DEADLY BIRD FLU STRAINS, HUMAN-TO-HUMAN TRANSMISSIONS, CONTROVERSIAL RESEARCH AND BIOTERRORISM

HUMAN TO HUMAN TRANSMISSIONS OF BIRD FLU?

Officials at the World Health Organization worry that bird flu could generate a catastrophically deadly pandemic if it spreads from person to person. Initially there were no reports of person-to-person spreading of the disease although for a while it was suspected that such transmissions may have happened in Vietnam and there were examples of clusters of infections in people in Indonesia, Vietnam and Thailand.

There have been a dozen or so cases in which human-to-human bird flu transmissions sem to ave occurred. In every case the transmission occurred between close blood relatives who had been in close contact with the virus, and the disease did not spread to the wider community. The majority of human cases of H5N1 infection have been associated with direct or indirect contact with infected poultry.

Human-to-human contact of bird flu has been suspected in Vietnam in 2004 by not confirmed. The 10th victim there case was a 26-year-old woman who is believed to have contracted the disease from her 11-year-old daughter. The daughter had earlier died in the woman’s arms coughing up blood. The girl’s aunt also caught the disease, possibly from human to human contact, and recovered. A simialr case occurred in Indonesia in April 2006. There a man died after nursing his sick son and seven people in the same family died. According to a WHO investigation: “Preliminary findings indicate that three of the confirmed cases spent the night of 29 April in a small room together with the initial case at a time when she was symptomatic and coughing frequently. All confirmed cases in the cluster can be directly linked to close and prolonged exposure to a patient during a phase of severe illness.”

Human-to-Human Transmission of Bird Flu in China

In November and December 2007 there was a case of human-to- human transmission of bird flu in the eastern province of Jiangxi Province in China involving a 52-year-old father and his 24-year-old son. The two were diagnosed with bird flu within a week of each other. Ths son picked up the virus from poultry while the father had no known contact with the virus except from his son. The son died. He was the 17th reported death from the disease in China.The father who was diagnosed at an early stage of the disease, survived.

The strains of H5N1 found in the father and son were almost identical. The father was treated with antivirals and plasm from a woman who had been vaccinated against H5N1 in a clinical trial, which suggests this method or similar methods may be useful in treating the disease,. The Chinese government was unusually forthcoming with data from the cases, which give the international researchers useful information to fight bird flu.

The Jiangxi father and son case was carefully studied by Chinese scientists who published a report in The Lancet. Among their findings, which were encouraging in terms that the virus still lacked a punch to become a pandemic, were: 1) the strain of the virus found in the father and son were similar to the standard strain which showed that little mutation had taken place; 2) the father and son came in close contact with 91 other people who didn’t catch the disease, which suggests it doesn’t pass easily to humans; and 3) the fact that two close relatives caught the disease, raises the possibility they might have a genetic susceptibility to the disease, and if that is case this could lead to better ways of treating the disease and even developing drugs and vaccine to fight it.

There have been a dozen cases of possible human-to-human bird flu transmissions. In every case the transmission occurred between close blood relatives who had been in close contact with the virus, and the disease did not spread to the wide community.

Human-to-Human Transmission of Bird Flu in Indonesia

Reporting from Jandi Meriah, Indonesia, Alan Sipress wrote in the Washington Post, Dowes Ginting, a wiry 32-year-old, had watched disease burn through his family over the previous two weeks, killing six and sickening two others, including himself. International health experts grew increasingly concerned when laboratory tests confirmed they were sickened by bird flu, the largest cluster of the disease ever recorded. [Source: Alan Sipress, Washington Post, August 30, 2006]

“Health investigators have concluded that the eight-person cluster in Sumatra began with Ginting's older sister, who fell ill in late April. They suspect she was infected with bird flu from live chickens sold in a market where she peddled oranges, limes and chili peppers, or from contaminated poultry droppings in manure used in her garden. She died and was buried before any samples were taken to confirm bird flu. [Ibid]

