A conflict that I’ve been following for months has finally been concluded. In August, research groups from the US and the Netherlands submitted papers to Science and Nature respectively, detailing their experiments creating laboratory strains of H5N1 influenza A that could spread among ferrets. This was rapidly followed by a call that the papers would not be published, or published without methods or results, from the National Science Advisory Board for Biosecurity (NSABB), amid fears that these findings could be used by bioterrorists or rogue nations to start a highly lethal flu pandemic. After months of meetings between flu experts, WHO, NSABB and several other parties, it was decided that the papers would be published in full, with additional information explaining the rationale behind the experiments and the biosafety and biosecurity precautions undertaken. The first paper was published in Nature last week.
So, what’s the big deal about H5N1? What did they actually do and find in this paper? Are there any risks? Why did they do it?
Influenza viruses are named based on two proteins – hemagglutinin (the H) and neuraminidase (the N). The hemagglutinin mediates binding of the virus to target cells, and allows the virus to infect the cell. The neuraminidase is involved in releasing new viruses from infected cells, allowing the virus to spread. Different combinations of H’s and N’s make different viruses, which humans may or may not have immunity to, depending if you’ve been infected by a similar virus before (ex. If you’ve had H1N1, you likely would not get sick, or have a milder infection with H1N2). Flu viruses can “mix” together to make new H and N combinations. What makes this problematic is that some flu viruses from other species (birds or pigs) can mix with human flu viruses to make a brand new virus that can infect humans, but which we would have no prior immunity to because humans have never seen that combination before. That’s what is happening with H5N1 – it is considered an avian flu virus, but it is capable of infecting humans. Since humans have no immunity to it, there is a very high death rate (60%). H5N1 doesn’t spread well between people, which has prevented it from becoming a highly deadly pandemic. If the H5N1 virus develops a mutation that makes it able to spread between people easily, and retains the high death rate, a lot of people would die.
In the paper by Yoshihiro Kawaoka’s group they mutated the hemagglutinin of H5N1 to find viruses that should be able to infect human cells. They used sections of human trachea and lung tissues to see if the viruses could infect human cells. Those mutated viruses that were able to infect human cells were combined with gene segments from H1N1 (2009 swine flu) to generate a reassortment virus. Since H5N1 and H1N1 are circulating at the same time, and since pigs can be infected with human, avian or swine flu, it is possible that these two viruses could mix together to make a highly pathogenic virus able to spread easily between people. They used ferrets to study the transmissibility and pathogenesis of the virus, because ferrets are a widely accepted animal model for flu studies. They found that the virus needed to acquire an additional mutation to be able to replicate in ferrets. The virus needed to acquire another mutation to be able to spread efficiently between ferrets (4 mutations total required). No ferrets died from the infection. This means that although the flu virus was able to spread between ferrets, it lost its’ ability to kill those infected with it.
These experiments were carried out at the second highest biosafety level possible. I’m not familiar with this biosafety level (enhanced BSL3), but I do work at BSL3. Our facility requires a passcode and biometric scan to enter the facility. You are required to change out of all of your street clothes (including socks and underwear) and into facility scrubs, gowns, etc. All work with a virus that can transmit through the air has to be done wearing a PAPR (http://www.maxair-systems.com/700-shroud-system.html), in a biosafety cabinet. The entire facility is under negative pressure, so no air escapes at any time. Nothing leaves the facility, including people, until you are 100% sure it is no longer infectious. All infectious inventory is monitored, so it is known where every tube or cell that could have virus goes – if any cannot be accounted for, the government is contacted immediately. All of this is for the biosafety level BELOW the one the H5N1 work was done. In addition, they state that all people working with H5N1 underwent risk assessment by the United States Criminal Justice Information Services Division. It seems like this research group has done everything possible to ensure that the work is done safely, and no unauthorized people have access to the viruses. Realistically, most researchers trained in virological, immunological or microbiological techniques could probably replicate these studies, even without the methods published with the paper. But, the likelihood that those with malicious intents have access to everything necessary to replicate these studies safely is very low. Combined with the fact that the virus did not kill any of the ferrets, I believe there is little risk to the general population from these studies.
So, why do these studies? They have identified that 4 mutations can make H5N1 transmissible among ferrets. Although it is not known if these are the only 4 mutations possible to make H5N1 transmissible, surveillance programs can now monitor H5N1-infected people or poultry for these (or similar) mutations that occur in the wild. This could significantly decrease response time or lead to viral eradication that could prevent a pandemic. In addition, antivirals and vaccines against this virus can be tested and relevant stockpiles generated. This type of study is all about preparation for the worst. A small risk now could have a big effect in a future pandemic.
C.
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