Here, we have analyzed the plasmablast responses induced by pandemic H1N1 infection and generated a panel of monoclonal antibodies (mAbs) from these cells to analyze their characteristics in detail. In contrast to seasonal vaccination, we show that a majority of the neutralizing antibodies induced by infection were broadly cross-reactive with all recent annual H1N1 strains, as well as the highly pathogenic 1918 H1N1 and avian H5N1 strains. These neutralizing antibodies bound predominantly to conserved epitopes in the hemagglutinin (HA) stalk region (Ekiert et al., 2009; Sui et al., 2009) , with some binding to novel epitopes in the HA globular head. The high frequency of these HA-stalk binding antibodies is of particular interest, as this epitope is a promising target for a broadly protective influenza vaccine (Steel et al., 2010) . Furthermore, the cross-reactive antibodies carried highly mutated immunoglobulin genes, indicative of extensive affinity maturation. Together, these findings support a model in which infection predominantly activated broadly cross-reactive memory B cells that then underwent further affinity maturation. We propose that the expansion of these rare types of memory B cells may explain why most people did not become severely ill, even in the absence of preexisting protective antibody titers. Recent studies in mice strongly support the idea that consecutive immunizations with antigens from divergent influenza stains can indeed hone the antibody response to preferentially target broadly protective conserved epitopes Wei et al., 2010) . Our findings demonstrate that cross-reactive antibodies can be preferentially induced in humans given the right immunogen, providing further support for the feasibility of generating a pan-influenza vaccine. Finally, in vivo challenge experiments showed that the neutralizing antibodies isolated protected mice challenged with a lethal dose of pandemic H1N1 influenza virus, even when administered therapeutically 72 h after infection, and also provided protection against antigenically distinct H1N1 influenza strains. These antibodies are thus promising as therapeutics against pandemic H1N1, as well as activated by pandemic H1N1 infection. Consistent with the frequency of plasmablasts secreting antibodies binding annual influenza strains by ELISPOT analyses (Fig. 1 C) , a majority (29/46, or 63%) of the pandemic H1N1-specific antibodies also cross-reacted with seasonal influenza viruses (Fig. 2,  A and B ). In fact, by ELISA, one third of these antibodies bind to the prepandemic strains at lower concentrations than they did to the pandemic H1N1 strain, suggesting higher avidity binding. By comparison, only 22% (11/50) of plasmablasts induced by annual H1N1 strains before the pandemic could bind the pandemic H1N1 influenza (Fig. S1 B) . We propose that the cross-reactivity of pandemic H1N1-induced cells derives from the activation of memory cells originally specific for past influenza immunizations in an original antigenic sin fashion.