate one of those superpowered antibodies, and starting in 2006, Doria-Rose joined Mascola in setting out to catalog the immune systems of exceptional HIV fighters. They first had to find HIV patients who had been infected for years but had remained relatively healthy; then, from each of those people, they had to collect and analyze samples of blood to know if the donors were among the estimated 1 percent of people with the virus who made highly effective antibodies. The blood was processed through machines that quickly separated out antibody-producing cells, called B cells, which were then deposited into the tiny wells of a tray resembling a Keebler elf’s muffin tin. From there, Mascola’s team would capture the antibodies produced by each cell cocooned in the individual wells.
Next, they tested the antibodies for strength. They took a line of specially engineered human cells, designed to glow green when infected with an HIV-like virus, and bathed them in antibodies. Then they exposed the cells to the virus. If the antibody was a dud, the infected cells would glow; if it had superpowers, they wouldn’t. Most of the time the mixture glowed. This went on for months; hundreds of samples failed.
But one day in 2009, while Mascola was sitting in the laboratory break room about to eat a sandwich, one of his scientists bounded toward him with a big smile on her face: They’d found the no-glow they’d been looking for.
That antibody came from a man known as Donor 45. Doria-Rose, who met with study participants when they came in for their regular checkups, says that Donor 45 was an exceedingly private gay Black man in his sixties from the Washington, DC, area. They dubbed the antibody VRC01—the first from the Vaccine Research Center.
It took almost a decade to develop a drug from this antibody and set up a clinical trial to make sure it was safe and effective. Other HIV researchers going down different roads came up with anti-retroviral drugs—the famous “triple cocktail”—that effectively treat and prevent HIV infections by interfering with the virus’s ability to make copies of itself. The crisis wasn’t over. People still contracted HIV, but with the antiretrovirals they could live mostly normal lives. As access to those drugs expanded, the effort to use antibodies to make HIV drugs became less urgent. It plugged along, a clinical trial was started, but not as many people were paying much attention.
And then came Covid-19. That day in January 2020, Mascola immediately saw that everything he and his colleagues had learned from studying HIV antibodies could be mobilized to treat the new pathogen. It would be “the culmination of a life’s work,” he says.
Mascola is a restrained kind of guy. He communicates with economy. “When he puts one exclamation point in an email, you know you have done something phenomenal!” Doria-Rose wrote to me. So when he came to her office, they got straight down to business. Doria-Rose began asking team members to fire up the cell-sorting machines and fill the tiny muffin tins and engineer test cells that glowed. They overhauled their work schedules and went all in.
EVEN BEFORE YOU were born, your immune system started making antibodies to fight potential pathogens. They are stunningly diverse: The average person has billions of B cells that can produce somewhere between 9 and 17 million distinct antibodies. Antibody molecules are Y-shaped, and their tips have nooks and crannies that can lock onto specific viruses or bacteria. [One antibody molecule to one bad instance.] When that binding happens, the antibodies block the invaders [that antibody instance block that invader instance] from attaching to healthy cells [that healthy cell]and shuttle them [shuttles it] away. The truly ingenious thing, however, is not just that an antibody can seek out its enemy for destruction, but that the act of locking onto the pathogen is also a signal to the immune system to make more of that particular shape. Even one antibody can call up the troops, allowing your immune system to wage war against an invading army.
Unfortunately, when an entirely new pathogen like HIV or the new coronavirus emerges, a well-matching shape is rare, even in our massive preexisting natural repertoire of antibodies. Vaccines, which typically consist of a weakened virus or fragments of a virus, train the body to develop a locking antibody—one that will bind to and neutralize the real pathogen when we encounter it in the world. This is known as active immunity. The body’s immune system goes to basic training, and it emerges with a fit fighting force. In contrast, antibody therapies like the ones Mascola worked on for HIV give you passive immunity: A mercenary army is introduced into the body to temporarily do the work for you.
The discovery of passive immunity reaches back to the end of the 19th century, when Emil Behring, a German scientist with sad, hooded eyes and a trim beard, began injecting 220 children with animal blood. The children had all contracted diphtheria, a gruesome disease that slowly suffocated its victims. Behring had been trying to treat the disease, experimenting with rabbits, guinea pigs, goats, and horses, giving infected animals the blood of recovered ones. He didn’t know why, but the sick animals improved. So he gave the children the blood of diphtheria-exposed animals, and in 1894 he published the results: About twice as many children as would normally be expected to survive actually did survive. Behring’s “serum therapy” approach was deemed such a success that he later received the first-ever Nobel Prize in Physiology or Medicine.
