Epidemic

by Reid Wilson

  Though Ebola has been known to Western medicine for decades, the small scale of previous outbreaks meant few pharmaceutical companies had the incentive to spend money on researching and developing cures. The size and scope of the outbreak in West Africa changed that, and sent behemoth manufacturers scrambling for research.

  The most well-known potential cure, ZMapp, was so difficult to produce that only thirty-six patients had ever received it. Eight of those patients died, but seven succumbed before the full course of the medicine could be delivered.

  The drug, manufactured by a Kentucky-based company and derived from tobacco plants, won fast-track status from the U.S. Food and Drug Administration in September 2015. The full course of the drug sends particles that attach to the outside of the Ebola virus itself, neutralizing the virions while attracting killer immune cells. Scientists calculated a 91 percent probability that ZMapp could lead to a favorable outcome.6

  A similar drug, dubbed MIL 77, underwent initial testing in China. Produced by Beijing Mabworks, the drug was used on British and Italian patients who survived. But it was so similar to ZMapp that the drug set off a fight between the American and Chinese governments over claims of patent infringements.

  At least one more potential treatment, GS5734, showed early promise too. The drug quickly advanced from concept to phase one trials, then phase two trials by the summer of 2015. Travis Warren, the U.S. Army Medical Research Institute for Infectious Diseases (USAMRIID) scientist, called its progress “a phenomenal development time.”

  Others fell short.

  The French National Institute of Health and Medical Research conducted trials of Favipirivir, a drug normally used to combat influenza viruses, for five months in Gueckedou, Guinea; Favipirivir showed promise among those with lower viral loads, but it did little to help those who were very sick.7

  Developed by a company called Biocryst, BCX4430 showed promise inhibiting filoviruses in human cells and protected macaques from Marburg.8 Amiodarone, a drug used to treat cardiac dysrhythmia, was tested on eighty patients in Sierra Leone through an Italian nongovernmental organization called Emergency. The tests were so poorly handled that fourteen British medical staffers stopped work at an Ebola treatment center in Freetown because they believed the drug would harm patients.9

  Intravenous doses of TKM-130803 failed to improve conditions in a dozen patients in Port Loko. The manufacturer of brincidofovir tested its product in Monrovia, in a study led by Oxford University, and pulled out within a month when results went south.10

  At the same time, scientists were working on a series of potential vaccines, which showed greater promise. Vaccines typically prime the body to recognize a foreign invader by infecting recipients with dead virus cells—as in influenza vaccines—or with a carrier virus that is not harmful to humans. Once the body’s immune system is tipped off that viruses with certain proteins or structures must be attacked, the system will recognize a potentially harmful invader with a similar structure, like Ebola.

  At the head of the pack was a drug with the maddeningly complicated name recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing surface glycoprotein of Zaire Ebolavirus, or rVSV-ZEBOV for short.

  Tests between April 1 and July 20, 2015, on 4,123 subjects in Conakry and eight other communities in Guinea showed a 100 percent efficacy rate after just a single injection. So did tests in Tonkolili and Bombali, in Sierra Leone. The vaccine, developed at USAMRIID and licensed to Merck Pharmaceuticals, created antibodies without inflicting any harm on humans.11 In December 2016, scientists published their results in the Lancet, concluding that the vaccine had worked.12 The U.S. Food and Drug Administration and the European Union fast-tracked the rVSV vaccine for approval, but even before it had cleared those hurdles public health officials had stockpiled 300,000 doses, in case of the next flare-up.

  “While these compelling results come too late for those who lost their lives during West Africa’s Ebola epidemic, they show that when the next Ebola outbreak hits, we will not be defenseless,” said Marie-Paule Kieny, WHO’s assistant director general and the lead author of the study, when the study was published.13

  Another vaccine, replication-defective chimpanzee adenovirus 3 vector vaccine expressing Zaire Ebola virus glycoprotein—ChAd3-ZEBOV in the medical literature—served a similar function. The vaccine removes one protein from a chimp adenovirus, harmless to humans, and replaces it with a glycoprotein from the Ebola virus. That glycoprotein sticks out from the side of the virion, which gives the immune system an early warning, enabling it to recognize any foreign invader with a similar glycoprotein—that is, Ebola.14

  The ChAd3 vaccine was given to 4,150 health-care workers in Mali, the United States, and Sierra Leone, to ensure that it is safe. The drug is in the process of advancing to phase-three testing. The only problem was it had to be stored at –80 degrees Celsius, a difficult prospect in the heat and humidity of equatorial Africa.

  The number of vaccine and treatment candidates, and the promise they showed, gave global health officials reason to believe that the outbreak in West Africa would spawn a once-and-for-all cure for Ebola virus.

  Speed, as in other areas of the outbreak response, was of the essence, and every day that a vaccine or a treatment was held up in trials was another day a patient in need was not getting drugs. But pharmaceutical companies are by nature cautious beasts, thanks to skittish legal departments, and the potential for exposing a global conglomerate to legal jeopardy tended to slow down the testing process.

