A Synthetic Carbohydrate-Protein Conjugate Vaccine Candidate against Shigella flexneri 2a Infection

Abstract

The protective Ag of Shigella, the Gram-negative enteroinvasive bacterium causing bacillary dysentery, or shigellosis, is its O-specific polysaccharide (O-SP) domain of the LPS, the major bacterial surface component. As an alternative to the development of detoxified LPS-based conjugate vaccines, recent effort was put into the investigation of neoglycoproteins encompassing synthetic oligosaccharides mimicking the protective Ags of the O-SP. We previously reported that when coupled to tetanus toxoid via single point attachment, a synthetic pentadecasaccharide representing three biological repeating units of the O-SP of Shigella flexneri 2a (SF2a), one of the most common Shigella serotypes, elicits a better serum anti-LPS 2a Ab response in mice than shorter synthetic O-SP sequences. In this study, we show that the pentadecasaccharide-induced anti-LPS 2a Abs protect passively administered naive mice from Shigella infection. Therefore, this three repeating units sequence, which is recognized by anti-SF2a sera from infected patients, acts as a functional mimic of the native polysaccharide Ag. Analyses of parameters influencing immunogenicity revealed that an investigational SF2a vaccine displaying a pentadecasaccharide:tetanus toxoid molar loading of 14:1 triggers a high and sustained anti-LPS Ab response, without inducing anti-linker Ab, when administered four times at a dose corresponding to 1 g of carbohydrate. In addition, the profile of the anti-LPS Ab response, dominated by IgG1 production (Th2-type response), mimics that observed in human upon natural SF2a infection. This synthetic carbohydrate-based conjugate may be a candidate for a SF2a vaccine.

Design of Glycoconjugate Vaccines against Invasive African Salmonella enterica Serovar Typhimurium

“…To design glycoconjugates with the potential of being effective vaccines, several biochemical factors need to be evaluated that can affect the immunogenicity and tolerability of the final product. Among the most important parameters are the carrier protein (9,40,41) and the conjugation chemistry chosen (9,12,42), but additional factors, including the molecular weight (MW) of the polysaccharide (43)(44)(45), saccharide modifications (such as O-acetylation and glucosylation) (12,43), and the sugar/carrier ratio (25,44,46), need to be explored (47).…”

Synthetic β-(1→6)-Linked N-Acetylated and Nonacetylated Oligoglucosamines Used To Produce Conjugate Vaccines for Bacterial Pathogens

“…Synthetic carbohydrate vaccines are rarely studied due to the complexity of production, but conjugate vaccines containing synthetic poly(ribosyl-ribitol phosphate) provide protective immunity against H. influenzae type b infections and are licensed for human use (41 (31). Other synthetic oligosaccharide vaccines for a variety of pathogens are currently in various stages of development (32), indicating that more success with this technology is likely to come.…”

Vaccines for viral and bacterial pathogens causing acute gastroenteritis: Part II: Vaccines forShigella,Salmonella,enterotoxigenicE. coli(ETEC) enterohemorragicE. coli(EHEC) andCampylobacter jejuni

“…In studies performed with these molecules at NIH and Institute Pasteur in France, vaccinated animals produced antibodies against the corresponding bacterial LPS. [36][37][38][39] However, these vaccine candidates have a narrow spectrum of protection, producing an immune response only directed at the bacterial strain from which the synthetic conjugate was obtained, it is for this reason that they remain in the development stage. The most advanced conjugate vaccine candidates, S. flexneri O-SP-rEPA and S. sonnei O-SPrEPA, were discussed above.…”