Text S1 Model structure and details of the model analyses Found at: doi:10.1371/journal.pone.0001558.s001 (0.10 MB PDF) Cross-subtype Immunity against Avian Influenza in Persons Recently Vaccinated for Influenza Avian influenza virus (H5N1) can be transmitted to humans, resulting in a severe or fatal disease. The aim of this study was to evaluate the immune cross-reactivity between human and avian influenza (H5N1) strains in healthy donors vaccinated for seasonal influenza A (H1N1)/(H3N2). A small frequency of CD4 T cells specific for subtype H5N1 was detected in several persons at baseline, and seasonal vaccine administration enhanced the frequency of such reactive CD4 T cells. We also observed that seasonal vaccination is able to raise neutralizing immunity against influenza (H5N1) in a large number of donors. No correlation between influenza-specific CD4 T cells and humoral responses was observed. N1 may possibly be a target for both cellular and humoral cross-type immunity, but additional experiments are needed to clarify this point. These findings highlight the possibility of boosting cross-type cellular and humoral immunity against highly pathogenic avian influenza A virus subtype H5N1 by seasonal influenza vaccination. I nfl uenza viruses are segmented, negative-sense RNA viruses belonging to the family Orthomyxoviridae. According to the antigenic differences in nucleoprotein and matrix proteins, 3 types of infl uenza viruses (A, B, and C) have been described. Infl uenza viruses A and B are associated with seasonal illness and death, whereas infl uenza virus C causes mild infections (1, 2) . Infl uenza A viruses are subtyped on the basis of the antigenic differences on external hemagglutinin (HA) and neuraminidase (NA) glycoproteins. Human type A infl uenza virus subtypes have been limited to H1, H2, and H3 and to N1 and N2 (3) . Several HAs and NAs have been isolated from avian hosts; occasionally, they have been associated with human outbreaks (4, 5) .