  GlaxoSmithKline, developing the ChAd3 vaccine candidate, told the Obama administration that it was particularly concerned about lawsuits. Any company that developed an Ebola vaccine would receive little in the way of profits; after all, the disease strikes only occasionally. A single lawsuit would wipe out those profits.

  The White House turned to an obscure law for a solution: the Public Readiness and Emergency Preparedness (PREP) Act, passed after a swine flu vaccine made some recipients ill in 1976. The law allows the secretary of Health and Human Services to provide pharmaceutical companies with immunity from liability in tests of vaccines the government deems critical. Secretary Sylvia Burwell signed a PREP Act declaration covering vaccines in December 2014, and another covering proposed treatments in February 2015.

  “We knew it would be a long time before we would really get any vaccine on any kind of widespread basis. So the question was, could you prevent these legal issues from getting in the way of the clinical trials,” Ron Klain said later. GlaxoSmithKline had said it would not release its potential vaccine for clinical trials until it got immunity; the PREP Act declaration gave them an out.

  Still, the American solution did not sit well with some in the global health community, and with others in West Africa. From the perspective of a poor African country, the United States had just given big multinational corporations an excuse to experiment on their citizens, and the country would have no legal recourse. That could give pharmaceutical giants unstated permission to circumvent some of their normal, careful procedures, and instead rush into the field with a drug candidate that could do more harm than good.

  Gavi, the Global Vaccine Alliance, raised its own questions about the arrangement, which they feared would increase their costs, as drug makers demanded immunity from lawsuits relating to polio vaccines or other common treatments.

  There were other public relations problems to consider as well. GlaxoSmithKline researchers believed their vaccine would be 85 to 90 percent effective. From a public health standpoint, that rate of success would be high enough to ensure that an outbreak like Ebola would die out, for lack of unvaccinated hosts in which to live. But the 10 to 15 percent for whom the vaccine would not be effective would inevitably turn the blame back on the pharmaceutical company when they contracted the virus—potentially undermining the broader success of a vaccination campaign.

  The biological facts of the Ebola virus were less important than the structural and
societal reasons that an outbreak in a remote town had mushroomed into an international crisis—and very nearly a global catastrophe. In comprehensive case studies produced by everyone from the WHO to the CDC and smaller nongovernmental organizations, those who now turned their task toward preventing the next deadly disease identified seven main causes of Ebola’s spread, and the solutions to those problems that would limit future outbreaks.

  The causes, and their solutions, could be reasonably grouped into three broad categories: they were local, national, or international in nature.

  At the local level, responders found three nations poorly equipped to provide access to basic services like water and sanitation. Second, tradition required family members to care for the ill and the dead, and West African funerary customs had undoubtedly helped the disease spread widely. The third cause was evident even to those who had never set foot in West Africa before Ebola descended like a fog—the lack of trust between local communities and their central governments in Conakry, Monrovia, and Freetown created an atmosphere in which the communities that most needed organized assistance were most reluctant to accept the help.

  Nongovernmental organizations like Global Communities had spent years building proper sanitation and water service capacity. The villages that fully embraced the Global Communities Improved Water, Sanitation and Hygiene (IWASH) program, and therefore the connection between hygiene and health, experienced almost no Ebola cases. The Liberian environmental health technicians, who had helped those communities build their safer, more sanitary systems, then made up the burial teams who would enter villages and sit through long, drawn-out conversations explaining what Ebola was and what they were there to do to properly lay a victim to rest, without exposing other villagers. It was a message only Liberians could deliver to fellow Liberians, not one that westerners in their terrifying moon suits could convey. That led epidemiologists to conclude that a locally driven response, conducted by those who understood traditional customs and mores, helped break the virus’s back. In some ways, a social science, anthropology, broke through what the hard sciences of biology and chemistry could not.

  “We really broke through on some cultural practices,” the National Security Council’s Amy Pope recalled later. “We would now suggest that we should have anthropologists in any response.”

  Dan Martin, the CDC virologist who had been in the field in Sierra Leone, saw value in communicating a positive message. Early on, the World Health Organization and health ministries in all three countries tried to convey the danger of the Ebola virus by warning of its high fatality rate. That scared many who got sick, and convinced them to avoid the Ebola treatment units where they could receive treatment—and, more important, where they would be quarantined before they could infect family members and friends. Martin recalled:

  Before this epidemic, most of us really thought of Ebola virus as, if you get Ebola, you’re dead. You might as well say your prayers and do your will because you’re on your way out. That was not an unreasonable thing for people to believe.… But one of the things that we saw, and we still don’t have it fully nailed down on the science, but anecdotally we all know this to be the case, is that if we got people early on, when they first had their fever, when they first had their muscle aches, gave them oral rehydration solution, got them on IV, sustained their body so it didn’t crash so badly during the dehydration and everything else of the disease, they actually stood a chance of fighting it off.

  After initially scaring communities with messages about Ebola’s dangers, the WHO later highlighted the growing number of survivors who returned home having beaten the disease. Those survivors proved that entering an Ebola treatment unit was not a death sentence.

