Most convincingly, there was a particularly high frequency of cross-reactive antibodies overall, with a high level of somatic mutations found particularly among the variable genes of cross-reacting cells (Fig. 2 and Fig. S3 ). In fact, by ELISA most antibodies were cross-reactive and one third of the broadly cross-reactive binding (Fig. 3 B) and have functional activity against multiple recent and older H1N1 strains (Fig. 3 C) . These antibodies were all highly effective at providing prophylactic protection against infection with a lethal dose of mouse-adapted pandemic H1N1 in 6-8-wk-old BALB/c mice (Fig. 5) . Moreover, all three antibodies were effective therapeutically, even when they were administered as late as 60 h after the lethal challenge infection, well after the mice were symptomatic. For EM-4C04, we have successfully treated mice as far out as 72 h post-infection (unpublished data). Infected mice were already showing measurable weight loss that was reversed by administration of the antibody, demonstrating therapeutic potential even after the onset of disease. Viral clearance was analyzed in mice treated at 48 h after infection with EM4C04 (Fig. S4) . As early as day 4, the antibody-treated mice exhibited more than a log reduction in viral titers; titers continued to decline, such that by day 6, virus was undetectable or present at very low levels. The untreated mice perished by day 7 or 8, whereas the treated mice cleared the infection with no detectable virus on day 12. Finally, 1009-3B06 and 70-1F02, which showed activity against several current and older H1N1 seasonal influenza strains in vitro (Fig. 3 C) , were also tested in vivo against antigenically distinct influenza strains. For these experiments, mice were treated with 200 µg of mAb intraperitoneally 12 h before infection with a lethal dose of either pandemic H1N1 influenza or either of the two common influenza laboratory strains PR/8/34 or FM/1/47. 1009-3B06 and 70-1F02 showed protection against these antigenically distinct H1N1 influenza strains, as illustrated in Fig. 5 . EM-4C04, which is highly specific Figure 6 . Breadth of in vivo prophylactic efficacy in mice. 6-8-wk-old BALB/c mice were treated with 200 µg (10 mg/kg of body weight) EM-4C04, 70-1F02, or 1009-3B06 human mAb intraperitoneally. Control mice were treated with PBS only, a control mAb or polyclonal human IgG. 12 h later, they were challenged with a 3xLD50 dose of mouse adapted pandemic H1N1, PR/8/34, or FM/1/47 influenza virus. All mice were monitored daily for body weight changes and any signs of morbidity and mortality. Percentage of initial body weight (left) and survival curves (right) are plotted. Infected, untreated mice showed clear signs of sickness 4-5 d after infection and perished by day 8-9. Figure shows one representative experiments of at least three independent repeat experiments. Antibody treatment conferred significant protection as determined by comparison of weights in untreated versus prophylaxis, and at the time of treatment versus 12 d after infection (unpaired, two-tailed Student's t test, P < 0.05). The log-rank test indicated significant survival as well (P < 0.003). seroconversion, or by the presence of highly potent antibodies, such as EM-4C04, whose activities were less likely to titer out. The highly specific nature of the response from this patient may have contributed to this advantage, ultimately better targeting the epitopes of the pandemic H1N1 strain. In contrast, patient 1009 had relatively low HAI and MN serum titers but the highest frequency of broadly neutralizing antibodies and a less severe disease course. One possibility is that our sampling from this patient was done before peak serological responses. Another possibility is that the high frequency of these potent antibodies in the memory B cell compartment may have resulted in rapid resolution of infection, precluding the development of a high serological response. A third possibility is that despite broader protection, the stalk-reactive antibodies are on the whole less potent and more rapidly titrated out than the highly specific antibodies to the HA globular head. These various possibilities will be of significant interest to study in the future.