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

Abstract

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...

Group B Streptococcus and Streptococcus suis Capsular Polysaccharides Induce Chemokine Production by Dendritic Cells via Toll-Like Receptor 2- and MyD88-Dependent and -Independent Pathways

“…1D). These data suggest that there are intra-and interspecies variations in the immunogenic properties exerted by the sialic acid moiety (49)(50)(51).…”

“…Some bacterial CPS motifs, including sialic acid, are very similar to molecules expressed by human cells or tissues, which could result in immune evasion through molecular mimicry (69). Therefore, chemical alteration of sialic acid of N. meningitidis type B CPS by de-N-acetylation or deletion of this sugar in GBS type V CPS improved the immunogenicity of these two CPSs (50,70). However, the consequences of capsular sialic acid manipulation on the capacity of CPS to acti-…”

Development of a glycoconjugate vaccine to prevent meningitis in Africa caused by meningococcal serogroup X

“…3A). (40,41). SBA assays were performed with pooled sera collected 2 wk after the second and the third immunization against the same strain used for MenX PS production, and indicated that antibodies induced by immunization with the MenX-CRM 197 conjugates were functional (Table 3).…”

Streptococcus suis Capsular Polysaccharide Inhibits Phagocytosis through Destabilization of Lipid Microdomains and Prevents Lactosylceramide-Dependent Recognition

“…Macrophages can efficiently internalize latex beads to form nascent phagosomes displaying all their properties, such as maturation protein markers like LAMP1 (12,23). To obtain CPSlinked latex beads, we adapted a technique commonly used to conjugate a protein carrier to CPS (21), replacing the protein by a latex bead with amine groups at its surface, which covalently link purified CPS. We obtained an artificial particle about the size of a bacterium, which allowed us to discriminate biological effects on phagocytes directly related with CPS without interference from other virulence factors.…”