Preclinical development of a well-defined semisynthetic glycoconjugate vaccine against Haemophilus influenzae type b

Vaccines are the most effective method for preventing bacterial infections. Identification of the best hapten is an essential step in the development of third-generation Haemophilus influenzae type b (Hib) conjugate vaccines. A comprehensive understanding of the relationship between Hib oligosaccharide chain length and immunological activities remains elusive. A series of Hib capsular polysaccharide (CPS) oligosaccharide derivatives of different lengths were synthesized to establish carbohydrate structure-function relationships. Glycan microarray screening and immunological evaluation of oligosaccharides revealed that tetramer 4, comprising four repeated disaccharide units, is the key immunogenic epitope of CPS. The investigation into the influence of carrier proteins, adjuvants, and vaccination dose on immunogenicity demonstrated that an equivalent dose of glycoconjugate 4-TT without adjuvant can induce a similar immune response as a licensed Hib vaccine (MINHAI Hib). Adjuvant-free 4-TT glycoconjugates can induce both a humoral and a cellular immune response as efficiently as licensed Hib vaccine. This formulation exhibited protective efficacy in a mouse septic infection model through effective pathogen clearance from the circulation to the liver-resident macrophage Kupffer cells and sinusoidal endothelial cells in a mouse septic infection model. In conclusion, a well-defined semisynthetic glycoconjugate vaccine candidate 4-TT was developed with a more straightforward and adaptable manufacturing process and demonstrated excellent efficacy comparable to licensed Hib vaccine, providing a rationale for further evaluation in clinical trials.