VACCINE ADJUVANTS

"Chemical Synthesis, Immunologic Evaluation and Conformational Analysis by NMR Spectroscopy of Complex Glycoconjugate Adjuvants for Anti-Cancer and Anti-Viral Vaccine Therapies"

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 Obiettivo del progetto (Objective)

'The development of therapeutic vaccines often includes the use of synthetic small molecule antigen constructs to elicit immune response. However, many subunit antigen vaccines are less immunogenic than those employing attenuated microorganisms. As a result, they often require co-administration with an adjuvant or immunostimulating complex, a substance that is itself not necessarily immunogenic but functions in concert with the antigen to enhance/prolong immune response. Whereas the design of subunit antigen constructs has played an influential role in the development of clinically viable vaccine therapies, efficacy modulation of vaccines through the design and chemical synthesis of distinct molecular adjuvants has been comparatively less common given the structural complexity of these substances. With the aid of several chemical glycosylation methodologies developed in Professor Gin laboratories, the first synthesis and structure verification of several complex triterpene saponins have been achieved. Through collaborations with immunologists and clinicians, current efforts are also devoted to the generation of designed structural analogs for the development of more powerful and stable adjuvants for both anti-cancer and anti-viral therapeutic vaccines. At a final stage, recent progress made in Professor Jiménez-Barbero group on the application of NMR methods to study the structural and recognition properties of carbohydrates will allow us to gain insights into the conformational behavior and the immunostimulating activity of these newly synthesized adjuvants. Thus, we will carry out advanced NMR experiments to assess the conformational features and aggregation properties of these compounds . As a consequence, we are in a unique position to conduct systematic structure-activity investigations on this class of natural product with the goal of unraveling its as yet unknown mechanism of immunostimulatory activity.'

Introduzione (Teaser)

Vaccination has long been at the forefront of tackling infectious diseases. Ongoing efforts aim to enhance the performance of existing vaccines and develop new ones against novel targets.

Descrizione progetto (Article)

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.