Over the next century, scientists discovered that antibodies in the blood serum accounted for the success of the diphtheria treatment. They were then able to figure out how to isolate individual antibodies from lab animals and manufacture them. A defining moment came in 1986, when the US Food and Drug Administration approved the first monoclonal therapy. It was derived from mice and stopped the body from attacking and rejecting transplanted organs.
HIV, however, is tricky. One of the wiliest viruses, it mutates rapidly, shape-shifting to outmaneuver the body’s attempts to find a locking antibody. In the early 1990s, when the struggle to combat HIV accelerated, an immunologist at the Scripps Research Institute in La Jolla, California, named Dennis Burton set his sights on solving that problem.
First, Burton had to find an antibody that worked against many different strains of HIV—what he called a “broadly neutralizing” antibody. He and his collaborators landed on one from a man in the US, in 1994. They called it B12, and it neutralized many of the virus strains they tested against it. Finally, there was proof that finding and deploying antibodies against HIV was possible. Burton’s work inspired Mascola and his colleagues, who discovered VRC01.
Since then, some 100 antibody drugs have arrived on the market in the US or the European Union. About half are designed to fight cancer, and most of the rest work against autoimmune disorders. Very few of them target infectious diseases. In fact, only seven such treatments have ever been approved by the FDA—the first for a deadly lung infection in 1998 and the most recent for Ebola, more than two decades later. For Covid-19, there are more than 40 efforts to produce antibody-based treatments. Just as Covid-19 revved up vaccine researchers to do in a year what used to take a decade, so has it sped up development of new infectious disease treatments. [Not exactly. It's at the cost of Governments assuming the liability for any future accidents. –FNC]
BORN IN A suburb of Boston, Mascola came to the National Institutes of Health after medical school and various government research positions. His defining character trait is an absorbed single-mindedness. About 20 colleagues in a meeting once pranked him by each wearing a sweatshirt printed with an image of his face. The joke was to see how long it would take him to notice. “I think they clocked it at like two and a half minutes,” Mascola says, “which obviously is a long time.”
Outwardly reserved, Mascola is inwardly optimistic. When he switched gears in January to focus on the coronavirus, he was buoyed by the apparent stability of SARS-CoV-2. While extremely contagious, it did not seem to mutate quickly. Unlike with HIV, scientists wouldn’t need to find someone whose antibodies had kept a virus at bay over a long period of time. They just needed to find someone who had definitely been sick with Covid-19 and whose body had mounted a successful response.
When the first US cases emerged in Washington state, a vial of blood from a patient who had recovered was shipped to a Canadian company called AbCellera for analysis. The firm’s specialized machines and software enabled it to screen more than 5 million immune cells from the very first sample and identify more than 500 antibodies within five days. AbCellera FedExed tiny plastic vials of some of these antibodies to Mascola’s team in Bethesda. Over years of studying HIV, Doria-Rose and others had developed more automated and efficient methods of vetting antibodies, and the staff tested them against SARS-CoV-2, all day and on nights and weekends.
Around the time the antibodies were arriving at the Vaccine Research Center in late February, the institute went into lockdown. Doria-Rose attended weekly video conferences with AbCellera scientists and experts around North America. At one of those meetings in March, a colleague shared a spreadsheet of the antibodies isolated from one of the first individuals from Seattle who had been hospitalized and volunteered to donate blood to the effort. The sheet was color-coded (though, for the layperson, counterintuitively): Green rows indicated antibodies that bound weakly to SARS-CoV-2, yellow rows were for moderately good antibodies, and red rows indicated antibodies that were the best candidates to turn into drugs. “You’re scanning down an Excel spreadsheet looking for red,” Mascola told me. “And it was a little bit disappointing at first. There were lots of green—lots of weaks—and a couple of yellows. Within hundreds and hundreds of rows from that one patient, there were just a couple of reds.”
One of them, number 555, stood out. The antibody seemed to be a potent neutralizer. It worked well against SARS-CoV-2 at lower concentrations than any other in the spreadsheet. A promising lead.
The Vaccine Research Center can do a lot of things, but it’s still a government agency. It doesn’t have factories where it manufactures drugs. So it shared its findings with AbCellera, which inked a partnership with Eli Lilly, a maker of monoclonal antibodies for cancer and other illnesses. The antibody that stood out in the spreadsheet became known as LY-CoV555.
