TY - JOUR
T1 - Anti-HA Glycoforms Drive B Cell Affinity Selection and Determine Influenza Vaccine Efficacy
AU - Wang, Taia T.
AU - Maamary, Jad
AU - Tan, Gene S.
AU - Bournazos, Stylianos
AU - Davis, Carl W.
AU - Krammer, Florian
AU - Schlesinger, Sarah J.
AU - Palese, Peter
AU - Ahmed, Rafi
AU - Ravetch, Jeffrey V.
N1 - Funding Information:
We thank the Rockefeller University Hospital and all hospital staff involved in conducting the clinical study, in particular, Marina Caskey for helpful discussions, Noreen Buckley and Arlene Hurley for assistance in several aspects of protocol implementation and helpful discussions, and Joel Correa da Rosa for statistical assistance. We thank Sheng Zhang at the Cornell Proteomics and Mass Spectrometry Facility for helpful discussions and Robert Sherwood at the Cornell Proteomics and Mass Spectrometry Facility for helpful discussions and excellent technical support. T.T.W. thanks Barry Coller and the Rockefeller University KL2 Clinical Scholars Program for training and support. Research reported in this publication was supported by the National Institute of Allergy And Infectious Diseases of the NIH under Award Number U19AI111825 (J.V.R.) and U19AI109946 (P.P.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. T.T.W. was supported as a Rockefeller University Clinical Scholar in part by the Iris and Junming Le Foundation, the Rockefeller University Center for Clinical and Translational Science grant # UL1 TR000043 from the National Center for Advancing Translational Sciences, NIH and the Clinical and Translational Science Award program. F.K. was supported in part by the Centers of Excellence for Influenza Research and Surveillance, contract # HHSN266200700010C. Support and infrastructure were also provided by The Rockefeller University.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/7/3
Y1 - 2015/7/3
N2 - Summary Protective vaccines elicit high-affinity, neutralizing antibodies by selection of somatically hypermutated B cell antigen receptors (BCR) on immune complexes (ICs). This implicates Fc-Fc receptor (FcR) interactions in affinity maturation, which, in turn, are determined by IgG subclass and Fc glycan composition within ICs. Trivalent influenza virus vaccination elicited regulation of anti-hemagglutinin (HA) IgG subclass and Fc glycans, with abundance of sialylated Fc glycans (sFc) predicting quality of vaccine response. We show that sFcs drive BCR affinity selection by binding the Type-II FcR CD23, thus upregulating the inhibitory FcγRIIB on activated B cells. This elevates the threshold requirement for BCR signaling, resulting in B cell selection for higher affinity BCR. Immunization with sFc HA ICs elicited protective, high-affinity IgGs against the conserved stalk of the HA. These results reveal a novel, endogenous pathway for affinity maturation that can be exploited for eliciting high-affinity, broadly neutralizing antibodies through immunization with sialylated immune complexes.
AB - Summary Protective vaccines elicit high-affinity, neutralizing antibodies by selection of somatically hypermutated B cell antigen receptors (BCR) on immune complexes (ICs). This implicates Fc-Fc receptor (FcR) interactions in affinity maturation, which, in turn, are determined by IgG subclass and Fc glycan composition within ICs. Trivalent influenza virus vaccination elicited regulation of anti-hemagglutinin (HA) IgG subclass and Fc glycans, with abundance of sialylated Fc glycans (sFc) predicting quality of vaccine response. We show that sFcs drive BCR affinity selection by binding the Type-II FcR CD23, thus upregulating the inhibitory FcγRIIB on activated B cells. This elevates the threshold requirement for BCR signaling, resulting in B cell selection for higher affinity BCR. Immunization with sFc HA ICs elicited protective, high-affinity IgGs against the conserved stalk of the HA. These results reveal a novel, endogenous pathway for affinity maturation that can be exploited for eliciting high-affinity, broadly neutralizing antibodies through immunization with sialylated immune complexes.
UR - http://www.scopus.com/inward/record.url?scp=84934290153&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2015.06.026
DO - 10.1016/j.cell.2015.06.026
M3 - Article
C2 - 26140596
AN - SCOPUS:84934290153
SN - 0092-8674
VL - 162
SP - 160
EP - 169
JO - Cell
JF - Cell
IS - 1
ER -