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.

Ekaterina A Kurbatova,Nikolay E Nifantiev,Dmitriy V Yashunsky,Marina L Gening,Nadezhda B Egorova,Elena V Sukhova,Yury E Tsvetkov,Nelli K Akhmatova,Natalya E Yastrebova,Elina A Akhmatova

doi:10.3389/fimmu.2017.00659

Ekaterina A Kurbatova, Nikolay E Nifantiev + Show 8 more

Open Access

https://doi.org/10.3389/fimmu.2017.00659

Copy DOI

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.

Highlights

Streptococcus pneumoniae are Gram-positive bacteria that cause invasive and non-invasive, often lethal, infections in multiple anatomic locations in adults and children [1, 2]
Post-immunization anti-capsular polysaccharide (CP) Ab titer levels were determined in individual murine blood sera in enzyme-linked immunosorbent assay (ELISA) using S. pneumoniae type 14 CP as the coating antigen (Figure 2)
IgG1 Ab titers in sera of mice immunized with conjugated pneumococcal vaccine Prevenar-13 were evaluated using each neoglycoconjugates, synCP, and bacCP as coating antigens (Figure 3)

Summary

Introduction

Streptococcus pneumoniae are Gram-positive bacteria that cause invasive and non-invasive, often lethal, infections in multiple anatomic locations in adults and children [1, 2]. Based on the chemical structure of capsular polysaccharides (CPs), more than 90 different serotypes of S. pneumoniae have been identified, approximately 20 of which are responsible for 80–90% of all pneumococcal infections [4, 5]. Studies of unconjugated polysaccharide-based pneumococcal vaccine of the firstgeneration confirmed its efficacy and safety in adults [6]. Disadvantages of such vaccines have been observed, including inefficiency in children less than 2 years of age and in certain risk groups [7], absence of boosting effects upon revaccination, suggesting insufficient development of immune memory [8]

Methods

Results

Conclusion