Target identification and elucidation of the molecular mechanism of action of saponin vaccine adjuvants QS-21 (QS21Mech)

Project Information

QS21-Mech

Grant agreement ID: 898128

DOI

10.3030/898128

Project closed

EC signature date 21 February 2020

Start date 1 March 2020

End date 23 May 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 172 932,48

EU contribution

€ 172 932,48

Coordinated by

ASOCIACION CENTRO DE INVESTIGACION COOPERATIVA EN BIOCIENCIAS
Spain

Periodic Reporting for period 1 - QS21-Mech (Target identification and elucidation of the molecular mechanism of action of saponin vaccine adjuvants QS-21 (QS21Mech))

Reporting period: 2020-03-01 to 2022-02-28

Summary of the context and overall objectives of the project

- Adjuvants are natural or chemical substances added to vaccines that enhance the immune response to a co-administered antigen to levels significantly higher than those induced by the antigen alone, resulting in more robust immune responses and longer-term vaccine protection. Moreover, they also enable to reduce the amount of antigen and number of immunizations needed, facilitating dose-sparing, and making vaccination more cost-effective and accessible worldwide. The saponin natural product QS-21 isolated from the bark of Quillaja saponaria (QS), has risen some significant interest as an adjuvant for vaccines, as it showed an unparalleled ability to enhance immunological responses against a variety of different antigens. However, the mechanism by which QS-21 potentiates the immune response is not fully elucidated. Despite its great potential as a vaccine adjuvant, QS-21 suffers from dose-limiting toxicity, hydrolytic instability, and an unknown mechanism of action, which greatly hampered its licensing for human vaccines. Nonetheless, it has been used as an investigational adjuvant in over 100 clinical trials, including Phase III, and has recently been approved for use in two vaccines against malaria, shingles, Covid-19 vaccine. Despite of this, the unknown mechanism of action for QS-21 is a long-standing question in immunology and a concern for its further clinical applications.

- This novel research represents a unique opportunity to address long-standing mechanistic questions concerning saponin immunopotentiation that have not been resolved so far. The unprecedented identification of the involved receptor proposed herein will allow us to determine for the first time the mechanism of action of QS21. This combined knowledge will, in turn, give us the opportunity to rationally design saponin adjuvants with the highest potency for each individual antigen (depending on the different pathways the antigen is being processed by the immune system), resulting in new and more effective subunit vaccine for the benefit of the society.

- The overall objective of this original proposal is to elucidate the mechanism of action by which the saponin adjuvant QS-21 potentiates the immune response. To achieve this ambitious but feasible goal, three main objectives have been proposed:
1: Synthesis of a variety of novel saponin photoaffinity probes (SPAPs), consisting of QS-21 derivatives as bioactive ligands, linked to a photoreactive group (benzophenones, and diazirines) and biotin as a reporter group.
2: Identification of the saponin lead compound in terms of a) best adjuvant activity/immunological response in mice, and b) selective capture of the putative target by the SPAPs via the photoreactive group.
3: Identification of involved molecular target via in vitro studies with murine DCs, followed by chemical proteomic analysis.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We have designed and synthesized a wide variety of saponin photo-affinity probes (SPAPs) to identify the putative receptor(s) of QS21. We designed and synthesized six compounds based on QS21 bearing photoaffinity groups in 2 extremities of the molecule to ensure obtaining sufficient adjuvant activity and interaction with the target receptor(s). We have successfully synthesized 6 derivatives; two sugar-truncated analogues (XX and XX), simplified compounds 25 and 31 (achieved in total 27 and 30 steps respectively starting from the QS bark extract) and QS-21-functionalized compounds (38 and 39) achieved in total 8 and 6 steps respectively starting from the commercially available original QS21.

Dissemination. Since all the WPs of “QS21Mech” have not been fully completed due to complicated and long synthetic route and additionally COVID19 pandemic, the dissemination of the final scientific results will be presented in appropriate international conferences to be held either by the end of 2022 or early 2023. In the meantime, I have communicated some of our preliminary results in a Summer School in Biomedical Glycoscience, Venue: Jaca (Huesca, Spain). Dates: 8th-10th June 2022, Organized by the Carbohydrates Group of the Spanish Royal Society of Chemistry, through a poster presentation. Moreover, I have attended the “3rd Glycobasque Meeting” held in CIC bioGUNE, (Derio, Bizkaia), on March 12nd-13th, 2020 and had the opportunity with well-known scientist to share the idea of “QS21Mech”. Since I am still working on the project thanks to Prof Fernandez Tejada’s lab funds for an additional year, we are optimistic about finalizing “QS21Mech”. The high value of the results will be disclosed in scientific journals of the highest impact (Open Access according to EC policy), such as Nature, Science, Nature Chem, Nat Chem Biol, J Am Chem Soc or Angew Chem Int Ed. I am expecting to publish in a high-impact, peer-reviewed journals, although care will be taken to not jeopardize possible exploitation of results due to the translational aspect of our project. Once we will have final conclusion of the project, I will use the available tools from the European Commission (http://horizon-magazine.eu/) to publish some short articles or online news headlines (http://cordis.europa.eu/wire) based on our achievements. I have already used the platform Junior Research Seminar Series in 2022, Jan 9 from CIC bioGUNE’s strategies of dissemination where I share the advances of this project with my colleagues.

Exploitation and IPR issues. The outcomes of the proposed research i.e. the identification of receptors of saponin adjuvants are capable of ultimately leading to novel, tailored saponin adjuvants that can be exploited by the pharmaceutical industry in the development of novel vaccines to effectively combat diseases of a world-wide significance including cancer, tuberculosis, HIV, malaria and Ebola. There are different pharmaceutical companies that already use adjuvant systems containing QS-21 in various vaccines in all three stages of clinical trials and will be interested in the results of QS21Mech. In fact, Prof. Fernández-Tejada has had the opportunity to establish initial contacts with both companies on a basic level, and has established a solid relationship with an additional biopharma company as a collaboration partner. In addition, CIC bioGUNE Technology Transfer Manager, has broad experience in the translation of results from academia to companies and will fully support me along the project implementation once it is finalized.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Since the final goal of the project has not been yet completed, such progress has not been fully developed so far. We assume that the results of this project will be very exciting, and the outcome will be beneficial for the society.