1. “An Evolving Situation”
There are three moments in the yearlong catastrophe of the COVID-19 pandemic when events might have turned out differently. The first occurred on January 3, 2020, when Robert Redfield, the director of the Centers for Disease Control and Prevention, spoke with George Fu Gao, the head of the Chinese Center for Disease Control and Prevention, which was modelled on the American institution. Redfield had just received a report about an unexplained respiratory virus emerging in the city of Wuhan.
The field of public health had long been haunted by the prospect of a widespread respiratory-illness outbreak like the 1918 influenza pandemic, so Redfield was concerned. Gao, when pressed, assured him that there was no evidence of human-to-human transmission. At the time, the theory was that each case had arisen from animals in a “wet” market where exotic game was sold. When Redfield learned that, among twenty-seven reported cases, there were several family clusters, he observed that it was unlikely that each person had been infected, simultaneously, by a caged civet cat or a raccoon dog. He offered to send a C.D.C. team to Wuhan to investigate, but Gao said that he wasn’t authorized to accept such assistance. Redfield made a formal request to the Chinese government and assembled two dozen specialists, but no invitation arrived. A few days later, in another conversation with Redfield, Gao started to cry and said, “I think we’re too late.”
Lawrence Wright on how the pandemic response went wrong.
Perhaps Gao had just been made aware that the virus had been circulating in China at least since November. Certainly, Redfield didn’t know that the virus was already present in California, Oregon, and Washington, and would be spreading in Massachusetts, Wisconsin, Iowa, Connecticut, Michigan, and Rhode Island within the next two weeks—well before America’s first official case was detected.
Redfield is convinced that, had C.D.C. specialists visited China in early January, they would have learned exactly what the world was facing. The new pathogen was a coronavirus, and as such it was thought to be only modestly contagious, like its cousin the SARS virus. This assumption was wrong. The virus in Wuhan turned out to be far more infectious, and it spread largely by asymptomatic transmission. “That whole idea that you were going to diagnose cases based on symptoms, isolate them, and contact-trace around them was not going to work,” Redfield told me recently. “You’re going to be missing fifty per cent of the cases. We didn’t appreciate that until late February.” The first mistake had been made, and the second was soon to happen.
Matthew Pottinger was getting nervous. He is one of the few survivors of Donald Trump’s White House, perhaps because he is hard to categorize. Fluent in Mandarin, he spent seven years in China, reporting for Reuters and the Wall Street Journal. He left journalism at the age of thirty-two and joined the Marines, a decision that confounded everyone who knew him. In Afghanistan, he co-wrote an influential paper with Lieutenant General Michael Flynn on improving military intelligence. When Trump named Flynn his national-security adviser, Flynn chose Pottinger as the Asia director. Scandal removed Flynn from his job almost overnight, but Pottinger stayed, serving five subsequent national-security chiefs. In September, 2019, Trump appointed him deputy national-security adviser. In a very noisy Administration, he had quietly become one of the most influential people shaping American foreign policy.
At the Journal, Pottinger had covered the 2003 sars outbreak. The Chinese hid the news, and, when rumors arose, authorities minimized the severity of the disease, though the fatality rate was approximately ten per cent. Authorities at the World Health Organization were eventually allowed to visit Beijing hospitals, but infected patients were reportedly loaded into ambulances or checked into hotels until the inspectors left the country. By then, sars was spreading to Hong Kong, Hanoi, Singapore, Taiwan, Manila, Ulaanbaatar, Toronto, and San Francisco. It ultimately reached some thirty countries. Because of heroic efforts on the part of public-health officials—and because sars spread slowly—it was contained eight months after it emerged.
The National Security Council addresses global developments and offers the President options for responding. Last winter, Pottinger was struck by the disparity between official accounts of the novel coronavirus in China, which scarcely mentioned the disease, and Chinese social media, which was aflame with rumors and anecdotes. Someone posted a photograph of a sign outside a Wuhan hospital saying that the E.R. was closed, because staff were infected. Another report said that crematoriums were overwhelmed.
On January 14th, the N.S.C. convened an interagency meeting to discuss the virus. Early that morning, the W.H.O.—relying on China’s assurances—tweeted that there was no evidence of human-to-human transmission. The N.S.C. recommended that screeners take the temperatures of any passengers arriving from Wuhan.
The next day, President Trump signed the first phase of a U.S.-China trade deal, declaring, “Together, we are righting the wrongs of the past and delivering a future of economic justice and security for American workers, farmers, and families.” He called China’s President, Xi Jinping, “a very, very good friend.”
On January 20th, the first case was identified in the U.S. On a Voice of America broadcast, Dr. Anthony Fauci, the head of the National Institute of Allergy and Infectious Diseases, said, “This is a thirty-five-year-old young man who works here in the United States, who visited Wuhan.” Trump, who was at the World Economic Forum, in Davos, Switzerland, dismissed the threat, saying, “It’s one person coming in from China. It’s going to be just fine.”
On January 23, 2020, all the members of the U.S. Senate gathered for the second day of opening arguments in President Trump’s impeachment trial. It was an empty exercise with a foreordained result. Mitch McConnell, the Majority Leader, had already said that he would steamroll Democratic attempts to introduce witnesses or new evidence. “We have the votes,” he decreed.
