Broadly neutralizing anti-influenza human monoclonal antibodies and their possible role in predictive medicine

Influenza virus is to date a major threat for humans, causing annual epidemics and sporadic pandemics. A high genomic mutation rate enables the virus to both escape the pre-existing humoral immunity andrapidly become resistant to the main antiviral drugs in use. Moreover, its broad diffusion among different mammal and avian species poses the threat of new viral strains to become highly pathogenic in humans. PN-SIA49 and PN-SIA28, two human monoclonal antibodies (mAbs) selected from peripheral B-lymphocytes, are endowed with a unique neutralizing activity against highly divergent viral subtypes. In vitro PNSIA49 neutralizes influenza isolates belonging to phylogenetic group 1,while PN-SIA28 has specificity for viral strains belonging to both group 1 and group 2. When tested in vivo PN-SIA49 showed high efficacy in protecting mice after the lethal challenges of influenza virus strains belongingto H1N1 and H5N1. Antibody epitopes were characterized using different approachesincluding the generation of escape viral variants and the alanine scanning and peptide panning techniques. Their epitopes localize in an extremely conserved but poorly immunogenic domain of hemagglutinin stem region. The molecular cloning of PN-SIA28 and PN-SIA49 points out that, although seldomly, a broad humoral response against influenza virus can be induced in humans. Potential uses of these mAbs span from the development of new drugs to treat severe cases of influenza infection,to the development of new epitope-based vaccinal approaches. In the short term, due to their unique biological activity, these mAbs can be used to assess the efficacy of vaccine preparations and predict the severity of the annual influenza virus epidemics.