“Several days after she became sick, the extended family gathered in the village of Kubu Sembilang for a feast of roast pig and chicken curry to celebrate the annual harvest festival. That night, many of the relatives slept in the same small room with the sister, who had developed a serious cough. By the time she died, a sister, a brother, two sons, a niece and a nephew had become ill. Flu specialists said the final victim, Dowes Ginting, in turn likely caught the virus from his infected son. Pigs in the village where the family lived also tested positive for bird flu. [Ibid]

“Health experts have concluded this was the first time the bird flu virus was passed from one person to another and then on to a third person. "None of us thought it was bird flu. We thought it was black magic," said Anestia Tarigan, the wife of the youngest Ginting brother, Jones, the only victim to survive. "Everyone in the family was getting sick and no one else was. Someone had put a spell on our family. Black magic is very common in our place." [Ibid]

Deadly Egyptian Bird Flu Strain and Other Worrisome Strains

Donald G. McNeil Jr. wrote in the New York Times, “Another mutation, increasingly common in Egypt, where the disease is still raging through poultry and occasionally infecting humans, is called M230I. Scientists do not know what it does, but its persistence is worrisome, says Henry L. Niman, a Pittsburgh biochemist who runs a Web site tracking the genetics of flu cases. M230I is also found in typical annual flu strains like H1N1, H3N2 and influenza B; in H7 flus, which pass easily from birds to humans but usually cause nothing more serious than pinkeye; and in H3N8, the flu that has spread from dog to dog in many American kennels, often fatally. [Source: Donald G. McNeil Jr., New York Times, March 27, 2007]

“All the human cases in Egypt with M230I have been fatal, Dr. Niman said, and those without it have not been, although that may be coincidence. Mutations that confer resistance to Tamiflu have also been found in Egypt. Any antiviral resistance is worrisome because the world still has very few weapons against the flu. H5N1 long ago became resistant to older “M2 inhibitors” like amantadine, possibly because farmers in China are suspected of feeding those drugs to their chickens in the late 1990s. Tamiflu is in another class, known as neuraminidase inhibitors, including Relenza and peramivir. After Tamiflu resistance was found in Egypt, the World Health Organization, moving to stave off panic, said the same change was seen in Vietnam years before. Still, the Vietnam cases led doctors to start doubling the typical Tamiflu dose, effectively halving the world’s stockpiles of it. [Ibid]

“An American Navy research lab in Cairo found that two Egyptian cases had a dangerous mutation known as N294S even before they got Tamiflu. That implies that it exists in Egyptian poultry, though it has not been found yet. Every flu virus is different, and it is impossible to predict exactly what constellation of changes will turn one into a pandemic strain. [Ibid]

“Dr. Nancy Cox and Dr. Ruben Donis, influenza virologists at the Center for Disease Control in Atlanta, said they would be most worried if they saw spontaneous human-avian crossovers like those they created, or if they saw multiple changes in the virus’s hemagglutinin gene, the attachment “spike” on the virus’s shell. “We’re looking very, very carefully at the viruses that exhibit changes at the receptor binding pocket,” Dr. Cox said. “But it’s clear that these single changes don’t allow the virus to move from person to person efficiently.” [Ibid]

“And even if H5N1 fails to become a plague, Dr. Webster of St. Jude in Memphis has what he styles his “hit list” of others waiting their turn. They include H7N7, which infected 89 chicken industry workers in the Netherlands in 2003 but killed only one veterinarian; H9N2, which he says is in “every poultry house in Eurasia” and causes no symptoms but every once in a while jumps into immuno-suppressed people; and H2N2, which is in the wild bird population in the United States. [Ibid]

Deadly Strain of Bird Flu Shows Up in China and Vietnam

In August 2011, virologists warned of a mutant strain of the virus called H5N1-2.3.2.1 spreading across China and Vietnam for which there is no effective vaccine. AP reported: “The United Nations warned Monday of a possible resurgence of the deadly bird flu virus, saying wild bird migrations had brought it back to previously virus-free countries and that a mutant strain was spreading in Asia. A mutant strain of H5N1, which can apparently sidestep defenses of existing vaccines, is spreading in China and Vietnam, Tthe U.N. Food and Agriculture Organization said in a statement Monday. It urged greater surveillance to ensure that any outbreaks are contained. [Source: AP, August 29, 2011]

The World Health Organization reported that a 6-year-old Cambodian girl had died Aug. 14 from bird flu, the eighth person to die from H5N1 avian influenza this year in Cambodia. Vietnam suspended its springtime poultry vaccination this year, FAO said. Most of the northern and central parts of the country where the virus is endemic have been invaded by the new strain.

