Towards improved vaccination adjuvants

Vaccines often contain adjuvants that enhance the immune response by improving the immunogenicity of the antigen. Adjuvants can also extend the immunotherapeutic benefits of vaccination to poor responders such as children or the elderly. However, only a limited number of immunological adjuvants meet the necessary requirements and acceptable toxicity levels for vaccine use.

Among the most promising adjuvants is QS-21, a member of the naturally occurring class of compounds known as saponins. However, the limited availability and heterogeneity of the natural product, its side effects and chemical instability impede the further commercial advancement of QS-21. In answer to this, the EU-funded VACCINE ADJUVANTS (Chemical synthesis, immunologic evaluation and conformational analysis by NMR spectroscopy of complex glycoconjugate adjuvants for anti-cancer and anti-viral vaccine therapies) project set out to develop structurally simpler and improved QS-21 variants that could be utilised in vaccines.

For this purpose, scientists developed a semi-synthetic approach for the preparation of stable QS-21 analogues with more robust chemistry. They also investigated the influence of the different domains in adjuvant activity and toxicity. These second-generation saponin derivatives were evaluated in pre-clinical vaccination models using antigens of variable immunogenicity. Researchers identified one new analogue that exhibited similar activity to QS-21 with lower toxicity, a promising lead for further development towards clinical evaluation.

In addition, VACCINE ADJUVANTS provided critical information about the three-dimensional structural features required for adjuvant activity and found a strong correlation between the two. In vivo bio-distribution studies unveiled that active adjuvants accumulated in the lymph nodes where they facilitated antigen presentation to dendritic cells.

Overall, the activities of the project provided novel insight into the molecular and cellular mechanisms of action of saponin-based adjuvants. At the same time, they opened up new avenues towards the optimisation of adjuvant-antigen combinations in vaccine development.