Interference at Influenza Hemagglutinin Antigenic-Sites Determines Antibody Levels and Specificities after Repeat Vaccination

Abstract Background It is recommended that children receive a dose of the influenza vaccine at 6 months of age and a second dose the following season. In some years, the second dose will be the same vaccine formulation, in others years it with be re-formulated to include HA proteins derived from antigenically drifted or shifted circulating influenza strains. In addition, natural exposure to influenza can create permanent changes to the memory B cell repertoire and specificities. The effect that the specificity of pre-existing humoral immunity has on antibody levels and specificity after repeat vaccination is an ongoing research area. Methods We used a computational framework (ssMod.v1) to simulate scenarios that occurred during the 2009 influenza pandemic: children receiving a second dose who have previously exposed to the 2009 influenza HA antigen, children previously exposed to an HA antigen antigenically similar to the 2009 influenza HA antigen, and children previously exposed to an antigenically dissimilar strain. To assess the contribution of pre-existing immunity, two experimental permutations in the sMod.v1 were made: elimination of antibody-mediated antibody clearance of vaccine (HA) antigen by pre-existing antibodies and elimination of the ability of memory B cells to form germinal centers. In the simulation, 30 days after repeat vaccination antibody specificities were examined against 12 antigenically historical vaccine/HA variant influenza strains for each of the five canonical antigenic-sites and the subdominant, conserved, stalk antigenic-site. Results We found that elimination of antibody-mediated antigen clearance significantly increased antibody levels while elimination of the ability of memory B cells to form germinal center reactions significantly decreased the total antibody levels, but this was dependent on the antigenic relationship between the original vaccine and repeat vaccine and the particular antigenic-site. Moreover, highly-cross-reactive antibody was highest when the antigenic distance between original vaccine HA antigen and repeat vaccine HA antigen was larger and antibody-mediated antigen clearance was eliminated.