Studying the antibody repertoire after vaccination: practical applications

Galson, Jacob D.; Pollard, Andrew J.; Trück, Johannes; Kelly, Dominic F.

doi:10.1016/j.it.2014.04.005

Cited by 89 publications

(90 citation statements)

References 109 publications

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“…‘Next-generation’ sequencing (NGS) technologies perform large-scale DNA sequencing (6), allowing in-depth analysis of the B cell receptor (BCR) repertoire of the circulating B cell pool (7, 8). The Roche 454 platform generates reads of sufficient length to interrogate the entire recombined heavy chain VDJ region.…”

Section: Introductionmentioning

confidence: 99%

Identification of Antigen-Specific B Cell Receptor Sequences Using Public Repertoire Analysis

Trück

Ramasamy

Galson

et al. 2015

The Journal of Immunology

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High-throughput sequencing allows detailed study of the B cell receptor (BCR) repertoire post-immunization but it remains unclear to what extent the de novo identification of antigen-specific sequences from the total BCR repertoire is possible. A Hib-MenC-TT conjugate vaccine containing H. influenzae type b (Hib) and group C meningococcal (MenC) polysaccharides as well as tetanus toxoid (TT) was used to investigate the BCR repertoire of adult humans following immunization and test the hypothesis that public or convergent repertoire analysis could identify antigen specific sequences. A number of antigen-specific BCR sequences have previously been reported for Hib and TT which made a vaccine containing these 2 antigens an ideal immunological stimulus. Analysis of identical complementarity determining region (CDR)3 amino acid (AA) sequences that were shared by individuals in the post-vaccine repertoire identified a number of known Hib-specific sequences but only one previously described TT sequence. The extension of this analysis to non-identical but highly similar CDR3 AA sequences revealed a number of other TT-related sequences. The anti-Hib avidity index post-vaccination was strongly correlated with the relative frequency of Hib-specific sequences, indicating that the post-vaccination public BCR repertoire may be related to more conventional measures of immunogenicity correlating with disease protection. Analysis of public BCR repertoire provided evidence of convergent BCR evolution in individuals exposed to the same antigens. If this finding is confirmed, the public repertoire could be used for rapid and direct identification of protective antigen-specific BCR sequences from peripheral blood.

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Section: Introductionmentioning

confidence: 99%

Identification of Antigen-Specific B Cell Receptor Sequences Using Public Repertoire Analysis

Trück

Ramasamy

Galson

et al. 2015

The Journal of Immunology

Self Cite

112

105

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show abstract

“…An increased understanding of the repertoire of plasma cells produced in response to vaccination could potentially be gained by sequencing their B cell receptor (BCR) heavy chain variable regions1415. Knowing the exact nucleotide sequences allows determination of mutation numbers, which can be used to distinguish between the plasma cells activated from naïve B cells vs. pre-existing memory B cells.…”

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confidence: 99%

Investigating the effect of AS03 adjuvant on the plasma cell repertoire following pH1N1 influenza vaccination

Galson

Trück

Kelly

et al. 2016

Sci Rep

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Influenza pandemics require rapid deployment of effective vaccines for control. Adjuvants such as AS03 improve vaccine immunogenicity, but this mechanism is poorly understood. We used high-throughput B cell receptor sequencing of plasma cells produced following AS03-adjuvanted and non-adjuvanted 2009 pandemic H1N1 vaccination, as well as pre-pandemic seasonal influenza vaccination to elucidate the effect of the adjuvant on the humoral immune response. By analyzing mutation levels, it was possible to distinguish sequences from cells that were recently activated from naïve B cells from those that were activated by memory recall. We show that the adjuvant functions through two mechanisms. First, the adjuvant stimulates increased activation of naïve B cells, thus reducing immune interference with previous vaccine responses. Second, the adjuvant is able to increase the adaptability of the recalled cells to give improved specificity to the new vaccine antigen. We thus show how AS03 enhances pH1N1 immune responses, and reduces immune interference.

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“…This technology has been used to characterize the Ab repertoires in disease states and following vaccination, and is a valuable tool for Ab discovery (Galson et al, 2014; Galson et al, 2015; Georgiou et al, 2014; Herfst et al, 2012; Imai et al, 2012; Reddy et al, 2010; Saggy et al, 2012). Here, we explored the feasibility of building an NGS-based antibody discovery platform with the ultimate goal of isolating MAbs that can broadly cross-neutralize multiple strains of virus.…”

Section: Discussionmentioning

confidence: 99%

“…Another promising approach that bypasses traditional high-throughput screening technologies relies on next generation sequencing (NGS) and the analysis of antibody gene repertoires (Friesen et al, 2010; Galson et al, 2015; Georgiou et al, 2014). Here, we describe a technology platform for isolating therapeutic MAbs by analyzing the IgVH repertoire of immunized mice using a CDRH3 search algorithm, whose diversity in length, peptide sequence and IgVH and IgHJ gene usage helps define IgVH clonotype (Galson et al, 2014; Galson et al, 2015). As an initial proof of concept, we produced 35 MAb candidates, 17 (49%) of which specifically bound rH5N1 HA.…”

Section: Introductionmentioning

confidence: 99%

Selection of therapeutic H5N1 monoclonal antibodies following IgVH repertoire analysis in mice

et al. 2016

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The rapid rate of influenza virus mutation drives the emergence of new strains that inflict serious seasonal epidemics and less frequent, but more deadly, pandemics. While vaccination provides the best protection against influenza, its utility is often diminished by the unpredictability of new pathogenic strains. Consequently, efforts are underway to identify new antiviral drugs and monoclonal antibodies that can be used to treat recently infected individuals and prevent disease in vulnerable populations. Next Generation Sequencing (NGS) and the analysis of antibody gene repertoires is a valuable tool for Ab discovery. Here, we describe a technology platform for isolating therapeutic monoclonal antibodies (MAbs) by analyzing the IgVH repertoires of mice immunized with recombinant H5N1 hemagglutinin (rH5). As an initial proof of concept, 35 IgVH genes selected using a CDRH3 search algorithm, co-expressed in a murine IgG2a expression vector with a panel of germline murine kappa genes, and culture supernatants screened for antigen binding. Seventeen of the 35 IgVH MAbs (49%) bound rH5VN1203 in preliminary screens and 8 of 9 purified MAbs inhibited 3 heterosubtypic strains of H5N1 virus when assayed by HI, and 2 MAbs demonstrated prophylactic and therapeutic activity in virus-challenged mice. This is the first example in which an NGS discovery platform has been used to isolate anti-influenza MAbs with relevant therapeutic activity.

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Studying the antibody repertoire after vaccination: practical applications

Cited by 89 publications

References 109 publications

Identification of Antigen-Specific B Cell Receptor Sequences Using Public Repertoire Analysis

Identification of Antigen-Specific B Cell Receptor Sequences Using Public Repertoire Analysis

Investigating the effect of AS03 adjuvant on the plasma cell repertoire following pH1N1 influenza vaccination

Selection of therapeutic H5N1 monoclonal antibodies following IgVH repertoire analysis in mice

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