title: Carrier priming effect of CRM197 is related to an enhanced B and T cell activation in meningococcal serogroup A conjugate vaccination. Immunological comparison between CRM197 and diphtheria toxoid.
abstract: Glycoconjugate vaccines are composed of capsular polysaccharides (CPSs) of a pathogenic bacteria covalently linked to carrier proteins. Pre-exposure to the carrier is known to influence the efficacy of the glycoconjugate, by inducing enhanced or suppressed anti-CPS response. Following our previous work on the immunogenicity of diphtheria toxin mutant CRM197 and formaldehyde-treated diphtheria toxoid (DT) as carriers for meningococcal A (MenA) conjugates in mouse model, we further investigated the role of the carrier on the immunological response to glycoconjugate vaccines. We previously showed that high dosage DT priming could result in carrier-induced epitopic suppression (CIES), an event that did not occur for CRM197 priming, and we observed that anti-DT IgGs could cross-react with DT based conjugates in vitro. Here, we confirmed the cross-reactivity of anti-carrier IgGs with DT conjugates in vivo. Furthermore, we analyzed the splenocytes of animals primed with the carrier and subsequently immunized with the MenA conjugate. Pre-exposure to the carrier protein, both CRM197 and DT, resulted in increased carrier-specific plasma and memory B cell response. However, only for CRM197 priming an enhanced carbohydrate-specific plasma cell response was observed. Analysis of circulating IgGs confirmed these observations. Memory to the CPS resulted to be non-influenced by carrier priming. Analysis of T helper response showed an enhancement effect for CRM197 priming, while DT priming resulted in constrained T cell activation. Stimulation with CRM197, which does not require formaldehyde detoxification, of splenocytes from animal immunized with DT suggested that the formaldehyde treatment used to produce DT might be the cause of limited presentation of the antigen to the T cells. We concluded that the dominant carrier-specific B cell response in case of limited T cell recruitment might explain the previously observed CIES phenomenon in case of DT priming.
authors.affiliation: GSK Vaccines, Research, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pecetta
authors.affiliation: GSK Vaccines, Research, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Tontini
authors.affiliation: GSK Vaccines, Research, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Faenzi
authors.affiliation: GSK Vaccines, Research, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Cioncada
authors.affiliation: GSK Vaccines, Research, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Proietti
authors.affiliation: GSK Vaccines, Research, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Seubert
authors.affiliation: GSK Vaccines, Research, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Nuti
authors.affiliation: GSK Vaccines, Research, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Berti
authors.affiliation: GSK Vaccines, Research, Via Fiorentina 1, 53100 Siena, Italy. Electronic address: maria.r.romano@gsk.com.
authors.forename: M R
authors.initials: MR
authors.lastname: Romano
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology*; D004168:Diphtheria Toxoid / Q000276:immunology*; D006001:Glycoconjugates / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D022401:Meningococcal Vaccines / Q000276:immunology*; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000276:immunology; D018074:Vaccines, Conjugate / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D002352:Carrier Proteins; D004168:Diphtheria Toxoid; D006001:Glycoconjugates; D007074:Immunoglobulin G; D022401:Meningococcal Vaccines; D018074:Vaccines, Conjugate; C028581:CRM197 (non-toxic variant of diphtheria toxin)
keywords: CRM(197); Carrier priming; Glycoconjugates; Meningococcal vaccines