In 1918, patients suffering from a highly contagious flu were sent to camps like this one in Lawrence, Mass.
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Fear of the bird flu sweeping across Asia has played a major role in the government's flurry of preparations for a worldwide epidemic.
That concern prompted President Bush to meet with vaccine makers on Friday to try to persuade them to increase production, and it led Health and Human Services Secretary Michael O. Leavitt to depart yesterday for a 10-day trip to at least four Asian nations to discuss planning for a pandemic flu.
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In 1918, patients suffering from a highly contagious flu were sent to camps like this one in Lawrence, Mass. |
But scientists say that although the threat from the current avian virus is real, it is probably not immediate.
Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, said a bird flu pandemic was unlikely this year.
"How unlikely, I can't quantitate it," Dr. Fauci said. But, he added, "You must prepare for the worst-case scenario. To do anything less would be irresponsible."
Dr. Jeffery Taubenberger, chief of the molecular pathology department at the Armed Forces Institute of Pathology, said, "I would not say it's imminent or inevitable." Dr. Taubenberger said he believes that there will eventually be a pandemic, but that whether it will be bird flu or another type, no one can say.
The Bush administration is in the final stages of preparing a plan to deal with pandemic flu. A draft shows that the country is woefully unprepared, and it warns that a severe pandemic will kill millions, overwhelm hospitals and disrupt much of the nation.
What worries scientists about the current strain of bird flu, known as H5N1, is that it has shown some ominous traits. Though it does not often infect humans, it can, and when it does, it seems to be uncommonly lethal. It has killed 60 people of the 116 known to have been infected.
Alarm heightened on Thursday when a scientific team led by Dr. Taubenberger reported that the 1918 flu virus, which killed 50 million people worldwide, was also a bird flu that jumped directly to humans.
There is a crucial difference, however; the 1918 flu was highly contagious, while today's bird flu has so far shown little ability to spread from person to person. But a mutation making the virus more transmissible could set the stage for a pandemic.
Another concern is that H5N1 has become widespread, killing millions of birds in 11 countries and dispersing further as migratory birds carry it even greater distances. This month, it was reported in Romania.
Meanwhile, the flu is spreading widely among birds in Asia. And it has unusual staying power, persisting in different parts of the world since it emerged in 1997.
"Most bird flus emerge briefly and are relatively localized," said Dr. Andrew T. Pavia, chief of the division of pediatric infectious diseases at the University of Utah and chairman of the pandemic influenza task force of the Infectious Diseases Society of America. The most worrisome thing about H5N1, Dr. Pavia said, is that it has not gone away.
Some scientists suspect that if H5N1 has not caused a pandemic by now, then it will not, because it must be incapable of making the needed changes. But others say there is no way to tell what the virus will do as time goes on. And they point out that no one knows how long it took for the 1918 virus to develop the properties that led to a pandemic.
Meanwhile, H5N1 seems to be finding its way into more and more species. Once known to infect chickens, ducks and the occasional person, the virus is now found in a wide range of birds and has infected cats.
"It killed tigers at the Bangkok zoo, which is quite remarkable because flu is not traditionally a big problem for cats," Dr. Pavia said.
It has also infected pigs, which in the past have been a vehicle to carry viruses from birds to humans.
"We should be worried but not panicked," Dr. Pavia said.
The timing of the bird flu's emergence also makes scientists nervous, because many believe that based on history, the world is overdue for a pandemic. Pandemics occur when a flu virus changes so markedly from previous strains that people have no immunity and vast numbers fall ill.
"In the 20th century there were three pandemics, which means an average of one every 30 years," Dr. Fauci said. "The last one was in 1968, so it's 37 years. Just on the basis of evolution, of how things go, we're overdue."
Dr. Bruce Gellin, director of the National Vaccine Program Office, said: "You get this sense of compounding risks. First, it's in some birds. Then more. Then more area, then more mammals and then to humans, albeit inefficiently."
