Referee 1's review:

The challenge infections were performed with reassortant influenza viruses harboring the M1, the HA and NA segments derived from H5N1 strains and the other segments derived from PR8. Thus, they did not use a true avian H5N1 influenza virus. Such approach is justified by the high pathogenicity of some avian H5N1 influenza viruses and consequently the needs of the use of high level security facility to carry out the experiments.

The reassortant viruses used in their experiments have modified HA segments that lost the polybasic cleavage site, the most determinant of pathogenicity in poultry, mice, and ferrets. In addition, it has been found that the high pathogenicity of H5N1 is multifactorial and is also related to other viral proteins such as the PB2 and NS1. In their study, the authors used reassortant viruses which displayed the two previously mentioned proteins derivated from PR8 viruses , a non pathogenic virus. Thus, their results perhaps do not represent those that would be obtained if the animals were infected by a true ,high pathogenic avian virus. The information about the multifactorial nature of the high pathogenicty of H5N1 influenza viruses should be mentioned in the introduction section of their manuscript and also should be discussed in the Discussion section.

Moreover, the statement found in the first paragraph of the Discussion section: “Our results show that BALB/c mice…were effectively protected from disease and death when challenged by distinct strains of H5N1 influenza viruses” is wrong, because the animals were not infected by true H5N1 viruses.

The authors list some advantages about the use of the VLP vaccines against potentially pandemic influenza viruses. It is noteworthy that these same advantages could be found in inactivated influenza vaccines that are produced by cell cultures. (in cell cultures).

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N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.