NEWCARBOVAX · New generation of carbohydrate-based vaccines via rational understanding of their immunological mechanism

New generation of carbohydrate-based vaccines via rational understanding of their immunological mechanism

Glycoconjugates are among the safest and most efficacious vaccines developed against infectious diseases. They have been developed to improve the immunogenicity of polysaccharide vaccines which are T cell independent, poorly immunogenic in infants and young children < 2 years of age, do not induce immunological memory and can lead to hyporesponsiveness to repeat vaccination. Glycoconjugates have provided enormous health benefits globally, but they have been less successful in some populations at high risk for developing disease. They are composed by a sugar antigen covalently linked to a carrier protein. The traditional hypothesis of immune activation by glycoconjugate vaccines suggests that only peptides generated from glycoconjugate processing can be presented to and recognized by T cells, and this contribution is crucial for their immunogenicity. Recently, new findings offer a rational explanation for how conjugates work and may render vaccine development a more straightforward process. In contrast with the classical mechanism, this new model suggests that carbohydrate presentation to the T cell by antigen-presenting cell (APC) may strongly enhance antibody response. The key strategy is to conjugate the carbohydrate to peptides which anchor the conjugate via MHC class II (antigen-presenting molecule). Application of this principle resulted in a GBSIII vaccine strongly protective in a mouse model and 50–100 times more immunogenic than a traditional vaccine composed by random linking of the sugar on a protein carrier. Although the principle has been demonstrated much remains to be done to generally apply the concept to generate vaccines for clinical use. In the proposed study, we have extended the approach by analyzing different variables (peptide carrier, glycan chain length, conjugation chemistry and microbial antigen), with the aim of using the increased understanding of basic immunological mechanisms to develop a new translational platform for optimized and cost-effective carbohydrate-based vaccines. Throughout NEWCARBOVAX, we have developed new-generation glycoconjugate vaccines – by a rational approach based on their immunological mechanism - and showed an improved protective capacity compared to traditional glycoconjugates. We have characterized the humoral response and identified possible correlate of the higher functional activity, and started a structural investigation of MHCII-antigen interaction. The information obtained will direct the rational design of a new generation of vaccines.

Data: CORDIS, © European Union