The Fatal Strain

by Alan Sipress

  At the funeral, the boy’s older sister had embraced his body. Soon she came down with the same symptoms. The family took her to a slightly better clinic, where an ultrasound scan revealed lung damage, and then across the nearby border for medical care in Vietnam. It was too late. By the time the next two fell sick, Uy Ngoy had lost faith in modern medicine. “I decided to try another way,” he recounted. He dispatched them first to a Buddhist priest and then to a witch doctor in the mountains. These family members later recovered.

  There was no public education about the virus, and local public health was hardly any better. The health workers at the two local clinics told me in separate interviews that they had believed the siblings had routine pneumonia, common among villagers. The clinicians never thought to report the cases to Ly Sovann’s bureau or any other official. After Ly Sovann learned about the woman’s death from media reports, he rushed to Kampot with his team and stayed for a week. Blood samples were taken from family members, villagers were canvassed, and health warnings were broadcast from loudspeakers mounted on motorbikes. Ly Sovann’s mobile phone rang relentlessly.

  Several weeks later, he returned to the province, setting out from Phnom Penh before dawn on the three-hour drive. He had put on a white dress shirt with sleeves buttoned to the wrists and a dark striped tie fastened with a clip. His black hair was slicked to the side. He wanted to look as authoritative as possible. He had to convince the villagers to start reporting suspicious illnesses. Too many lives could be at stake. When he arrived at a community hall in Kampot town, he set up his laptop computer for a slide presentation and fished his PDA from the breast pocket. Then, over the hum of the ceiling fans, he made his pitch. The farmers, provincial officials, and community activists in the audience were skeptical. Some approached the microphone to question whether bird flu was even real.

  Foreign governments were far more unnerved than these locals. Flu specialists worried that cases were being missed and warned of a stealth outbreak in an utterly unprepared land. Over the following two years, foreign donors provided $13 million in emergency assistance. It wasn’t a lot, but in a small country it went a long way. Cambodia established rapid-response squads in every province. Composed mostly of doctors, these two-member teams were trained to investigate any suspected human case. Twenty-nine thousand village volunteers were mobilized to report rumors of unusual illnesses. Antiviral drugs and protective gear for health-care workers were purchased and pre-positioned in each province. Building on Ly Sovann’s cell-phone network, Cambodia pioneered a program in which local health officials could report a variety of diseases, including unusual respiratory outbreaks, by text message directly to a central computer.

  Cambodia soon had more foreign aid for the flu fight than its tiny cadre of medical professionals could handle. Yet the funding was short-term, good only for about three or four years. Cambodian health officials and their WHO colleagues remained anxious. After the emergency funding for bird flu was exhausted, who would pay to keep the rapid-response teams trained and send them to the field? Who would pay to replenish the antiviral drugs as they expired and conduct lab tests on samples? Who would pay to print the flyers and brochures distributed to villagers warning of the virus? Who would pay for the cell-phone calls?

  Nearly a year after I wrote about Ly Sovann for the Washington Post, I happened across a surprising item in Vanity Fair magazine. It was a long piece about bird flu that mentioned this Cambodian hero. Turns out, the magazine reported, the Post article had done Ly Sovann some good. The publicity had gotten him a raise. Two dollars more a month.

  David Nabarro was an effusive speaker. Yet when it came to money for fighting flu, the world’s wealthiest countries got him to bite his tongue. Nabarro was an Oxford-trained physician, a veteran of development efforts in Asia and Africa, and, as a senior United Nations official, he had worked some of the world’s most horrifying disasters, including the Indian Ocean tsunami and the genocidal conflict in Sudan’s Darfur region. He had been in the UN’s Baghdad headquarters in 2003 when it was devastated by a car bombing that killed twenty-two of his colleagues. After all that, he had become the global flu czar. As United Nations System Senior Coordinator for Avian and Human Influenza, he was responsible for coordinating the alphabet soup of UN agencies involved with flu.

