Yoshihiro Kawaoka

Can Dangerous Bird Flu Virus Fly Between Humans?

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Since a new bird flu virus began sickening and killing people in China in March, one of the most pressing questions has been whether the virus, H7N9, would easily spread from human to human, possibly kicking off a global pandemic. Fortunately, no convincing signs of such transmission surfaced, and the outbreak—which led affected Chinese cities to close poultry markets and cull birds—seems to have ground to a halt. But three new studies in ferrets show that the virus can spread in the air between mammals, reawakening worries of human-to-human transmission.

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Today, a team led by virologist Hualan Chen of China’s Harbin Veterinary Research Institute reports online in Science that in experiments with ferrets, an H7N9 virus isolated from a human was what the researchers described as “highly transmissible” by respiratory droplets. In the ferret model, widely regarded as one of the best ways to assess human-to-human transmission, researchers intentionally infect animals in one cage and determine whether the virus spreads to others in an adjacent cage. When Chen and colleagues inoculated three ferrets in one cage with H7N9 virus samples from a person who fell ill with the disease in Anhui province, all three ferrets in an adjacent cage became infected, and the viruses isolated from them matched the ones used in the test. The researchers repeated the experiment and found the same outcome. Two other viral samples from different patients spread to only one of three exposed animals, as did one taken from a bird.

Although the ferret model has its limitations, Chen and co-workers conclude that their findings portend future problems. “Currently, implementation of compulsory control measures in H7N9 virus-positive live poultry markets is preventing further human infections; however, the elimination of the H7N9 virus from nature is a huge and long-term challenge,” they write. “Its replication in humans will provide further opportunities for the virus to acquire more mutations and become more virulent and transmissible in the human population.”

But a group at the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta that performed a similar experiment with the same Anhui province sample came to a different conclusion. After inoculating two groups of three ferrets, they found that it spread to two of six ferrets in adjacent cages. A different human sample had the same transmission frequency by the respiratory route. As the CDC researchers conclude in the 10 July issue ofNature, the virus “did not transmit readily by respiratory droplets.” In contrast to Chen’s team, they emphasize “that additional virus adaptation in mammals would be required to reach the high-transmissible phenotypes observed by the respiratory droplet route with pandemic and seasonal influenza A viruses.” CDC did not respond to a request for an interview.

A second study published in the same issue of Nature, led by Yoshihiro Kawaoka, a virologist at the University of Wisconsin, Madison, and the University of Tokyo, reported the Anhui sample infected one in three ferrets—the same percentage as CDC found. However, the researchers drew a different conclusion from the CDC group, writing that the respiratory transmission they observed contributes to their assessment that H7N9 viruses pose “a formidable threat to public health.”

Although the Chen group’s findings differ from those of the CDC and Kawaoka teams—and those two labs appear to reach different conclusions about the severity of the threat—virologist Ron Fouchier of Erasmus MC in Rotterdam, the Netherlands, notes that the results are not as disparate as they may seem. “H7N9 clearly transmits via aerosol or respiratory droplets in ferrets,” says Fouchier, whose own ferret studies with the H5N1 subtype caused an international uproar when he intentionally made that bird flu virus transmit through the air to help tease out responsible mutations. “In general, human flu viruses transmit in 100% of ferrets, avian in 0%, and this one is in between.”

Nor are the studies likely to be the end of the debate. Statistically, Fouchier says, the experiments included too few ferrets to arrive at conclusions about the likelihood of transmission to exposed animals. “Do you say the glass is half full or half empty?” Fouchier asks. “CDC are the optimists, while the other groups are more pessimistic.” Fortunately, the bottom line at the moment is that H7N9 has not spread efficiently between humans—although a few mutations could tip the scale in the virus’s favor, which warrants close monitoring of how it behaves in birds and us.

Source: sciencemag.org

H5N1: Flu transmission work is urgent.

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Yoshihiro Kawaoka explains that research on transmissible avian flu viruses needs to continue if pandemics are to be prevented.

Highly pathogenic avian H5N1 influenza viruses first proved lethal in humans in 1997 in Hong Kong. Since 2003, 578 confirmed infections have resulted in 340 deaths. Now widespread in parts of southeast Asia and the Middle East, H5N1 viruses have killed or led to the culling of hundreds of millions of birds.

