The Man-made H5N1 Controversy Heats Up: What Next? (Part Three A)

Posted on by Laurie Garrett

Today 22 scientists are gathered in Geneva at the World Health Organization to decide the fate of man-made flu viruses, including whether details regarding how the dangerous strains of H5N1 were made. The viruses – at least one form made by Dutch scientists – may constitute the most dangerous microbes our species has ever confronted, combining both the potential to spread rapidly from human-to-human, and the highest virulence ever seen with influenza.

This is the third of a daily series of blog postings over the next week that will dwell on issues surrounding the H5N1 controversy.

Today we address: The Public Health Rationale for Doing the Experiments

On the public health side, the debate has slanted toward a decidedly influenza-specific perspective. Advocates argue the H5N1 work benefits public health because it identifies strains of flu that should be targets for both surveillance and vaccine production. But public health is far broader than the flu-focused view implies. A serious debate should include front-line disease investigators like anthrax-hunter Marcelle Layton of the New York City Department of Health; SARS-chasers from the Singapore Ministry of Health; veterinary surveillance teams from the OIE; developing country animal experts like Oyewale Tomori, a veteran of the African Ebola outbreaks; experts on human travel such as leaders of the airline industry andMigration Health, Inc. From a broader range of public health voices policymakers would learn that:

- Surveillance of emerging viruses is only as good as the skills and numbers of personnel on the front lines, particularly in environments where human ecology overlaps with natural systems such as rain forests, river deltas, and glacial melt zones. The ranks of such personnel are woefully thin. Knowing which nucleotides must mutate to turn H5N1 into a human-to-human virus does not easily translate into international public health mobilization. Indeed, few outbreaks of H5N1 anywhere in the world are currently identified based on laboratory isolation of the culprit virus: It is the dead bodies of birds or humans that sound the alarms.

- Animal ecologies in poor and middle income countries are small and complex. Egypt, for example, is rife with H5N1, and an outbreak is unfolding in both chickens and people in that country right now. Two factors contribute to Egypt’s inability to control H5N1: chicken “flocks” are parts of every household, even in the middle of Cairo, so that control measures cannot be executed at industrial scale, and the country is hard-pressed to execute any grand government efforts given its post-Arab Spring chaos. Imagining Egyptian health authorities gathering H5N1 samples from backyard “flocks” of two or three chickens located all over the nation, and submitting those samples to genetic analysis for the Fouchier mutations is akin to envisioning a team of astronauts from Chad soaring to the Moon tomorrow.

- A key lesson of the last decade of outbreaks (Ebola, SARS, H1N1, etc.) is that attempting to control global spread by limiting human movement is a fruitless waste of resources.

The primary rationale for conducting the experiments is determination of the likelihood that a human-to-human transmissible form of the bird flu could emerge, and in what genetic form it would need to be.

Ron Fouchier and Albert Osterhaus published experimental justification as:

Our research project has direct practical implications. Currently, our knowledge of determinants of airborne transmission of influenza virus is virtually nonexistent. If we knew which mutations and biological traits can change the zoonotic H5N1 virus into a virus with major public health impact, detection of specific mutations in circulating avian viruses should trigger more aggressive control programs than those employed currently. Moreover, if a HPAI H5N1 virus has the potential to cause a future pandemic, our last resort would consist of implementing societal measures (such as quarantine and travel restrictions), surveillance, vaccination, and the use of antiviral drugs. Diagnostic tests, antiviral drugs, and prepandemic H5N1 vaccines are currently evaluated using HPAI H5N1 strains with biological properties that are similar (but may not be identical) to the strain that would cause the pandemic. Because surveillance and effectiveness of vaccination and antiviral drugs may depend on virus lineage and specific mutations, these measures need to be evaluated in the context of viruses with the most relevant genetic and biologic properties.