  He was also the money guy. By 2007, donor countries and international institutions like the World Bank had pledged $2.3 billion toward fighting bird flu and preparing for pandemic. That was a significant sum, equivalent to what I later learned was being spent in the Washington area to replace an aging interstate highway bridge over the Potomac River. About $1 billion of the promised funding had already been delivered by the end of 2007, mostly to poorer countries. But as Nabarro reviewed the figures in advance of an avian-flu conference in New Delhi in December of that year, he realized that even if all the pledges were met, the needs would still far outstrip the available funds. He calculated the deficit would run into billions of dollars.

  Some donor countries didn’t want to hear it. They had already ponied up at a pair of similar conferences the previous year. They didn’t want to want to get tapped for more. “The donors convinced me not to come out with a strong statement about funding gaps,” Nabarro told me soon after.

  So in a briefing for reporters in New York before flying to New Delhi, he pulled his punches. He told the press that the world’s response to the pandemic threat was on the upswing but that “much more remains to be done.” He gave no dollar figure. That was the same equivocal message offered by a ninety-one-page progress report jointly released at the time by Nabarro’s office and the World Bank.

  Less than two weeks after the conference was over, Nabarro sent out a new version of the report. It was practically identical except for two extra pages inserted toward the beginning. They said what Nabarro had not. “There are signs of declining donor interest,” the updated edition warned. It disclosed that pledges were tumbling while the shortfall in emergency funding was on the rise. (The number of donors and amount of new money pledged would decline even further in 2008 as a senior U.S. diplomat warned of growing “flu fatigue.”) The updated document warned that the immediate fight against bird flu was now short about $1.3 billion. Most of that was money required by countries on the front line. In late 2006, the World Bank had helped estimate the funding these countries would need through the end of 2008. The document reported that nearly half of this was still unmet. Most notably, countries in sub-Saharan Africa still needed $462 million and those in East Asia were short $341 million. Those figures did not even address the longer-term needs that Ly Sovann in Cambodia and his counterparts across the developing world would soon face.

  To careful readers of the original ninety-one pages, this staggering deficit should have been no surprise. The report detailed sector after sector where frontline countries were outgunned by the virus. More than one-third of Asian and African countries surveyed said they had no lab capacity to confirm human flu infections. About half of these countries said they didn’t have enough antiviral drugs to cover even 1 percent of their population. The situation was equally grim on the livestock side, where many countries said they lacked basic veterinary services and lab facilities. On average, these countries required more than a week to identify poultry outbreaks and notify international authorities, a potentially catastrophic time lag. About a quarter of African and Asian countries reported they had no lab capacity to detect bird flu viruses in poultry. Only a small percentage paid farmers enough compensation to get them to report infected flocks rather than cover them up.

  Looking five to ten years ahead, the report concluded, “Adequate financial support for long term technical assistance and for integrated country programs is essential.” How much would it all run? Nabarro declined to name a figure. He said an honest number would scare donor governments.

  With outside assistance uncertain, some in the developing world have sought their own solutions, their initiatives driven by pride and pra
gmatism. Professor Nguyen Thu Van was one. Behind the high gray double doors of her Hanoi laboratory, Van was on a quest for the Holy Grail: a vaccine against the novel flu strain. Her team of young Vietnamese researchers scurried around the small, second-floor lab, some nights breaking only long enough to steal a few hours of a sleep in some corner of the elegant French colonial building that houses her institute. They were attempting a new, unorthodox approach to accelerate their effort. It involved developing a vaccine strain with fast-growing cancer cells despite the risk of deadly contamination. Two months before I met her in April 2005, the team had successfully tested the prototype on monkeys. The researchers were now preparing to try it on themselves.

  At age fifty, Van was a veteran vaccine scientist with a proven record that had won her the top post at Vabiotech, a pharmaceutical company affiliated with Vietnam’s National Institute of Hygiene and Epidemiology. There was little about her appearance to suggest Van’s august place in her country’s emerging drug industry. She dressed simply in a plaid sweater over black slacks, with her plain, straight hair held back by a barrette. She had a quiet confidence to match. But her brown eyes gleamed when she predicted that Vietnam would soon outpace more advanced countries by developing the world’s first effective vaccine against the virus. She offered a warm smile that tempered the audacity of her boast.