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The trial posed difficulties for the four Democratic senators still running for President. As soon as the proceedings recessed, on Friday evenings, the candidates raced off to campaign for the weekend. One of them, Amy Klobuchar, of Minnesota, recalled, “I was doing planetariums in small towns at midnight.” Then it was back to Washington, to listen to an argument that one side would clearly win. In the midst of this deadened theatre, McConnell announced, “In the morning, there will be a coronavirus briefing for all members at ten-thirty.” This was the first mention of COVID in Congress.
The briefing took place on January 24th, in the hearing room of the Health, Education, Labor, and Pensions Committee, which Lamar Alexander, Republican of Tennessee, chaired. Patty Murray is the ranking Democratic member. A former preschool teacher, she has been a senator for twenty-seven years. Her father managed a five-and-dime until he developed multiple sclerosis and was unable to work. Murray was fifteen. The family went on welfare. She knows how illness can upend people economically, and how government can help.
A few days earlier, she had heard about the first confirmed COVID case in the U.S.—the man had travelled from Wuhan to Washington, her state. Murray contacted local public-health officials, who seemed to be doing everything right: the man was hospitalized, and health officials were tracing a few possible contacts. Suddenly, they were tracking dozens of people. Murray said to herself, “Wow, this is kinda scary. And this is in my back yard.”
But in the outbreak’s early days, when decisiveness mattered most, few other politicians were paying attention. It had been a century since the previous great pandemic, which found its way from the trenches of the First World War to tropical jungles and Eskimo villages. Back then, scientists scarcely knew what a virus was. In the twenty-first century, infectious disease seemed like a nuisance, not like a mortal threat. This lack of concern was reflected in the diminished budgets given to institutions that once had led the world in countering disease and keeping Americans healthy. Hospitals closed; stockpiles of emergency equipment weren’t replenished. The spectre of an unknown virus arising in China gave certain public-health officials nightmares, but it wasn’t on the agenda of most American policymakers.
About twenty senators showed up to hear Anthony Fauci and Robert Redfield speak at an hour-long briefing. The health authorities were reassuring. Redfield said, “We are prepared for this.”
That day, Pottinger convened forty-two people, including N.S.C. staffers and Cabinet-level officials, for a meeting. China had just announced a lockdown of Wuhan, a city of eleven million, which could mean only that sustained human-to-human transmission was occurring. Indeed, Pottinger’s staff reported that another city, Huanggang, was also locked down. The previous day, the State Department had heightened its travel advisory for passengers to the Wuhan region, and the meeting’s attendees debated how to implement another precaution: sending all passengers coming from Wuhan to five U.S. airports, where they could be given a health screening before entry.
The next day, Pottinger attended a Chinese New Year party on Capitol Hill. Old diplomatic hands, émigrés, and Chinese dissidents relayed stories about the outbreak from friends and family members. People were frightened. It sounded like sars all over again.
Pottinger went home and dug up files from his reporting days, looking for phone numbers of former sources, including Chinese doctors. He then called his brother, Paul, an infectious-disease doctor in Seattle. Paul had been reading about the new virus on Listservs, but had assumed that, like sars, it would be “a flash in the pan.”
If flights from China were halted, Matt asked, could America have more time to prepare?
Paul was hesitant. Like most public-health practitioners, he held that travel bans often have unintended consequences. They stigmatize countries contending with contagion. Doctors and medical equipment must be able to move around. And, by the time restrictions are put in place, the disease has usually infiltrated the border anyway, making the whole exercise pointless. But Matt spoke with resolve. Little was known about the virus except for the fact that it was spreading like wildfire, embers flying from city to city.
Paul told Matt to do whatever he could to slow the virus’s advance, giving the U.S. a chance to establish testing and contact-tracing protocols, which could keep the outbreak under control. Otherwise, the year ahead might be calamitous.
No one realized how widely the disease had already seeded itself. Fauci told a radio interviewer that COVID wasn’t something Americans needed to “be worried or frightened by,” but he added that it was “an evolving situation.”
2. The Trickster
In October, 2019, the first Global Health Security Index appeared, a sober report of a world largely unprepared to deal with a pandemic. “Unfortunately, political will for accelerating health security is caught in a perpetual cycle of panic and neglect,” the authors observed. “No country is fully prepared.” Yet one country stood above all others in terms of readiness: the United States.
During the transition to the Trump Administration, the Obama White House handed off a sixty-nine-page document called the Playbook for Early Response to High-Consequence Emerging Infectious Disease Threats and Biological Incidents. A meticulous guide for combatting a “pathogen of pandemic potential,” it contains a directory of government resources to consult the moment things start going haywire.
Among the most dangerous pathogens are the respiratory viruses, including orthopoxviruses (such as smallpox), novel influenzas, and coronaviruses. With domestic outbreaks, the playbook specifies that, “while States hold significant power and responsibility related to public-health response outside of a declared Public Health Emergency, the American public will look to the U.S. Government for action.” The playbook outlines the conditions under which various federal agencies should become involved. Questions about the severity and the contagiousness of a disease should be directed to the Department of Health and Human Services, the Federal Emergency Management Agency, and the Environmental Protection Agency. How robust is contact tracing? Is clinical care in the region scalable if cases explode? There are many such questions, with decisions proposed and agencies assigned. Appendices describe such entities as the Pentagon’s Military Aeromedical Evacuation team, which can be assembled to transport patients. Health and Human Services can call upon a Disaster Mortuary Operational Response Team, which includes medical examiners, pathologists, and dental assistants.
