Players in H5N1's debut ponder a decade's lessons

Dec 14, 2007 (CIDRAP News) – Dr. Keiji Fukuda still remembers the intense emotions that tumbled through his mind as he waited to board his hastily scheduled flight out of Atlanta. His destination was Asia. In Hong Kong, a newly identified avian influenza virus, recently dubbed H5N1, was making people desperately ill.

His objective was not the first-ever case of H5N1 in humans; that had surfaced 8 months earlier, killing a 3-year-old child. Instead, the focus of his emergency trip was the second and third cases, soon to grow to 18. The new illnesses were the signal that international health authorities had been dreading since that first case: evidence that the new flu's ability to sicken and kill humans was not a mysterious anomaly but a true and sustained threat.

"After the first case, there were a lot of questions, because there had never been any H5 infections in humans before," Fukuda said recently. "But once we had a second case, there were no more thoughts of lab contamination or error. The potential implications of an outbreak were immediately apparent."

He came to that realization somewhere over the Atlantic, 10 years ago this month. December 2007 marks the 10th anniversary of the revelation that a potentially pandemic strain of flu had emerged for the first time in years, and of the start of unprecedented scientific cooperation and commercial expansion—and political disagreement.

To mark the occasion, CIDRAP News asked some of the key players in the 1997 emergency response to recall their reactions as the Hong Kong outbreak developed and to reflect on the weaknesses H5N1 exposed in public health and medicine, as well as the unexpected gifts it brought.

Scientists were not prepared
Science had anticipated a possible pandemic strain for decades—the last pandemic, an unusually mild one, had been in 1968—and had attempted to respond to one, in the disastrous "swine flu" vaccination campaign of 1976.

Yet when the real thing appeared in May 1997, scientists found they were not prepared. At the Centers for Disease Control and Prevention (CDC) in Atlanta, virologist Jacqueline Katz, whose work focused on human immune responses to flu vaccination and infection, discovered that time-tested assays for identifying flu via antibody production were not sensitive enough to identify what appeared to be a flu strain isolated from the Hong Kong child.

"Very fortuitously, there was a limited set of reagents in a repository at the National Institutes of Health [NIH] that did allow the international influenza community to identify the virus," and permitted her team to develop an assay "on the fly," she said.

At NIH, Dr. Anthony Fauci, then and now director of the National Institute for Allergy and Infectious Diseases, was unnerved by the Hong Kong case, but unsurprised by the difficulty of responding to it.

"I have chronic anxiety about emerging and re-emerging infections," he said. "I did feel we were not prepared at many levels for a major pandemic."

The CDC was unprepared in an even more basic way: It had no spare laboratory space with the level of biosecurity required to work on the virus. So it borrowed space in a facility 50 miles away in Athens, Ga., the secure avian disease labs of the Southeast Poultry Research Laboratory, part of the US Department of Agriculture (USDA).

"My first impression, with the first case, was that it might have been an anomaly of a human infection," said David Swayne, then and now the poultry lab's director. "But as fall went on and cases reappeared in the live poultry markets and then human cases began to blossom, we came to the realization that this was a pretty significant and severe problem that was going to make history."

The first publication hinting at what had happened—identifying the cause of the child's illness as avian influenza with a subtype of H5N1—came in a letter to Nature in early October 1997, signed by three faculty from Erasmus University in the Netherlands, one from the Hong Kong hospital that had treated the child, and Robert G. Webster of St. Jude Children's Research Hospital in Memphis. Webster, who had been warning for years on the threat of novel flu strains, had placed the reagents at NIH that allowed the CDC to begin its research.

That effort bore fruit in January 1998 with a paper in Science—by Katz, Swayne, and 14 others—that revealed the sequence of genes in the child's isolate that coded for the novel virus's surface proteins. It also confirmed that the virus had jumped intact from birds to humans without passing through an intermediate host—and it bore an ominous editor's note: "Since the submission of this report, there have been 12 additional confirmed human cases of influenza A (H5N1) infections in Hong Kong."