In just a few instances, Dr. Gellin noted, the virus does appear to have spread from person to person.
"The only thing it hasn't done is to become an efficient transmitter among humans," he said. "It's done all the other things that are steps toward becoming a pandemic virus."
But not everyone is equally worried about the bird flu.
The fear "is very much overdone, in my opinion," said Dr. Edwin Kilbourne, an emeritus professor of immunology at New York Medical College, who has treated flu patients since the 1957 pandemic and has studied the 1918 flu.
The bird flu, he said, is distantly related to earlier flus, and humans have already been exposed to them, providing some resistance.
Scientists also say that the death rate may not be as high as it appears, because some milder cases may not have been reported.
Dr. Kilbourne and other experts also noted that when viruses become more transmissible, they almost always become less lethal. Viruses that let their hosts stay alive and pass the disease on to others, he explained, have a better chance of spreading than do strains that kill off their hosts quickly.
Moreover, he said, while much has been made of comparisons between the current avian flu and the 1918 strain, the factors that helped increase the flu's virulence in 1918 - the crowding together of millions of World War I troops in ships, barracks, trenches and hospitals - generally do not exist today for humans.
But an essential difference is that people carrying the flu today can board international flights and carry the disease around the world in a matter of hours.
Dr. Kilbourne emphasized that medical care had improved greatly since 1918. Although some flu victims then turned blue overnight and drowned from blood, with fluid leaking into their lungs, many more died of what are now believed to be bacterial infections, which can be treated with antibiotics.
Although the death toll from that flu was high, the actual death rate was less than 5 percent.
In addition, more people now live in cities, where they have probably caught more flus, giving them immunity to later ones. "In 1918, you had a lot of farm boys getting their first contact with city folks who'd had these things," Dr. Kilbourne said.
What researchers wish they could do now is look at a flu virus like H5N1 and predict whether it is heading down the genetic road to becoming a pandemic strain.
"I hope in the future we will be able to do that, work out which mutations are critical," Dr. Taubenberger said. "We know the 1918 strain had everything it needed."
Andrew Pollack and Donald G. McNeil Jr. contributed reporting for this article.
The mysteries of the 1918-1919 influenza pandemic that killed an estimated 50 million people across the globe are finally beginning to be solved.
Two scientific papers published last week provide insights into the virus that caused the most deadly influenza outbreak in modern history.
This virus was unusual because it spread so quickly, was so deadly and exacted its worst toll among the young and healthy.
In just over one year, the virus infected one-third of the world's population with death rates approximately 50 times higher than those associated with regular seasonal influenza.
The harsh reality of the 1918 pandemic is never far from the minds of scientists and public health officials who are monitoring the current influenza outbreak occurring in Asia.
Since December 2003, a strain of influenza virus that usually infects only birds has sickened at least 116 people and killed 60 in Thailand, Vietnam, Cambodia and Indonesia.
This virus, known as H5N1 avian influenza A virus, has killed or forced the culling of more than 100 million chickens in 13 countries, has infected ducks and other migratory birds and has been transmitted to tigers, cats and pigs.
So far, the virus is not easily passed from birds to humans, and, thankfully, is not efficiently spread from one person to another when it does cross species.
However, influenza viruses are notoriously capable of changing, and should the avian virus develop the ability to spread easily among people, a worldwide influenza pandemic could ensue, potentially rivaling in impact the 1918-1919 pandemic.
Understanding why and how influenza virus can reach global proportions and cause so many deaths is now an urgent imperative.
The new research, published in the journals Science and Nature, provide critical clues to the genesis of the 1918 pandemic and why it was so lethal.
The findings reveal essential information to help us speed our preparation for - and potentially thwart - the next influenza pandemic.
For the first time, researchers have deciphered the entire gene sequence of the 1918 virus and have used techniques to assemble viruses that bear some or all of these genes so their effects can be understood.