AP reported in February 2012: Officials have issued fresh warnings for farmers to beef up surveillance, especially since they can no longer rely on the latest poultry vaccine in the north and central aress where it is weak or useless against a new strain that has emerged in the region. "We have to increase biosecurity," said Thanh, the animal diagnostics director. [Source: AP, February 17, 2012]

“The new strain had earlier been identified in China and was also recently found in Bangladesh and Nepal, where it likely spread via wild birds, said Jan Slingenbergh, a senior animal health officer at the U.N. Food and Agriculture Organization in Rome. The U.N. agriculture agency warned of a possible resurgence in bird flu outbreaks after the new strain was identified, potentially increasing risk to humans. However, Vietnam's two recent deaths occurred in the southern Mekong Delta, where the vaccine remains effective. WHO stressed it is also normal to see a spike in cases and poultry outbreaks during this time of year. [Ibid]

"WHO has always said that as long as the virus is entrenched in poultry, which it is, there continues to be the risk of bird-to-human transmission," spokesman Gregory Hartl said in Geneva. "That risk means that you cannot predict exactly if the transmission will happen and if it will be regular, but there is the risk so that's why it's not surprising to see cases." [Ibid]

“Vietnam buys most of its poultry vaccine from China, which has continued with its robust vaccination campaign of some 15 billion doses despite the emergence of the new strain. Researchers there have developed a new version that works against the strain, but it's unclear when it might be ready for distribution, said Keith Hamilton, an animal influenza expert at the Paris-based World Organization of Animal Health. "We emphasize that vaccination is a complementary tool," he said. "It has to be used in conjunction with other control measures - biosecurity on farms, early detection is essential, so is a rapid response to contain and eliminate sources of disease." [Ibid]

“But in Ha Nam province, on the outskirts of Vietnam's capital, Hanoi, animal health officials are desperate to contain a poultry outbreak that hit last week. They have ordered 1 million doses of vaccine, hoping it will provide at least some protection. "I wish to have an effective vaccine against bird flu as soon as possible, so I can go on raising ducks," said farmer Nguyen Van Duong, whose entire flock was slaughtered after the virus was detected. "I am devastated at losing my investment on the ducks, but we will do anything to work with the authorities to stop it from spreading. The last thing we want is an outbreak to happen again." [Ibid]

Dutch Scientist Develops Particularly Contagious Form of Bird Flu

Michael Specter wrote in The New Yorker: “For the past decade the threat of an airborne bird flu lingered ominously in the dark imaginings of scientists around the world. Then, in September 2011, the threat became real. At the annual meeting of the European Scientific Working Group on Influenza, in Malta, several hundred astonished scientists sat in silence as Ron Fouchier, a Dutch virologist at the Erasmus Medical Center, in Rotterdam, reported that simply transferring avian influenza from one ferret to another had made it highly contagious.[Source: Michael Specter, The New Yorker, March 12, 2012]

“Fouchier explained that he and his colleagues “mutated the hell out of H5N1"---meaning that they had altered the genetic sequence of the virus in a variety of ways. That had no effect. Then, as Fouchier later put it, “someone finally convinced me to do something really, really stupid.” He spread the virus the old-fashioned way, by squirting the mutated H5N1 into the nose of a ferret and then implanting nasal fluid from that ferret into the nose of another. After ten such manipulations, the virus began to spread rapidly around the ferret cages in his lab. Ferrets that received high doses of H5N1 died within days, but several survived exposure to lower doses. When Fouchier examined the flu cells closely, he became even more alarmed. There were only five genetic changes in two of the viruses’ eight genes. But each mutation had already been found circulating naturally in influenza viruses. Fouchier’s achievement was to place all five mutations together in one virus, which meant that nature could do precisely what he had done in the lab.” Around the same time Dr. Yoshihiro Kawaoka, of the University of Wisconsin-Madison, did some similar experiments with ferrets and also found that bird flu could be made contagious.” [Ibid]

