Semisynthetic glycoconjugate vaccine candidate against Streptococcus pneumoniae serotype 5

Abstract

Glycoconjugate vaccines based on isolated capsular polysaccharide (CPS) save millions of lives annually by preventing invasive pneumococcal disease caused by Some components of the glycoconjugate vaccine Prevnar13 that contains CPS antigens from 13 serotypes undergo modifications or degradation during isolation and conjugation, resulting in production problems and lower efficacy. We illustrate how stable, synthetic oligosaccharide analogs of labile CPS induce a specific protective immune response against native CPS using serotype 5 (ST-5), a problematic CPS component of Prevnar13. The rare aminosugar l-PneuNAc and a branched l-FucNAc present in the natural repeating unit (RU) are essential for antibody recognition and avidity. The epitope responsible for specificity differs from the part of the antigen that is stabilized by chemical modification. Glycoconjugates containing stable, monovalent synthetic oligosaccharide analogs of ST-5 CPS RU induced long-term memory and protective immune responses in rabbits superior to those elicited by the ST-5 CPS component in multivalent Prevnar13.

Improving vaccines against Streptococcus pneumoniae using synthetic glycans

“…Minimal protective glycan epitopes are identified using synthetic homogeneous oligosaccharides that constitute one or more repeating units of bacterial CPS. Glycoconjugates containing such synthetic antigens have been previously tested individually for their antigenicity, immunogenicity, and protective effects in animal challenge models of disease, and have been shown to be effective in some cases (9,10,(17)(18)(19). We aimed to expand S. pneumoniae vaccine coverage by including serotype antigen conjugates ( Fig.…”

“…The ST3 antigen already present in Prevnar13 triggers an antibody response similar to that of sPCV5 and coformulated Synflorix+ST2+ST3+ST8. The ST5 antigen present in licensed vaccines is problematic as the ketone moiety in the ketoamino sugar 2-acetamido-2,6-dideoxy-D-xylose-hexos-4-ulose (Sugp) becomes reduced during vaccine production, yielding a mixture of different antigens and decreased immunogenicity (9). On the other hand, the reduced ST5 antigen used here with reducing end 2-N-acetyl-2-deoxy-β-D-fucopyranoside ( Fig.…”

“…The medicinal chemistry approach has identified di-to tetrasaccharides as potential vaccine candidates (11). The immunogenicity of the CPS depends among other factors on rare sugars and labile functional groups (9,17,19). Stable oligosaccharide analogs can fix production problems such as those encountered for ST5 CPS due to the labile ketone present in the repeating unit (9).…”

“…The immunogenicity of the CPS depends among other factors on rare sugars and labile functional groups (9,17,19). Stable oligosaccharide analogs can fix production problems such as those encountered for ST5 CPS due to the labile ketone present in the repeating unit (9). Defined oligosaccharide antigens have been identified as vaccine candidates to protect against bacterial infections caused by S. pneumoniae, C. difficile, K. pneumoniae, and N. meningitides via the medicinal chemistry approach (3,16,19,22).…”

Microarray Strategies for Exploring Bacterial Surface Glycans and Their Interactions With Glycan-Binding Proteins

“…Thus, in serotype 2 the GlcAα(1-6)Glcα(1-2) branch (GlcA being glucuronic acid) was found to be an important substructure of the hexasaccharide repeating unit (Emmadi et al, 2017), while in serotype 7F the two side chains that decorate the linear tetrasaccharide backbone, i.e., Galβ(1-and GlcNAcα(1-2)Rhaα(1-, played a key role (Menova et al, 2018). Gal modification with a pyruvate ketal in the linear tetrasaccharide unit of serotype 4 was observed to be an important determinant, although pyruvate-independent epitopes were also unveiled (Geissner et al, 2016), whereas in the serotype 5 pentasaccharide unit the rare aminosugar N-acetyl-L-pneumosamine (PneuNAc, Figure 2) together with branched N-acetyl-L-fucosamine (FucNAc) were essential for antibody recognition and avidity (Lisboa et al, 2017). These findings could be of relevance for designing efficient synthetic glycoconjugate vaccines against S. pneumoniae.…”