Critical quality attributes and manufacturing techniques for Streptococcus pneumoniae capsular polysaccharide in pneumococcal vaccines: A review

Capsular polysaccharides (CPSs) have been proven to be effective antigens in eliciting protective immunity against invasive infections of encapsulated bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis. The use of polysaccharide and protein-polysaccharide conjugate vaccines has markedly decreased the morbidity and mortality caused by encapsulated pathogens through both direct immune protection and herd immunity. Among these, the pneumococcal CPS-based vaccines are widely used and represent the most powerful tool for controlling severe invasive pneumococcal disease (IPD). Whether active pharmaceutical ingredient is composed of CPSs alone or protein-conjugated CPSs, a crucial step in the preparation of pneumococcal vaccines is to manufacture CPSs that meet strict quality standards in terms of both immunogenicity and safety. This article firstly introduces the biosynthetic mechanism of pneumococcal CPSs and the key enzymes involved in the regulating of molecular weight and chemical modifications of pneumococcal CPSs. Then, the critical quality attributes (CQAs) of CPSs related to the immunogenicity and safety are systematically reviewed. Subsequently, this review comprehensively describes the available manufacturing processes and recent advancements for the preparation of S. pneumoniae CPSs, which include the production strains, fermentation, inactivation, purification and depolymerization of CPSs. Moreover, this review summarizes the potential effects of manufacturing processes on the purity and immunogenicity of CPSs, aiming to improve the quality of CPS antigens. Overall, this review provides practical guidance for developing efficient and robust manufacturing process for high yield and premium quality CPSs, as well as insights into frontier research in genetically modified expression of pneumococcal polysaccharide and protein-polysaccharide conjugates.