The Trump Administration jettisoned the Obama playbook. In 2019, H.H.S. conducted Crimson Contagion, a simulation examining the government’s ability to contain a pandemic. Among the participants were the Pentagon, the N.S.C., hospitals, local and regional health-care departments, the American Red Cross, and twelve state governments. The scenario envisioned an international group of tourists visiting China who become infected with a novel influenza and spread it worldwide. There’s no vaccine; antiviral drugs are ineffective.
The Crimson Contagion exercise inspired little confidence that the government was prepared to handle such a crisis. Federal agencies couldn’t tell who was in charge; states grew frustrated in their attempts to secure enough resources. During the simulation, some cities defied a C.D.C. recommendation to close schools. Government policies, the report concluded, were inadequate and “often in conflict.” The Public Health Emergency Fund and the Strategic National Stockpile were dangerously depleted; N95 masks and other medical essentials were in short supply, and domestic manufacturing capacity was insufficient. Congress was briefed on the findings but they were never made public. By the time COVID arrived, no meaningful changes had been made to address these shortcomings.
“I just love infectious diseases,” John Brooks, the chief medical officer of the COVID response team at the C.D.C., admitted to me. “I know diseases are terrible—they kill people. But something about them just grabs me.”
Each generation has its own struggle with disease. In 1939, Brooks’s mother, Joan Bertrand Brooks, developed polio. Her legs were covered with surgical scars, and her right leg was noticeably shorter than her left. “She spoke about that experience often—how she was teased, stigmatized, or blatantly discriminated against,” Brooks recalled.
For Brooks, who is gay, the disease of his generation was H.I.V./AIDS. He grew up near the Dupont Circle neighborhood of Washington, D.C., which had a large gay population, and watched men he knew disappear: “Guys would get thin and develop lesions and then be gone. It was scary.” Science offered no solution, and that was on Brooks’s mind when he decided to become a doctor. The day he was accepted at Harvard Medical School, he and his mother went to lunch to celebrate. “Afterward, we dropped into a ten-dollar palm reader, who said she saw me marrying a tall Swedish woman and owning a jet with which I flew around the world with our three children,” he told me. “We had a good laugh. I should have asked for a refund.”
In 2015, Brooks became the chief medical officer of the H.I.V./AIDS division at the C.D.C. Every H.I.V. researcher has been humbled by the various manifestations of this disease. “At every turn, there was something different,” Brooks said. “All these opportunistic infections show up. What in the world is this all about? Very cool.” The experience of studying H.I.V. helped prepare him for the myriad tricks that COVID would present.
The C.D.C. was founded in 1946, as the Communicable Disease Center. Atlanta was chosen as its home because the city was in the heart of what was called “the malaria zone.” Five years later, America was declared malaria-free. The C.D.C.’s mission expanded to attack other diseases: typhus, polio, rabies. In 1981, the organization, by then renamed the Centers for Disease Control, reported the first known cases of AIDS, in Los Angeles. Until this year, the C.D.C. maintained a reputation as the gold standard for public health, operating above politics and proving repeatedly the value of enlightened government and the necessity of science for the furthering of civilization. During the twentieth century, the life span of Americans increased by thirty years, largely because of advances in public health, especially vaccination.
The C.D.C. campus now resembles a midsize college, with more buildings under construction, including a high-containment facility for the world’s most dangerous diseases. Lab animals—mice, ferrets, monkeys—inhabit cages inside Biosafety Level 4 chambers. Humans move around them like deep-sea divers in inflated suits, tethered to an overhead airflow system.
The Emergency Operations Center is a large, bright room, with serried rows of wooden desks facing a wall of video screens. The place exudes a mixture of urgency and professional calm. On one side of the room, operators triage incoming phone calls. In 2014, during the Ebola crisis, Brooks received a call from Clay Jenkins, a county judge in Dallas. A Liberian citizen visiting the city, Thomas Eric Duncan, had contracted the disease. Jenkins wanted advice about how to safely approach Duncan’s fiancée and her family members. On a monitor, Brooks could see the fiancée’s apartment complex, shot from above by cameras on helicopters. Brooks told Jenkins that he could safely enter the apartment as long as the family had no symptoms: it would be an important public gesture for him to choose compassion over fear. Brooks watched footage of Jenkins escorting the family out of the complex. (Thomas Duncan eventually died; two nurses who had cared for him were infected but survived.)
Brooks was working on the COVID response team with Greg Armstrong, a fellow-epidemiologist. Armstrong oversaw the Advanced Molecular Detection program, which is part of the C.D.C.’s center for emerging and zoonotic infectious diseases. (Zoonotic diseases come from animals, as coronaviruses typically do.) Humanity’s encroachment into formerly wild regions, coupled with climate change, which has forced animals out of traditional habitats, has engendered many new diseases in humans, including Ebola and Zika. At first, SARS-CoV-2—as the new virus was being called—presented itself as a less mortal coronavirus, like the common cold, spreading rapidly and sometimes asymptomatically. In fact, SARS-CoV-2 was more like polio. Most polio infections are asymptomatic or very mild—fever and headaches. But some are deadly. The polio cases that doctors actually see are about one in every two hundred infections. Stealth transmission is why polio has been so hard to eradicate.