To date, H5N1 viruses have not been transmitted between humans. Some experts have argued that it is impossible. But given the potential consequences of a global outbreak, it is crucial to know whether these viruses can ever become transmissible. Work by my group (accepted by Nature) and an independent study (accepted by Science) led by Ron Fouchier of the Erasmus Medical Center in Rotterdam, the Netherlands, suggest that H5N1 viruses have the potential to spread between mammals. As the risks of such research and its publication are debated by the community, I argue that we should pursue transmission studies of highly pathogenic avian influenza viruses with urgency.

To determine whether H5N1 viruses could be transmitted between humans, my team generated viruses that combined the H5 haemagglutinin (HA) gene with the remaining genes from a pandemic 2009 H1N1 influenza virus. Avian H5N1 and human pandemic 2009 viruses readily exchange genes in experimental settings, and those from a human virus may facilitate replication in mammals. Indeed, we identified a mutant H5 HA/2009 virus that spread between infected and uninfected ferrets (used as models to study the transmission of influenza in mammals) in separate cages via respiratory droplets in the air. Thus viruses possessing an H5 HA protein can transmit between mammals.

Our results also show that not all transmissible H5 HA-possessing viruses are lethal. In ferrets, our mutant H5 HA/2009 virus was no more pathogenic than the pandemic 2009 virus — it did not kill any of the infected animals. And, importantly, current vaccines and antiviral compounds are effective against it.

Fouchier and his team also generated a transmissible H5 HA-possessing virus — meaning that two independent studies have demonstrated the potential for transmissibility of H5 HA-possessing viruses between ferrets. Their mutant H5 HA virus, generated in the genetic background of an H5N1 virus, did kill infected ferrets.

Some people have argued that the risks of such studies — misuse and accidental release, for example — outweigh the benefits. I counter that H5N1 viruses circulating in nature already pose a threat, because influenza viruses mutate constantly and can cause pandemics with great losses of life. Within the past century, ‘Spanish’ influenza, which stemmed from a virus of avian origin, killed between 20 million and 50 million people. Because H5N1 mutations that confer transmissibility in mammals may emerge in nature, I believe that it would be irresponsible not to study the underlying mechanisms.

The new work has implications for pandemic preparedness. There is an urgent need to expand development, production and distribution of vaccines against H5 viruses, and to stockpile antiviral compounds. Both studies identify specific mutations in HA that confer transmissibility in ferrets to H5 HA-possessing viruses. A subset of these mutations has been detected in H5N1 viruses circulating in certain countries. It is therefore imperative that these viruses are monitored closely so that eradication efforts and countermeasures (such as vaccine-strain selection) can be focused on them, should they acquire transmissibility.

Consequently, I believe that the benefits of these studies — the knowledge that H5 HA-possessing viruses pose a risk and the ability to monitor them and develop countermeasures — outweigh the risks. High biosafety and security standards can be met. Our experiments were carried out in a high-containment facility by a small group of highly trained individuals who operate under strict procedures to prevent the accidental release of viruses.

However, the US National Science Advisory Board for Biosecurity (NSABB) has recommended that details of both studies (including the mutations that confer transmissibility) should be restricted, and released only to select individuals on a ‘need-to-know’ basis. I acknowledge the advisory role of the NSABB, but I do not concur with its decision.

The primary justification for the NSABB’s recommendation is that publication of our data “could enable replication of the experiments by those who would seek to do harm” .But redacting our papers will not eliminate that possibility — there is already enough information publicly available to allow someone to make a transmissible H5 HA-possessing virus.

The mechanism that the US government proposes for releasing data would also be unwieldy. Thousands of applications to access the research are likely to be filed, and potential background checks would create a huge administrative burden. We cannot afford to lose time if we are to combat emerging pandemic threats. Even if an efficient process can be established, it would be difficult to enforce continued confidentiality in the scientific community.

By contrast, wide data dissemination will attract researchers from other areas to contribute to the field. This is crucial, because new ideas are needed to answer some of the most urgent questions. For example, the specific mutations that we identified suggest that influenza transmission is more complex than anticipated and involves not only the receptor-binding properties of HA, but other biological and physical properties.

The redaction of our manuscript, intended to contain risk, will make it harder for legitimate scientists to get this information while failing to provide a barrier to those who would do harm. To find better solutions to dual-use concerns, the international community should convene to discuss how to minimize risk while supporting scientific discovery. Flu investigators (including me) have agreed to a 60-day moratorium on avian flu transmission research because of the current controversy. But our work remains urgent — we cannot give up.

Source:Nature.