A broadly neutralizing anti-influenza antibody reveals ongoing capacity of haemagglutinin-specific memory B cells to evolve

Abstract

Understanding the natural evolution and structural changes involved in broadly neutralizing antibody (bnAb) development holds great promise for improving the design of prophylactic influenza vaccines. Here we report an haemagglutinin (HA) stem-directed bnAb, 3I14, isolated from human memory B cells, that utilizes a heavy chain encoded by the IGHV3-30 germline gene. MAb 3I14 binds and neutralizes groups 1 and 2 influenza A viruses and protects mice from lethal challenge. Analysis of VH and VL germline back-mutants reveals binding to H3 and H1 but not H5, which supports the critical role of somatic hypermutation in broadening the bnAb response. Moreover, a single VLD94N mutation improves the affinity of 3I14 to H5 by nearly 10-fold. These data provide evidence that memory B cell evolution can expand the HA subtype specificity. Our results further suggest that establishing an optimized memory B cell pool should be an aim of ‘universal' influenza vaccine strategies.

Role of germinal centers for the induction of broadly-reactive memory B cells

“…After bNAb B cells are selected, they are often recruited into the memory compartment rather than the long-lived plasmacyte compartment [2–4]. Shinnakasu et al .…”

“…B mem cells, however, express BCR repertoires that are more broadly-reactive to viral variants than do populations of long-lived plasma cells, and thereby potentiate broader protection than that afforded by circulating antibody [2–4]. Germinal centers (GCs) provide a microenvironment for an affinity-driven selection of memory precursors based on competition for antigen and T-cell help [5], which acts, on average, to increase the affinity and specificity of “winner” B-cell clones but also narrows clonal diversity by removing “loser” clones [6,7].…”

Exploring Human Antimicrobial Antibody Responses on a Single B Cell Level

“…Patients who had previously been exposed to viruses or bacteria usually show tremendous levels of highly affinity matured immunoglobulins against one or more antigens of the same pathogen. Studies on single B cells suggest that pathogen-induced affinity maturation can be site specific and that somatic hypermutation (SHM) is connected to the evolution of bNAbs (6,12,13). In this short article, we focus on recent discoveries in the field of antimicrobial antibody responses that were achieved by single B cell analysis.…”

“…The 3I14 antibody derived from IGHV3-30 is able to bind the H3 and H1 subtypes but not H5 in its germ line configuration (D94). Interestingly, germ line reversion of the D94N somatic hypermutation significantly restores the binding to H5, underlining that certain residues are important for broad antiviral protection (13).…”

“…This implies that site-specific evolution of certain residues during antibody development is essential for the development of broadly neutralizing activity. Site-specific affinity maturation was also shown to be important in broadening the specificity for other influenza virus antibodies (13). The 3I14 antibody derived from IGHV3-30 is able to bind the H3 and H1 subtypes but not H5 in its germ line configuration (D94).…”