Induction of Cross‐Reactive Antibodies by Immunization of Healthy Adults with Types Ia and Ib Group B Streptococcal Polysaccharide–Tetanus Toxoid Conjugate Vaccines

Brigtsen, Anne Karin; Kasper, Dennis L.; Baker, Carol J.; Jennings, Harold J.; Guttormsen, Hilde-Kari

doi:10.1086/340324

Cited by 27 publications

(25 citation statements)

References 38 publications

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“…Of interest, the log 10 kill rate prior to immunization for these subjects (0.6) was somewhat higher than that of responders to GBS III-TT or II-TT/III-TT vaccines who did not develop crossreactive antibodies (0.2-0.4 log 10 reduction in colony-forming units, respectively) (figure 3) [23]. This finding of functionally competent cross-reactive antibodies contrasts with the findings of Brigsten et al [24], who evaluated postimmunization serum samples from healthy adults who received GBS type Ia-TT or Ib-TT conjugate vaccines. Although у4-fold increases in CPSspecific IgG were elicited to the heterologous serotype in more than two-thirds of subjects, these antibodies promoted the in vitro opsonophagocytosis and killing only of homologous, but not heterologous, GBS serotype strains.…”

Section: Discussionmentioning

confidence: 65%

Safety and Immunogenicity of a Bivalent Group B Streptococcal Conjugate Vaccine for Serotypes II and III

et al. 2003

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To determine whether 2 monovalent group B streptococcus (GBS) serotype II or III capsular polysaccharide (CPS)-tetanus toxoid (TT) conjugate vaccines combined in a single intramuscular dose would elicit immune responses comparable to those of monovalent vaccines, 75 healthy adults were randomized to receive GBS II-TT (3.6 micro g of CPS), GBS III-TT (12.5 micro g of CPS), or a bivalent mixture of GBS II-TT/III-TT vaccine (double-masked design). Vaccines were well tolerated. Four-fold or greater increases in GBS II or III CPS-specific IgG, respectively, were noted in postimmunization serum samples from 80%-90% of bivalent conjugate vaccine recipients, and these responses were similar to those of recipients of GBS II-TT or GBS III-TT monovalent vaccines. Immune serum samples promoted the opsonophagocytic killing of types II and III GBS in vitro. Unexpectedly, some recipients of these vaccines developed cross-reactive antibodies to the structurally similar heterologous polysaccharide. These results support the feasibility of a multivalent vaccine for the 5 prevalent invasive disease-causing GBS CPS serotypes.

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Section: Discussionmentioning

confidence: 65%

Safety and Immunogenicity of a Bivalent Group B Streptococcal Conjugate Vaccine for Serotypes II and III

et al. 2003

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“…For energy minimization of the obtained final model by molecular dynamics, the GROMACS package was used (38). Structure analysis was carried out in SwissPBD Viewer (39) and PyMol (www.pymol.org) visualization software using PDB2PQR (40), PropKa (41), and APBS (42) packages for charge surface calculations and HotPatch Web server (43) for hydrophobicity calculations.…”

Section: Homology Modeling and Structure Analysismentioning

confidence: 99%

A Point Mutation in the Amino Terminus of TLR7 Abolishes Signaling without Affecting Ligand Binding

Iavarone¹,

Ramsauer²,

Kubarenko

et al. 2011

The Journal of Immunology

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TLR7 is the mammalian receptor for ssRNA and some nucleotide-like small molecules. We have generated a mouse by N-nitrose-N′-ethyl urea mutagenesis in which threonine 68 of TLR7 was substituted with isoleucine. Cells bearing this mutant TLR7 lost the sensitivity to the small-molecule TLR7 agonist resiquimod, hence the name TLR7rsq1. In this work, we report the characterization of this mutant protein. Similar to the wild-type counterpart, TLR7rsq1 localizes to the endoplasmic reticulum and is expressed at normal levels in both primary cells and reconstituted 293T cells. In addition to small-molecule TLR7 agonists, TLR7rsq1 fails to be activated by ssRNA. Whole-transcriptome analysis demonstrates that TLR7 is the exclusive and indispensable receptor for both classes of ligands, consistent with the fact that both ligands induce highly similar transcriptional signatures in TLR7wt/wt splenocytes. Thus, TLR7rsq1 is a bona fide phenocopy of the TLR7 null mouse. Because TLR7rsq1 binds to ssRNA, our studies imply that the N-terminal portion of TLR7 triggers a yet to be identified event on TLR7. TLR7rsq1 mice might represent a valuable tool to help elucidate novel aspects of TLR7 biology.

