Identification and characterization of the constituent human serum antibodies elicited by vaccination

被引:186
作者
Lavinder, Jason J. [1 ,2 ]
Wine, Yariv [1 ,2 ]
Giesecke, Claudia [8 ,9 ]
Ippolito, Gregory C. [3 ]
Horton, Andrew P. [4 ,5 ]
Lungu, Oana I. [1 ,2 ]
Hoi, Kam Hon [5 ]
DeKosky, Brandon J. [1 ]
Murrin, Ellen M. [1 ]
Wirth, Megan M. [1 ]
Ellington, Andrew D. [2 ,4 ,6 ,7 ]
Doerner, Thomas [8 ,9 ]
Marcotte, Edward M. [2 ,4 ,6 ]
Boutz, Daniel R. [2 ,4 ]
Georgiou, George [1 ,2 ,3 ,5 ]
机构
[1] Univ Texas Austin, Dept Chem Engn, Austin, TX 78712 USA
[2] Univ Texas Austin, Inst Cellular & Mol Biol, Austin, TX 78712 USA
[3] Univ Texas Austin, Sect Mol Genet & Microbiol, Austin, TX 78712 USA
[4] Univ Texas Austin, Ctr Syst & Synthet Biol, Austin, TX 78712 USA
[5] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA
[6] Univ Texas Austin, Dept Chem & Biochem, Austin, TX 78712 USA
[7] Univ Texas Austin, Appl Res Labs, Austin, TX 78712 USA
[8] Charite, Dept Med Rheumatol & Clin Immunol, D-10098 Berlin, Germany
[9] Deutsches Rheumaforschungszentrum Berlin, D-10117 Berlin, Germany
基金
美国国家卫生研究院;
关键词
B-cell repertoire; proteomics; MEMORY B-CELLS; PLASMA-CELLS; MONOCLONAL-ANTIBODIES; TETANUS; REPERTOIRE; MECHANISMS; DURATION; VACCINES;
D O I
10.1073/pnas.1317793111
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Most vaccines confer protection via the elicitation of serum antibodies, yet more than 100 y after the discovery of antibodies, the molecular composition of the human serum antibody repertoire to an antigen remains unknown. Using high-resolution liquid chromatography tandem MS proteomic analyses of serum antibodies coupled with next-generation sequencing of the V gene repertoire in peripheral B cells, we have delineated the human serum IgG and B-cell receptor repertoires following tetanus toxoid (TT) booster vaccination. We show that the TT+ serum IgG repertoire comprises similar to 100 antibody clonotypes, with three clonotypes accounting for >40% of the response. All 13 recombinant IgGs examined bound to vaccine antigen with K-d similar to 10(-8)-10(-10) M. Five of 13 IgGs recognized the same linear epitope on TT, occluding the binding site used by the toxin for cell entry, suggesting a possible explanation for the mechanism of protection conferred by the vaccine. Importantly, only a small fraction (< 5%) of peripheral blood plasmablast clonotypes (CD3(-)CD14(-)CD19(+)CD27(++)CD38(++)CD20(-)TT(+)) at the peak of the response (day 7), and an even smaller fraction of memory B cells, were found to encode antibodies that could be detected in the serological memory response 9 mo postvaccination. This suggests that only a small fraction of responding peripheral B cells give rise to the bone marrow long-lived plasma cells responsible for the production of biologically relevant amounts of vaccine-specific antibodies (near or above the K-d). Collectively, our results reveal the nature and dynamics of the serological response to vaccination with direct implications for vaccine design and evaluation.
引用
收藏
页码:2259 / 2264
页数:6
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