  “As we were able to get the message out that engaging with the system actually increases your chances for survival, that not only gave the community something to respond to, it gave us something to hang on to,” Martin said. “We weren’t just trying to keep people from taking somebody else with them while they died, we were actually trying to help these people get treatment so they could in fact recover.”

  At the national level, the weak public health systems in all three countries left their populations vulnerable to the spread of a deadly disease like Ebola, not to mention the more prevalent illnesses like Lassa, malaria, and cholera. Fragile infrastructure plagued responders trying to ferry supplies along rutted roads and into airports with bumpy tarmacs, while the lack of medical facilities meant that Liberia, Guinea, and Sierra Leone simply did not have enough space in which to safely treat Ebola patients.

  “Lack of capacity made the Ebola virus chase us, more than we chased the Ebola virus,” Tolbert Nyenswah told a conference at the Kaiser Family Foundation’s headquarters in Washington in 2016.

  Elements of the international response, from the CDC Foundation’s purchase of hundreds of trucks and motorcycles to USAMRIID’s laboratories and the rapid construction of Ebola treatment units, helped build that capacity. Military helicopters carrying blood samples from field hospitals to laboratories cut the diagnostic time from two or more days to a matter of just a few hours. So much capacity was added so quickly, first by Médecins Sans Frontières (MSF) and WHO, then by the U.S. military and other nongovernmental organizations, that some Ebola treatment units never admitted a single patient. By April 2015, only twenty-eight Ebola patients had been treated at two units built by the U.S. Army.15

  As the world waits for the next major outbreak, the hodgepodge of national and international agreements covering vaccine and treatment clinical trials—and, more important, the gaps between those agreements—remain a significant and unaddressed challenge.

  “We don’t really have a global legal structure to deal with issues around that,” Klain said.

  Beyond drug treatments, governments and corporations used the Ebola outbreak to innovate in other areas, particularly in the types of equipment that health responders could use in the field.

  The personal protection equipment that had been available worked, when used properly. But training responders to properly don and doff the bulky, cumbersome moon suits took days, and even some of the world’s most experienced epidemiologists got it wrong. Both Tom Frieden from the CDC and Raj Shah from USAID were reprimanded when they missed steps in the safe doffing process.

  “When you go in to treat a patient, you enter a hot zone. In that zone, you have to be fully clad: Gown, mask, gloves, double gloves, boot covers,” Shah recalled. “Take 45 minutes in the zone, you’re sweating, you have to pee, you’re exhausted.” Then the doffing profess begins, a twenty-step procedure as technicians spray the suit down with chlorine as each layer is removed.

  To spur an easier system, the U.S. Global Development Lab brought together agencies and corporations from around the country. Steve VanRoekel, who had served as the Obama administration’s chief information officer, was dispatched to USAID to help coordinate efforts between NASA, Motorola, DuPont, and the Gates Foundation, among dozens of others, to come up with new equipment. The result was a special suit designed for treating patients in the field, outfitted with protected zippers and extra safety measures that reduced the safe doffing procedure from twenty minutes to thirty seconds.

  Finally, on the international level, those evaluating the spread of Ebola cited the overcentralized nature of the World Health Organization, and the delays in international response caused by a bureaucratic behemoth that overestimated its own ability to respond to a crisis.

  As the disease died down, officials from across the globe began taking a hard look at just what the response had gotten right, and more important, what agencies had gotten wrong. Virtually everyone, including the World Health Organization itself, pointed fingers at WHO. The agency had fallen flat in its ability to diagnose the severity of the Ebola outbreak, its ability to organize a global response, and even in its ability to offer assistance once it was on the ground. The United Nations Mission for Ebola Emergency Response (UNMEER) program, set up through the
United Nations on the fly, had been such a disaster that American and other foreign officials frequently did not bother interacting with the rotating cast of uninformed and ill-prepared UN officials who parachuted in and out. The world, in short, needed a better answer for the next crisis.

  Even before the outbreak was over, the first of several panels meant to assess the WHO’s faults and failings came together. The WHO Ebola Interim Assessment Panel called the outbreak “a defining moment for the health to the global community,” and it recommended wholesale changes at headquarters in Geneva.16

  After months of review, the panel concluded that WHO had been woefully underfunded, and that it did not even have an emergency fund to pay for a fast response. Bureaucratic red tape meant it was impossible to place strong, independent directors in regional headquarters.

  “WHO needs to be more operational, as distinct from normative. We’re a really normative agency. In other words, we gather scientific evidence and provide advice on the nature of ill health,” WHO’s Chris Dye said in an interview. “We’re not typically an operational agency. In other words, we don’t do what the World Food Program does. We don’t do what UNICEF does. We’re not in the trenches.”

  The panel made six core recommendations. They suggested that the WHO enforce international health regulations that would spur countries to report outbreaks early, and to create a plan to build the capacity it would need to respond to any new epidemic. They wanted WHO to become more independent of its member nations, and to create a new threat level system that could respond to more minor outbreaks before they became epidemics.