Research

Charting new horizons: Unlocking the potential of NOD1, a versatile force in immunity

Code:

J3-70142

Range:

01. March 2026 - 28. February 2029

Range:

1.25 FTE

Leader:

Žiga Jakopin

Field:

3.01 Medical sciences/ Microbiology and immunology

Abstract:

Currently, our world is facing an acute shortage of vaccine adjuvants. The recent progress in our understanding of innate immunity has opened up new avenues for adjuvant development. The innate immune system is comprised of APCs, in particular dendritic cells (DCs), which contain a series of innate immune receptors. Agonists of these receptors 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. Innate immune ligands can elicit potent systemic immune response, but are not necessarily sufficiently effective. In addition, toxicity and tolerance may occur upon administration. Simultaneous activation of distinct innate immune receptors by a mixture of agonists can bypass this tolerance and permits signal amplification, thus leading to a more efficient immune response. Covalent linkage of these agonists can further enhance this response. Finding synergistic combinations of adjuvants to produce potent immune responses is therefore crucial for rational design and development of vaccines. At the same time, this allows us to reduce the dose of the adjuvant, which concomitantly reduces the potential dose-limiting toxicity.

Our critical research goal is to develop innovative adjuvants capable of enhancing the immunogenicity of vaccines. To that end, we propose two approaches: (i) optimization of NOD1 agonists, which are known to induce immune responses; and (ii) 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 bivalent conjugates, composed of NOD1 agonists and other innate immune 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 innate immune system. Since nanoparticles and liposomes have successfully been used as carriers of antigens and adjuvants while also improving compound stability, our compounds 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 next-generation vaccines. Our innovative adjuvants will find medical applications as part of vaccines for treatment of infectious diseases caused by novel and existing pathogens thus improving public health, while our findings will also shed light on the underlying mechanisms of innate immunity.