Immune history profoundly affects broadly protective B cell responses to influenza

Abstract

Generating a broadly protective influenza vaccine is critical to global health. Understanding how immune memory influences influenza immunity is central to this goal. We undertook an in-depth study of the B cell response to the pandemic 2009 H1N1 vaccine over consecutive years. Analysis of monoclonal Abs generated from vaccine-induced plasmablasts demonstrated that individuals with low preexisting serological titers to the vaccinating strain generated a broadly reactive, HA stalk-biased, response. Higher preexisting serum antibody levels correlated with a strain-specific HA head-dominated response. We demonstrate that this HA head immunodominance encompasses poor accessibility of the HA stalk epitopes. Further, we show polyreactivity of HA stalk-reactive antibodies that could cause counterselection of these cells. Thus, preexisting memory against HA head epitopes predominate, inhibiting a broadly protective response against the HA stalk upon revaccination with similar strains. Consideration of influenza exposure history is critical for new vaccine strategies designed to elicit broadly neutralizing antibodies.

Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus

“…Despite having lower affinity than 9H10, XY102 is capable of competing for binding, because the HA head domain on virus particles and on the surface of infected cells is substantially more accessible than the HA stalk domain. These data are consistent with recent studies showing that poor accessibility of the stalk domain is partly responsible for the relatively low quantities of HA stalk-specific antibodies produced under normal conditions (43).…”

Cell-Mediated Immunity Against Antigenically Drifted Influenza A(H3N2) Viruses in Children During a Vaccine Mismatch Season

“…PBs have been shown to be derived from preexisting MBCs with the help of pT FH and are enriched with vaccine antigen-specific ASCs [16][17][18][19]. IIV elicited significant PB responses (GMP FC, 1.55; 95% CI, 1.23-1.96) overall (Table 1).…”

Antibody-guided vaccine design: identification of protective epitopes

“…Thus, an ideal vaccine should contain a sufficiently high number of T and B cell epitopes and should be formulated to effectively prime the germinal center reaction [50]. In addition, the finding that preexisting immunity can shape the antibody response to new structurally related antigens [51][52][53] suggests modalities of prime-boost immunization to optimize the antibody response [54].…”