Comparison of the influenza virus-specific effector and memory B-cell responses to immunization of children and adults with live attenuated or inactivated influenza virus vaccines

Abstract

Cellular immune responses to influenza virus infection and influenza virus vaccination have not been rigorously characterized. We quantified the effector and memory B-cell responses in children and adults after administration of either live attenuated (LAIV) or inactivated (TIV) influenza virus vaccines and compared these to antibody responses. Peripheral blood mononuclear cells were collected at days 0, 7 to 12, and 27 to 42 after immunization of younger children (6 months to 4 years old), older children (5 to 9 years old), and adults. Influenza virus-specific effector immunoglobulin A (IgA) and IgG circulating antibody-secreting cells (ASC) and stimulated memory B cells were detected using an enzyme-linked immunospot assay. Circulating influenza virus-specific IgG and IgA ASC were detected 7 to 12 days after TIV and after LAIV immunization. Seventy-nine percent or more of adults and older children had demonstrable IgG ASC responses, while IgA ASC responses were detected in 29 to 53% of the subjects. The IgG ASC response rate to LAIV immunization in adults was significantly higher than the response rate measured by standard serum antibody assays (26.3% and 15.8% by neutralization and hemagglutination inhibition assays, respectively). IgG ASC and serum antibody responses were relatively low in the younger children compared to older children and adults. TIV, but not LAIV, significantly increased the percentage of circulating influenza virus-specific memory B cells detected at 27 to 42 days after immunization in children and adults. In conclusion, although both influenza vaccines are effective, we found significant differences in the B-cell and antibody responses elicited after LAIV or TIV immunization in adults and older children and between young children and older age groups.

Figures

FIG. 1.

Quantities of circulating influenza virus-specific ASC present on day 0, day 9 (range, day 7 to 12), and day 30 (range, day 27 to 47) following vaccination with LAIV (▪) or TIV (□) in adults (A and C) and 5- to 9-year-old children (B and D). Influenza virus-specific IgA ASC (A and B) and IgG ASC (C and D) were measured by ELISPOT assay. The dashed horizontal line in each column indicates the mean value. Asterisks indicate a highly significant difference (P < 0.01, GLM).

FIG. 2.

Comparison of the quantity of circulating influenza virus-specific ASC 9 days (range, day 7 to 12) after TIV vaccination in 0.5- to 4-year-old children, 5- to 9-year-old children, and adults. Influenza virus-specific IgA (A) and IgG (B) ASC were measured by ELISPOT. Adults and 5- to 9-year-old children received one dose of TIV as shown in Fig. 1. In 0.5- to 4-year-old children, influenza virus-specific ASC were measured 9 days (range, 9 to 11 days) after the first or second dose of TIV immunization. The horizontal dashed line in each column indicates the mean value. An asterisk indicates a significant difference (P < 0.05, GLM).

FIG. 3.

Comparison of day zero (baseline) titers of neutralizing antibody and HAI to the A/Wyoming H3N2 strain. Neutralizing antibody (A) and HAI (B) titers in the serum of children 0.5 to 1 years old, 2 to 4 years old, and 5 to 9 years old and of adults 21 to 48 years old were measured by neutralizing and HAI assay. The horizontal dashed line in each column indicates the mean value. Asterisks indicate a highly significant difference (P < 0.01, MM).

FIG. 4.

Comparison of the titers of neutralizing antibody to the A/Wyoming H3N2 strain before and 30 days (range, 27 to 47 days) after vaccination. Neutralizing antibody titers in the serum of adults (A) and 5- to 9-year-old children (B) at baseline (day 0) and 30 days after vaccination with LAIV (▪) or TIV (□) vaccination were measured. The horizontal dashed line in each column indicates the mean value. One asterisk or two asterisks indicate significant and highly significant differences (P < 0.05 and P < 0.01, respectively; GEE).

FIG. 5.

Comparison of titers of neutralizing antibody to the A/Wyoming H3N2 strain 9 days (range, 9 to 11 days) after dose one or two of TIV in 0.5- to 4-year-old children. Neutralizing antibody titers were determined before (day 0) and after one dose (day 9) or two doses (day 39 or day 9 after second vaccination) of TIV. The horizontal dashed line in each column indicates the mean value. Asterisks indicate a highly significant difference (P < 0.01, GEE).

FIG. 6.

Comparison of prevaccination percentages of influenza virus-specific memory B cells between age groups. Influenza virus-specific memory IgA cells (A) and IgG cells (B) in individuals 0.5 to 1 year old, 2 to 4 years old, 5 to 9 years old, and 21 to 48 years old were measured by a memory B-cell assay. The horizontal dashed line in each column indicates the mean value. Asterisks indicate a highly significant difference (P < 0.01. GLM).

FIG. 7.

Percentage of influenza virus-specific memory B cells in the circulation before and 30 days (range, 27 to 47 days) after vaccination. Influenza virus-specific memory IgA cells (A and B) and IgG cells (C and D) in adults (A and C) and 5- to 9-year-old children (B and D) before and after LAIV (▪) or TIV (□) vaccination were measured by memory B-cell assay as described in the text. Asterisks indicate a highly significant difference (P < 0.01, GLM and paired t test).