Most of the anti-influenza heterosubtypic neutralizing mAbs described thus far, derived from the VH1-69 germline, bind to a conserved epitope in the HA stem region present only on group 1 influenza A viruses. The binding is mainly through highly hydrophobic amino acidic residues in the heavy chain CDR2 [20, 21, 22, 23, 24, 25] . Instead, the heavy chain variable region of PN-SIA49 results from VH3-23 gene rearrangement with the D3-3 and JH6 gene segments demonstrating that, despite the preferential usage of VH1-69 in the heterosubtypic response to influenza HA [20] , an in-vivo heterosubtypic protection may be conferred also by non VH1-69 derived Abs.