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Identification and Characterization of the Constituent Human Serum Antibodies Elicited by Vaccination

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Identification and Characterization of the Constituent Human Serum Antibodies Elicited by Vaccination Identification and characterization of the constituent human serum antibodies elicited by vaccination Jason J. Lavindera,b,1, Yariv Winea,b,1, Claudia Gieseckec,d, Gregory C. Ippolitoe, Andrew P. Hortonf,g, Oana I. Lungua,b, Kam Hon Hoig, Brandon J. DeKoskya, Ellen M. Murrina, Megan M. Wirtha, Andrew D. Ellingtonb,f,h,i, Thomas Dörnerc,d, Edward M. Marcotteb,f,h,2, Daniel R. Boutzb,f,2, and George Georgioua,b,e,g,2 aDepartment of Chemical Engineering, bInstitute for Cellular and Molecular Biology, eSection of Molecular Genetics and Microbiology, fCenter for Systems and Synthetic Biology, gDepartment of Biomedical Engineering, hDepartment of Chemistry and Biochemistry, and iApplied Research Laboratories, University of Texas at Austin, Austin, TX 78712-1062; cDepartment of Medicine, Rheumatology, and Clinical Immunology, Charité University Medicine Berlin, 10098 Berlin, Germany; and dDeutsches Rheumaforschungszentrum Berlin, 10117 Berlin, Germany Edited* by Stephen R. Quake, Stanford University, Stanford, CA, and approved January 2, 2014 (received for review September 24, 2013) Most vaccines confer protection via the elicitation of serum the serum play a key role in protection against pathogen chal- antibodies, yet more than 100 y after the discovery of antibodies, lenge, technical difficulties have precluded direct determination the molecular composition of the human serum antibody reper- of the identities of the mAbs that comprise the serum antibody toire to an antigen remains unknown. Using high-resolution liquid response to vaccination. However, recent studies showing that chromatography tandem MS proteomic analyses of serum anti- flu vaccination elicits not only neutralizing antibodies but also bodies coupled with next-generation sequencing of the V gene antibodies that enhance infection by different flu strains (15) repertoire in peripheral B cells, we have delineated the human underscore the pressing need to develop approaches for de- serum IgG and B-cell receptor repertoires following tetanus toxoid lineating the sequences and functionalities of the serum anti- (TT) booster vaccination. We show that the TT+ serum IgG reper- bodies elicited by vaccination (16). toire comprises ∼100 antibody clonotypes, with three clonotypes Single-cell cloning has been used to identify neutralizing accounting for >40% of the response. All 13 recombinant IgGs exam- antibodies encoded by mBCs or plasmablasts in peripheral blood −8 −10 (17). However, although extremely useful for understanding of ined bound to vaccine antigen with Kd ∼ 10 –10 M. Five of 13 IgGs recognized the same linear epitope on TT, occluding the binding the structural mechanisms that can lead to the blockade of site used by the toxin for cell entry, suggesting a possible explanation pathogen infection, the interrogation of single peripheral B cells for the mechanism of protection conferred by the vaccine. Impor- alone cannot provide information on whether antibodies enco- tantly, only a small fraction (<5%) of peripheral blood plasmablast ded by single B cells are also produced as secreted IgGs from − − + ++ ++ − + clonotypes (CD3 CD14 CD19 CD27 CD38 CD20 TT ) at the peak BM LLPCs, and hence whether they contribute to the serological memory induced by vaccination. A detailed understanding of the of the response (day 7), and an even smaller fraction of memory B diversity of serum antibodies elicited by vaccination, their func- cells, were found to encode antibodies that could be detected in the tionality (e.g., antigen affinity, epitope specificity), and their serological memory response 9 mo postvaccination. This suggests relative concentrations in the blood can provide key insights that only a small fraction of responding peripheral B cells give rise toward vaccine evaluation and development. to the bone marrow long-lived plasma cells responsible for the Here, we deployed high-resolution liquid chromatography production of biologically relevant amounts of vaccine-specific (LC) tandem MS (MS/MS) (18–20) for the molecular-level antibodies (near or above the Kd). Collectively, our results reveal analysis of the serum IgG repertoire, combined with deep se- the nature and dynamics of the serological response to vaccination quencing of the V gene repertoire of peripheral B lymphocyte with direct implications for vaccine design and evaluation. Significance B-cell repertoire | proteomics Most vaccines confer immunity by eliciting long-term pro- ost approved vaccines confer protection against infectious duction of antibodies that bind to and neutralize the vaccine Mdiseases by the induction of long-lived plasma cells antigen. Remarkably, very little is known regarding the iden- (LLPCs), which secrete antibodies that serve to neutralize and – tities, sequence diversity, relative concentrations, or binding opsonize the pathogen for many years or decades (1 3). Addi- functionalities of the mAbs that comprise the serum repertoire tionally, the