Armstrong was in Salt Lake City, conducting a training session, when he noticed an article on the Web site of The New England Journal of Medicine: “Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia.” The article was one of the first to describe the virus’s spread among humans, a development that didn’t surprise Armstrong: “Anybody with any epidemiology experience could tell you it was human-to-human transmission.” Then he noticed Table 1, “Characteristics of Patients,” which noted the original source of their infection. Of the Chinese known to have contracted the virus before January 1st, twenty-six per cent had no exposure either to the Wuhan wet market or to people with apparent respiratory symptoms. In subsequent weeks, the number of people with no obvious source of infection surpassed seventy per cent. Armstrong realized that, unlike with sars or mers—other coronavirus diseases—many infections of SARS-CoV-2 were probably asymptomatic or mild. Contact tracing, isolation, and quarantine would likely not be enough. These details were buried in Table 1.
Other reports began to emerge about possible asymptomatic spread. Although SARS-CoV-2 was genetically related to the sars and MERS viruses, it was apparently unlike them in two key ways: people could be contagious before developing symptoms, and some infected people would never manifest illness. In late February, University of Texas scientists, led by Lauren Ancel Meyers, reported that it could have a “negative serial interval,” meaning that some infected people showed symptoms before the person who had given it to them.
The C.D.C.’s early guidance documents didn’t mention that possibility, because the evidence of asymptomatic spread was deemed insufficient. “In the beginning, for every mathematical analysis that indicated a shorter serial interval than incubation period, others reported no difference,” Brooks said. “When the science changed, we changed. And our recommendations changed, too.” But, by that time, the C.D.C. had been muzzled by the Trump Administration.
“There are three things this virus is doing that blow me away,” Brooks told me. “The first is that it directly infects the endothelial cells that line our blood vessels. I’m not aware of any other human respiratory viruses that do this. This causes a lot of havoc.” Endothelial cells normally help protect the body from infection. When SARS-CoV-2 invades them, their powerful chemical contents get dumped into the bloodstream, resulting in inflammation elsewhere in the body. The rupture of individual endothelial cells coarsens the lining in the blood vessels, creating breaks and rough spots that cause turbulent blood flow.
The second surprise was hypercoagulability—patients had a pronounced tendency to develop blood clots. This reminded Brooks of Michael Crichton’s 1969 novel, “The Andromeda Strain,” in which a pathogen causes instant clotting, striking down victims in mid-stride. “This is different,” Brooks said. “You’re getting these things called pulmonary embolisms, which are nasty. A clot forms—it travels to the lung, damaging the tissues, blocking blood flow, and creating pressures that can lead to heart problems.” More puzzling was evidence that clots sometimes formed in the lungs, leading to acute respiratory distress. Brooks referred to an early report documenting autopsies of victims. Nearly all had pulmonary thromboses; until the autopsy, nobody had suspected that the clots were even present, let alone the probable cause of death.
“The last one is this hyperimmune response,” Brooks said. Most infectious diseases kill people by triggering an excessive immune-system response; COVID, like pneumonia, can unleash white blood cells that flood the lungs with fluid, putting the patient at risk of drowning. But COVID is unusual in the variety of ways that it causes the body to malfunction. Some patients require kidney dialysis or suffer liver damage. The disease can affect the brain and other parts of the nervous system, causing delirium, strokes, and lasting nerve damage. COVID could also do strange things to the heart. Hospitals began admitting patients with symptoms of heart attack—chest pains, trouble breathing—and preparing emergency coronary catheterizations. “But their coronary vessels are clean,” Brooks said. “There’s no blockage.” Instead, an immune reaction had inflamed the heart muscle, a condition called myocarditis. “There’s not a lot you can do but hope they get through it.” A German study of a hundred recovered COVID patients with the average age of forty-nine found that twenty-two had lasting cardiac problems, including scarring of the heart muscle.
Even after Brooks thought that COVID had no more tricks to play, another aftereffect confounded him: “You get over the illness, you’re feeling better, and it comes back to bite you again.” In adults, it might just be a rash. But some children develop a multi-organ inflammatory syndrome. Brooks said, “They have conjunctivitis, their eyes get real red, they have abdominal pain, and then they can go on to experience cardiovascular collapse.”
When I was around six, I woke up one morning and couldn’t get out of bed: I was paralyzed from the waist down. It was during the polio era, in the early fifties, before there was a cure. I remember the alarm in my mother’s eyes. Our family doctor made a house call. He sat on the edge of the bed, and took my temperature and pulse; there was little else he could do. The terror of polio haunted children and parents everywhere.
I was lucky. After a day or so, I could move my legs again. I was never certain what had caused my brief paralysis, but the memory was searing. Soon after the polio vaccine, invented by Jonas Salk, became available, in 1955, I was inoculated, along with millions of other children.
So I had a personal interest when I entered Building 40 of the main campus of the National Institutes of Health, in Bethesda, Maryland, which houses the National Institute of Allergy and Infectious Diseases. Dr. Barney S. Graham, the deputy director of the Vaccine Research Center and the chief of the Viral Pathogenesis Laboratory and Translational Science Core, works on the second floor. He studies how viruses cause disease, and he designs vaccines.
