More importantly, PN-SIA28 represents the molecular evidence that an extremely wide unusual neutralizing immunity although, uncommon, may be elicited during the course of a natural infection and, potentially, even after a new-generation vaccinal approach focused on its epitope [40] . As a consequence, PN-SIA28 could be crucial in the identification of promising HAbased vaccinal strategies aimed at the elicitation of a broadly heterosubtypic protective immunity similar to the one represented by this human mAb. As described for a few other mAbs [25, 26, 27, 28, 29, 30, 31, 32, 41] , PN-SIA28 is mainly directed against the highly conserved HA2 domain whose use in novel anti-influenza vaccinal approaches is being widely investigated. However, PN-SIA28 demonstrates that not all antibodies directed against the stem region have the same characteristics, and that their neutralizing activity is modulated by the specifically recognized epitope. Indeed, the data presented in this paper show that in the design of such innovative approaches (i.e. the so-called ''headless approach'' [16] ) it is important to identify also residues belonging to HA1 domain to be preserved to elicit the widest immunity. Several immunogens are usually obtained on the basis of in silico analysis, but their real protective potential can only be ascertained after time-consuming and expensive in vivo studies. Under this perspective, PN-SIA28 could therefore be an extremely important reagent to identify immunogens more likely to stimulate antibodies with a similar broad heterosubtypic neutralizing activity that will constitute the best candidates for further in vivo studies.