Viruses and antigens. The pandemic H1N1 influenza virus (A/California/ 04/2009) was provided by R.J. Webby (St. Jude Childrens Hospital, Memphis, TN). Influenza virus stocks used for the assays were freshly grown in eggs, antibodies bound to past annual viral antigens at lower concentrations, suggesting higher avidity to past influenza strains than to the current pandemic H1N1 virus. Further, crossreacting cells that bind with higher affinity to the pandemic H1N1 strain also have the highest frequency of variable-gene mutations (Fig. S3 B) . Antibodies that were broadly crossreactive were among the more highly mutated clones (Fig. S3 B) . We propose that many of these cells were specific for crossreactive epitopes present in annual influenza strains that then underwent further affinity maturation and adaptation to the infecting pandemic H1N1 virus. Supporting this conjecture, Corti et al. (2010) first demonstrated that naturally occurring HA stalk-reactive memory B cells could be isolated from the blood of people recently immunized with the annual vaccine, before the outbreak of pandemic H1N1. The nature of that study was to screen EBV-transformed memory cell lines, thus precluding the determination of precise frequencies of these stalk-reactive B cells. However, these antibodies were estimated to be quite rare; occurring at one in thousands to one in hundreds of influenza-binding B cells, varying by individual. In contrast, we show that plasmablasts activated by infection with the highly novel pandemic H1N1 influenza strain have substantially increased targeting to the HA stalk region epitopes, totaling 10% of all influenza-specific antibodies and half of the neutralizing antibodies (Fig. 4) . In fact, most specific antibodies isolated in this study were cross-reactive to past influenza strains. Collectively, the data described supports a model in which divergent viruses that are conserved only at the most critical regions for function will elicit a higher proportion of cross-reactive and neutralizing antibodies. Thus, although the activated plasmablasts of relatively few patients could be analyzed in detail at the monoclonal antibody level, we proffer that with the proper immunogen, the long-sought development of a pan-influenza vaccine might be possible.