The first thing you notice about Graham is that there’s a lot of him: he’s six feet five, with a gray goatee and a laconic manner. Graham’s boss at niaid, Anthony Fauci, told me, “He understands vaccinology better than anybody I know.”
Bookshelves in Graham’s office hold colorful 3-D printouts of viruses that he has worked with, including Ebola, Zika, and influenza. While I was researching “The End of October,” a novel that I published earlier this year, about a deadly pandemic, Graham helped me design a fictional virus, and then concocted a vaccine for it. As we collaborated, I came to understand that researchers like Graham are essentially puzzle solvers. This past year, he solved one of the most consequential puzzles in modern science. He is the chief architect of the first COVID vaccines authorized for emergency use. Manufactured by Moderna and Pfizer, they differ only in their delivery systems.
On Graham’s wall is a map of Kansas, where he grew up. His father was a dentist and his mother was a teacher. For part of his childhood, they lived on a hog farm. Barney and his brother did much of the farming. Working with the animals, he learned a lot about veterinary medicine. At Rice University, he majored in biology. He earned a medical degree at the University of Kansas, where he met his wife, Cynthia Turner-Graham, a psychiatrist. In 1978, on an infectious-disease rotation in medical school, he spent time at the N.I.H., where he first encountered Fauci. “Cynthia noticed when I came back how excited I was,” Graham recalled. “People were willing to battle each other’s ideas. She thought I would end up here.”
First, he and Cynthia had to complete residencies. They wanted to be in the same town, a problem many professional couples face, but additionally complicated in their case because Cynthia is Black. She suggested Nashville: he could apply to Vanderbilt School of Medicine and she to Meharry Medical College, a historically Black institution. Tennessee had only recently repealed a ban on interracial marriage.
Driving back to Kansas from Maryland on Christmas Eve, Graham stopped in at Vanderbilt. To his surprise, the director of the residency program, Thomas Brittingham, was in his office and willing to meet with him immediately. When the interview was over, Graham told Brittingham, “I know this is the South. I’m going to marry a Black woman, and if that makes a difference I can’t come here.” Brittingham said, “Close the door.” He welcomed Graham on the spot. Cynthia was accepted at Meharry, and so they moved to Nashville.
By 1982, Graham had become the chief resident at Nashville General Hospital. That year, he saw a patient suffering from five simultaneous infections, including cryptococcal meningitis and herpes simplex. It was a mystery: most infections are solitary events. The medical staff was terrified. Graham realized that he was treating Tennessee’s first AIDS patient. “We kept him alive for three weeks,” he said.
Millions of lives would be changed, and so many ended, by this remorseless, elusive disease. Immunology, then a fledgling field, was transformed by the battle. “It took us a couple years just to figure out that H.I.V. was a virus,” Graham said. He started running vaccine trials. “It was not till the mid-nineties that we had decent treatments. There were some really hard years. Almost everyone died.”
In 2000, the N.I.H. recruited Graham to create a vaccine-evaluation clinic. He insisted on keeping a research lab. With space for two dozen scientists, his lab focusses on vaccines for three categories of respiratory viruses: influenza, coronaviruses, and a highly contagious virus called respiratory syncytial virus (RSV), which ended up playing a key role in the development of a COVID vaccine.
RSV causes wheezing pneumonia in children, and sends more kids under five years old to the hospital than any other disease. One of the last childhood infectious diseases without a vaccine, RSV also kills about as many of the elderly as seasonal influenza. It’s wildly infectious. In order to stop its spread in a hospital pediatric ward, staff must wear gloves, masks, and goggles; if any of these items is omitted, RSV will surge. Like COVID, it is dispersed through particle droplets and contaminated surfaces. In the nineteen-sixties, a clinical trial of a potential RSV vaccine made children sicker and led to two deaths—a syndrome called vaccine-enhanced disease. Graham spent much of two decades trying to solve the riddle of what causes RSV, but the technology he needed was still being developed.
In 2008, he had a stroke of luck. Jason McLellan, a postdoc studying H.I.V., had been squeezed out of a structural-biology lab upstairs. H.I.V. has proved invulnerable to a vaccine solution, despite extraordinary technological advances and elegant new theories for designing one. “I thought, Let’s try things out on a more tractable virus,” McLellan recalled. “Barney thought RSV would be perfect for a structure-based vaccine.”
A vaccine trains the immune system to recognize a virus in order to counter it. Using imaging technology, structural biologists can intuit the contours of a virus and its proteins, then reproduce those structures to make more effective vaccines. McLellan said of his field, “From the structure, we can determine function—it’s similar to how seeing a car, with four wheels and doors, implies something about its function to transport people.”
The surface of an RSV particle features a protein, designated F. On the top of the protein, a spot called an epitope serves as a landing pad for antibodies, allowing the virus to be neutralized. But something extraordinary happens when the virus invades a cell. The F protein swells like an erection, burying the epitope and effectively hiding it from antibodies. Somehow, McLellan had to keep the F protein from getting an erection.
Until recently, one of the main imaging tools used by vaccinologists, the cryogenic electron microscope, wasn’t powerful enough to visualize viral proteins, which are incredibly tiny. “The whole field was referred to as blobology,” McLellan said. As a work-around, he developed expertise in X-ray crystallography. With this method, a virus, or even just a protein on a virus, is crystallized, then hit with an X-ray beam that creates a scatter pattern, like a shotgun blast; the structure of the crystallized object can be determined from the distribution of electrons. McLellan showed me an “atomistic interpretation” of the F protein on the RSV virus—the visualization looked like a pile of Cheetos. It required a leap of imagination, but inside that murky world Graham and McLellan and their team manipulated the F protein, essentially by cloning it and inserting mutations that kept it strapped down. McLellan said, “There’s a lot of art to it.”
