Abstract
Streptococcus pneumoniae 19A (ST19A) and 19F (ST19F) are among the prevalent serotypes causing pneumococcal disease worldwide even after introduction of a 13-valent pneumococcal conjugate vaccine (PCV13). Synthetic glycoconjugate vaccines have defined chemical structures rather than isolated polysaccharide mixtures utilized in marketed vaccines. Ideally, a minimal number of synthetic antigens would cover as many bacterial serotypes to lower cost of goods and minimize the response to carrier proteins. To demonstrate that a chimeric oligosaccharide antigen can induce a protective immune response against multiple serotypes, we synthesized a chimeric antigen (ST19AF) that is comprised of a repeating unit of ST19A and ST19F capsular polysaccharide each. Synthetic glycan epitopes representing only ST19A, and ST19F were prepared for comparison. Semisynthetic glycoconjugates containing chimeric antigen ST19AF induced high antibody titers able to recognize native CPS from ST19A and ST19F in rabbits. The antibodies were able to kill both strains of pneumococci. Chimeric antigens are an attractive means to induce an immune response against multiple bacterial serotypes.
Highlights
Invasive pneumococcal diseases (IPD) caused by Streptococcus pneumoniae (Sp), are a major cause of morbidity and mortality in toddlers and older adults worldwide.[2,3] Despite the introduction of a 13-valent pneumococcal conjugate vaccine (PCV13) in 2010, Streptococcus pneumoniae 19A (ST19A) remains a major pathogen worldwide[4,5,6,7,8] that is associated with 14% of all IPD cases.[9]
The ST19 CPS is among the most labile polysaccharides used for vaccine production as the phosphate diester groups can be cleaved during puri cation and conjugation resulting in severely suppressed immunogenicity.[13,14]
Trisaccharides 6 or 7 can be synthesized via a linear synthetic approach from the reducing to the nonreducing end using the building blocks 8,41 9,42 10,43 and 11.44 For the assembly of trisaccharide building block 6, glucosyl imidate 10 was coupled to rhamnosyl acceptor 8 to obtain alinked disaccharide 12 (1JC–H 1⁄4 170.5 Hz) in 82% yield (Scheme 1A)
Summary
Invasive pneumococcal diseases (IPD) caused by Streptococcus pneumoniae (Sp), are a major cause of morbidity and mortality in toddlers and older adults worldwide.[2,3] Despite the introduction of a 13-valent pneumococcal conjugate vaccine (PCV13) in 2010, ST19A remains a major pathogen worldwide[4,5,6,7,8] that is associated with 14% of all IPD cases.[9]. Glycoconjugate vaccines contain polysaccharides isolated from bacterial cell cultures, that are conjugated to proteins to create heterogeneous vaccine compositions.[12] The ST19 CPS is among the most labile polysaccharides used for vaccine production as the phosphate diester groups can be cleaved during puri cation and conjugation resulting in severely suppressed immunogenicity.[13,14] Phosphate diesters in the polysaccharide of Salmonella typhimurium and Clostridium difficile PSII are crucial for inducing a strong immune response to the native polysaccharide.[15,16] Synthetic oligosaccharide conjugates containing well-de ned antigens, have proven very effective in preventing bacterial infections caused by encapsulated bacteria,[17,18,19,20,21,22,23,24,25,26,27] and the conjugation process does not impair antigens having phosphate diester groups. The saccharide to protein ratio (glycan loading) is an important parameter for glycoconjugate vaccine development. The novel strategy described here, helps to reduce the amount of protein used and may simplify the formulation of multicomponent vaccines against bacterial pathogens
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