“Fouchier’s report caused a sensation. Scientists harbored new fears of a natural pandemic, and biological-weapons experts maintained that Fouchier’s bird flu posed a threat to hundreds of millions of people. The most important question about the continued use of the virus, and the hardest to answer, is how likely it is to escape the laboratory. In December 2011, the National Science Advisory Board for Biosecurity, a panel of science, defense, and public-health experts, was asked by the Department of Health and Human Services to evaluate Fouchier’s research. The panel recommended that the two principal scientific journals, Science and Nature, reconsider plans to publish information about the methods used to create the H5N1 virus. It was the first time that the Advisory Board, which was formed after the anthrax attacks of 2001, had issued such a request. Widespread alarm led Science and Nature to agree to postpone publication. [Ibid]

Bird Flu as a Terrorist Weapon

The main concern was that terrorists couldn't use the "recipe" to produce a deadly, transmissible human flu that could, in the words of a New York Times editorial, "kill tens or hundreds of millions of people if it escaped confinement or was stolen by terrorists." On the subject The Economist reported: “The threat from influenza is real. So-called Spanish flu, which infected 500m people in 1918-19, claimed the lives of one in five of those who caught it. Subsequent flu epidemics, though not as bad, have still cut swathes through humanity whenever they have arisen. But terrorism is real, too. Though there is no known case of biological warfare in the past 100 years, many countries have experimented with the idea; and there is concern that some terrorist groups, motivated not by specific political grievances but by a general hatred of the West, might unleash the uncontrollable mayhem of a viral epidemic purely out of spite. So who is right---the researchers who want to publish their findings, or the governments that want to stop them? [Source: The Economist, April 28, 2012]

“In this particular case, probably the researchers. And, to their credit, the authorities seem to have recognised that. After months of fraught deliberation involving the world's leading virologists, journal editors, security experts, ethicists and policymakers, the Americans reversed their stance on April 20th. The reason is that, as bioterrorists go, humans pale in comparison with nature. Even America's security services, which might be expected to err on the side of caution, seem to agree that the odds of a bioterror attack are long. Biological weapons require skilled scientists working in state-of-the-art facilities. Even then, they are unpredictable---and therefore difficult to control.

A deadly bug might come back to bite its maker, possibly before it had been made into a weapon. Aum Shinrikyo, a sect with sophisticated scientific capability, toyed with anthrax in 1993. But for its most brazen attack, when it killed 13 people in the Tokyo metro two years later, it preferred nerve gas. In September 2001 al-Qaeda plumped for aeroplanes. “Nature, by contrast, has form in this area. From the Black Death via Spanish flu to AIDS, bacteria and viruses have killed on a scale that terrorists and dictators can only dream of. The more you gag scientists or hide data, the harder it is for them to look for cures; you also probably drive bright young researchers away towards less fraught, blander areas.” [Ibid]

How Dangerous Is the Contagious Form of Bird Flu?

Wendy Orent, an author of books on diseases and viruses, wrote in Los Angeles Times, the teams lead by Fouchier and Kawaoka “used strains of highly virulent H5N1 avian flu that had been engineered to make them communicable to ferrets, though not in a way that ferrets could easily pass the virus among one another. Researchers used nasal swabs to infect a ferret, and once it was infected, they took a nasal swab from it and infected the next ferret. By the end of a chain of 10 or so ferrets, the virus had mutated to become transmissible through respiratory droplets alone, meaning it could be far more easily passed from one animal to another, even when they were in separate cages. [Source: Wendy Orent, Los Angeles Times, January 15, 2012]

“ The fallacy in all this is that it's not the exact "recipe"---the molecular changes---needed to turn a non-transmissible mammalian virus into a transmissible one that's so important here. It's the method by which the mutations were accomplished. And that method---passing the virus from ferret nose to nose---has been known for quite a while. Daniel Perez at the University of Maryland, for example, published a paper in 2009 describing the same technique using a low-pathogenic virus. [Ibid]