In 2013, Graham and McLellan published “Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus,” in Science, demonstrating how they had stabilized the F protein in order to use it as an antigen—the part of a vaccine that sparks an immune response. Antibodies could now attack the F protein, vanquishing the virus. Graham and McLellan calculated that their vaccine could be given to a pregnant woman and provide enough antibodies to her baby to last for its first six months—the critical period. The paper opened a new front in the war against infectious disease. In a subsequent paper in Science, the team declared that it had established “clinical proof of concept for structure-based vaccine design,” portending “an era of precision vaccinology.” The RSV vaccine is now in Phase III human trials.
In 2012, the mers coronavirus emerged in Saudi Arabia. It was extremely dangerous to work with: a third of infected people died. Ominously, it was the second novel coronavirus in ten years. Coronaviruses have been infecting humans for as long as eight centuries, but before sars and mers they caused only the common cold. It’s possible that, in the distant past, cold viruses were as deadly as COVID, and that humans developed resistance over time.
Like RSV, coronaviruses have a protein that elongates when invading a cell. “It looks like a spike, so we just call it Spike,” Graham said. Spike was large, flexible, and encased in sugars, which made it difficult to crystallize, so X-ray crystallography wasn’t an option. Fortunately, around 2013, what McLellan calls a “resolution revolution” in cryogenic electron microscopy allowed scientists to visualize microbes down to one ten-billionth of a metre. Finally, vaccinologists could truly see what they were doing.
Using these high-powered lenses, Graham and McLellan modified the mers spike protein, creating a vaccine. It worked well in mice. They were on the way to making a version for humans, but, after mers had killed hundreds of people, it petered out as an immediate threat to humans—and the research funding petered out, too. Graham was dismayed, realizing that such a reaction was shortsighted, but he knew that his energies hadn’t been wasted. About two dozen virus families are known to infect humans, and the weapon that Graham’s lab had developed to conquer RSV and mers might be transferrable to many of them.
What was the best way to deliver a modified protein? Graham knew that Moderna, a biotech startup in Cambridge, Massachusetts, had encoded a modified protein on strips of genetic material known as messenger RNA. The company had never brought a vaccine to market, concentrating instead on providing treatments for rare disorders that aren’t profitable enough to interest Big Pharma. But Moderna’s messenger-RNA platform was potent.
In mice, Graham had proved the effectiveness of a structure-based vaccine for mers and also for Nipah, a particularly fatal virus. In 2017, Graham arranged a demonstration project for pandemic preparedness, with mers and Nipah serving as prototypes for a human vaccine using Moderna’s messenger-RNA platform. Almost three years later, as he was preparing to begin human trials for the Nipah vaccine, he heard the news from Wuhan.
Graham called McLellan, who happened to be in Park City, Utah, getting snowboard boots heat-molded to his feet. McLellan had become a star in structural biology, and was recruited to the University of Texas at Austin, where he had access to cryogenic electron microscopes. It took someone who knew Graham well to detect the urgency in his voice. He suspected that China’s cases of atypical pneumonia were caused by a new coronavirus, and he was trying to obtain the genomic sequence. It was a chance to test their concept in a real-world situation. Would McLellan and his team like to get “back in the saddle” and help him create a vaccine?
“Of course,” McLellan said.
“We got the sequences Friday night, the tenth of January,” Graham told me. They had been posted online by the Chinese. “We woke up on the eleventh and started designing proteins.”
Nine days later, the coronavirus officially arrived in America.
Within a day after Graham and McLellan downloaded the sequence for SARS-CoV-2, they had designed the modified proteins. The key accelerating factor was that they already knew how to alter the spike proteins of other coronaviruses. On January 13th, they turned their scheme over to Moderna, for manufacturing. Six weeks later, Moderna began shipping vials of vaccine for clinical trials. The development process was “an all-time record,” Graham told me. Typically, it takes years, if not decades, to go from formulating a vaccine to making a product ready to be tested: the process privileges safety and cost over speed.
Graham had to make several crucial decisions while designing the vaccine, including where to start encoding the spike-protein sequence on the messenger RNA. Making bad choices could render the vaccine less effective—or worthless. He solicited advice from colleagues. Everyone said that the final decisions were up to him—nobody had more experience in designing vaccines. He made his choices. Then, after Moderna had already begun the manufacturing process, the company sent back some preliminary data that made him fear he’d botched the job.
Graham panicked. Given his usual composure, Cynthia, his wife, was alarmed. “It was a crisis of confidence that I just never see in him,” she said. So much depended on the prompt development of a safe and effective vaccine. Graham’s lab was off to a fast start. If his vaccine worked, millions of lives might be spared. If it failed or was delayed, it would be Graham’s fault.
After the vaccine was tested in animals, it became clear that Graham’s design choices had been sound. The first human trial began on March 16th. A week later, Moderna began scaling up production to a million doses per month.