Importantly, they have identified gene sequences that may predict when an influenza virus strain is likely to spread among humans. They also have determined in the test tube and in mice which genes are most likely to account for the lethal effects of the 1918 virus.
The new studies could have an immediate impact by helping scientist focus on detecting changes in the evolving H5N1 virus that might make widespread transmission among humans more likely.
For example, on the basis of these studies, we know that the H5N1 virus currently circulating in Asia has acquired five of the 10 gene sequence changes associated with human-to-human transmission in the 1918 virus.
In addition, the findings also may lead to identification of new targets for drugs and vaccines to treat and prevent influenza, now and in the future.
The techniques described in these reports are not new and are already accessible to anyone with the will and means to conduct similar experiments.
Nevertheless, some have understandably questioned whether these research findings should be reported in scientific journals because of concern that this knowledge could be used by those with nefarious intent.
Prior to publication, these scientific papers were reviewed by the National Science Advisory Board for Biosecurity, an advisory committee to the U.S. secretary of Health and Human Services and to the heads of all federal departments and agencies that conduct or support life science research.
The board was established to provide advice on ways to minimize the possibility that knowledge and technologies emanating from vitally important biological research will be misused to threaten public health or national security.
The board comprises members with a broad range of expertise in molecular biology, infectious diseases, biosafety, public health, veterinary medicine, plant health, national security, biodefense, law enforcement, scientific publishing and related fields.
The board unanimously endorsed publication of the manuscripts and recommended "making such information widely available to the scientific community for the purpose of validating the research findings, building upon the research and advancing the development of diagnostic assays, treatments and preventative measures."
The rationale for publishing the results and making them widely available to the scientific community is to encourage additional research at a time when we desperately need to engage the scientific community and accelerate our ability to prevent pandemic influenza.
It would be impossible and counterproductive to attempt to enforce a worldwide ban on conducting research on the 1918 influenza virus or similar viruses because of fear of the misuse of such knowledge.
Likewise, the dissemination of information emanating from this research should not be suppressed; rather, we must foster a culture of responsibility among the scientific community such that research is conducted under the safest possible conditions and research results are presented openly and responsibly for the purpose of improving human health.
We concur fully with the recommendations of the NSABB.
Moving forward with research conducted by the world's top scientists and openly disseminating their research results remain our best defense against H5N1 avian influenza virus and other dangerous pathogens that may emerge.
With better tools for detection and more effective countermeasures, the threat posed by such dangerous pathogens can be greatly reduced.
We feel that the certain benefits to be obtained by a robust and responsible research agenda aimed at developing the means to detect, prevent and treat these threats far outweigh any theoretical risks associated with such research.
Anthony S. Fauci is director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, and Julie L. Gerberding is director of the Centers for Disease Control and Prevention.
source: http://www.jsonline.com/news/editorials/oct05/361499.asp
The 1918 influenza virus, the cause of one of history's most deadly epidemics, has been reconstructed and found to be a bird flu that jumped directly to humans, two teams of federal and university scientists announced yesterday.
It was the culmination of work that began a decade ago and involved fishing tiny fragments of the 1918 virus from snippets of lung tissue from two soldiers and an Alaskan woman who died in the 1918 pandemic. The soldiers' tissue had been saved in an Army pathology warehouse, and the woman had been buried in permanently frozen ground.
"This is huge, huge, huge," said John Oxford, a professor of virology at St. Bartholomew's and the Royal London Hospital who was not part of the research team. "It's a huge breakthrough to be able to put a searchlight on a virus that killed 50 million people. I can't think of anything bigger that's happened in virology for many years."
The scientists painstakingly traced the genetic sequence, synthesized the virus using tools of molecular biology, and infected mice and human lung cells with it in a secure laboratory at the Centers for Disease Control and Prevention in Atlanta. The research is being published in the journals Nature and Science.