Paradigm shattered, poultry slaughtered
Fukuda, who in 1997 was the chief of epidemiology in the CDC's influenza branch, was not the only scientist sent rushing to Hong Kong by the revelation of spreading cases of H5N1 flu. Dr. Klaus Stohr, then the project leader of the World Health Organization's (WHO's) global influenza program, was on his way as well.

The WHO flu program had been on alert since the Nature authors attributed the child's illness to a strain not seen in humans before. "The moment when a paradigm crumbles to pieces is very exciting," Stohr said. "None of us thought avian influenza would ever make it into humans. Here we had something totally unexplained."

The ad hoc team that assembled in Hong Kong included representatives of the CDC, WHO, long-time flu researchers including Webster from St. Jude's and Malik Peiris from Hong Kong University, and both public health and animal health officials from the Hong Kong government. Veterinary involvement was unusual, but it turned out to be essential: As the epidemic curve rose, reaching more than 60 suspected illnesses, 18 confirmed infections, and 6 deaths, evidence mounted that the virus was circulating among the city's many live-poultry stalls.

"We began to be extremely concerned about the possibility of a human flu virus and the H5 virus reassorting and creating a more transmissible virus," Fukuda recalled. "We had a vision of virus spreading in many different locations and a real fear of a reassortment event if it was not brought under control."

Just before Christmas that year, teams from the territory's Department of Agriculture and Fisheries brought in evidence that H5N1 infection had spread widely through poultry sold by the innumerable small-scale dealers throughout the city. The Hong Kong government decided to take a radical step: to slaughter all of the territory's 1.4 million chickens within 24 hours.

The count of hundreds of millions of birds that have died of H5N1 or been culled to prevent its spread in the ensuing decade may obscure what an extraordinary act that was—especially given that the link between humans and poultry had not been scientifically proved, though it was intuitively understood.

"There were protests, including by religious groups," Fukuda said. "There was a lot of unease. It was a very dramatic step to take back then."

The gamble paid off: As the New Year ticked over, no new human cases appeared. The team disassembled, piece by piece. Late in January 1998, before flying back to Geneva, Stohr joined a small delegation looking at poultry-raising conditions in Guangdong, just over the Hong Kong border. He came away convinced that conditions on Chinese farms would favor a resurgence.

"This is not the end of H5N1," he thought, flying out. "If it can happen once, it will happen again."

A reawakening for flu research
Stohr was right, of course. Avian flu H5N1 lay low for several years, popped up episodically in birds and humans in 2002 and 2003, and in early 2004 began the westward expansion that has infected birds in more than 60 countries and sickened 340 humans, killing 208 of them.

The urgent international research program—since 1997, more than 1,700 peer-reviewed papers dealing with H5N1 have been published—has revealed both new insights into flu and the neglected state of flu science before the Hong Kong cases rang the alarm bell.

Paradoxically, researchers say, it took H5N1's reminder of the true dimensions of flu's threatening nature to jolt flu defenses out of a quiescent complacency.

"It reemphasized something that we should have always known: Avian influenza is a virus that always changes, and therefore there are always new questions arising that need research answers," said Swayne.

The H5N1 threat, which brought the human and animal health worlds closer than they had been in decades, prompted new initiatives at Swayne's lab. The anomaly of an avian flu strain that was highly pathogenic in both birds and humans underlined the inadequacy of the traditional lab method of virus isolation, which uses chicken eggs. In response, scientists David Suarez and Erica Spackman developed a real-time polymerase chain reaction (PCR) test that is now used worldwide for rapid diagnostics in poultry. The group also pushed for a new research program in poultry vaccines, which had not been a high priority in the United States, and developed a live-virus vaccine that can be given to chickens from 1 day of age and that has been licensed for emergency use by the USDA.

Of course, H5N1's emergence also stimulated human flu vaccine research, which had languished for decades, thanks to stagnant demand and low profitability for seasonal flu shots. In the past few years—largely since President George W. Bush released the National Strategy for Pandemic Influenza and pressed Congress for $7 billion in flu funds in November 2005—research has begun to show results on moving away from egg-based production, understanding the cross-reactivity that might allow prepandemic vaccination, and reaching for a universal, rather than strain-specific, vaccine.