At Lilly, the person responsible for managing the developing Covid antibody treatments was Dan Skovronsky, the company’s chief scientific officer. It was up to him to decide whether to go ahead and test LY-CoV555 in a clinical trial or wait to see if a better antibody would crop up later. It was a weighty choice. Clinical trials and drug development cost hundreds of millions of dollars. For Skovronsky, though, expense wasn’t the main consideration. Lilly had factories that could produce monoclonal antibodies at a large scale, but at the time there were limited free slots in the assembly line. “If we picked wrong,” he says, “we could have been delayed by as much as a couple of months before there was another slot and another molecule could go in.”
Skovronsky’s team was divided. Some people thought they should wait for a better antibody candidate. Lilly’s computer algorithms, designed to predict how well antibodies would perform, were suggesting that LY-CoV555 would clear rapidly from the patient’s body, presumably reducing its efficacy. But there was no time to rigorously test that assumption. In normal times the next step would be monthslong efficacy tests in different animals. But the coronavirus was spreading rapidly. It was April, and cities had shut down. Hospitals in New York and New Orleans were overrun. More than 13,000 people in the US had already died of the virus. Time was critical.
Finally, one Saturday evening during dinner, Skovronsky excused himself and took his plate to his home office, where he dialed in to a long call with about a dozen collaborators from Lilly and AbCellera. He had to make a decision. Going forward with the antibody meant rejecting the findings of the company’s predictive algorithm, a step Lilly had introduced at great cost in order to make more sensible drug development decisions. But by the end of the call, he’d decided to move forward with LY-CoV555. It continued to work better at lower concentrations than other antibodies studied by Lilly and its academic collaborators. He emailed his team to let them know. The next day—a Sunday—the company started the lengthy process of manufacturing enough of the antibody for the clinical trials it hoped to launch by early summer.
Settling on LY-CoV555 so early was a risk. But it turned out to be a worthwhile gamble: Skovronsky’s team kept looking for more powerful antibodies over the next several months and none came along. “Remarkably,” he says, “555 still looks to be the best, the most potent antibody—which we can only say is luck.”
THIS SPRING, ALEX Stemer, a medical director within the Symphony Care Network, a chain of nursing homes in the Midwest, got an unexpected call from an old friend and former medical student he had mentored named Myron Cohen. An infectious disease specialist at the University of North Carolina at Chapel Hill, Cohen also helped design clinical trials and knew that Eli Lilly needed older volunteers, who were among the most vulnerable, to test its new preventive Covid therapy. He’d instantly thought of Stemer and the nursing home residents.
In March, Symphony had experienced a terrible tragedy. At its facility in Joliet, Illinois, a maintenance worker diligently installed tables in residents’ rooms so they wouldn’t risk spreading Covid while mingling in the dining hall. But in a horrible twist, the worker turned out to be a presymptomatic carrier of the virus. An outbreak followed, and within a month 26 people had died, including the maintenance worker himself.
Read all of our coronavirus coverage here.
Stemer was an obvious choice to oversee the chain’s Covid-19 response. He has been passionate about treating infectious diseases ever since he alerted his colleagues to a salmonella outbreak in a hospital while he was a medical resident. Stemer, who had worked in the field for years in Indiana, was eager to participate in the Lilly trial. He connected Cohen with the Symphony leaders. In his first call, Cohen made his pitch with all the scientific nitty-gritty of how antibody therapies work. Then the conversation took an unexpectedly emotional turn. The Symphony team wanted to start collaborating right away. Cohen had to explain that it would take weeks or perhaps months before the antibodies were ready and available for testing. “But people are dying right now,” they told him. “It was probably one of the more upsetting conversations I’ve ever had,” Cohen says. The urgency continued in follow-up calls. “I literally just about cried after every phone call,” he says.
It took until the end of May to manufacture enough doses of LY-CoV555 for clinical testing to get going. Lilly began launching some of the four key clinical trials, starting with people already sick with Covid-19 in a hospital. Near the end of August, Stemer got a call that set things into motion: An employee at Symphony’s assisted living facility in Chesterton, Indiana, had tested positive for Covid-19. On Saturday, August 29, after Stemer was done making his rounds, he made his way into a large conference room. There, about 30 residents along with Stemer and other staff, were given an intravenous infusion containing either saline solution (the experimental control) or molecules of LY-CoV555. Could the drug prevent the spread in the center? The trial could provide an answer.