generation of memory B cells (mBCs) provides both elicited by vaccination. Here, we have delineated the constit- a mechanism for the rapid synthesis of affinity matured, antigen- uent antibodies of the human serum IgG repertoire after vac- specific antibodies following rechallenge and a means to diversify cination and examined their relationship to the antibody V IMMUNOLOGY the humoral immune response to confer protection against gene repertoire encoded by circulating B cells. The results detail rapidly evolving viruses or bacteria (4). Although some vaccines the molecular composition and characteristics of the vaccine- elicit antibody titers that remain virtually constant for many specific serum antibody repertoire and demonstrate differ- decades, for others, including the tetanus toxoid (TT) vaccine, ences between the end-point response (the serum antibodies) antibody titers wane monotonically over time (5). Booster im- and the peripheral B cells responding to the vaccine. munization triggers the rapid expansion and differentiation of cognate B cells, generating antigen-specific plasmablasts that Author contributions: J.J.L., Y.W., C.G., T.D., and G.G. designed research; J.J.L., Y.W., C.G., peak in concentration in peripheral blood after 6–7 d and sub- G.C.I., A.P.H., O.I.L., K.H.H., B.J.D., E.M. Murrin, M.M.W., and D.R.B. performed research; sequently rapidly decline to nearly undetectable levels (6, 7). J.J.L., Y.W., A.D.E., T.D., E.M. Marcotte, D.R.B., and G.G. analyzed data; and J.J.L., Y.W., Some, but not all, of these peak-wave plasmablasts migrate to C.G., G.C.I., T.D., D.R.B., and G.G. wrote the paper. specialized niches overwhelmingly located in the bone marrow The authors declare no conflict of interest. (BM) and survive as LLPCs (8), which constitute the major *This Direct Submission article had a prearranged editor. source of all classes of Ig in the serum (9). 1J.J.L. and Y.W. contributed equally to this work. The establishment of serological memory following either 2To whom correspondence may be addressed. E-mail: [email protected], primary or booster vaccination is not understood well (10–14). [email protected], or [email protected]. Even though antibody production is the most critical effector This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. function of B-cell immunity, and antigen-specific antibodies in 1073/pnas.1317793111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1317793111 PNAS | February 11, 2014 | vol. 111 | no. 6 | 2259–2264 Downloaded by guest on September 24, 2021 + subsets (20) and subsequent expression and characterization of Serum Proteomics of the TT-Specific IgG Repertoire. The TT serum representative serum antibodies, to map the dynamics of the IgG repertoires at t = day 0, t = 7d,t = 3 mo, and t = 9mo human humoral response to vaccination in unprecedented detail. postboost were analyzed using recently developed LC-MS/MS We elected to analyze the response to booster immunization of proteomic methodology (20). Importantly, in F(ab′)2 resulting the TT vaccine because (i) it elicits a highly effective neutralizing from trypsin digestion of IgG, the presence of a conserved response that is protective toward Clostridium tetani challenge; cleavage site (Arg) directly upstream of the CDR-H3 and at the (ii) the vaccine is highly efficacious, and as a result, no deaths fourth residue of the downstream CH1 constant region (Lys) from tetanus intoxication have been reported in the United consistently yields a peptide encompassing the highly informative States for individuals who have completed at least primary im- CDR-H3 and the J region (Fig. S3). Proteolysis of the F(ab′)2 munization (21); (iii) TT has been used as a model for analyzing with other selective proteases (e.g., GluC/LysC) resulted in B-cell development following vaccination in humans (6, 22, peptide identifications of very few additional clonotypes (<8% 23); and (iv) although early serological and mAb studies had additional high-confidence identifications of those found in pointed to the C-terminal fragment of the toxin heavy chain trypsinized sample for HD2 at day 0), the vast majority of which [recombinant TT fragment C (rTT.C)] as the target for anti- were of low abundance. For peptide identifications, a custom body-mediated protection (24), the precise mechanism by database of the antibody repertoire was built using high-quality which antibodies elicited by the vaccine mediate neutraliza- V gene sequences from the peripheral B cells in each donor tion has remained unclear. (Table S1), in conjunction with a standard shotgun proteomic We show that the anti-TT serum IgG repertoire at steady state pipeline with a high-mass accuracy filter (average mass deviation is composed of a limited number of antibody clonotypes (∼80– <1.5 ppm) to minimize false identifications (20). Frequencies of 100) displaying uniformly high antigen affinity (low nanomolar antigen affinity chromatography elution- and flow-through– or subnanomolar), that most of the serum repertoire postboost derived CDR-H3 peptides mapping to a unique clonotype in the comprises preexisting (i.e., prevaccination) serum antibody clo- 454 donor-specific sequence database are shown in Fig.
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