“It might be hard to perform the initial molecular tweaks that made the flu something to which ferrets were susceptible, but the crucial step of causing the virus to evolve so that it was more easily transmitted was simple. These scientists created a disease factory for ferrets---essentially what farmers in Asia do by cramming 5 million chickens together. "It's not rocket science," says Adolfo Garcia-Sastre, an influenza researcher from Mount Sinai School of Medicine in New York. [Ibid]

The justification for creating a ferret disease factory was to study how such mutations could evolve in nature and trigger a pandemic. The experiments, said Perez, help scientists to know what to look for. But the idea that these laboratory-created mutations could now pop up together in some Asian chicken and launch a lethal pandemic is implausible. That's not how evolution works. Evolutionary biologist Paul Ewald of the University of Louisville predicted in 1993 that packing chickens in factory farms would allow the evolution of lethal chicken viruses. And that's exactly what happened: Chicken viruses evolved that killed chickens. Even H5N1, which eventually evolved so it could transmit to humans, remained a far better chicken virus than a human one. Though it certainly infected---and killed---many humans around the globe, it never developed into an effective human virus, which is why it has never caused the kind of global pandemic initially feared. [Ibid]

“None of this is to say, however, that the ferret experiments weren't important. What they showed is how quickly natural selection can transform a virus. "You put selection pressure on the system for increased transmissibility, and you quickly get the outcome that you expect to get," says Ewald. Influenza has a high mutation rate, and natural selection then picks the most transmissible of the viral strains that mutations generate, pushing the virus toward ever-greater transmissibility. This is what makes the ferret experiments with highly virulent H5N1 so alarming to contemplate. [Ibid]

“But to become a world-destroying pandemic, a virus would need a so-called human disease factory in which to refine its mutations. Virologist Vincent Racaniello of Columbia University considers the entire ferret flu frenzy a massive overreaction. As he points out: "Ferrets are a good model for influenza, but they are a model---they don't duplicate every aspect of influenza as it occurs in humans." [Ibid]

Controversial Bird Flu Paper Published

In June 2012, Donald G. McNeil Jr. wrote in the New York Times, “The more controversial of two papers describing how the lethal H5N1 bird flu could be made easier to spread was published six months after a scientific advisory board suggested that the paper’s most potentially dangerous data be censored. The paper, by scientists at Erasmus Medical Center in the Netherlands, identified five mutations apparently necessary to make the bird flu virus spread easily among ferrets, which catch the same flus that humans do. [Source: Donald G. McNeil Jr., New York Times, June 21, 2012]

“The paper’s publication, in the journal Science, ended an acrimonious debate over whether such results should ever be released. Critics said they could help a rogue scientist create a superweapon. Proponents said the world needed to identify dangerous mutations so countermeasures could be designed. “There is always a risk,” Dr. Anthony S. Fauci, the director of the National Institute for Allergy and Infectious Diseases, said in a telephone news conference held by Science. “But I believe the benefits are greater than the risks.” [Ibid]

“The controversy erupted in December when the National Science Advisory Board for Biosecurity asked that details be removed before the papers were published. On March 30, it reversed itself after a similar panel convened by the World Health Organization recommended publication without censorship. Dr. Fouchier had to delay until the Dutch government gave him permission, on April 27. He told The New Yorker: “Those data could help scientists determine rapidly whether existing vaccines or drugs are effective against such a virus, as well as help the development of new medications.” [Ibid]

“Some of the early alarm was fed by Dr. Fouchier speaking at conferences and giving interviews last fall in which he boasted that he had “done something really, really stupid” and had “mutated the hell out of H5N1" to create something that was “very, very bad news.” He said his team had created “probably one of the most dangerous viruses you can make.” After the controversy erupted, he claimed the news media had overblown the danger. [Ibid]

