Synthesis of Streptococcus pneumoniae 6A/6C Oligosaccharides for Vaccine Applications

Streptococcus pneumoniae (SPn) is a Gram-positive bacterium and a leading cause of serious and potentially life-threatening diseases such as pneumonia, sepsis, and meningitis1. A key virulence factor of SPn is its polysaccharide capsule (CPS), which protects the bacterium from phagocytosis by the host immune system. According to the World Health Organization (WHO), vaccination is the most cost-effective strategy for preventing bacterial infections. Currently available polysaccharide conjugate vaccines (PCVs) have significantly reduced the incidence of invasive pneumococcal disease caused by vaccine-included serotypes. However, their overall efficacy has been undermined by the growing prevalence of infections caused by non-vaccine serotypes (NVT), a phenomenon known as serotype replacement. A notable example is serogroup 6: following widespread administration of vaccines targeting serotypes 6A and 6B, a marked increase in infections caused by the non-vaccine serotype 6C was observed2. In carbohydrate-based vaccines, conjugating the saccharide fragment to an immunogenic protein is essential to induce a T cell-dependent immune response. However, the large amount of carrier protein used in multivalent vaccines, containing multiple glycoconjugates targeting different virulent serogroups, can sometimes lead to diminished immune responses due to pre-existing anti-carrier immunity. Consequently, identifying novel antigens capable of eliciting cross-protective immunity against multiple serotypes is critical for the next generation of more effective vaccines. The structural differences between the repeating units of SPn serogroup 6 are minimal: Serotypes 6A and 6B share a common saccharide backbone, galactose-glucose-rhamnose-ribitol phosphate, but differ in the glycosidic linkage between the ribitol and rhamnose residues. In contrast, 6A and 6C have the same glycosidic linkage, but differ in one monosaccharide composition3. Given this context, the development of a new, versatile vaccine capable of providing effective cross-protection against different serogroups is important. The primary objective of this project is the synthesis of hybrid structures combining elements of the 6A and 6C CPS (compounds 1–4, Fig. 1). Another key objective of this project is the design and synthesis of a chimeric structure that integrates the repeating units of both SPn 6A and 6C. The synthesized oligosaccharides will be linked to a carrier protein, and the resulting neoglycoconjugates will be thoroughly evaluated through immunological studies, in parallel with the natural fragments of SPn 6A and 6C, to compare their immunogenicity.