Activation Dynamics and Immunoglobulin Evolution of Pre-existing and Newly Generated Human Memory B cell Responses to Influenza Hemagglutinin

• Published in: Immunity (Cambridge, Mass.) Vol. 51; no. 2; pp. 398 - 410.e5
• Main Authors: Andrews, Sarah F., Chambers, Michael J., Schramm, Chaim A., Plyler, Jason, Raab, Julie E., Kanekiyo, Masaru, Gillespie, Rebecca A., Ransier, Amy, Darko, Sam, Hu, Jianfei, Chen, Xuejun, Yassine, Hadi M., Boyington, Jeffrey C., Crank, Michelle C., Chen, Grace L., Coates, Emily, Mascola, John R., Douek, Daniel C., Graham, Barney S., Ledgerwood, Julie E., McDermott, Adrian B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.08.2019; Elsevier Limited
• Subjects: activated B cells; Adult; Antibodies, Viral - metabolism; Antibody Formation; Antigens; B-Lymphocyte Subsets - immunology; B-Lymphocytes - immunology; Binding sites; Biosensors; Cell activation; Cells, Cultured; Clinical trials; Epitopes; Epitopes - immunology; Evolution; Female; Flow cytometry; H7N9; hemagglutinin; Hemagglutinin Glycoproteins, Influenza Virus - immunology; Hemagglutinins; Human behavior; Humans; Ig repertoire; Immunity; Immunoglobulins; Immunologic Memory; Immunological memory; Influenza; Influenza A; Influenza A Virus, H7N9 Subtype - physiology; Influenza Vaccines - immunology; Influenza, Human - immunology; Kinetics; Lymphocyte Activation; Lymphocytes B; Male; memory B cells; Memory cells; Middle Aged; Pandemics; Phenotype; Phenotypes; Receptors, Antigen, B-Cell - genetics; Single-Cell Analysis; Statistical analysis; Tbet; Vaccination; vaccine response; Vaccines; Viruses; Young Adult; influenza; Ig repertoire; hemagglutinin; activated B cells; Tbet; H7N9; memory B cells; vaccine response
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2019.06.024

Vaccine-induced memory B cell responses to evolving viruses like influenza A involve activation of pre-existing immunity and generation of new responses. To define the contribution of these two types of responses, we analyzed the response to H7N9 vaccination in H7N9-naive adults. We performed comprehensive comparisons at the single-cell level of the kinetics, Ig repertoire, and activation phenotype of established pre-existing memory B cells recognizing conserved epitopes and the newly generated memory B cells directed toward H7 strain-specific epitopes. The recall response to conserved epitopes on H7 HA involved a transient expansion of memory B cells with little observed adaptation. However, the B cell response to newly encountered epitopes was phenotypically distinct and generated a sustained memory population that evolved and affinity matured months after vaccination. These findings establish clear differences between newly generated and pre-existing memory B cells, highlighting the challenges in achieving long-lasting, broad protection against an ever-evolving virus. [Display omitted] •Newly generated memory B cells evolve and affinity mature over several months•Long-term pre-existing memory B cells evolve little upon re-vaccination•Newly generated memory B cells transiently become atypical, T-bethi CD21lo CD27−•T-betlo CD21hi CD27−, but not CD27+, resting memory B cells are maintained long-term Influenza vaccination occurs in the context of pre-existing immunity. Andrews et al. compare the pre-existing memory IgG B cell response recognizing conserved epitopes on influenza hemagglutinin with the newly generated response to strain-specific epitopes upon H7N9 vaccination. The differences in magnitude, phenotype, and affinity maturation between the two responses highlight the challenges in achieving long-lasting, broad protection against an ever-evolving virus.