Referee 2's review (Cecil Czerkinsky):

In this study, an adjuvanted split H5N1 (A/H5N1/Vietnam/1194/04) clade 1 candidate vaccine, shown recently to be safe and immunogenic even at low doses in humans was found to induce intra-subtypic cross-protection against challenge infection with clade 2 H5N1 (/A/Indonesia/5/05) in ferrets.

Neutralizing antibodies to both clade 1 and clade 2 viruses were raised in most ferrets receiving two doses of adjuvanted split H5N1. Importantly, viral shedding in the upper respiratory tract of vaccinated animals was strongly reduced suggesting that vaccination with this adjuvanted split vaccine might also reduce viral transmission.

The data presented are spectacular, their interpretation is sound and the manuscript is very well written. The results suggest that this adjuvanted H5N1 candidate vaccine could be especially useful as a tool for implementing pandemic flu preparedness. The potential impact of this study is obvious and it raises realistic hopes since it is the first candidate vaccine already shown to be safe and immunogenic in humans in which cross-protection against virus from a distinct clade was demonstrated in ferrets, a widely accepted animal model.

The only reservation that this manus raises is the relative mystery made around the adjuvant used. This could be briefly mentioned in the section Results+Discussion with a comment (even a tantalizing one) on the possible mechanism of action of this adjuvant.

----------
N.B. These are the general comments made by the reviewer when reviewing this paper in light of which the manuscript was revised. Specific points addressed during revision of the paper are not shown.