"Ten years down the pike, we have come a long way," Fauci said. "There is still a lot to do, I am not saying we are anywhere near where we should be. But [H5N1] served as an important catalyst to jump-start the field."

Stohr felt so strongly about the neglected state of flu vaccine research that he left his WHO position to help boost it. He is now director of influenza franchises in vaccines and diagnostics for the vaccine maker Novartis Pharma AG, one of several companies working on the possibility of using adjuvants to stretch the available supply of flu vaccine.

For Katz, who is now chief of the CDC's flu immunology and pathogenesis branch, the ongoing unpredictability of H5N1 has proved the need to prepare for other flu surprises as well.

The H5N1 experience "created a new awareness that we need to be better prepared for novel influenza viruses," she said. "H5N1 by necessity has been the primary target, but all of that work is applicable to the potential emergence of H7 and H9 flu strains as well."

Scientific and policy hurdles remain
But highlighting the stimulus that H5N1 brought to flu science also underlines how much research remains neglected. For Katz, the biggest unresolved question is the ability to measure immunity to H5N1, something that cannot be achieved until accurate correlates of immunity are identified. For Stohr, the most nagging questions remain very basic ones (incubation periods, length of time virus is excreted) and also very practical ones (how to measure the effectiveness of the nonpharmaceutical interventions such as masks and social distancing that may be used in a pandemic before vaccine arrives).

Swayne, who welcomes the renewed attention and funding that H5N1 brought to animal health research, simultaneously worries that findings have not gone far enough.

"The virus is fairly widespread in Indonesia, Nigeria, Egypt and some Asian countries," he said. "It is going to take many years of very concerted effort from us on the research side in developing new tools to get it eradicated."

For Fukuda, who is now coordinator of the WHO's global influenza program, the issues that received a boost from the attention directed at H5N1 and the issues that remain neglected are the same—and they are not specifically scientific.

The re-emergence of H5N1 and the near-simultaneous 2003 eruption of SARS "brought home to both the public and decision makers that emerging infectious diseases really pose very large threats to populations," he said. "And not just a threat in terms of killing some people: This can affect travel patterns. It can bring down economies. It can have very drastic social and political effects."

The lesson of both outbreaks, he said, is that defenses against emerging infections are more robust and complete when they are assembled in advance and over time. And that the best defense includes not only investments in surveillance, vaccines, and diagnostics, but also social and political attitudes that allow the money to be spent far in advance of when the defenses might be needed.

H5N1's protean qualities—its ability to spread over long distances, penchant for subsiding and flaring episodically, and adaptability to many mammalian species—emphasize that broad preparation is more protective in the long run than attempting to predict any single virus's behavior.

"As a scientist, I have to say that I have no crystal ball: I have no idea what this virus will do," Fukuda said. "But as a person who has worked in public health for a long time and who has a lot of experience with this virus, I have to say that it makes me really nervous.

"It is durable and persistent and still does things that take us by surprise. It has more staying power than the media or politicians have attention. We cannot second-guess it. So we should focus on the things that we can do."

See also:

Nature letter on the first human H5N1 case:
De Jong JC, Claas EC, Osterhaus AD, et al. A pandemic warning? (Letter) Nature 1997 Oct 9;389(6651):554

1998 Science report detailing the genetic sequence of H5N1 from the first human case:
Subbarao K, Klimov A, Katz J, et al. Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science 1998 Jan 16;279(5349):393-6 [Full text]

World Organization for Animal Health (OIE) list of countries affected by H5N1
http://www.oie.int/downld/AVIAN%20INFLUENZA/A_AI-Asia.htm

Avian flu timelines:
WHO: http://www.who.int/influenza/human_animal_interface/avian_influenza/H5N1_avian_influenza_update.pdf

Nature: http://www.nature.com/avianflu/timeline/index.html

New Scientist: http://www.newscientist.com/channel/health/bird-flu/dn9977-timeline-bird-flu.html

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