New adjuvants with multicomponent reaction.
The production of effective adjuvants plays an important role in the development of new vaccines. These vaccine boosters enable a strong and targeted immune response that protects against emerging viruses and multidrug-resistant bacteria. IPB chemists and Cuban scientists have now succeeded in creating a library of new adjuvants and potential precursor molecules. They took the phytoceramide α-galactosylceramide (α-GalCer), already used as a vaccine booster, and diversified it with different functional side chains using a multi-component reaction. The range of molecules attached to α-GalCer includes both hydrophobic and hydrophilic moieties, as well as reactive groups such as amines and aldehydes, which can be used for further modifications. What is unique about the new adjuvants is that, for the first time, the side chains were attached to the main α-GalCer molecule at the amide linkage - a position that previously had not been used for derivatization. As a result, the researchers obtained more than 20 α-GalCer derivatives, whose vaccine-enhancing effect they extensively investigated together with partners from the Helmholtz Centre for Infection Research in Braunschweig, Germany.
All compounds were tested in cell-based studies and in mice for induction of both the cellular non-specific immune response by natural killer cells and the humoral immune response with the production of specific antibodies by activated B lymphocytes. Both pathways rely on the activation of various T helper cells, to whose receptors the potential adjuvants must bind in order to elicit an effective immune response. Among the α-GalCer compounds produced, derivatives were found that enhanced either the cellular or the humoral pathway, or both. Adjuvants that stimulate both immune pathways are currently in demand because they can be used to cover a broader vaccine spectrum. In addition, the scientists analyzed all compounds for their efficacy when administered intramuscularly or nasally. Here, too, promising candidates emerged that showed good and in some cases even better efficacy than the basic adjuvant α-GalCer, especially when administered through the nasal mucosa.
The experiments were supported by modelling approaches. These virtual analyses provided initial insights into the relationship between the structure of each derivative and its effect, laying the foundation for knowledge-based access to even better products. With their study in Angewandte Chemie, the Halle scientists have identified a new diversification hotspot of α-GalCer that is ideally suited for conjugation with other side chains and therefore has great potential to greatly expand the spectrum of future vaccine boosters. Given the great potential of mucosal vaccines, the development of mucosal adjuvants is of particular interest for future vaccine production.
