Next generation conjugate vaccines; development from lab bench towards clinical trials

Abstract

New conjugate vaccines are under development targeting different diseases. This is directly related to the introduction of new synthetically designed and manufactured antigens that are becoming more and more available. This has substantial advantages with respect to the conventional extraction processes as historically applied to polysaccharides. Additionally, new protein carriers are being investigated and used in the field as well. Here we do see trends towards the introduction of nanoparticles and proteins replacing the traditional carriers. The combination of nanoparticle carriers and synthetic antigens require new, sophisticated methods to characterize and evaluate their quality both physiochemically and immunologically. In this thesis we provide a stepwise progression from an extracted polysaccharide conjugated through random coupling to tetanus toxoid towards site-specific conjugation of an intricate synthetically produced oligosaccharide. This conjugation method is then further evaluated for the development of an OMV-based synthetic peptide vaccine. For all three vaccines described in this thesis (Haemophilus influenzae type b (Hib), Shigella flexneri 2a and OMV-peptide), we used and developed an indispensable set of quality control tests for physicochemical characterization. Also Design of Experiments (DoE) was utilized for the optimization of conjugation processes. This approach provided a pivotal tool to reduce time and costs during development and optimization of the production process.