  Flu specialists outside Vietnam did not share her enthusiasm. To outsiders, her unconventional methods looked like reckless endanger ment. Yet to Vietnam, already facing recurring bird flu outbreaks, it was necessity, a clear case of national security. “We cannot wait,” Van told me.

  Few pharmaceutical endeavors could save as many lives as the development of a pandemic flu vaccine. Yet the obstacles are many. For years, international research into any kind of flu vaccine languished, in large part because government investment was directed toward AIDS and other diseases considered more pressing. The drug industry had no incentive to put its own money into influenza at a time when anemic public demand even for seasonal flu shots often fell short of existing supply. As a result, the technique for making flu vaccines, an unwieldy process that uses fertilized chicken eggs, remained largely unchanged since the 1950s. Since bird flu began proliferating in Asia, researchers have been chipping away at the challenge. But without significant scientific advances, vaccines against a pandemic strain will only become available long after it has circled the globe because of delays inherent in the technology. An analysis in 2007 found it would take more than half a year after the pandemic strain emerged for the first doses to be delivered. This reflects a timeline that includes about a month for WHO to isolate and distribute the seed strain, a month and a half to ramp up manufacturing, and another four months to produce the vaccine and release it for use. And even after the initial doses debut, most people will still have a long wait because of the world’s modest production capacity.

  The H5N1 strain has been particularly nettlesome. The virus has continued to rapidly evolve, spinning off various subtypes that confound efforts to develop a single vaccine in anticipation of an epidemic. The strain has also proven unusually resistant to experimental vaccines. This means higher doses are required to produce immunity, and the higher the dose, the less vaccine there is to go around.

  Scientists have been experimenting with new ways to get over these hurdles. One has centered on using cells, rather than chicken eggs, to incubate vaccines. This could cut the production time for a pandemic vaccine in half while increasing available doses. Initial clinical trials of a bird flu vaccine made by Baxter Bioscience using this technology showed promising results, according to a 2008 report.

  Another approach has centered on the use of chemicals called adjuvants, which enhance the effectiveness of a given dose by stimulating a person’s immune response. In 2007 the Belgian drug company GlaxoSmithKline reported the results of a study showing that an experimental vaccine against bird flu containing an adjuvant worked at lower doses than even seasonal flu shots. Later that year, WHO announced that these boosters could radically increase the global supply of pandemic vaccines. The agency predicted that by 2010, the world might be able to produce enough to immunize 4.5 billion people per year. But as WHO acknowledged, this would still fall short of what would be required to protect everyone on Earth.

  Even with these scientific advances, Vietnam has long suspected it would be at the back of the line if it waited for someone else to come up with a vaccine. Health officials in Hanoi—as well as those in Bangkok, Jakarta, and other Asian capitals—often told me they were sure industrialized countries would look after their own people first. And even if there were enough to go around, who could afford it? The drug industry “can’t provide vaccines to the world free of charge,” stressed Wayne Pisano, chief executive of French vaccine-maker Sanofi Pasteur.

  Van had no illusions. “If another country develops this vaccine, the cost will be very, very high,” she explained. “Vietnam is still very poor and could not afford a vaccine with a high cost. We need to provide this essential vaccine through local production at an affordable cost.”

  She had been down this road before. In 1997 she had been involved in developing a local vaccine against hepatitis B, which at the time infected at least 15 percent of all Vietnamese. The availability of this low-cost alternative to imported vaccines allowed Vietnam to immunize millions of children against the potentially fatal disease. Five years later, using genetic engineering, Van’s company produced a new generation of vaccines against both hepatitis A and B. She crowed at the time that Vietnam was one of only three countries able to make them. The potential savings were tremendous. At sixty cents per dose, the locally produced hepatitis A vaccine cost less than one-fifteenth the price of those on the international market.