The findings, the scientists say, reveal a small number of genetic changes that may explain why this virus was so lethal. It is significantly different from flu viruses that caused the more recent pandemics of 1957 and 1968. Those viruses were not bird flu viruses but instead were human flu viruses that picked up a few genetic elements of bird flu.
The research also confirms the legitimacy of worries about the bird flu viruses, called H5N1, that are emerging in Asia. Since 1997, bird flocks in 11 countries have been decimated by flu outbreaks. So far nearly all the people infected - more than 100, including more than 60 who died - contracted the sickness directly from birds. However, there has been little transmission between people.
The 1918 virus, in contrast, was highly infectious, and in recent weeks the fear that a transformation of one of the current bird flus could make it infectious in humans has prompted politicians of both major parties to scramble to demonstrate that they are taking the threat of an avian flu outbreak seriously.
Bush administration officials have been talking about pandemic flu preparedness for years, and they say they will soon release a pandemic flu plan, in the works for more than a year. Senate Democrats say that the administration is not doing enough, and they are writing their own bills that call for more spending and coordination.
President Bush this week asked the leaders of the world's top vaccine manufacturers - Chiron, Sanofi-Aventis, Wyeth, GlaxoSmithKline and Merck - to come to the White House on Friday to discuss preparations for pandemic flu, said people with knowledge of the meeting who insisted on anonymity because the White House has not yet announced the meeting.
The research on the 1918 virus is directly applicable to current concerns, Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, and Dr. Julie L. Gerberding, director of the Centers for Disease Control and Prevention, said in a joint statement. "The new studies could have an immediate impact by helping scientists focus on detecting changes in the evolving H5N1 virus that might make widespread transmission among humans more likely," they said.
The bird flu viruses now prevalent share some of the crucial genetic changes that occurred in the 1918 flu, scientists said, but not all. The scientists suspect that with the 1918 flu, changes in just 25 to 30 out of about 4,400 amino acids in the viral proteins turned the virus into a killer. The new work also reveals that 1918 virus acts much differently from ordinary human flu viruses. It infects cells deep in the lungs of mice and infects lung cells, like the cells lining air sacs, that would normally be impervious to flu. And while other human flu viruses do not kill mice, this one, like today's bird flus, does.
Other scientists said the new work was immensely important, leading the way to identifying dangerous viruses before it is too late and to find ways to disable them.
The 1918 flu, which killed as many as 50 million people worldwide, showed how terrible that disease can be. It had been "like a dark angel hovering over us," said Dr. Oxford, the virology professor at St. Bartholomew's. The virus spread and killed with terrifying speed, preferentially striking the young and the healthy. Alfred W. Crosby, author of "American's Forgotten Pandemic: The Influenza of 1918," said that it "killed more humans than any other disease in a similar duration in the history of the world."
The research, and its publication, raised concerns about whether scientists should actually resurrect this killer that vanished from the earth nearly a century ago.
"It is something we take seriously," said Dr. Fauci, whose institute helped pay for the work. The work was extensively reviewed, he added, and the National Science Advisory Board for Biosecurity was asked to decide whether the results should be made public. The board "voted unanimously that the benefits outweighed the risk that it would be used in a nefarious manner," Dr. Fauci said.
Others are not convinced.
Richard H. Ebright, a molecular biologist at Rutgers, said he had serious concerns about the reconstruction of the virus. "There is a risk verging on inevitability, of accidental release of the virus; there is also a risk of deliberate release of the virus." And the 1918 flu virus, Dr. Ebright added, "is perhaps the most effective bioweapons agent ever known."
But Dr. D. A. Henderson, a resident scholar at the University of Pittsburgh Center for Biosecurity and a leading expert on bioterrorism, said he agreed with the decision to reconstruct the virus and publish its genetic sequence. "This work is of the greatest importance, and it is very important that it be published," he said.
The story of the resurrection of the 1918 flu began in 1995. Until then, scientists had thought the task hopeless. Viruses had not been discovered in 1918, so no one had isolated and saved the one that caused the flu.
