Journal Digest — From Science: How animal RNA makes human viruses worseThe genetic genesis of a killer flu
WASHINGTON, Sept. 6, 2001 - It swept across the planet, less than 100 years ago, like the Black plague: A few people living today still remember the coffin shortages, the overflowing hospital wards, the friends who were alive one week and gone the next. In 1918, the so-called Spanish flu blanketed a world at war with a second devastation, killing more than 20 million people in a few short months. What made the Spanish flu such a killer? A report in Friday’s issue of the journal Science suggests that the 1918 pandemic may have been sparked by an unusual recombination of pig and human flu genes.
There have been other flu outbreaks in the past century, including severe epidemics in 1957 and 1968, and a short-lived scare with the Hong Kong chicken flu in 1997. But none has rivaled the virulence of 1918 flu. The detective story behind the 1918 outbreak would have been impossible to write just a few short years ago, because the story’s central focus — the virus itself — was unknown. With no living copies of the virus available to study, enterprising researchers located and recovered fragments of the flu genome in carefully preserved and archived lung tissues from World War I soldiers, and in one case, from an Inuit woman buried in the Alaskan permafrost.
The RNA sequences recovered from these time-capsule tissues confirmed that the 1918 flu was a variant of the H1N1 subtype of influenza, versions of which still circulate among humans today. Early analyses suggested that the flu was most closely related to mammal flu viruses, and that the ancestors of the virus must have infected mammals several years before 1918. Yet this first look at the 1918 flu yielded few clues about its unusual virulency.
A lethal combination
Flu viruses are basically strands of RNA, enveloped in a layer of fat and studded on the surface with spikes of hemagglutinin and euraminidase proteins. Hemagglutinin helps the virus attach to host cells, while neuraminidase helps the viral particles eventually escape from the host cell and spread the infection. The body develops antibodies against these two proteins to protect itself from flu.
The genes behind these proteins are constantly mutating, however, gradually taking on different “looks” that existing antibodies find harder to recognize and combat. This never-ending cycle is the reason why new flu vaccines must be created every year, to match the new variants that have sprung up since the last flu season.
In some cases, new versions of these genes abruptly appear, and the virus’ hosts are suddenly faced with a threat against which they have no antibodies. The introduction of bird hemagglutinin genes into human flu strains before the 1957 and 1968 flu epidemics, for instance, show how these sudden shifts can produce new virulent strains.
New viral genes can also arise through a process called recombination, where pieces of a gene from two or more parent viruses combine to form one new gene. Research by Mark J. Gibbs, his father Adrian J. Gibbs, and John A. Armstrong of the Australian National University on plant viruses suggests that recombination can create especially virulent strains. Although recombination had never been seen in flu genes, the team decided to see if recombination posed a similar threat among those viruses.
“We talked about looking at flu sequences, but we didn’t know where to start with flu because there are so many sequences, more than 6,000, and recombination in flu was thought to be very rare,” said Mark Gibbs. Then, one night, Adrian Gibbs came across an article about the newly recovered 1918 virus and decided to examine it for signs of recombination. In a few hours, he had found an unusual signal in the sequence data.
Pig and human
he data in question was the complete sequence for the 1918 flu’s hemagglutinin gene. After exhaustively comparing the sequences with hemagglutinin sequences from a variety of bird, pig, and human flu types, the researchers concluded that the 1918 hemagglutinin was a chimera, a true recombinant gene made up of sequence from a pig flu virus and a human flu virus.
Their analysis showed that the beginning and end parts of the gene sequence came from human flu, while the middle part of the gene sequence came from pig flu. These different regions of the gene encode different parts of hemagglutinin: The ends encode the stalk that attaches the protein to the viral coat, while the middle encodes hemagglutinin’s globular head. Mark Gibbs suggests that this relatively neat breakdown may have been a factor in the recombinant gene’s survival.
“This is the first known case where a viable gene has been produced from the parts of other influenza genes,” said Mark Gibbs. In addition to its unusual virulence, the 1918 flu was notorious for killing an extraordinary number of young adults. Younger people were perhaps more vulnerable to the flu, the new research suggests, because their immune systems had never encountered the new recombination, and thus couldn’t recognize or fight it.
Did the recombination of the hemagglutinin gene actually launch the flu pandemic of 1918? The pig/human gene emerged about the same time as the pandemic, suggesting that, indeed, genetic reshuffling may have triggered this public-health disaster. “The start of the pandemic coincided with a recombination event that might produce the phenotypic novelty required to trigger a pandemic,” the Science article concludes. “This coincidence suggests a causal link.”
Moreover, recombination “can result in increased virulence,” A second study in the same issue of Science seems to support this notion: In mice, a single amino acid substitution in the PB2 gene and hemagglutinin gene strongly influences infection rates of the 1997 Hong Kong chicken flu. This report, by Yoshihiro Kawaoka of the University of Wisconsin-Madison and the University of Tokyo, with Masato Hatta and others, is “consistent with the concept that influenza virus pathogenicity is multigenic.”