4. “It’s more like 1918”
Since 2016, Dr. Rick Bright has run the Biomedical Advanced Research and Development Authority. A division of H.H.S., the authority is responsible for medical countermeasures in the event of bioterrorism or a pandemic. According to a whistle-blower complaint, on January 22nd Bright received an e-mail from Mike Bowen, an executive at the Texas-based firm Prestige Ameritech, the country’s largest maker of surgical masks. Bowen wrote that he had four “like new” N95 manufacturing lines, which weren’t in use. He added, “Reactivating these machines would be very difficult and very expensive but could be achieved in a dire situation and with government help.” In another message, Bowen wrote, “We are the last major domestic mask company. . . . My phones are ringing now, so I don’t ‘need’ government business. I’m just letting you know that I can help you preserve our infrastructure if things ever get really bad. I’m a patriot first, businessman second.”
Bright had already been worried about the likely shortage of personal protective equipment in the Strategic National Stockpile. He also felt that not enough was being done to develop diagnostics for the virus from Wuhan. On January 23rd, at an H.H.S. leadership meeting with Secretary Alex Azar, he warned that the “virus might already be here—we just don’t have the tests to know.” Many Trump Administration officials seemed determined to ignore scientists who shared bad news.
On January 25th, Bowen wrote Bright again, saying that his company was getting “lots of requests from China and Hong Kong” for masks—a stunning piece of intelligence. About half the masks used in the U.S. come from China; if that supply stopped, Bowen said, American hospitals would run out. Bright continued pushing for immediate action on masks, but he found H.H.S. to be unresponsive. On January 27th, Bowen wrote, “I think we’re in deep shit. The world.”
The same day, at the White House, Matt Pottinger convened an interagency meeting of Cabinet officers and deputies. Attendees fell into four camps. There was the public-health establishment—Redfield, Fauci, Azar—data-driven people who, at the moment, had no data. Another group—the acting White House chief of staff, Mick Mulvaney, along with officials from the Office of Management and Budget and the Transportation Department—was preoccupied with the economic damage that would result if drastic steps were taken. A State Department faction was concerned mainly with logistical issues, such as extracting Americans from Wuhan. Finally, there was Pottinger, who saw the virus not just as a medical and economic challenge but also as a national-security threat. He wanted dramatic action now.
For three weeks, the U.S. had been trying unsuccessfully to send medical experts to China. The public-health contingent didn’t want to make decisions about quarantines or travel bans without definitive intelligence, but the Chinese wouldn’t supply it. When Pottinger presented a proposal to curtail travel from China, the economic advisers derided it as overkill. Travel bans upended trade—a serious consideration with China, which, in addition to P.P.E., manufactured much of the vital medicine that the U.S. relied on. Predictably, the public-health representatives were resistant, too: travel bans slowed down emergency assistance, and viruses found ways to propagate no matter what. Moreover, at least fourteen thousand passengers from China were arriving in the U.S. every day: there was no way to quarantine them all. These arguments would join other public-health verities that were eventually overturned by the pandemic. Countries that imposed travel bans with strict quarantines, such as Vietnam and New Zealand, kept the contagion at a manageable level.
The State Department’s evacuation of Americans, particularly diplomatic staff in Wuhan, outraged the Chinese; Tedros Adhanom Ghebreyesus, the director-general of the W.H.O., said that the U.S. was overreacting. In part to placate the Chinese, the 747s that were sent to collect Americans were filled with eighteen tons of P.P.E., including masks, gowns, and gauze. It was a decision that many came to regret—especially when inferior substitutes were later sold back to the U.S., at colossal markups.
The morning after the meeting, Pottinger spoke to a doctor in China who was treating patients. People were getting infected and there was no way to know how and where it happened—a stage of contagion called community spread.
Pottinger asked, “Is this going to be as bad as sars?”
“Don’t think 2003—it’s more like 1918,” the doctor said. That flu lasted two years, and killed between forty and a hundred million people.
On January 28th, the national-security adviser, Robert O’Brien, brought Pottinger into the Oval Office, where the President was getting his daily intelligence briefing. According to contemporaneous notes from someone present at this meeting, the briefer mentioned the virus, but didn’t present it as the top threat. O’Brien warned the President, “This will be the biggest national-security threat you will face.” Trump asked if the outbreak posed as big a danger as sars, and the briefer responded that it wasn’t clear yet.
Pottinger leaped to his feet and recounted what he’d heard from his sources—most shockingly, that more than half the disease’s spread was attributed to asymptomatic carriers. Yet, every day, thousands of people were flying from China to the U.S.
“Should we shut down travel?” Trump asked.
“Yes,” Pottinger advised.
Pottinger left the Oval Office and walked to the Situation Room, where a newly formed Coronavirus Task Force was meeting. People were annoyed with him. “It would be unusual for an asymptomatic person to drive the epidemic in a respiratory disorder,” Fauci said. That certainly had been true of sars. He still wanted U.S. scientists to report from China, in order to get more data. Redfield, of the C.D.C., considered it too early for disruptive actions. He said that there were only a handful of cases outside China, and that in the U.S. the pathogen wasn’t moving that fast. The public-health contingent was united. “Let the data guide us,” they advised.
Pottinger pointed out that the Chinese continued to block such efforts: “We’re not getting data that’s dependable!”