But Dr. Jeffery Taubenberger, chief of the molecular pathology department at the Armed Forces Institute of Pathology in Washington, had an idea for finding that ancient virus. He recalled that his institute had a warehouse of autopsy tissue, established by President Lincoln.
Dr. Taubenberger investigated and found tissue from two soldiers who died of the 1918 flu, one in Massachusetts, one on Long Island. The tissue was snips of lung soaked in formalin and encased in little blocks of wax. In that tissue was the virus, broken and degraded, but there, untouched for nearly 80 years.
Then Dr. Taubenberger received a third sample, from a woman who had died in Brevig, Alaska, when the flu swept through her village, killing 72 adults and leaving just five. The dead were buried in a mass grave in the permafrost. A retired pathologist, Johan Hultin, hearing of Dr. Taubenberger's quest, had traveled from his home in San Francisco at his own expense. He dug up the grave with the villagers' permission, extracted the woman's still frozen lung tissue and sent it to Dr. Taubenberger.
Dr. Taubenberger and his colleagues spent nearly a decade carefully extracting and piecing together the viral genes, like putting together a jigsaw puzzle. Along the way, they published findings that they and others used to try to understand the 1918 flu, but until now they had published only the sequences of five of the eight genes that make up the virus. The last three, which make up half of the virus's length, are published today in their paper in Nature.
In August, Terrence M. Tumpey of the Centers for Disease Control and his colleagues used the viral genome to reconstruct the 1918 virus, and they wondered what would happen if they infected mice and if they infected tissue from human lungs. And, they asked, would the virus remain as lethal if they switched some of its genes with genes from today's influenza viruses?
The scientists took great precautions, Dr. Gerberding said, using special labs that were designed to protect the researchers and prevent the spread of the viruses. "We have erred on the side of caution at every step of the process," she added.
And now, the scientists say, the work is starting to unmask that virus's secrets.
In gene-swapping experiments, the scientists found that small substitutions weakened the reconstructed virus so that it could no longer replicate in the lungs of mice, kill animals, or attach itself to human lung cells in the lab.
The ultimate goal, Dr. Taubenberger says, is to make a checklist of changes to look for in the bird viruses. "Now you have all these viruses going around and we don't know, is it going to adapt to humans? Is it going to cause a pandemic? We don't understand the rules," he said. "There is a lot of science to go."
Gardiner Harris contributed reporting from Washington for this article.
There is a new reason to worry that the avian-flu virus could erupt with little notice into a global pandemic that kills millions of people: It happened already.
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Flu Factor Estimated
deaths* caused by 1918 Spanish flu 50.0 (world) 1957 Asian flu 0.7 (U.S.) 1968 Hong Kong flu 0.5 (U.S.) Annual seasonal flu 0.4 (U.S.) * 1918 number represents world-wide deaths; other data are for the U.S. source: CDC |
After nearly a decade of research, teams of scientists said yesterday that they had re-created the historic influenza virus that by some estimates killed 50 million people world-wide in 1918 and 1919. The scientists concluded that the virus originated as an avian bug and then adapted and spread in humans by undergoing much simpler changes than many experts had previously thought were needed for a pandemic.
Some mutations of the 1918 virus have been detected in the current avian-flu virus, suggesting the bug "might be going down a similar path that led to 1918," says Jeffery Taubenberger, chief of molecular pathology at the U.S. Armed Forces Institute of Pathology, who led one of two studies.
The studies, published yesterday in the journals Nature and Science by researchers from the Armed Forces institute, the Centers for Disease Control and Prevention, and Mount Sinai School of Medicine, suggest that a bird-flu pandemic could erupt in more ways than previously thought — and could be as lethal as its predecessor. Unlocking the mysteries of the 1918 bug "has taken on new urgency," says Dr. Taubenberger.
