br Materials and Methods br Results br Discussion

Materials and Methods
Results
Discussion This is the study to perform quantitative and qualitative multivariate analyses of antibody responses to RSV and F protein. The results suggested that children\'s antibody responses to RSV are matured over months and years in at least 5 stages: 1st stage responses where IgG3 for F protein is significantly induced but levels of IgG3 for F protein in the convalescent phase (F IgG3 C) are low in infants at 0 to 3months old; 2nd stage responses where F IgG3 C levels are average and GMRs C/A of NT, F IgG1, and F IgG2 levels are low in infants at 4 to 6months old; 3rd stage responses where F IgG3 C levels are high, GMRs C/A of NT, F IgG1, and F IgG2 levels are high, and the antibody affinity maturation and the cross reactivity of IgG for G SW033291 of groups A and B are induced in infants at 7months and older; 4th stage responses where low levels of neutralization epitope-specific IgG are induced in children at 13 to 18months old; 5th stage responses where levels of NT, F IgG1, F IgG2, F neutralization epitope-specific IgG, and F IgGk in the convalescent phase are high after repetitive RSV infections in children 19months and older (Table 4). In accordance with the results of other previous clinical studies, in this study the presence of maternal antibody was also suggested in infants <6months old. Although the infants\' own antibody responses to neutralize RSV were actually induced since all child participants recovered from RSV infection in the convalescent phase, it was suggested that serum neutralization titers induced by the infants\' own immunity were too low to be discriminated in the presence of the maternal antibody. In spite of different concentrations of IgG subclasses specific to F protein, the kinetics of IgG1 and IgG2 for F protein was similar to that of the serum neutralization activity. In contrast, although concentrations of IgG3 for F protein were almost 1/20 of IgG1, GMRs C/A of F IgG3 were higher even in newborns and young infants <4months old. The results suggested that levels of maternal IgG3 for F protein were low enough to discriminate infants\' own IgG3 for F protein. Such evidence enables us to use it as one of the best biomarkers of infants\' own immune responses to RSV infection, although biological roles of IgG3 for F protein in protection against RSV have not yet been elucidated. Since levels of IgG1 and IgG2 but not IgG3 are increased in accordance with the maturation of the immune system after birth, it was suggested that the relative levels of IgG3 to other subclasses decrease accordingly in life. In contrast, it has been proposed that a finite number of FcRn, an essential transporter of maternal systemic IgG to the fetal circulation, determines levels of total IgG transfer and ratios of IgG subclass transfer to the fetus. In addition, a previous research revealed that FcRn-mediated transport of IgG3 is inhibited in the presence of IgG1 (Stapleton et al., 2011). It was therefore suggested that a lower amount of IgG3 relative to IgG1 or IgG2 is transferred into the fetus. Levels of serum IgG competitiveness with neutralization monoclonal antibodies also correlated with serum neutralization titers. The kinetics of PLNA in samples of children aged at 25 to 36months old and adults reasonably correlated with the trough level of palivizumab, 40μg/mL, in view of viral clearance in the course of the clinical stage. A recent study, however, has demonstrated that palivizumab has the potential to compete with both neutralization antibodies and non-neutralization antibodies, suggesting that PLNA evaluated in this study may contain non-neutralization antibodies. With regard to GMRs of PLNA titers, antigenic site I neutralization antibody titers, and antigenic site IV neutralization antibody titers, the lower limits of 95% CI were >4.5, 2.2, and 5.8 in adults. In addition, percentages of significant higher levels, as determined by >4-fold increase of GMRs of PLNA titers, antigenic site I neutralization antibody titers, and antigenic site IV neutralization antibody titers, were 69.6%, 43.5%, and 73.9% in adults, suggesting that such ratios reflect antibody responses specific to RSV infection.