Project description:The pathobiont S. aureus (SA) induces non-protective antibody imprints that underlie ineffective staphylococcal vaccination. However, the mechanism by which SA modify antibody activity is not clear. Herein, we show that IL-10 is the decisive factor that abrogates antibody protection. SA-induced B10 cells drive antigen-specific vaccine suppression that affects both recalled and de novo developed B cells. Released IL-10 promotes STAT3 binding upstream of sialyltransferase ST3gal4 and increases ST3gal4 expression by B cells, leading to hyper- a2,3 sialylation of antibodies and loss of protective activity. IL-10 enhances a2,3 sialylation on cell-wall associated IsdB, IsdA and MntC antibodies along with suppression of the respective SA vaccines. Consistent with mouse findings, human anti-SA antibodies as well as anti-pseudomonal antibodies from cystic fibrosis subjects are hyper-sialylated, compared to anti-GAS and pseudomonal antibodies from normal individuals. Overall, we demonstrate a pathobiont-centric mechanism that modulates antibody glycosylation through IL-10 leading to loss of staphylococcal vaccine efficacy.
Project description:Heterologous ChAdOx1-BNT162b2 vaccination induces a stronger immune response than two doses of BNT162b2. Yet, the molecular transcriptome, the germline allelic variants of immunoglobulin loci and anti-Omicron antibody levels induced by the heterologous vaccination have not been formally investigated. Moreover, there is a paucity of COVID-19 vaccine studies including diverse genetic populations. Here, we show a robust molecular immune transcriptome and antibody repertoire in 46 office and lab workers from the Republic of Korea after heterologous vaccination, ChAdOx1 followed by BNT162b2. Anti-spike-specific IgG antibody levels against the ancestral SARS-CoV-2 strain increased from 70 AU/ml immediately following the first vaccination to 14,000 U/ml within three days after the second vaccination and 142,000 AU/ml after seven days. Antibody titers against more recent variants, including Omicron, were two- to three-fold lower, yet higher than those obtained after the second dose of a BNT162b2-BNT162b2 homologous vaccination. RNA-seq conducted on peripheral immune cells demonstrated a strong activation of interferon-induced genetic programs in the heterologous cohort and an increase of specific IGHV clonal transcripts encoding neutralizing antibodies was detected. Enrichment of B cell and CD4+ T cell responses was observed following both ChAdOx1-BNT162b2 heterologous and BNT162b2-BNT162b2 homologous vaccination using scRNA-seq, but clonally expanded memory B cells were relatively stronger in the heterologous cohort. In summary, a heterologous vaccination with ChAdOx1 followed by BNT162b2 provides an innate and adaptive immune response exceeding that seen in homologous BNT162b2 vaccination.
Project description:Heterologous ChAdOx1-BNT162b2 vaccination induces a stronger immune response than BNT162b2-BNT162b2. Here we investigated the molecular transcriptome, germline allelic variants of immunoglobulin loci, and anti-Omicron antibody levels in 46 office and lab workers from the Republic of Korea following ChAdOx1-BNT162b2 vaccination. Anti-spike-specific IgG antibody levels against the ancestral SARS-CoV-2 strain increased from 70 AU/ml to 14,000 AU/ml to 142,000 AU/ml one, three and seven days following the second vaccination. Titers against VOC, including Omicron, were two- to three-fold lower, yet higher than those measured following BNT162b2-BNT162b2 vaccination. RNA-seq of peripheral immune cells demonstrated activation of interferon pathways with increased IGHV clonal transcripts encoding neutralizing antibodies. scRNA-seq revealed enriched B cell and CD4+ T cell responses in both ChAdOx1-BNT162b2 and BNT162b2-BNT162b2 recipients, but a stronger clonal expansion of memory B cells with ChAdOx1-BNT162b2. In summary, heterologous ChAdOx1-BNT162b2 provides an innate and adaptive immune response that exceeds homologous BNT162b2 vaccination.
Project description:To find baseline markers that accurately predict vaccine reactivity and evaluate the correlation between baseline blood and urine proteomics and antibody titers after COVID-19 vaccination.
Project description:Heterologous ChAdOx1-BNT162b2 vaccination induces a stronger immune response than two doses of BNT162b2. Yet, the molecular transcriptome, the germline allelic variants of immunoglobulin loci and anti-Omicron antibody levels induced by the heterologous vaccination have not been formally investigated. Moreover, there is a paucity of COVID-19 vaccine studies including diverse genetic populations. Here, we show a robust molecular immune transcriptome and antibody repertoire in 46 office and lab workers from the Republic of Korea after heterologous vaccination, ChAdOx1 followed by BNT162b2. Anti-spike-specific IgG antibody levels against the ancestral SARS-CoV-2 strain increased from 70 AU/ml immediately following the first vaccination to 14,000 U/ml within three days after the second vaccination and 142,000 AU/ml after seven days. Antibody titers against more recent variants, including Omicron, were two- to three-fold lower, yet higher than those obtained after the second dose of a BNT162b2-BNT162b2 homologous vaccination. RNA-seq conducted on peripheral immune cells demonstrated a strong activation of interferon-induced genetic programs in the heterologous cohort and an increase of specific IGHV clonal transcripts encoding neutralizing antibodies was detected. Enrichment of B cell and CD4+ T cell responses was observed following both ChAdOx1-BNT162b2 heterologous and BNT162b2-BNT162b2 homologous vaccination using scRNA-seq, but clonally expanded memory B cells were relatively stronger in the heterologous cohort. In summary, a heterologous vaccination with ChAdOx1 followed by BNT162b2 provides an innate and adaptive immune response exceeding that seen in homologous BNT162b2 vaccination.