  In the 1970s, Van had studied biochemistry in the Soviet Union before returning to get her doctorate in Vietnam. She had done subsequent training in Japan, Russia, and twice at the CDC in Atlanta. For most of her three decades at the institute, hepatitis had been her specialty. But after bird flu erupted in 2003, one of her mentors, a senior Vietnamese virologist who had earlier developed the vaccine that helped eradicate polio in their country, suggested that Van tackle influenza. He told her to hurry. “It was difficult at the beginning, because we did not have the experience,” she recounted, smiling and laughing softly. “But it isn’t really new for me. Any vaccine has similar steps and similar techniques.”

  With Japanese assistance, Van’s researchers obtained samples of the flu virus and then engineered a prototype vaccine strain by reverse genetics. The team began growing vaccine in monkey kidney cells, the same method the institute had used in making hepatitis A and polio vaccines. But before clinical trials could begin, WHO asked Vietnam in February 2005 to apply the brakes.

  A special WHO delegation, which included officials from agency headquarters in Geneva and the U.S. Department of Health and Human Services in Washington, was sympathetic to Vietnam’s predicament. “No licensed H5N1 vaccine for human use is available from vaccine manufacturers and future availability to Vietnam is doubtful,” the mission wrote.

  But the visiting officials objected that Van’s approach was too hazardous. Her team had flouted international guidelines by using monkey kidney cells, which were unapproved for making flu vaccines and might allow the virus to mutate into epidemic form. The use of cancer cells to accelerate the growth of the vaccine strain could introduce another fatal ingredient. Moreover, her lab lacked strong enough safety measures to ensure that the new, genetically engineered strain would not escape. The WHO mission also raised “serious ethical reservations” about the institute’s plan to ask its own scientists to volunteer as guinea pigs. The issue was coercion. “There are concerns that the volunteer ‘spirit’ may not be universally shared and some volunteers may feel uncomfortable and unable to state that for various reasons,” WHO wrote.

  Members of the delegation later told me they had received official guarantees from Vietnam that it would abandon th
e program. But Van had been in those two days of meetings and came away with a different impression. “I believe in our procedures and all the laboratory testing,” she said. “I’m sure our vaccine is safe. So I’m not concerned.”

  Clinical trials would go ahead in five months, Van told me. The first phase would involve about twenty volunteers. She would be one of the first. If production stayed on schedule, her company could deliver a half-million doses by the end of the year.

  When senior health officials in Geneva and Washington read Van’s comments on the front page of the Washington Post several weeks later, they were taken aback. The United States dispatched the health attaché at its Hanoi embassy to privately confront NIHE’s director and insist that Vietnam make good on its pledge to suspend the program. WHO officials made the same demand in public. Under duress, senior Vietnamese health officials sidetracked the vaccine program, and for a time Van’s drive for national self-sufficiency ran aground on the conflicting anxieties of rich and poor.

  Finally, in early 2008, clinical trials began. It was the same vaccine, developed in monkey kidney cells. And it was initially tested, as long planned, on researchers at the institute, ten in all. Then the vaccine was tested on what Vietnamese officials described as thirty student volunteers at the country’s Military Medical Institute, with larger trials planned. “Good results,” Van reported. Her institute planned to start mass production by late 2009. Each dose would cost 30,000 Vietnamese dong, or a mere $1.80.

  If Van confronted global inequities with determination and forbearance, Indonesia’s Siti Fadilah Supari was far less patient. And on a crisp Geneva morning on a climactic day in 2007, Dr. Supari was already running late. Her scheduled flight on a British airliner had been grounded. But she had been lucky enough to find a later flight to Geneva, this one on Lufthansa. She had flown through the night and, once on the ground, had to wait again, this time for nearly everyone else on board to file out. There had only been room for her at the very back of the plane, even though she was a cabinet member from the world’s fourth-largest country.