Production of Pneumococcal Multivalent Glycoconjugates as Vaccine Candidates with Ugi Multicomponent Bioconjugation.
IPB scientists and partners from Cuba have developed a multicomponent reaction for the production of multivalent pneumococcal glycoconjugates. For this purpose, they coupled in a one-pot reaction two different capsular polysaccharides of Streptococcus pneumoniae to a carrier protein. The generated glycoconjugate triggered a T-cell immune response in rabbits with corresponding production of functional, specific IgG antibodies against the polysaccharide antigens. It can therefore be used as a multivalent vaccine. The results were recently published in Bioconjugate Chemistry of the American Chemical Society. First author Ana R. Humpierre, who is currently working as a DAAD fellow at the IPB, won the first poster prize for her results at the #LatinXChem Twitter Conference 2020 in the category Organic Chemistry.
Streptococcus pneumoniae, the causative agent of sepsis, pneumonia, otitis media and meningitis, causes annually more than 500,000 deaths worldwide in children under five years. The development of suitable vaccines faces many challenges. First, the bacterium's capsular polysaccharides alone are not immunogenic enough to trigger an efficient T-cell-based immune response in immunocompromised patients. Rather, the generation of anti-polysaccharide antibodies and thus long-term immunity requires additional protein epitopes that enhance the immune response. Currently, tetanus and diphtheria toxoids are used as suitable carrier proteins for a wide range of vaccinations - not only against pneumococci. However, this carries the risk of epitope suppression - a weakening of the specific anti-polysaccharide immune response caused by already existing anti-carrier antibodies, which have been formed due to previous vaccinations.
The second challenge in vaccine development is the variability of the pathogen. Pneumococci form over 90 different serotypes worldwide, which differ slightly in the composition of their capsular polysaccharides, i.e. their surface antigens. In the human immune system, each individual serotype triggers its own specific immune response. Unfortunately, there are no cross-reactions with other serotypes. In order to provide a good protection against several serotypes, the vaccine is always a mixture of multiple capsular polysaccharide antigens. Currently pneumococcal vaccines contain up to 20 different capsular polysaccharide antigens of the most invasive serotypes. Each individual antigen is coupled to its own carrier protein, which may enhance the epitope suppression.
Multivalent unimolecular glycoconjugates, that have different polysaccharides bound to a single carrier protein could theoretically reduce carrier epitope suppression while still inducing potent anti-polysaccharide and anti-carrier immune responses. The Halle-based scientists have now succeeded in generating these by coupling two different pneumococcal capsule polysaccharides to a single tetanus toxoid carrier protein. The multicomponent reaction allowed a three-component assembly in a single reaction step and is currently the fastest way to produce multivalent unimolecular vaccines.