Could it happen again?
Though such evidence seems convincing, it’s still not possible to say with absolute certainty whether a change in the hemagglutinin gene gave the 1918 flu its extra kick, Graeme Laver of Australian National University and Elspeth Garman of the University of Oxford say in a related essay. The bigger question now, they write, is whether similarly virulent flu strains are likely to strike again — and whether modern medicine will be ready in the event of a new pandemic.Mass vaccination, as attempted in 1976 when a swine flu outbreak occurred among army recruits at Fort Dix, N.J., can be problematic, Laver and Garman say. In that case, the preventive efforts were undermined by vaccine side effects and litigation tangles, as well as disappointing antibody responses. Current flu vaccines, containing hemagglutinin and neuraminidase from various strains of cultured flu virus, only target particular versions of the virus. Developing and safety-testing enough vaccine to fight a new virus would take time — perhaps six months — as well as high levels of research investment.
The most promising “first line of defense,” Laver and Garman propose, is antiviral drugs, particularly neuraminidase inhibitors. But, they point out, “for the drugs to be of any use, huge quantities would need to be immediately available, and means for their rapid distribution would need to be in place beforehand.”
Unfortunately, current supplies are “woefully inadequate,” Laver and Garman say. Robert G. Webster of St. Jude Children’s Research Hospital echoes this sentiment: “During the period between detection of a pandemic strain and the availability of a vaccine,” Webster writes, “antiviral drugs will be essential. It is gravely disquieting that no action has yet been taken to create strategic stockpiles of such drugs.”
Journal Digest — From : How Protest and Politics Threaten the Biotech Revolution
Hard truths about bird flu
The issues surrounding the possibility of a pandemic of the H5N1 strain of avian flu are extraordinarily complex, encompassing medicine, epidemiology, virology, and even politics and ethics. Moreover, there is tremendous uncertainty about exactly when H5N1, which now primarily affects birds, might mutate into a form that is transmissible between humans, and how infectious and lethal it might be.
It is thus hardly surprising that commentaries about avian flu often miss the mark. A recent New York Times editorial, for example, decried wealthy countries’ “me first” attitude toward a possible H5N1 pandemic, because “[t]he best hope of stopping a pandemic, or at least buying time to respond, is to improve surveillance and health practices in East Africa and Asia, where one would probably begin.”To be sure, good surveillance is needed in order to obtain early warning that a strain of H5N1 flu transmissible between humans has been detected, so that nations around the world can rapidly initiate a variety of public health measures, including a program to produce large amounts of vaccine against that strain. But the massive undertaking required to “improve health practices in the poorest countries of the world” plays better on the editorial page than on the ground. Intensive animal husbandry procedures that place billions of poultry and swine in close proximity to humans, combined with unsanitary conditions, poverty, and grossly inadequate public health infrastructure of all kinds, make it unlikely that a pandemic can be prevented or contained at the source. It is noteworthy that China’s chaotic effort to vaccinate 14 billion chickens has been compromised by counterfeit vaccines and the absence of protective gear for vaccination teams, which might actually spread disease by carrying fecal material on their shoes from one farm to another.
In theory, it is possible to contain a flu pandemic in its early stages by performing “ring prophylaxis” – using anti-flu drugs and quarantine aggressively to isolate relatively small outbreaks of a human-to-human transmissible strain of H5N1. According to Johns Hopkins University virologist Donald S. Burke, “it may be possible to identify a human outbreak at the earliest stage, while there are fewer than 100 cases, and deploy international resources – such as a WHO stockpile of antiviral drugs – to rapidly quench it. This ‘tipping point’ strategy is highly cost-effective.” However, a strategy can be “cost-effective” only if it is feasible. Although ring prophylaxis might work in Minneapolis, Toronto, or Zurich, in the parts of the world where flu pandemics begin, the probability of success approaches zero. In places like Vietnam, Indonesia, and China – where the pandemic strain will likely originate – expertise.
The response in Turkey – where as many as 50 possible cases have appeared in the eastern part of the country – is instructive. Officials in that region warned the government on December 16 of a surge in bird deaths, but it took 12 days for an investigation to begin. When a fourteen-year-old boy became Turkey’s first avian flu mortality last week (soon followed by two siblings), a government spokesman criticized doctors for mentioning the disease because they were “damaging Turkey’s reputation.” This is ominously reminiscent of China’s initial response to SARS in 2003.
For now, it seems that all of the human H5N1 infections have been contracted from contact with infected poultry. But the situation in Turkey is what the outbreak of a human to human pandemic could look like at its earliest stages: the rapid spread of confirmed cases (and deaths) from an initial site to nearby villages and cities. We would expect to see a large number of illnesses among both employees and patients in hospitals where the victims are treated, and soon someone (perhaps even a carrier who is not ill) would spread it to Ankara, Istanbul, Tbilisi, Damascus, Baghdad, and beyond. The anti-flu drugs Tamiflu and Relenza are extremely expensive and in short supply. History suggests that if we were to make these drugs available to poor countries for ring prophylaxis, they would often be administered improperly – such as in sub-optimal doses – in a way that would promote viral resistance and only intensify a pandemic. Or perhaps they would be sold on the black market to enrich corrupt government officials.
