Influence of prior influenza vaccination on antibody and B-cell responses

Abstract

Currently two vaccines, trivalent inactivated influenza vaccine (TIV) and live attenuated influenza vaccine (LAIV), are licensed in the USA. Despite previous studies on immune responses induced by these two vaccines, a comparative study of the influence of prior influenza vaccination on serum antibody and B-cell responses to new LAIV or TIV vaccination has not been reported. During the 2005/6 influenza season, we quantified the serum antibody and B-cell responses to LAIV or TIV in adults with differing influenza vaccination histories in the prior year: LAIV, TIV, or neither. Blood samples were collected on days 0, 7-9 and 21-35 after immunization and used for serum HAI assay and B-cell assays. Total and influenza-specific circulating IgG and IgA antibody secreting cells (ASC) in PBMC were detected by direct ELISPOT assay. Memory B cells were also tested by ELISPOT after polyclonal stimulation of PBMC in vitro. Serum antibody, effector, and memory B-cell responses were greater in TIV recipients than LAIV recipients. Prior year TIV recipients had significantly higher baseline HAI titers, but lower HAI response after vaccination with either TIV or LAIV, and lower IgA ASC response after vaccination with TIV than prior year LAIV or no vaccination recipients. Lower levels of baseline HAI titer were associated with a greater fold-increase of HAI titer and ASC number after vaccination, which also differed by type of vaccine. Our findings suggest that the type of vaccine received in the prior year affects the serum antibody and the B-cell responses to subsequent vaccination. In particular, prior year TIV vaccination is associated with sustained higher HAI titer one year later but lower antibody response to new LAIV or TIV vaccination, and a lower effector B-cell response to new TIV but not LAIV vaccination.

Figure 1. HAI titer to influenza A/California (H3N2) strain before and 30 days after TIV or LAIV administration.

Subjects are divided into three groups based on the status of influenza vaccination in the prior year (2004–2005): TIV ('04-T), LAIV ('04-L), or no vaccination ('04-N). A: Baseline HAI titer. B: fold-increase of HAI titer from baseline to day 30 of LAIV ('05-LAIV) or TIV ('05-TIV). The dashed-bars in each graph indicate the geometric mean values. **, significant difference after sequential Bonferroni adjustment for multiple comparisons. *, results with a P value of <.05 in an individual unpaired t-test but nonsignificant after sequential Bonferroni adjustment for multiple comparisons.

Figure 2. Frequency of circulating influenza-specific ASC after LAIV or TIV vaccination.

Influenza-specific IgA ASC and IgG ASC were measured with a direct ELISPOT assay at days 7–9 after LAIV ('05-LAIV) or TIV ('05-TIV) vaccination. A: Influenza-specific IgA and IgG ASC in all subjects after administration of '05-LAIV or '05-TIV. B: Influenza-specific IgA and IgG ASC after '05-LAIV or '05-TIV in the three sub-groups based on influenza vaccination status in the prior year: TIV ('04-T), LAIV ('04-L), or no vaccination ('04-N). The dashed-bars in each graph indicate the geometric mean values. **, P<.01 unpaired t-test (A) or significant difference after adjustment for multiple comparisons (B). *, result with a P value of <.05 in an individual test but not significant after adjustment for multiple comparisons (B).

Figure 3. Kinetics of effector IgA and IgG ASC responses after TIV or LAIV vaccination.

Plotted is the frequency of influenza-specific effector IgA and IgG ASC as a function of days after TIV or LAIV vaccination for the 2004 and 2005 studies. Observed data are plotted as circles and triangles. Lines provide the fit of the GEE regression model. Of interest was comparing the difference in the slopes of these fitted lines over days 7–11 post-vaccination between TIV and LAIV. Regression analysis assumed that this difference between TIV and LAIV did not depend on year (2004 vs. 2005).

Figure 4. The percentage of circulating influenza-specific memory B cells before and after LAIV or TIV vaccination.

Percentages of influenza-specific memory IgG B-cells and IgA B-cells before (day 0) and 30 day (21–35 days in 2005 study, 27–47 days in 2004 study) after LAIV or TIV vaccination were measured. A: Comparisons of the percentages of influenza-specific memory IgA and IgG B-cells on day 0 and day 30 after LAIV ('05-LAIV) or TIV ('05-TIV) vaccination. B: Comparisons of memory IgG B-cell levels before vaccination in sub-groups based on the influenza vaccine received in the prior year: TIV ('03-T, '04-T), LAIV ('03-L), or no vaccination ('04-N). C: Comparisons of memory IgG B-cell levels one month after vaccination with '05-LAIV or '05-TIV between sub-groups '04-N and '04-T. The horizontal bars indicate the mean values. *, P<.05, **, P<.01, unpaired t-test.