Development of innate immune receptor-targeting chimeras as custom-tailored vaccine adjuvants

Code:

J3-2517

Range:

01. September 2020 - 31. August 2023

Range:

1,4 FTE

Leader:

Žiga Jakopin

Field:

3.01 Medical sciences/ Microbiology and immunology

Research Organisation:

https://cris.cobiss.net/ecris/si/en/project/18280

Researchers:

https://cris.cobiss.net/ecris/si/en/project/18280

Content:

https://cris.cobiss.net/ecris/si/en/project/18280

Abstract:

Currently, our world is facing an acute shortage of novel vaccine adjuvants. Adjuvants enhance the immunogenicity of vaccines, therefore they constitute essential components of vaccines. They are needed not only to increase the magnitude of the response but also to guide the type of response to produce the most effective type of immunity against distinct pathogens/tumors. The recent progress in our understanding of innate immunity has opened up new avenues for vaccine development. The innate immune system is comprised of APCs, in particular dendritic cells (DCs), which contain a series of pattern recognition receptors (PRRs). PRR agonists engage DCs to more effectively uptake and present antigens and provide indispensable initial signals that determine the type, magnitude and durability of adaptive response, therefore they constitute promising leads in vaccine adjuvant development. Simultaneous activation of distinct PRRs permits signal amplification. Covalent linkage of several PRR agonists can further enhance their adjuvant activity. Finding synergistic combinations of adjuvants to produce potent immune responses is therefore crucial for rational design and development of vaccines.

Our critical research goal is to develop innovative adjuvants capable of enhancing the immunogenicity of different vaccines. In the scope of this project, we propose an advanced multi-targeted approach to adjuvant development, by imparting the synergies of innate immune system to a single molecule. To achieve this, we will use an advanced chemical strategy to direct the immune system by constructing covalently linked multivalent agonists with unprecedented synergistic combinations. These conjugates will allow for simultaneous targeting of multiple targets within the same cell, thus enabling cross-activation of several arms of the innate immune system. Since liposomes and nanoparticles have successfully been used as carriers of antigens and adjuvants and also promote a potent cellular response while improving compound stability against enzymatic stress, our conjugates will be formulated in these carriers. The ground-breaking results of this project will allow us to harness the full strength of immune system and pave the way for a next-generation vaccines. Beyond this, it can be foreseen that these highly innovative adjuvants will find medical applications as part of vaccines for treatment of infectious diseases thus improving public health, while our findings will also reveal fundamental new information about how immune cells operate and uncover the underlying mechanisms.

Phases:

In order to achieve the goals of the proposed project, the work-packages and tasks are elaborated in detail in the following section. The project is organized around four highly interconnected work-packages targeting at specific objectives: Design and synthesis of conjugates (WP1), Biological evaluation in vitro (WP2), Investigation of adjuvant properties (WP3) and Management and dissemination (WP4). The first two phases: Design and synthesis of conjugates and Biological evaluation in vitro will often take place simultaneously and the results obtained in one cycle will be used as a basis for the next development cycle. By applying design and synthesis in several iterative cycles, highly interconnected with biological evaluation in vitro, innovative conjugates with custom-tailored properties will be constructed. Finally, the selected conjugates will progress into phase 3, the Investigation of adjuvant properties. WP4 – Management and dissemination will control the work-flow and make sure that the obtained results will be appropriately and timely communicated and disseminated. WP1: The main objectives of WP1 are to: (i) design and synthesize novel dual and triple conjugate libraries for biological screening; (ii) optimize pharmacodynamic properties of synthesized conjugates (iii) functionalize conjugates with (phospho)lipids to improve their pharmacokinetic properties; WP2: The overall aims of WP2 are to: (i) pharmacologically characterize and validate new conjugates provided by WP1 as multiple PRR agonists; (ii) perform mode-of-action studies and comprehensive pharmacological profiling for the most promising conjugates. The tasks described in WP2 have been planned to provide a seamless link with activities and outputs of WP1 and WP3 to provide pharmacological profiles of conjugates; WP3: The overall aims of WP3 are to: (i) investigate in vitro adjuvant activity of the most potent conjugates identified in WP2; (ii) formulate the most prominent conjugates identified in WP2 into liposomes/nanoparticles; (iii) investigate in vivo adjuvant activity of selected conjugate formulations; and WP4: The main objectives of WP4 are to coordinate and manage the successful execution of the proposed project.as well as disseminate and communicate information and results of the project among scientific community, stakeholders and general public.

Bibliographical references, arising directly from the implementation of the project:

https://cris.cobiss.net/ecris/si/en/project/18280

Financed by:

Research projects (co)funded by the Slovenian Research Agency.