Glycoconjugate vaccines consist of a polysaccharide (carbohydrate) antigen covalently linked to a carrier protein. Research over the last 30 years has demonstrated that glycoconjugate vaccines are the safest and most effective as the can provide long-lasting antibody production even in children under 2 years of age. This occurs because the carrier protein is presented to, and recognised by T cells that would otherwise not react to the T cell-independent polysaccharide antigens.
Optimising glycoconjugate vaccine production
In most cases, vaccine conjugation processes have been set up empirically leading to inefficient antigen presentation and lower vaccine efficacy. To address this problem, the NEWCARBOVAX project developed a vaccine platform for the synthesis of the next generation of glycoconjugate vaccines. The research was undertaken with the support of the Marie Skłodowska-Curie (MSC) programme and relied on findings from Professor Kasper’s lab at Harvard Medical School on the mechanism of vaccine-generated immunity. According to these findings, carbohydrate presentation to T cells by antigen-presenting cells (APCs) may strongly enhance antibody response. To do so, the carbohydrate must be attached to peptides which anchor the conjugate via MHC class II molecules, rendering the vaccine up to 100 times more immunogenic. “Based on this improved understanding of basic immunological mechanisms, our goal was to develop a new translational platform for optimised and cost-effective carbohydrate-based vaccines,” outlines the MSC research fellow Giuseppe Stefanetti. The scientists used the capsular polysaccharide from Group B Streptococcus type III as a model, and tested different saccharide chain lengths, different peptide carriers, and conjugation sites. They also evaluated innovative chemistry strategies for attaching the polysaccharides to the peptides and tested the immunogenicity of the generated constructs in animal models. Results showed that the conjugation site of the peptide carrier to the carbohydrate significantly impacted the antibody concentration, or titre, induced by the conjugate vaccine, as well as the conferred protection to a subsequent bacterial challenge.
Design of new vaccines
Using the NEWCARBOVAX platform, scientists developed a glycoconjugate vaccine able to protect, for the first time, against intranasal challenge with Francisella tularensis, one of the most pathogenic bacteria. Researchers coupled the O polysaccharide of the bacteria to an optimised peptide and observed significant protection. Interestingly, the new generation vaccines induced low titres of highly efficacious antibodies. This was attributed to the different mechanisms of presentation to T cells which depends on the structure of the polysaccharide used.
Advantages and future prospects of the NEWCARBOVAX vaccine platform
Apart from improved effectiveness, the newly designed vaccines induce protection against intracellular bacterial pathogens, a class of microbes traditionally hard to treat by standard glycoconjugate vaccines. “Importantly, the NEWCARBOVAX methodology produces a well-characterised pharmaceutical product thereby facilitating the investigation of structure-activity relationship,” emphasises project beneficiary Luigi Lay. Project results will lay the foundation for the rational design of a new generation of vaccines against practically any bacterial species. Moreover, the induction of high-affinity antibodies may be the future in the treatment of emerging infectious diseases and the NEWCARBOVAX platform could be the entry point for generating them. “Further investigation into the interaction of highly functional antibodies and the target antigen is necessary for highly effective vaccines,” concludes Stefanetti.
NEWCARBOVAX, glycoconjugate vaccine, polysaccharide, peptide