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“…Epitope specificity of macaque sera was assessed by inhibition ELISA, with native and chemically modified CPSs used as inhibitors (47).…”

Section: Efficacy In Micementioning

confidence: 99%

Rational chemical design of the carbohydrate in a glycoconjugate vaccine enhances IgM-to-IgG switching

Guttormsen

Paoletti²,

Mansfield³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Many pathogens are sheltered from host immunity by surface polysaccharides that would be ideal as vaccines except that they are too similar to host antigens to be immunogenic. The production of functional IgG is a desirable response to vaccines; because IgG is the only isotype that crosses the placenta, it is of particular importance in maternal vaccines against neonatal disease due to group B Streptococcus (GBS). Clinical studies found a substantially lower proportion of IgG-relative to IgM-among antibodies elicited by conjugates prepared with purified GBS type V capsular polysaccharide (CPS) than among those evoked by CPSs of other GBS serotypes. The epitope specificity of IgG elicited in humans by a conjugate prepared with type V CPS is for chemically desialylated type V CPS (dV CPS). We studied desialylation as a mechanism for enhancing the ability of type V CPS to induce IgM-to-IgG switching. Desialylation did not affect the structural conformation of type V CPS. Rhesus macaques, whose isotype responses to GBS conjugates match those of humans, produced functionally active IgG in response to a dV CPS-tetanus toxoid conjugate (dV-TT), and 98% of neonatal mice born to dams vaccinated with dV-TT survived lethal challenge with viable GBS. Targeted chemical engineering of a carbohydrate to create a molecule less like host self may be a rational approach for improving other glycoconjugates.C apsular polysaccharides (CPSs) dominate the surface of some bacteria and are the major target of the immune system's attack, which primarily involves antibodies, complement, and phagocytic cells. CPSs are considered T cell-independent antigens; their use in vaccines has been optimal only with protein-carrier chemical conjugation, which elicits T cell help for B cells recognizing the carbohydrate, with consequent isotype switching from IgM to IgG (1). Successful glycoconjugate vaccines have been developed against Haemophilus influenzae type b (2) and several serogroups of Streptococcus pneumoniae (3) and Neisseria meningitidis (4). However, the human immune system sometimes fails to mount an adaptive immune response to microbial CPS because of great structural similarity of the CPS to the host's own cells. For example, the ␣-2,8-linked sialic acid homopolymeric capsule of serogroup B meningococci structurally resembles saccharides on human neural cell adhesion molecules (5) and oligosaccharides on fetal tissues (6). Likewise, the hyaluronic acid capsule of group A Streptococcus is identical to carbohydrate structures on human tissue (7). Humans do not respond with antibodies to these two molecules, presumably because such a response would generate autoimmunity.Group B Streptococcus (GBS) is a major cause of serious infection in neonates and the elderly (8). Of the 10 identified serotypes (9, 10), five (Ia, Ib, II, III, and V) are commonly associated with human disease. Antibodies to the CPSs of these serotypes are protective against neonatal infection and are acquired by the neonate through transplacental passage of CPS-specifi...

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Induction of Cross‐Reactive Antibodies by Immunization of Healthy Adults with Types Ia and Ib Group B Streptococcal Polysaccharide–Tetanus Toxoid Conjugate Vaccines

Cited by 27 publications

References 38 publications

Safety and Immunogenicity of a Bivalent Group B Streptococcal Conjugate Vaccine for Serotypes II and III

Safety and Immunogenicity of a Bivalent Group B Streptococcal Conjugate Vaccine for Serotypes II and III

A Point Mutation in the Amino Terminus of TLR7 Abolishes Signaling without Affecting Ligand Binding

Rational chemical design of the carbohydrate in a glycoconjugate vaccine enhances IgM-to-IgG switching

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