ANTIBODY THERAPIES DIDN'T need a hype man, but they found one in President Trump. On October 8, he tweeted a video of himself standing on the sunny White House lawn, six days after receiving the drug made by Regeneron. “I went into the hospital a week ago; I was very sick and I took this medicine and it was incredible,” he said. Not long after, Chris Christie, who spent seven days in the ICU, said he received antibodies from Lilly. After Christie recovered, he thanked Lilly for access to “their extraordinary treatments,” although nobody can say for sure whether the drugs helped either of these politicians more than any of the other treatments they were given.
Both Regeneron and Lilly released preliminary data from their trials last fall, reporting that people who got their drugs were less likely to require hospital or emergency room care than the people who got the saline-solution placebo. That prompted the FDA to bless both companies’ monoclonal antibodies with an emergency use authorization, allowing doctors to prescribe them for people who have tested positive for the new coronavirus. The US government committed to buying 1.5 million doses of Regeneron’s drug to distribute at no cost to patients, along with almost a million doses from Lilly.
It took just 10 months from Mascola’s conversation with Doria-Rose to get to a drug with provisional approval from the FDA. In some ways, though, that ended up being the easy part. Monoclonals work best when administered to Covid-19 patients within days of their first symptoms. But to get them within a recommended 10-day window, you need a Covid-19 test result and must meet certain eligibility requirements. In many places, patients simply don’t learn they are eligible in time and are disqualified from getting the treatment. Hospitals feared there would be a shortage of the drugs, but in fact they often go unused. The delivery mechanism for monoclonals like Lilly’s—a slow IV infusion rather than a quick stab in the bicep—can be another barrier to distribution. The wards where infusions typically take place are reserved for cancer treatments; hospitals are understandably averse to seating infectious Covid-19 patients in areas with vulnerable cancer patients. In the midst of a pandemic, many haven’t had the staff or facilities to do it elsewhere.
By January, two vaccines had been approved for use in the US, but their rollout has been achingly slow. At the same time, new variants of Covid-19 have been detected in the United Kingdom, South Africa, and Brazil. There’s worry, based in part on data from Lilly’s own lab experiments, that individual monoclonal treatments might not be effective on some emerging variants.
Still, health officials in different parts of the country are optimistic about the drug. Jeremy Cauwels, chief physician of Sanford Health, a network of hospitals in the Midwest, believes that the antibody treatments will prove their worth during these months as people are waiting for the vaccine—and after, for those who refused to get it and become ill. Several hospitals he oversees did manage to create antibody drug infusion centers by repurposing spaces and recruiting surgical and other nurses who were less busy during the pandemic. By his calculations, over several months these medications prevented an estimated 35 people from having to be admitted into the Sanford system. Those 35 people got to go home and be treated as outpatients, which was good for them. And their absence translated into more than 200 days of open hospital beds, which was good for the patients who needed them.
The data from the trial of nursing home staff and residents in which Alex Stemer had participated gave new hope.
In early December, health officials in El Paso, Texas, made the infusions of monoclonal antibodies available at the city’s convention center, which had been operating as a dedicated Covid treatment site for people with mild to moderate cases of the disease. Those patients didn’t have to go to the hospital to get infusions. “That, for us, was sort of a game changer in terms of everybody then feeling comfortable not only talking about it but disseminating it and getting it to patients,” says Ogechika Alozie, an infectious disease specialist and a cochair of El Paso’s Covid-19 task force. “The first two or three weeks were really slow. All of a sudden, around Christmas, it ramped up.”
On January 21, Lilly issued a press release. The company said it had data from the trial of nursing home staff and residents in which Alex Stemer had participated. The results gave new hope. The company said that bamlanivimab could actually prevent people from getting infected with the pandemic coronavirus. While the results have yet to be peer-reviewed, the data suggested that the drug reduced the risk of infection with SARS-CoV-2 by 57 percent among the participants, and up to 80 percent among the particularly vulnerable nursing home residents. The next week, Regeneron released data suggesting that its antibody combination could also reduce the risk of becoming infected by the pandemic coronavirus.