The findings could also help researchers hone their efforts to develop vaccines and treatments for avian flu by pinpointing which pieces of the virus made it so virulent. CDC researchers narrowed in on a gene in the re-created 1918 virus that allows the bug to attach itself to cells and multiply. With the gene, the virus was highly lethal; it lost its virulence when researchers removed it. Those findings and the genetic makeup of the virus will now be publicly available. The U.S. National Science Advisory Board for Biosecurity endorsed making the genetic information public to promote development of tests, treatments and preventive measures, the CDC said.
Deciphering clues from the bug has never been so urgent. Avian flu continues to spread in poultry flocks and is jumping to humans with increasing frequency. The lethal strain has claimed 60 lives in Indonesia, Vietnam, Thailand and Cambodia since late 2003.
Most of those cases occurred in people who had direct contact with infected poultry. But health officials are concerned that the virus could mutate and begin spreading between humans, and that when it does, it will rapidly sweep the globe. On Tuesday, President Bush unexpectedly announced he would consider using the military to enforce quarantines in the event of an outbreak in the U.S.
"If 1918 happened like this, why couldn't or shouldn't 2005 happen like this?" says Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, who has warned in several papers that the H5N1 virus could morph into a 1918-like pandemic. "These viruses are kissing cousins."
Precisely why and how the 1918 virus killed so many people has been considered one of the greatest remaining secrets of virology, and the team led by Dr. Taubenberger has spent the past nine years trying to decipher it. According to historical accounts, suffocating victims turned deep shades of blue; many hemorrhaged, bleeding even from their eyes and ears. More people died during the pandemic than in World War I. Unlike with most flu epidemics, most of the casualties were otherwise-healthy people ranging in age from 15 to 34.
But studying the virus was nearly impossible until recently because virus samples weren't preserved at the time. In February 2004, Dr. Taubenberger and his team published sequences for five of the 1918 virus's eight genes, using material preserved from the lungs of U.S. soldiers killed by the flu, as well as the body of an Inuit woman exhumed in 1997 from the Alaskan permafrost. The team completed sequencing the remaining three genes, and their work is published this week in Nature.
They concluded that the pandemic was caused by an avian virus. The scientists also discovered 10 changes in amino acids that distinguish the 1918 virus from avian bugs, suggesting that the virus mutated on its own, without mixing with another virus, to become transmissible in humans, they say. The current avian bug has made five of the 10 changes found in the 1918 virus.
In the study in Science, researchers from the CDC, Mount Sinai, and others then re-created the virus using a process known as reverse genetics to determine which of its features made it so lethal. The virus was then injected into embryonated chicken eggs and mice and was found to be "exceptionally virulent," says Terrence Tumpey, a senior scientist at the CDC who led the effort. The team also found that the bug had an unusual ability to penetrate cells that flu viruses don't usually reach deep in the lungs, providing some clues as to why the disease's symptoms were so severe.
While the research advances scientists' understanding of the avian-flu threat, it raises questions about how to keep the virus from escaping from a laboratory or falling into the hands of bioterrorists. Not only has the virus now been created in a CDC lab, but its genetic information will be published in GenBank, a public genetic-sequence database maintained by the National Institutes of Health.
Dr. Tumpey says the experiments were approved by two CDC committees with internal and external experts, and were conducted under strict safety and security standards inside a CDC lab.
The 1918 flu virus would be unlikely to cause a pandemic today, Dr. Tumpey says. This virus is in the same family as the seasonal influenza viruses that have been circulating for several years. Many people today have some immune protection from these types of viruses because they have been exposed to the seasonal flu viruses either through natural infection or vaccination.
The researchers say they are pushing ahead with their work. Dr. Tumpey says he and his colleagues plan to analyze the remaining four of the eight genes whose virulence they didn't study, with the hope of identifying more virus proteins. Dr. Taubenberger of the Armed Forces Institute says his team's goal is to create a "checklist" that would help researchers tracking viruses determine which mutations are important and which are minor.
"We hope to work out in the future the rules of how this happens, how a bird virus becomes a human virus," he says.
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