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Spec-seq unveils transcriptional subpopulations of antibody-secreting cells following influenza vaccination.

ABSTRACT: Vaccines are among the most effective public health tools for combating certain infectious diseases such as influenza. The role of the humoral immune system in vaccine-induced protection is widely appreciated; however, our understanding of how antibody specificities relate to B cell function remains limited due to the complexity of polyclonal antibody responses. To address this, we developed the Spec-seq framework, which allows for simultaneous monoclonal antibody (mAb) characterization and transcriptional profiling from the same single cell. Here, we present the first application of the Spec-seq framework, which we applied to human plasmablasts after influenza vaccination in order to characterize transcriptional differences governed by B cell receptor (BCR) isotype and vaccine reactivity. Our analysis did not find evidence of long-term transcriptional specialization between plasmablasts of different isotypes. However, we did find enhanced transcriptional similarity between clonally related B cells, as well as distinct transcriptional signatures ascribed by BCR vaccine recognition. These data suggest IgG and IgA vaccine-positive plasmablasts are largely similar, whereas IgA vaccine-negative cells appear to be transcriptionally distinct from conventional, terminally differentiated, antigen-induced peripheral blood plasmablasts.

SUBMITTER: Neu KE

PROVIDER: S-EPMC6307935 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Spec-seq unveils transcriptional subpopulations of antibody-secreting cells following influenza vaccination.

Neu Karlynn E KE Guthmiller Jenna J JJ Huang Min M La Jennifer J Vieira Marcos C MC Kim Kangchon K Zheng Nai-Ying NY Cortese Mario M Tepora Micah E ME Hamel Natalie J NJ Rojas Karla Thatcher KT Henry Carole C Shaw Dustin D Dulberger Charles L CL Pulendran Bali B Cobey Sarah S Khan Aly A AA Wilson Patrick C PC

The Journal of clinical investigation 20181119 1

Vaccines are among the most effective public health tools for combating certain infectious diseases such as influenza. The role of the humoral immune system in vaccine-induced protection is widely appreciated; however, our understanding of how antibody specificities relate to B cell function remains limited due to the complexity of polyclonal antibody responses. To address this, we developed the Spec-seq framework, which allows for simultaneous monoclonal antibody (mAb) characterization and tran ...[more]

PMID: 30457979

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Project description:To better understand the antibody landscape changes following influenza virus natural infection and vaccination, we developed a high-throughput multiplex influenza antibody detection assay (MIADA) containing 42 recombinant hemagglutinins (rHAs) (ectodomain and/or globular head domain) from pre-2009 A(H1N1), A(H1N1)pdm09, A(H2N2), A(H3N2), A(H5N1), A(H7N7), A(H7N9), A(H7N2), A(H9N2), A(H13N9), and influenza B viruses. Panels of ferret antisera, 227 paired human sera from vaccinees (children and adults) in 5 influenza seasons (2010 to 2018), and 17 paired human sera collected from real-time reverse transcription-PCR (rRT-PCR)-confirmed influenza A(H1N1)pdm09, influenza A(H3N2), or influenza B virus-infected adults were analyzed by the MIADA. Ferret antisera demonstrated clear strain-specific antibody responses to exposed subtype HA. Adults (19 to 49?years old) had broader antibody landscapes than young children (<3?years old) and older children (9 to 17?years old) both at baseline and post-vaccination. Influenza vaccination and infection induced the strongest antibody responses specific to HA(s) of exposed strain/subtype viruses and closely related strains; they also induced cross-reactive antibodies to an unexposed influenza virus subtype(s), including novel viruses. Subsequent serum adsorption confirmed that the cross-reactive antibodies against novel subtype HAs were mainly induced by exposures to A(H1N1)/A(H3N2) influenza A viruses. In contrast, adults infected by influenza B viruses mounted antibody responses mostly specific to two influenza B virus lineage HAs. Median fluorescence intensities (MFIs) and seroconversion in MIADA had good correlations with the titers and seroconversion measured by hemagglutination inhibition and microneutralization assays. Our study demonstrated that antibody landscape analysis by the MIADA can be used for influenza vaccine evaluations and characterization of influenza virus infections.IMPORTANCE Repeated influenza vaccination and natural infections generate complex immune profiles in humans that require antibody landscape analysis to assess immunity and evaluate vaccines. However, antibody landscape analyses are difficult to perform using traditional assays. Here, we developed a high-throughput, serum-sparing, multiplex influenza antibody detection assay (MIADA) and analyzed the antibody landscapes following influenza vaccination and infection. We showed that adults had broader antibody landscapes than children. Influenza vaccination and infection not only induced the strongest antibody responses to the hemagglutinins of the viruses of exposure, but also induced cross-reactive antibodies to novel influenza viruses that can be removed by serum adsorption. There is a good correlation between the median fluorescence intensity (MFI) measured by MIADA and hemagglutination inhibition/microneutralization titers. Antibody landscape analysis by the MIADA can be used in influenza vaccine evaluations, including the development of universal influenza vaccines and the characterization of influenza virus infections.

Project description:BackgroundNon-neutralizing antibodies inducing complement-dependent lysis (CDL) and antibody-dependent cell-mediated cytotoxicity (ADCC) activity may contribute to protection against influenza infection. We investigated CDL and ADCC responses in healthy adults randomized to receive either non-adjuvanted or AS03-adjuvanted monovalent A(H1N1)pdm09 vaccine (containing 15 µg/3.75 ?g of hemagglutinin, respectively) on a 2-dose schedule 21 days apart.MethodsWe conducted an exploratory analysis of a subset of 106 subjects having no prior history of A(H1N1)pdm09 infection or seasonal influenza vaccination enrolled in a previously reported study (NCT00985673). Antibody responses against the homologous A/California/7/2009 (H1N1) vaccine strain and a related A/Brisbane/59/2007 (H1N1) seasonal influenza strain were analyzed up to Day 42.ResultsBaseline seropositivity determined with hemagglutination inhibition (HI), CDL and ADCC antibody titers against viral strains was high; A/California/7/2009 (HI [40.4-48.1%]; CDL [34.6-36.0%]; ADCC [92.1-92.3%]); A/Brisbane/59/2007 (HI [73.1-88.9%]; CDL [38.0-42.0%]; ADCC [86.8-97.0%]). CDL seropositivity increased following vaccination with both adjuvanted and non-adjuvanted formulations (A/California/7/2009 [95.9-100%]; A/Brisbane/59/2007 [75.5-79.6%]). At Day 21, increases in CDL and ADCC antibody geometric mean titers against both strains were observed for both formulations. After 2 doses of AS03-adjuvanted vaccine, vaccine responses of 95.8% (?9-fold increase from baseline in CDL titers) and 34.3% (?16-fold increase from baseline in ADCC titers) were seen against A/California/7/2009; and 22.4% and 42.9%, respectively, against A/Brisbane/59/2007. Vaccine responses after 2 doses of the non-adjuvanted vaccine were broadly similar.ConclusionsBroadly comparable non-neutralizing immune responses were observed following vaccination with non-adjuvanted and AS03-adjuvanted A(H1N1)pdm09 formulations; including activity against a related vaccine strain.

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Spec-seq unveils transcriptional subpopulations of antibody-secreting cells following influenza vaccination.

Publications

Spec-seq unveils transcriptional subpopulations of antibody-secreting cells following influenza vaccination.

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