Molecular-level analysis of the serum antibody repertoire in young adults before and after seasonal influenza vaccination.
Molecular understanding of serological immunity to influenza has been confounded by the complexity of the polyclonal antibody response in humans. Here we used high-resolution proteomics analysis of immunoglobulin (referred to as Ig-seq) coupled with high-throughput sequencing of transcripts encoding B cell receptors (BCR-seq) to quantitatively determine the antibody repertoire at the individual clonotype level in the sera of young adults before and after vaccination with trivalent seasonal influenza vaccine. The serum repertoire comprised between 40 and 147 clonotypes that were specific to each of the three monovalent components of the trivalent influenza vaccine, with boosted pre-existing clonotypes accounting for ∼60% of the response. An unexpectedly high fraction of serum antibodies recognized both the H1 and H3 monovalent vaccines. Recombinant versions of these H1 + H3 cross-reactive antibodies showed broad binding to hemagglutinins (HAs) from previously circulating virus strains; several of these antibodies, which were prevalent in the serum of multiple donors, recognized the same conserved epitope in the HA head domain. Although the HA-head-specific H1 + H3 antibodies did not show neutralization activity in vitro, they protected mice against infection with the H1N1 and H3N2 virus strains when administered before or after challenge. Collectively, our data reveal unanticipated insights regarding the serological response to influenza vaccination and raise questions about the added benefits of using a quadrivalent vaccine instead of a trivalent vaccine.
Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.
Jiwon
J
Lee
Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, Texas, USA.
Daniel R
DR
Boutz
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Veronika
V
Chromikova
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
M Gordon
MG
Joyce
Department of Bioengineering, Stanford University, Stanford, California, USA.
Christopher
C
Vollmers
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
Kwanyee
K
Leung
Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, Texas, USA.
Andrew P
AP
Horton
Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.
Brandon J
BJ
DeKosky
Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.
Chang-Han
CH
Lee
Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.
Jason J
JJ
Lavinder
Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.
Ellen M
EM
Murrin
Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.
Constantine
C
Chrysostomou
Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA.
Kam Hon
KH
Hoi
Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Yaroslav
Y
Tsybovsky
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
Paul V
PV
Thomas
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
Aliaksandr
A
Druz
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
Baoshan
B
Zhang
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
Yi
Y
Zhang
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
Lingshu
L
Wang
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
Wing-Pui
WP
Kong
Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.
Daechan
D
Park
Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA.
Lyubov I
LI
Popova
Department of Pediatrics, Stanford University, Stanford, California, USA.
Cornelia L
CL
Dekker
Howard Hughes Medical Institute, Stanford University, Stanford, California, USA.|Department of Microbiology and Immunology, Stanford University, Stanford, California, USA.
Mark M
MM
Davis
Center for Vaccines and Immunology, Department of Infectious Diseases, University of Georgia, Athens, Georgia, USA.
Chalise E
CE
Carter
Center for Vaccines and Immunology, Department of Infectious Diseases, University of Georgia, Athens, Georgia, USA.
Ted M
TM
Ross
Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, Texas, USA.|Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, USA.
Andrew D
AD
Ellington
Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA.
Patrick C
PC
Wilson
Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, Texas, USA.|Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, USA.
Edward M
EM
Marcotte
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
John R
JR
Mascola
Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, USA.
Gregory C
GC
Ippolito
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Florian
F
Krammer
Department of Bioengineering, Stanford University, Stanford, California, USA.|Howard Hughes Medical Institute, Stanford University, Stanford, California, USA.|Department of Applied Physics, Stanford University, Stanford, California, USA.
Stephen R
SR
Quake
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
Peter D
PD
Kwong
Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.|Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, Texas, USA.|Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA.|Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, USA.
George
G
Georgiou
D000328:Adult; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D002853:Chromatography, Liquid; D003429:Cross Reactions; D000939:Epitopes; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000071497:Immunogenicity, Vaccine; D007074:Immunoglobulin G / Q000276:immunology*; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology; D007252:Influenza Vaccines / Q000627:therapeutic use*; D007251:Influenza, Human / Q000517:prevention & control*; D008297:Male; D051379:Mice; D009975:Orthomyxoviridae / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000235:genetics; D017423:Sequence Analysis, RNA; D053719:Tandem Mass Spectrometry; D055815:Young Adult
D000914:Antibodies, Viral; D000939:Epitopes; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell