Neoglycoconjugate of Tetrasaccharide Representing One Repeating Unit of the Streptococcus pneumoniae Type 14 Capsular Polysaccharide Induces the Production of Opsonizing IgG1 Antibodies and Possesses the Highest Protective Activity As Compared to Hexa- and Octasaccharide Conjugates

Abstract

Identifying protective synthetic oligosaccharide (OS) epitopes of Streptococcus pneumoniae capsular polysaccharides (CPs) is an indispensable step in the development of third-generation carbohydrate pneumococcal vaccines. Synthetic tetra-, hexa-, and octasaccharide structurally related to CP of S. pneumoniae type 14 were coupled to bovine serum albumin (BSA), adjuvanted with aluminum hydroxide, and tested for their immunogenicity in mice upon intraperitoneal prime-boost immunizations. Injections of the conjugates induced production of opsonizing anti-OS IgG1 antibodies (Abs). Immunization with the tetra- and octasaccharide conjugates stimulated the highest titers of the specific Abs. Further, the tetrasaccharide ligand demonstrated the highest ability to bind OS and CP Abs. Murine immune sera developed against tetra- and octasaccharide conjugates promoted pathogen opsonization to a higher degree than antisera against conjugated hexasaccharide. For the first time, the protective activities of these glycoconjugates were demonstrated in mouse model of generalized pneumococcal infections. The tetrasaccharide conjugate possessed the highest protective activities. Conversely, the octasaccharide conjugate had lower protective activities and the lowest one showed the hexasaccharide conjugate. Sera against all of the glycoconjugates passively protected naive mice from pneumococcal infections. Given that the BSA-tetrasaccharide induced the most abundant yield of specific Abs and the best protective activity, this OS may be regarded as the most promising candidate for the development of conjugated vaccines against S. pneumoniae type 14 infections.

Improving vaccines against Streptococcus pneumoniae using synthetic glycans

“…The synthetic tetrasaccharide conjugate ST14 ( Fig. 1), resembling the previously identified repeating unit of the widespread S. pneumoniae ST14 serotype (21), was included to show that nonproblematic isolated serotypes can in principle also be substituted by synthetic antigens.…”

Conformation and Cross-Protection in Group B Streptococcus Serotype III and Streptococcus pneumoniae Serotype 14: A Molecular Modeling Study

“…Effective short, branched epitopes have also been identified for the Pn14 PS: Safari et al demonstrated that one RU of the Pn14 PS (Figure 1c) is essential and sufficient for inducing protective Pn14-specific antibodies: the presence of the trisaccharide branch point in an epitope is crucial for anti-Pn14 antibody recognition and the extra galactose contributes to the immunogenicity of the epitope [14]. Kurbatova et al recently identified a similar branched tetrasaccharide as the most effective epitope for Pn14 PS [15]. In contrast, linear Pn14 PS fragments were found to be completely ineffective: none of a range of short linear epitopes of the PS backbone were recognized by Pn14 antibodies [7].…”

Immunological and Epidemiological Aspects of the Immunogenicity of Streptococcus Pneumoniae Serotype 3 Capsular Polysaccharide in Pneumococcal Vaccines

“…Вариабельность бактериального КП S. pneu moniae серотипа 3 может оказывать влияние на качество вакцинных препаратов. Для устранения этого недостатка перспективным является использование протективных синтетических олигосахаридов строго определенного химического строения, являющихся аналогами КП S. pneumoniae серотипа 3, конъюгированных с белком-носителем для индукции Т-зависимого иммунного ответа и иммунологической памяти [52][53][54][55]. Для конструирования мультивалентной пневмококковой вакцины можно использовать конъюгированные синтетические олигосахариды или их комбинацию с бактериальными КП [56].…”