A politically incorrect but rational strategy would be for rich countries to devote resources to developing countries primarily for surveillance. They would obtain timely warning of the existence of an H5N1 strain that is transmissible from human to human, but would focus the vast majority of their funding on parallel, low- and high-tech approaches – vaccines, drugs, and other public health measures – that would primarily benefit themselves. If the pandemic were to begin relatively soon – say, within a year or two – there would be little that could be done to attenuate significantly the first wave of infections. But, if we’re ready to rush the pandemic strain into an emergency program to manufacture vaccine, we could possibly blunt the second wave. A flu pandemic will require triage on many levels, including not only decisions about which patients are likely to benefit from scarce commodities such as drugs, vaccines, and ventilators, but also broader public policy choices about how best – among, literally, a world of possibilities – to expend resources.
Journal Digest — From : Epidemic and Pandemic Alert and Response
Situation (human) in Thailand
The Ministry of Public Health in Thailand has confirmed the country’s sixth case of H5N1 infection. The case is a 13-year-old boy from Chaiyaphum Province. Preliminary investigation has linked the case to contact with diseased chickens near his home.
Situation (human) in Viet Nam
The Ministry of Health in Viet Nam has today confirmed an additional case of H5N1. The case, which was fatal, was in a 19-year-old man, who had been hospitalized in Ho Chi Minh City. To date, Viet Nam has reported 19 confirmed cases, of which 14 have been fatal.
First data on patients from Viet Nam
WHO is today publishing the first clinical and epidemiological data on 10 human H5N1 cases in the Viet Nam outbreak. The data have been compiled by Vietnamese clinicians, epidemiologists, and laboratory scientists involved in the first-hand treatment and investigation of cases. WHO is grateful to these authors for allowing immediate publication of their findings. Preliminary clinical and epidemiological description of influenza A (H5N1) in Viet NamClinical information on five laboratory-confirmed cases in Thailand will be published by WHO in the Weekly Epidemiological Record. Publication of clinical data for 15 cases in the present outbreak sheds important light on distinctive features of illness caused by H5N1 infection that should assist in worldwide surveillance and early detection of cases. A case definition for global reporting, supported by information on appropriate laboratory tests for confirmation of diagnosis, was published by WHO yesterday.
Clinical data from Hong Kong 1997
Up to now, knowledge about H5N1 disease in humans was limited to clinical studies of the 18 cases in Hong Kong in 1997. In that outbreak, patients, who ranged in age from 1 to 60 years, had gastrointestinal symptoms, hepatitis, renal failure, and pancytopenia. These findings indicate that H5N1 infection affects more body organs and systems than normal influenza, where respiratory symptoms are dominant. Also, unlike normal influenza, death in the six fatal cases occurred as a result of the primary viral infection rather than a secondary infection caused by bacteria.
One month into the outbreak
Laboratory results confirming the first 3 human cases of H5N1 infection were announced on 12 January. Today, one month into the outbreak, WHO is issuing a chronology of key events in both the human and poultry outbreaks, which are intricately interrelated. WHO is also stressing the need to maintain vigilance for suspected cases and to report suspected disease, in humans and animals, promptly and transparently. The disease in poultry is still spreading in several areas. In others, progress in controlling the avian outbreak does not mean that the risk to human health has been eliminated.
Several countries with outbreaks in poultry have weak health infrastructures, with weak capacity for the detection of cases, particularly in rural areas where the majority of domestic birds are raised. Capacity to diagnose a difficult disease such as H5N1 is also weak. Moreover, as the clinical material published today and tomorrow indicates, the full clinical spectrum of H5N1 illness is unknown. Milder cases of illness could be occurring, yet fail to reach the attention of health care staff. As today’s report from Viet Nam states, “These (10) cases were identified by alert clinicians in tertiary care hospitals and cannot be taken to be representative of the full range of illness that H5N1 may cause.” For all these reasons, the current small number of laboratory-confirmed cases cannot be taken as an accurate indication of the magnitude of the present or potential threat to human health.
Susceptibility of H5N1 viruses to antiviral drugs
Data received from the WHO Global Influenza Surveillance Network indicate that recent H5N1 viruses are susceptible to oseltamivir, one of the two licensed neuraminidase inhibitors. All strains tested (4 isolates from humans and 33 isolates from birds) demonstrated in vitrosusceptibility to this drug. Oseltamivir belongs to one of two classes of drugs that can be used to prevent or treat influenza in humans. Studies previously conducted by laboratories in the influenza network have shown that most recent H5N1 strains are resistant to the second class of drugs, the M2 inhibitors (amantadine and rimantadine).