“An important result of the controversy, Dr. Fauci said, is that the United States is now drafting new guidelines for dangerous research. For the moment, most researchers are honoring a voluntary moratorium on this line of flu research. Asked if a rogue researcher could now try to duplicate Dr. Fouchier’s work, Dr. Fauci said it was possible. But he argued that open discussion was still better than restriction to a few government-cleared flu researchers, because experts in unrelated fields, like X-ray crystallography or viral epidemiology, might take interest and eventually make important contributions, he said. “Being in the free and open literature makes it easier to get a lot of the good guys involved than the risk of getting the rare bad guy involved,” he said. Dr. Fouchier said that many papers are published about pathogens more dangerous than flu. Also, many scientists have said that the two papers have been so widely discussed that experts knew every detail anyway. [Ibid]

Findings of the Controversial Bird Flu Papers

Donald G. McNeil Jr. wrote in the New York Times, “Two of the five mutations are already common in the H5N1 virus in the wild, said Ron A. M. Fouchier, the paper’s lead author. One has been found in H5N1 only once. The remaining two have never been found in wild H5N1, but occurred in the H2 and H3 flus that caused the 1957 Asian flu pandemic and the 1968 Hong Kong flu. The Dutch team artificially introduced three mutations. The last two occurred as the virus was “passaged” through 10 generations of ferrets by using nasal washes from one to infect the next. Four changes were in the hemagglutinin “spike” that attaches the virus to cells. The last was in the PB2 protein. As the virus became more contagious, it lost lethality. It did not kill the ferrets that caught it through airborne transmission, but it did kill when high doses were squirted into the animals’ nostrils. Dr. Fouchier’s work proved that H5N1 need not mix with a more contagious virus to become more contagious. [Source: Donald G. McNeil Jr., New York Times, June 21, 2012]

“By contrast, the lead author of the other bird flu paper, Dr. Yoshihiro Kawaoka, of the University of Wisconsin-Madison, took the H5N1 spike gene and grafted it onto the 2009 H1N1 swine flu. One four-mutation strain of the mongrel virus he produced infected ferrets that breathed in droplets, but did not kill any. Dr. Kawaoka’s work was published by the journal Nature the previous month. [Ibid]

“Around the same time the Erasmus University study was published Science magazine published seven other articles about H5N1. One, by a team at Cambridge, concluded that it was not possible to accurately calculate the likelihood of all five mutations occurring in nature. Up to three in a single human is “a possibility,” said Derek J. Smith, the lead author. “Five mutations is pretty difficult, but we don’t yet know how difficult it is,” Dr. Smith said. Having H5N1 still circulating in birds is like “living on an active fault line,” he said. But asking whether a five-mutation strain could evolve in human hosts, he said, was like asking if it could ever snow in the Sahara---unlikely, but not inconceivable. Presumably, if an outbreak with several of the most dangerous mutations were spotted, the world would move quickly to try to eradicate it with vaccines and quarantine; whether it would work is an unanswered question. [Ibid]

Bird Flu Research and Funding

As of 2007, the United States had donated or pledged about $1 billion for bird flu research. At a conference on bird flu, held in Beijing in January 2006 as news breaking about the spread of the disease outside of East Asia to Turkey, nations pledged nearly $2 billion to bird flu research, with the U.S. pledging the most ($334 million), followed by Japan ($159 million) and the European Union ($120 million, with member nations together donating $138 million). China only donated $10 million. The World Bank made $500 million available in loans.

Flu researchers at the Center for Disease Control and in the Netherlands are deliberately mixing and matching genes from H5N1 and human flu viruses in a high-containment laboratory in an effort to create potentially deadly strains of flu and develop vaccines for them and figure out other ways to combat the disease before a pandemic breaks out in the real world.

A lot of research with bird flu is done using ferrets. The physiology of their lungs is similar to that of humans and avian flu viruses bind to the same receptor cells in their respiratory systems, meaning they catch the flu pretty much the same way people do.

Image Sources: Wikimedia Commons

Text Sources: New York Times, Washington Post, Los Angeles Times, Times of London, The Guardian, National Geographic, Smithsonian magazine, The New Yorker, Time, Newsweek, Reuters, AP, AFP, Wall Street Journal, The Atlantic Monthly, The Economist, Global Viewpoint (Christian Science Monitor), Foreign Policy, Wikipedia, BBC, CNN, NBC News, Fox News and various books and other publications.

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© 2008 Jeffrey Hays

Last updated November 2012

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