K., P. of exposures increased. Although repeated H3 exposures induced original antigenic sin phenomena in HAI titers against later exposed viruses, resultant ferret antibodies showed gradually enhanced avidity for different H3/hemagglutinin. Increased antibody avidity was found to be inversely correlated with decreased antigenic differences among H3 viruses characterized. Conclusions Our results suggest that repeated H3 exposures imprinted not only antibody quantity but also antibody quality. The naive ferret model currently used for vaccine strain selection does not recapitulate the complexity of human preexisting immunity. Vaccine strains identified hereby may not provide coverage sufficient for those who were frequently infected and/or vaccinated, leading to the reduced VE observed. ? .05 determined by 2-way analysis of variance was considered statistically significant. RESULTS Preexisting Immunity Affected Human H3-Specific HAI Cross-reactivity Because of lack of contamination/vaccination records, selected pediatric or adult postvaccination sera were grouped as previously reported [12, 14, 15, 18]: (1) undetectable H3-specific preexisting immunity (prevaccination HAI titer of 40 against SWZ/13), and (2) detectable H3-specific preexisting immunity (prevaccination Sulindac (Clinoril) HAI titer of 40 against SWZ/13). Compared to the pediatric or adult group with undetectable preexisting immunity, the corresponding age group with detectable preexisting immunity responded more evenly to all H3 viruses tested (Physique 1A and 1B). When these same postvaccination HAI titers were visualized using antigenic cartography (Physique 1CCF), interestingly, the groups with detectable preexisting immunity, regardless of ages, had difficulties in distinguishing different H3 clades as compared to the groups with undetectable preexisting immunity (Physique 1C vs ?vs1D1D and Figure ?Determine1E1E vs ?vs1F).1F). For instance, clade 3C.2a (green) and clade 3C.3a (red) viruses were well separated in the antigenic map derived from pediatric postvaccination sera with undetectable preexisting immunity, indicative of distinct antigenicity (Figure 1C). However, in the antigenic map derived from pediatric postvaccination sera with detectable preexisting immunity, these 2 clades tended to cluster together and were not distinctly separated (Physique 1D). Comparable phenomena were observed in the maps derived from adult postvaccination sera with and without detectable preexisting immunity (Physique 1E vs ?vs1F).1F). In particular, Sulindac (Clinoril) clade 3C.2a and clade 3C.3a viruses became completely indistinguishable in the adult map with detectable preexisting immunity (Physique Rabbit Polyclonal to Cytochrome P450 4F3 1F). The smaller antigenic distances in pediatric or adult map with detectable preexisting immunity indicated smaller antigenic differences among H3 viruses characterized (1.2763 vs 1.4629 and 0.8339 vs 1.0340 in children and adults with undetectable preexisting immunity, respectively; Physique 1G). Correlation coefficient analysis also showed that this maps with detectable preexisting immunity correlated poorly with those with undetectable preexisting immunity (Physique 1G). These results indicated that this postvaccination sera from the subjects with detectable preexisting immunity had different cross-reactivity toward H3N2 variants from those with undetectable preexisting immunity. Open in a separate window Physique 1. Different antigenic patterns of human postvaccination sera with or without detectable H3-specific preexisting immunity. and and and = .0006): higher antibody avidity and shorter antigenic distances (Figure 6). These results suggest that repeated H3N2 exposures enhance antibody avidity, thus affecting virus antigenic characterization. Open in a separate window Physique 6. Correlation between immunoglobulin G (IgG) avidities and antigenic distances determined by ferret antisera with different exposure histories. H3-specific IgG avidities of ferret antisera decided in Physique 4 were correlated with average antigenic distances determined by corresponding Sulindac (Clinoril) ferret antisera in Physique 5I using linear regression. Please see the Physique 2 legend for descriptions of influenza virus strains. DISCUSSION Current vaccine strain selection uses seronegative ferret model without influenza-specific preexisting immunity to detect epidemic viruses that are antigenically different from vaccine strains [11C13]. However, accumulated evidence indicates that early life exposure to influenza can leave an imprint on human antibody repertoires, and resulted residual protection may last a lifetime [15, 16, 21, 31C35]. Intensified global connectivity helps to spread antigenically drifted influenza strains [36]. Repeated annual vaccination also contributes to widespread influenza preexisting immunity in humans. Virtually all humans have been exposedasymptomatically.