Advances in vaccination

Vaccine development is deviating from the concept of using whole attenuated pathogens. Instead, vaccines are nowadays based on molecular antigens, offering improved safety and more precise targeting. However, this modern approach suffers from reduced immunogenicity and necessitates the use of adjuvants to enhance immune responses.

A number of adjuvants are undergoing clinical evaluation, and QS-21 constitutes an attractive candidate. QS-21 is a saponin-based natural derivative that, however, presents with a number of inherent limitations, including dose-limiting toxicity and chemical instability.

In addition, the unknown mechanism of QS-21 action impedes the rational design of less toxic analogues. To address this challenge, scientists on the EU-funded VACCINE ADJUVANTS project propose to chemically synthesise QS-21 analogues associated with more favourable therapeutic profiles.

So far, the consortium has defined specific substructures of the saponin scaffold responsible for its adjuvant activity. Based on these, they have developed a number of novel saponin chemical probes through chemical modification. These have served as a platform to understand the mechanism of its immune potency.

To evaluate the efficacy and toxicity of the QS-21 analogues, scientists are performing vaccination of mice with a multiple cocktail of clinically relevant antigens. Monitoring of antibody responses to the antigen and the adjuvant should provide important insight into adjuvant performance. Preliminary data point to a number of QS-21 variants with good efficacy, but considerably reduced toxicity.

Further chemical modification experiments with saponin have shown that an entire saccharide moiety could be omitted without interfering with the adjuvant potency of the molecule. Interestingly, pre-clinical evaluation of this truncated saponin has shown an attenuation of toxicity, clearly supporting its clinical exploitation.

Ongoing experiments into the structure-activity relationship of saponin products will unravel the mechanism of immunostimulatory activity. Importantly, findings will provide more chemical lead compounds for clinical evaluation.