Reply to “Studies on Influenza Virus Transmission between Ferrets: the Public Health Risks Revisited”

Lipsitch, Marc; Inglesby, Thomas V.

(i) There is no direct evidence that the ferret-passaged variants of H5N1 from Fouchier's laboratory are less virulent for humans, or indeed for ferrets, than wild-type H5N1. Such a comparison would require lower mortality from the ferret-transmissible strain following inoculations of the same doses by the same route. In Table 1 of reference 17, it is shown that 6/6 ferrets died from wild-type or ferret-transmissible virus when exposed by the intratracheal route: in this assay, their virulence was indistinguishable. Table 1 gives no data on wild-type H5N1 administered by the intranasal route, suggesting that ferret-passaged (but nontransmissible) wild-type H5N1 can be used as a stand-in. Even this suboptimal comparison, using four different isolates, is not statistically significant (2/2 versus 1/8; P Ï­ 0.07). When the engineered viruses were transmitted by aerosol to ferrets, 0/6 died, consistent with a 95% confidence interval for the probability of lethality in ferrets of 0 to 46%. We do not know the inoculum in these transmission experiments and how it compares to inocula in humans if they were infected by aerosol, or how this translates into fatality risk in humans. From a risk assessment perspective, the conservative assumption that human lethality of evolved strains is similar to that of the starting strains is well justified.