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.

Fig. 1.

Antibody responses in rhesus macaques to group B streptcoccal conjugate vaccines. Concentrations of GBS type V CPS-specific IgG (black symbols), IgM (white symbols), and IgA (gray symbols) in sera of three young female macaques before and after immunization with a single dose of III-TT (A), V-TT (B), or dV-TT (C). Concentrations are given as mean micrograms per milliliter ± SEM.

Fig. 2.

Epitope specificity of vaccine-induced antibody. Specificity of macaque V-TT-induced IgG (A), human V-TT-induced IgG (B), and macaque dV-TT-induced IgG (C). Inhibitors of antibody binding to V-HSA-coated microtiter plates were native type V CPS (152 RU; open squares), type V oligosaccharides (6 RU; closed squares), dV CPS (triangles), and type VII CPS (open circles).