THE COVID-19 PANDEMIC has brought so much death and economic devastation. But at least in the scientific response to the virus, we’ve been lucky—lucky that this fearsome coronavirus happens to mutate slowly; lucky that researchers had been working on relevant vaccine and treatment technology for years. But, of course, luck doesn’t truly describe what happened. It wasn’t chance that researchers knew exactly what to do when Covid-19 hit. They’d been well prepared by a long progression of meticulous, hard-fought scientific steps. But their work on this virus is also a cautionary tale. We might not be so prepared with the next virus. In fact, we’re still struggling with HIV.
HIV is trickier than SARS-CoV-2, despite the emergence of new concerning variants. Not only does HIV mutate much more quickly than the coronavirus, it also hides in a sugar coat that makes it an especially slippery target for antibodies to bind to. HIV still infects some 1.7 million people around the world every year. Antiretrovirals have made it possible to live with the disease, and even prevent transmission if taken daily. But the real goal is to stop people from getting HIV in the first place. Unfortunately, scientists have tried and failed for more than three decades to come up with a working HIV vaccine. Now, some of them say monoclonal antibody drugs—given prophylactically, rather than as a treatment—might be the best immediate bet to prevent new infections.
The fierce push for antibody drugs in the current coronavirus pandemic may ultimately give a lift to the HIV research that laid the groundwork in the first place. Companies like AbCellera and Regeneron have gotten faster and better at both finding and manufacturing monoclonals. Moreover, the benefit conferred by antibody drugs against the coronavirus in early clinical trials has also been encouraging. “The success of monoclonals in Covid is going to shine a brighter light on the potential of HIV monoclonals,” says Myron Cohen, “both in treatment and prevention.”
In January, results finally were presented from a pair of four-year-long clinical trials for the antibody against HIV that had come from Donor 45. The trials involved more than 4,600 people from Brazil to Botswana to Switzerland who were at high risk for contracting HIV. Researchers knew, based on testing in the lab, that certain strains of the virus are more susceptible to the antibody, and the results seemed to confirm it: The number of patients who contracted those strains was 75 percent lower than normal. But the antibody was no silver bullet. Overall, the drug didn’t significantly reduce HIV infections, because only about a third of the strains were susceptible to the powers of VRC01. Still, the trials were an important proof of concept: They showed that an antibody drug could block HIV infection. Mascola is quick to point out that, in recent years, even more potent antibodies against HIV have been discovered, including several that are already in clinical testing. “Some of these antibodies are about tenfold more potent than VRC01, and they also are active against a greater number of HIV viruses,” Mascola says. He remains an optimist.
The immune system is a randomizer, evolution’s way of preparing for uncertainty.
So why did Donor 45 possess an antibody that could fend off the worst of HIV’s assaults and survive for years while so many others died? No one really knows. The human immune system is bafflingly complex. When scientists sequenced the human genome two decades ago, they skipped over detailing the immune system genes, because these bits of DNA are so variable and have a propensity to rearrange randomly during cell division.
This ability, of course, is also what makes our immune system so amazing. According to the work of Dennis Burton, the Scripps researcher, and his collaborators, humans have the potential to generate 1,000,000,000,000,000,000 different kinds of antibodies, which means that we all, theoretically, possess the ability to neutralize a vast number of pathogens. The immune system is a randomizer, evolution’s way of preparing for uncertainty. We can’t predict exactly what terrible new virus will emerge, but we know one will. And by harnessing the most effective antibodies—like the antibodies from Donor 45—we might be able to find solutions for humanity.
Donor 45 died in 2013 but surpassed all expectations of how long someone could live with HIV without any medication. He and the other “elite neutralizers” who made potent antibodies were lucky, of course, to have survived longer with a disease that had killed so many of their friends and lovers. But their survival also left them alone, isolated. Doria-Rose kept a box of tissues in her office for these visits. “I cried with Donor 45 one time,” she says, recalling how the loneliness weighed on him, as did the burden of knowing he survived when others hadn’t.
When the Vaccine Research Center scientists isolated VRC01, it was Doria-Rose’s job to tell Donor 45 that his blood contained a powerful molecule that might help others. She printed out a copy of a scientific report detailing the findings and showed it to him when he next visited the clinic. He had expressed to her all along a desire to aid research so that others could benefit. Donor 45 did not live to see this month’s trial results, but on that day, he seemed to understand. “He got it,” she says, “that we had found what we had been looking for.” This time, they didn’t cry.
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Roxanne Khamsi is a science writer living in Montreal.
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