the lack of pre-1918 sera samples for analysis makes it impossible to test this hypothesis.

Thus, it seems clear that the H1N1 virus of the 1918 pandemic contained an antigenically novel hemagglutinin to which most humans and swine were susceptible in 1918. Given the severity of the pandemic, it is also reasonable to suggest that the other dominant surface protein, NA, also would have been replaced by antigenic shift before the start of the pandemic (Reid and Taubenberger, 1999; Taubenberger et al., 2000). In fact, sequence and phylogenetic analyses suggest that the genes encoding these two surface proteins were derived from an avian-like influenza virus shortly before the start of the 1918 pandemic and that the precursor virus did not circulate widely in either humans or swine before 1918 (Fanning et al., 2002; Reid et al., 1999, 2000) (Figure 1-4). It is currently unclear what other influenza gene segments were novel in the 1918 pandemic virus in comparison to the previously circulating virus strain. It is possible that sequence and phylogenetic analyses of the gene segments of the 1918 virus may help elucidate this question.

Samples of frozen and fixed lung tissue from five second-wave influenza victims (dating from September 1918 to February 1919) have been used to examine directly the genetic structure of the 1918 influenza virus. Two of the cases analyzed were U.S. Army soldiers who died in September 1918, one in Camp Upton, New York, and the other in Fort Jackson, South Carolina. The available material consists of formalin-fixed, paraffin-embedded autopsy tissue, hematoxylin and eosin-stained microscopic sections, and the clinical histories of these patients. A third sample was obtained from an Alaskan Inuit woman who had been interred in permafrost in Brevig Mission, Alaska, since her death from influenza in November 1918. The influenza virus sequences derived from these three cases have been called A/ South Carolina/1/18 (H1N1), A/New York/1/18 (H1N1), and A/Brevig