The economic advisers, meanwhile, were frantic—a travel ban would kill the airline industry and shut down the global supply chain. Larry Kudlow, the President’s chief economic adviser, had been questioning the seriousness of the situation. He couldn’t square the apocalyptic forecasts with the stock market. “Is all the money dumb?” he wondered. “Everyone’s asleep at the switch? I just have a hard time believing that.” (Kudlow doesn’t recall making this statement.)
Pottinger, sensing that he’d need backup, had brought along Peter Navarro, an abrasive economic adviser who had been part of the trade negotiations with China. Many White House officials considered Navarro to be a crackpot, but he was known to be one of the President’s favorites because he advocated tariff wars and other nationalist measures. Navarro warned the group, “We have got to seal the borders now. This is a black-swan event, and you’re rolling the dice with your gradualist approach.”
Within minutes, Navarro was at odds with everyone in the room. He pointed out that the new virus was spreading faster than the seasonal flu or sars. The possible economic costs and loss of life were staggering. Azar argued that a travel ban would be an overreaction. No progress was made in that meeting, but Navarro was so strident that Mulvaney barred him from future sessions.
Then data surfaced that shifted the argument. In mid-January, a Chicago woman returned from a trip to China. Within a week, she was hospitalized with COVID. On January 30th, her husband, who hadn’t been to China, tested positive. Fauci, Redfield, and others in the public-health contingent changed their minds: human-to-human transmission was clearly happening in America.
Trump was told the news. The timing couldn’t have been worse for him. The bitter trade war he had initiated with China had reached a tentative pause. Since then, he had been praising Xi Jinping’s handling of the contagion, despite evidence of a coverup. A travel ban would reopen wounds. Nevertheless, Trump agreed to announce one the next day.
It was a bold gesture, but incomplete. The Administration blocked non-Americans coming from China, but U.S. citizens, residents, and their family members were free to enter. A two-week quarantine was imposed on travellers coming from the Wuhan region, but, unlike Taiwan, Australia, Hong Kong, and New Zealand, which rigidly enforced quarantines, the U.S. did little to enforce its rules, and the leaks soon became apparent.
5. Flattening the Curve
In 1989, Dr. Howard Markel was in graduate school at Johns Hopkins, specializing in both pediatrics and the history of medicine. He had just lost his wife to cancer, a month after their first anniversary. Markel began volunteering at a local AIDS clinic. He found that helping men his own age who were facing their mortality, or their partner’s, was immensely consoling—“the most spiritually uplifting work I did in my entire clinical career.”
Markel’s patients often asked him, “Doc, do you think I’ll be quarantined because I have H.I.V.?” He’d reply that it wasn’t appropriate for the disease. But, realizing that these men feared being shut away, like victims of leprosy, he began studying “the uses and misuses of quarantine.” His first book was about two epidemics in New York City in 1892, one of typhus and one of cholera, in which Jewish immigrants were blamed for the outbreak and many were sent to quarantine islands.
In the early two-thousands, Markel studied “escape” communities that had essentially closed their doors during the 1918 flu pandemic—among them Gunnison, Colorado, and a school for the blind in Pittsburgh. All had survived the contagion virtually unscathed. In 2006, Markel continued his work on the 1918 flu with Martin Cetron, who now directs the Division of Global Migration and Quarantine, at the C.D.C. For an initiative undertaken by the George W. Bush Administration, Cetron and Markel were asked to help identify the best way to manage the early waves of a pandemic that had no vaccine or treatments. They considered school closures, public-gathering bans, business shutdowns—traditional tools of public health. Markel assembled a dozen researchers—“the Manhattan Project for historians,” he jokes—who combed through more than a hundred archives.
In 1918, Americans faced the same confounding choices as today. Twenty-five cities closed their schools once; fourteen did so twice, and Kansas City three times. More than half the cities were “double-humped”—suffering two waves of the flu. “They raised the bar too early because the natives got restless,” Markel, who is now a professor at the University of Michigan, told me. “They each acted as their own control group. When the measures were on, the cases went down. When the measures were off, the cases went up.” After Philadelphia permitted a Liberty Loans parade, there was a huge uptick in cases. St. Louis, by contrast, cancelled all parades, and local officials broadcast a unified message. The city’s health commissioner published an op-ed alerting citizens to the threat, immediately closing entertainment venues and banning public gatherings. St. Louis’s death rate was half of Philadelphia’s. By quickly imposing several nonpharmaceutical interventions, a city could dramatically lower the peak of infection—on a graph, it would look more like a rainbow than like a skyscraper. Markel compared each intervention to a slice of Swiss cheese; one layer by itself was too riddled with holes to be effective, but multiple layers made a profound difference. “Early, layered, and long” was the formula.
JAMA published the study in 2007. The authors declared, “We found no example of a city that had a second peak of influenza while the first set of nonpharmaceutical interventions were still in effect.” In the century since 1918, technology has transformed so much, but the tools for curbing a novel pandemic haven’t changed. Masks, social distancing, and frequent hand washing remain the only reliable ways to limit contagion until treatments or vaccines emerge.
One night, Markel and Cetron were in Atlanta, talking over their study, and they ordered Thai food. When their dinner arrived, Markel opened his Styrofoam container: instead of a fluffy mound of noodles, he gazed on a level, gelatinous mass. “Look,” Markel said. “They’ve flattened the curve, just like we’re trying to do.” A slogan was born.