The ferret (Chinese鼬, Deut. Frettchen, Esp. hurón, Fr. furet) is the favored animal model of influenza virologists in part because they sneeze like humans.
Is an animal or an engineered animal influenza virus that is readily transmissible between ferrets transmissible between humans? What we do know is that pandemic flu strains are transmissible between ferrets by the airborne route. Strictly speaking as infecting humans is unethical we’re left with an unfalsifiable proposition. However, it is likely that they are. What is less easy to assess is the severity of any human infection. Our genotype/phenotype/ferret model knowledge doesn’t run this far.
The present controversy erupted following a talk given by virologist Ron Fouchier from the Erasmus Medical Center (EMC) in The Netherlands at an influenza meeting in Malta on September 12, 2011. Fouchier reported the forced evolution of the avian H5N1 virus influenza A virus to become transmissible between ferrets by the airborne route. The talk was not recorded but a Scientific American reporter wrote up an account on her blog.
Fouchier used phrases like “this is a very dangerous virus”, “which seemed to be very bad news,” or “someone finally convinced me to do something really, really stupid,” took participants by surprise for they are not part and parcel of everyday conference parlance.
It took a little time for the Fouchier report to spread out but it reached the press by December 2011. The New York Times ran with the unambiguous story line “An Engineered Doomsday”
Hearsay has it that President Obama said something like “what the hell is going on?” and had his staff to look into it.
The outcry resulted in a self-imposed 2-month moratorium by influenza virologists
http://www.nature.com/nature/journal/v481/n7382/full/481443a.html
http://www.sciencemag.org/content/335/6067/400.long
The moratorium was extended yet accompanied by calls from flu virologists to halt the moratorium that appeared to have no end.
By a years’ end the moratorium was unilaterally lifted by the same group of researchers
http://www.sciencemag.org/content/339/6119/520.long
http://www.nature.com/nature/journal/v493/n7434/full/nature11858.html
There were in fact two contemporary studies of forced evolution of avian influenza A strains. Both Yoshi Kawaoka of the University of Wisconsin (USA) and Ron Fouchier had successfully adapted H5N1 strains to droplet transmission between ferrets. The manuscripts which were sent to Nature and Science were routed to the US National Science Advisory Board for Biosecurity (NSABB) for advice. They were finally published in Nature and Science.
The logic behind the work is the following: the reservoir for avian influenza A viruses is waterfowl such as ducks and shore-birds which can readily spread to birds and chickens. Due to intensive poultry farming the viruses can occasionally spill over to humans causing severe infections of the lower respiratory tract. Infections can be fatal – indeed the case fatality rate (CFR) is approximately 60% for the H5N1 virus. This means that approximately 60% of laboratory confirmed symptomatic H5N1 infections in patients result in death. For H5N1, most human infections appear to be symptomatic.
For other influenza A viruses asymptomatic or mild infections probably go unrecorded. Hence, the number of fatalities as a proportion of the total number of human infections is arguably somewhat lower, and may vary with the virus. 1
Serological studies of influenza A infection are far less common than genetic studies. They do suggest that many avian influenza viruses can cross over to humans with mild to no symptoms. Understandably, virologists tend to concentrate on symptomatic illnesses and use the number of deaths divided by the number of known infections to define the case fatality rate. By way of comparison the CFR for Spanish flu was estimated to be ~2.5% while that for the 2009 H1N1 human pandemic ~0.2% in the US
Infections such as human H5N1 influenza are what are called dead end infections. As the virus is not transmitted to another individual, it is either demolished by innate and adaptive immune responses and the individual recovers, or else it dies along with the patient. Dead end infections are well known in virology, rabies being a case in point. An infected individual doesn’t transmit the virus to contacts. The CFR for human rabies infections is close to 100% in the absence of prophylactic vaccination and represents some 55,000 deaths worldwide.
The recent H7N9, H10N8, H6N1 and H5N6 human infections in the Peoples Republic of China and Taiwan are again dead end infections. A very small number of secondary H5N1 and H7N9 infections were surmised. Secondary infections are human-to-human infections, probably by contact as they are usually family or close contacts of the infected case.
There are a set of questions scientists and public health officials would like answers to:
• Can a virus like H5N1 or H7N9 become readily transmissible between humans by the respiratory route?
• What mutations confer such a change?
• What is the probability that a H5N1 or H7N9 strain will naturally acquire these mutations?
• If the answer is yes to question 1, and the probability of emergence is not vanishingly small (question 3), how can we prepare for a potential pandemic?
The issue is one about the future and our ability to anticipate the evolution of avian influenza A viral strains in the wild. It is about predicting the evolution of rapidly mutating viruses in the aquatic bird population.
The contemporary virologist is an experimentalist. The first question would be morphed into how could I adapt an avian influenza A virus so that it becomes transmissible between ferrets by the airborne route? As experimental facilities for testing whether any influenza virus is transmissible between ferrets exist, putting H5N1 or H7N9 to the test is not difficult.
Is it indeed possible to mimic natural evolution in the test tube so to speak? How robust would these findings be since testing them on humans is ethically out of the question? Would the results of the experiments prove helpful to organizations like the World Health Organization (WHO), the US Centers for Disease Control (CDC) and other public health structures in heading off a potential influenza pandemic? Could the experimentally engineered viral strains so generated allow manufacture of a “pro-active” vaccine?
For the record the answers to these questions are yes, not robust, not obvious at all and no.
There is a savvy mix of virological and public health questions with the latter subordinated to the former. As mentioned above two groups succeeded in adapting H5N1 to infect ferrets via the airborne route.
The controversy that erupted has changed little since 2012. The flu community has stuck to its guns and maintains that the work should be done while opponents argue that the science isn’t as strong as that, that the risk of an accidental escape is too high given the slight benefits at best that, currently, might emanate from this work.
A turning point occurred on October 17, 2014 when the White House issued a statement enacting a pause in further funding of GOF research on influenza viruses and the SARS and MERS coronaviruses. Furthermore it “encourages those currently conducting this type of work – whether federally funded or not – to voluntarily pause their research while risks and benefits are being reassessed.”
US based researchers have complied with this request so there is effectively a moratorium on avian influenza GOF research. We are not aware of ongoing SARS and MERS coronavirus GOF research.
Hopefully there will now be a constructive dialogue and debate between the two sides with plenty of input from new parties such as risk experts, ethicists, lawyers, insurers, the military, learned societies, government departments and society.
