The results presented here provide evidence that vaccinees with lower baseline immunity to influenza A/H3N2 and B (ie, as indicated by lower pre-vaccination antibody titers) have significantly higher odds of shedding a strain-specific virus in the week after vaccination

The results presented here provide evidence that vaccinees with lower baseline immunity to influenza A/H3N2 and B (ie, as indicated by lower pre-vaccination antibody titers) have significantly higher odds of shedding a strain-specific virus in the week after vaccination. inhibition [HAI], microneutralization, and immunoglobulin G and immunoglobulin A (both serum and mucosal antibodies) and LAIV viral recovery in the week post-vaccination. We then tested for potential effect modification by baseline HAI titers (ie, 10 versus 10) and week 1 viral recovery on the LAIV-induced serum and mucosal immune responses, measured between days 0 and 21 post-vaccination. Results Higher levels of preexisting immunity to APH-1B influenza A/H3N2 and B were strongly associated with strain-specific prevention of viral shedding upon LAIV receipt. While evidence of LAIV immunogenicity was observed for all 3 strains, the magnitudes of immune responses were most pronounced in children with no evidence of preexisting HAI and in c-Kit-IN-2 those with detectable virus. Conclusions The results provide evidence for a bidirectional association between viral replication c-Kit-IN-2 and immunity, and underscore the importance of accounting for preexisting immunity when evaluating virologic and immunologic responses to c-Kit-IN-2 LAIVs. Clinical Trials Registration “type”:”clinical-trial”,”attrs”:”text”:”NCT01625689″,”term_id”:”NCT01625689″NCT01625689. values were calculated separately within each treatment/shedding group using paired values indicating the statistical significance of the interaction term c-Kit-IN-2 are from likelihood ratio tests. To mitigate the potential for false-positive results, a Bonferroni-corrected value of .0007 (ie, .05 70) was considered to be the threshold for significance. All values are from 2-sided statistical tests, and all analyses were performed using Stata, version 13.0 (StataCorp LP, College Station, TX) and R, version 3.2.5. RESULTS The relationships between preexisting immunity, vaccine virus detection, and LAIV-induced humoral and mucosal immune responses were examined in an analytical cohort comprising 145 LAIV recipients and 145 placebo controls, which represented 97% of the participants in the primary study [12]. At baseline, strong pairwise correlations were observed for the levels of strain-specific serum immune markers ( .0001 for all; Supplementary Figure 1). In each of the 3 strains, the most highly-correlated markers were microneutralization and serum IgG (Spearmans rho: A/H1N1pdm09, 0.82; A/H3N2, 0.78; B, 0.77). As reported in the companion, protocol-defined analyses, viral shedding patterns and immune responses in LAIV recipients differed by vaccine strains. Whereas the A/H1N1pdm09 virus was not detected over follow-up, the A/H3N2 and B vaccine viruses were detected in NPW specimens on 1 or more days from 46% (n = 67/145) and 59% (n = 86/145) of vaccinees, respectively. Of note, wild-type B viruses were also detected by Sanger sequencing in 3 placebo recipients, demonstrating the presence of intercurrent influenza B in circulation in Dhaka at the time of the trial. Baseline Immune Marker Levels and the Odds of Not Shedding Virus Upon Vaccine Receipt In comparing the vaccine recipients in whom a virus was detected versus those without virus detection for A/H3N2 and B (Table 1), the baseline titers of all of the measured serum immune markers were statistically significantly lower in the children from whom virus was detected after LAIV receipt. To examine the shape of the associations more directly, vaccine recipients were grouped into tertiles based on their preexisting antibody titers (Supplementary Table 1), and the odds of being c-Kit-IN-2 shedding-negative were compared between the groups (Figure 1). Across the panel of serum immune markers, the results consistently indicate the odds of not shedding a virus upon vaccine receipt increased progressively with each incremental change in preexisting immune titers. For both A/H3N2 and B mucosal IgA, children in the highest third had approximately 2-fold increased odds of being shedding-negative upon LAIV receipt, relative to children in the lowest third. Table 1. Cross-sectional Comparison of Strain-specific Serum and Mucosal Antibody Titers Value,Between Shedding GroupsValue,Between Shedding Groupsvalues are from values are from paired values are from paired values are from paired values are from likelihood ratio tests and indicate effect modification of.

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