Is It Possible to Develop a "Universal" Influenza Virus Vaccine? Immunogenetic Considerations Underlying B-Cell Biology in the Development of a Pan-Subtype Influenza A Vaccine Targeting the Hemagglutinin Stem

Abstract

Current influenza vaccines preferentially generate B-cell responses to the variable hemagglutinin (HA) head. Focusing vaccine-induced antibody responses on epitopes in the conserved HA stem may provide better protection against future drifted and pandemic strains. Understanding the basis for the dominant HA head and subdominant HA stem-specific responses at the level of B-cell activation and differentiation will be critical for designing vaccines that induce sustained stem-specific responses. Identifying antibody lineages with broad neutralizing activity against influenza A viruses and defining the structural mode of recognition for germline precursors of those antibodies will also guide future immunogen design.

Figure 1.

Diagram of the contact footprint of three hemagglutinin (HA) stem-binding antibodies with different influenza subtype specificity. Shown is the HA stem (highlighted by the black box on the diagram of whole HA on the far left) with two potential glycans shown in green. Group 1 HA has a glycan at N21, while group 2 HA is glycosylated at N38. Antibodies that bind the group 1 HA stem (left) have a contact footprint (shown in orange) that avoids the N21 glycan. Group 2 HA stem-binding antibodies (center, CR8020 contact footprint shown in purple) avoid the N38 glycan. Cross-group HA stem-binding antibodies (right, contact footprint of FI6 shown in light green) are able to bind in the presence of either glycan. Diagrams are based on published structural data (Ekiert et al. 2009; Sui et al. 2009; Corti et al. 2011; Dreyfus et al. 2012).

Figure 2.

Schematic of strategy used to identify recurring immunoglobulin classes that recognize conserved hemagglutinin (HA) stem epitopes. Two weeks after an H5N1 vaccine boost, peripheral blood IgG⁺ memory B cells capable of binding HA from different influenza subtypes were detected using an HA probe mutated to prevent nonspecific binding to sialic acid. B cells able to bind multiple group 1 subtypes (H5 and H1) or both group 1 and group 2 subtypes (H5 and H3) were single-cell sorted, and immunoglobulin heavy and light chains for each cell were polymerase chain reaction (PCR) amplified and sequenced. Representative heavy and light chain pairs were cloned, expressed as monoclonal antibodies and tested for binding and neutralization. The pie charts show the prominent IGHV genes expressed by B cells within each category with the number of sequences analyzed indicated in the center of each chart. The predominant IGHV gene used by group 1 HA-binding B cells was IGHV1-69. Few group 1/2 HA-binding B cells expressed IGHV1-69. Instead, three classes of cross-group HA stem-binding and neutralizing B cells encoded by IGHV1-18 and IGHV6-1 were identified in multiple donors after H5N1 vaccination as indicated. IGHV genes, including IGHV3-30 and others not referenced here, are colored in grey. More details can be found in Joyce et al. (2016).