Nature has just published the long-awaited paper by Kawaoka and colleagues describing the creation of a hybrid H5N1/pH1N1 virus which can be transmitted by respiratory droplets between ferrets:
There are many interesting facets to this study, but this blog will focus on a few key issues of interest to the flu preparedness community.
1. This was a hybrid virus. Only one of the eight genomic segments, haemagglutinin (HA), was derived from H5N1. The other 7 came from the pandemic H1N1 virus (pH1N1).
2. Four mutations in the H5N1 HA genomic segment were sufficient to allow the hybrid virus to spread from ferret to ferret.
3. None of the ferrets died during the course of the experiments. However, one virus was recovered from the brain of one of the ferrets. Since only a small number of ferrets were used, little can be concluded about the potential case fatality rate (CFR) of this virus if it were to occur in the human population except that it would not be rapidly lethal in 100% of the affected individuals. A much larger number of individuals would need to be tested to detect a fatality rate of 2%, the CFR of the 1918 flu virus.
4. A hybrid virus with its HA from H5N1 but the other genomic segments from pH1N1 would not necessarily be expected to be any more lethal than pH1N1. This is because HA is primarily involved in transmission of flu viruses. Although it plays a role in virulence, other genomic segments, for example, PB1, PB2, NA and NS, have been strongly implicated in the pathogenicity of flu viruses. Since these genomic segments were derived from pH1N1, it would not be surprising if the hybrid virus was about as lethal as pH1N1.
5. H5N1 and pH1N1 are genetically compatible. One type of hybrid was produced in these experiments, but others are possible. A hybrid which contained the PB1 or NS from H5N1 with other genomic segments from pH1N1 might have a very different CFR than the virus described in the current work.
6. The mutations which can cause H5N1 HA to permit mammal to mammal transmission are limited. The authors describe a range of mutations in H5N1 HA which did *not* result in increased transmissibility of the virus. Thus, we now know better which variants of H5N1 in the wild are likely to be most dangerous. This also sets the stage for the possibility of developing pre-emptive pandemic vaccines.
Publication of this work is long overdue. The fear that terrorists living in caves could use this information to produce a weapon seems quite ridiculous when reading this paper. The techniques and sophisticated analyses involved in this work are way beyond the limited intellects, knowledge base, and resources available to these groups. Nation-states run by dictators could develop biological weapons using the approaches described here. But if this was their intent, they likely have already pursued experiments to accomplish this without the many constraints researchers in free countries are subject to.
We now know that H5N1 could become easily transmittable between mammals. That knowledge alone will make us safer.