H5N1

A laboratory in the Netherlands has identified a lethal influenza H5N1 virus strain that is transmitted among ferrets. These findings are under review by the National Science Advisory Board for Biosecurity (NSABB) to ensure that they do not constitute a threat to human health. Meanwhile both the popular and scientific press has been calling this a ‘virus that could change world history’. Even the usually restrained Helen Branswell writes that “…the dangerous virus can mutate to become easily transmissible among ferrets — and perhaps humans…” Should we be frightened?

Details of Ron Fouchier’s experiments are not known because the results have not yet been published. Reports at CIDRAP and Science indicate that Fouchier was attempting to make the H5N1 virus more transmissible in ferrets. This strain of influenza is lethal in birds and humans – there have been over 500 human cases with over 50% mortality. However, the virus is not readily transmitted among humans. The virus is lethal in ferrets but does not transmit among the animals. Fouchier selected a transmissible H5N1 variant by ferret-to-ferret passage. This experiment involves infecting a ferret, harvesting virus from the animal, and infecting another ferret. After ten such passages, the H5N1 variant could spread from one ferret to another by airborne transmission. The two amino acid changes that permit airborne spread among ferrets were identified.

Scientists appear to be responsible for the hype surrounding this experiment. Fouchier called it ‘one of the most dangerous viruses you can make’. Paul Keim, chair of NSABB, ‘can’t think of another pathogenic organism that is as scary as this one’, and Richard Ebright, a molecular biologist at Rutgers University says the experiment should not have been done. Martin Enserink writing in ScienceInsider says that the virus could change world history, and similar proclamations of doom can be found in the popular press.

I cannot fault the press for not having the background to interpret these studies, but scientists should know better than to declare that this is a dangerous virus. First and foremost, ferrets are not humans. Every influenza researcher will say that ferrets are a good model for influenza – they display similar flu-like symptoms, immune responses, and pathological alterations such as elevated temperature, weight loss, and histological changes. But it would be foolish to conclude that ferret influenza is the same as human influenza in all aspects. For example, not all influenza virus strains have the same virulence in humans and ferrets. A good example is the 2009 pandemic H1N1 virus which caused severe infections in some ferret studies, but was relatively mild in humans.

In other words, just because the Fouchier H5N1 virus is transmissible among ferrets does not mean that it will be equally transmissible among humans. The experiment to answer this question cannot be done.

Passage of viruses in a different host is one strategy for reducing the virulence in humans. This concept is explained in this passage from Principles of Virology:

Less virulent (attenuated) viruses can be selected by growth in cells other than those of the normal host, or by propagation at nonphysiological temperatures. Mutants able to propagate better under these selective conditions arise during viral replication. When such mutants are isolated, purified, and subsequently tested for pathogenicity in appropriate models, some may be less pathogenic than their parent.

The possibility that passage of the H5N1 virus in ferrets will attenuate its virulence in humans has been ignored.

In my view, it is highly unlikely that laboratory-modified viruses will be able to cause extensive disease in humans. When humans tinker with viruses, they generally do not know what the virus needs to replicate efficiently, cause disease, and transmit in humans. Consequently, they are likely to introduce changes that attenuate pathogenesis in humans. Nature is far better at producing viruses that can kill – to think that we can duplicate the enormous diversity and selection pressures that occur in the wild is a severe case of scientific hubris.

Another aspect of this story that deserves comment is the review by the NSABB. That body is charged with reviewing experiments that would render a vaccine ineffective; confer resistance to antimicrobial agents; enhance the virulence of a pathogen or make a non-pathogen virulent; increase transmissibility of a pathogen; enable evasion of detection; and enable weaponization of a biological agent or toxin. It is not clear to me how this committee could make some of these conclusions without data from human experiments. Nevertheless, why would the NSABB recommend against publication of Fouchier’s data? Could the sequence of the ferret adapted H5N1 be used for bioterrorism? It seems unlikely: it is not known if the virus would be pathogenic and transmissible in humans. Bioterrorists do not want to carry out an experiment; they want to instill terror. Why use a laboratory modified H5N1 strain when the sequence of the 1918 influenza virus, known to be a lethal and transmissible human virus, is readily available? Ebright calls the 1918 virus “the most effective bioweapons agent now known”.

No one can guarantee that Fouchier’s virus would not be lethal and transmissible in humans. But the same could be said about any number of laboratory modified viruses, none of which have attracted the attention of the NSABB or the press. When dealing with viruses, both caution and restraint are necessary qualities.

This article is based on the conversation with Rich Condit and Alan Dove on TWiV 159 and 160.