Both Fouchier and Kawaoka, using very different methods, started with highly pathogenic forms of H5N1 that were known to have killed human beings in either Indonesia or Vietnam. Fouchier has acknowledged that definitive research will require repeating the work starting from several other H5N1 strains – in other words, he believes there will not be a meaningful answer to the question until he has made several strains of “super-flu” that are capable of passing airborne from person-to-person. In an interview withScienceInsider Fouchier was asked, "You also want to repeat the experiments with more H5N1 strains?"

"Yes,” Fouchier replied. “We did this with one genetic lineage of the H5N1 virus. The question is whether all lineages can become aerosol-transmissible. If they can't, if it's just this lineage, perhaps you can focus on the region where it came from and try to stop H5N1 outbreaks there to prevent a pandemic. If it can happen everywhere, you've got to work everywhere."

This means that the single dangerous strain Fouchier created is only the beginning: by his own insistence the Dutch scientist would need to create many such lethal forms of the avian virus in order to identify the range of forms a pandemic type of H5N1 might take. Moreover, he needs to prove that the base strain of natural Indonesian H5N1 that he worked with is not a fluke – predisposed to become a human killer.

This ups the ante in the debate. More deadly viruses will be made and then locked in university freezers; more animals will be infected, coughing their deadly microbes in the Erasumus BSL-3 environs.

Are these experiments worth their inherent biosecurity risks?

The animal used as a substitute for humans is the ferret – commonly deployed for flu experimentation. While monkeys and primates might provide more definitive clues to human risk, the simians are extremely expensive, access is limited both for animal protection reasons and due to species extinction concerns, and care facilities are prohibitively expensive for most researchers. Ferrets, which are a bit like weasels, are abundant, cheap, and use the same respiratory receptor molecules as human beings.

In the NYAS debate on February 2, Peter Palese of Mt. Sinai Medical School argued that ferrets are a weak research model. It was a curious comment, as Palese’s lab funneled NIH money to the Dutch lab to finance the experiment. But Palese’s point in disparaging the utility of the ferret model was to dismiss risk. What kills a ferret, or infects the animals, does not necessarily kill or infect human beings. In general, Palese insists H5N1 is a fairly harmless virus, unlikely to ever take on a dangerous form.

The U.S. Food and Drug Administration (FDA) tested specific H5N1 strains known to have sickened and killed human beings, using ferrets to study the pathogenicity. The FDA team found that the symptoms and sites of infection in the lab animals closely mirrored those reported in the humans from whom the strains were extracted.

Science magazine’s Jon Cohen analyzed the pros and cons of ferret flu research. Fouchier told Cohen, “We always have to be really, really critical about what we do. We cannot say [because] it transmitted in ferrets, it must be transmissible in humans.”

Cohen points out that Kawaoka used ferrets to assess the dangers of the H1N1 swine flu virus in 2009, getting frightening results. The ferrets died in large numbers, sufficient to indicate the swine flu pandemic would be dire for humanity. It was, in contrast, a highly contagious but mildly dangerous flu in human beings. It turns out the limits of ferret research are all about immunity. Lab animals are completely influenza-naïve, having been raised in confinement. Humans, in contrast, are exposed every year to one or more circulating flu strains, so that the H1N1 virus met up with antibody resistance in Homo sapiens that had not existed in Kawaoka’s ferrets.

“We have to be really, really careful to interpret our data in ferret transmission in a quantitative way,” Fouchier told Cohen. “You cannot say if you got two out of four transmissions that your virus is 50 percent transmissible.” His group’s new study has little to say about the kinetics and efficiency of transmission of its mutant virus in humans. “I can’t tell if this virus were released now to the world whether it would transmit efficiently. The only thing we say is it can be airborne.”

Many defenders of the experiments have argued that Fouchier and Kawaoka’s H5N1 work shows that five nucleotide changes in the natural virus leads to a humanly-transmissible virus that is roughly 60 percent lethal, and likely to infect about 75 percent of exposed human beings. Those terrifying numbers would translate into not only the most dangerous virus in the history of Homo sapiens, but also a potential kill rate that would dwarf everything but total thermonuclear weapons exchange.

But is it true? Is there any way to know? Go to today's Part B for the answers.

chained test tubes from Jakarta Globe.PNG