Interestingly, the highly specific antibody EM-4C04 was derived from a patient that had a very severe disease course, with persistent viral shedding over several weeks. In addition, the variable genes from the plasmablasts of this patient had the lowest average number of somatic mutations (Fig. 2 B , outlier, and Fig. S3 B) . Collectively, the unique specificity against pandemic H1N1, the low levels of somatic mutation, and the unusually severe disease in the absence of predisposing conditions suggest that this patient may have mounted a primary immune response to the pandemic H1N1 influenza infection. The complete lack of preexisting immunity may have contributed to the more severe disease observed in this patient. In contrast, the activation of broadly cross-neutralizing memory B cells in those with immune experience to annual strains might have contributed to the less severe disease of most infected patients during the pandemic.