Project description:Proteomic analysis of serum IgG antibody repertoire against influenza vaccine HAs in infant donors vaccinated with Fluzone 2017-18/18-19. Dataset consists of peak-response (days 14 and 21 post-vaccination) serum IgG samples eluted by affinity chromatography against IAV or IBV hemagglutinin and the flow-throughs.
Project description:Immunosuppressive tumor microenvironments (TME) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSC), precursors to cancer-associated fibroblasts (CAFs), dictate tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells that results in inhibition of effector functions. The role of sialylation in dictating MSC/CAF immunosuppression in the TME is unknown. In this study, we show that tumor-conditioned stromal cells have increased sialyltransferase expression, α2,3/6-linked sialic acid and Siglec ligands. Tumor-conditioned stromal cells and CAFs induce exhausted immunomodulatory PD-1, Siglec-7 and Siglec-9-expressing T cell phenotypes. In vivo, targeting stromal cell sialylation reverses stromal cell-mediated immunosuppression, as evidenced by infiltration of CD25 and granzyme B-expressing T cells in the tumor and draining lymph node. Targeting stromal cell sialylation may overcome immunosuppression in the CRC TME.
Project description:Chronic inflammatory bowel disease (IBD) causes disability, suffering and risk of colon cancer in over 30 million people globally. Here, we investigate 3 kindreds of IBD with mutations in the N-acetylgalactosamide alpha-2,6-sialyltransferase 1/ST6GALNAC1 (ST6) glycosyltransferase gene that is uniquely expressed in the goblet cells (GCs). These mutations cause defective sialic acid (SA) conjugation, elimination of the onco-antigen S-Tn (Sialyl-Tn), and altered glycosylation of the MUC2 protein, a key component of intestinal mucus. Decreased MUC2 sialylation increases susceptibility to bacterial proteolytic degradation and compromises the gastrointestinal (GI) mucus barrier. Mice harboring the patient ST6 mutations recapitulate human colitis and reveal that defective sialylation causes dysbiosis, butyrate overproduction, and impaired GI stem cell proliferation during injury. Thus, this new genetic disease illustrates how sialylation controls host-microbe homeostasis and reveals several new potential approaches to IBD treatment.
Project description:Current seasonal and pre-pandemic influenza vaccines induce short-lived predominantly strain-specific and limited heterosubtypic responses. To better understand how vaccine adjuvants AS03 and MF59 may provide improved antibody responses to vaccination, we interrogated serum from subjects who received 2 doses of inactivated monovalent influenza A/Indonesia/05/2005 vaccine with or without AS03 or MF59 using hemagglutinin (HA) microarrays (NCT01317758 and NCT01317745). The arrays were designed to reflect both full length and globular head HA derived from 17 influenza A subtypes (H1 to H16 and H18) and influenza B strains. We observed significantly increased strain-specific and broad homo- and hetero-subtypic antibody responses with both AS03 and MF59 adjuvanted vaccination with AS03 achieving a higher titer and breadth of IgG responses relative to MF59. Adjuvanted vaccine was also associated with the elicitation of stalk directed antibody. We established good correlation of the array antibody responses to H5 antigens with standard HA inhibition and microneutralization titers.
Project description:Current seasonal and pre-pandemic influenza vaccines induce short-lived predominantly strain-specific and limited heterosubtypic responses. To better understand how vaccine adjuvants AS03 and MF59 may provide improved antibody responses to vaccination, we interrogated serum from subjects who received 2 doses of inactivated monovalent influenza A/Indonesia/05/2005 vaccine with or without AS03 or MF59 using hemagglutinin (HA) microarrays (NCT01317758 and NCT01317745). The arrays were designed to reflect both full length and globular head HA derived from 17 influenza A subtypes (H1 to H16 and H18) and influenza B strains. We observed significantly increased strain-specific and broad homo- and hetero-subtypic antibody responses with both AS03 and MF59 adjuvanted vaccination with AS03 achieving a higher titer and breadth of IgG responses relative to MF59. Adjuvanted vaccine was also associated with the elicitation of stalk directed antibody. We established good correlation of the array antibody responses to H5 antigens with standard HA inhibition and microneutralization titers.