Next-generation adjuvants for mucosal vaccines

Currently, our world is facing an acute shortage of mucosal vaccine adjuvants. The recent progress in our understanding of innate immunity has opened up new avenues for mucosal vaccine development. The innate immune system is comprised of APCs, in particular dendritic cells (DCs), which contain a series of innate immune receptors. Ligands 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 both mucosal and systemic immune responses, 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 mucosal 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 mucosal vaccines. To that end, we propose two approaches: (i) pharmacokinetic optimization of NOD2 agonists, which are known to induce mucosal 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 multivalent conjugates, composed of NOD2 agonists and other innate immune ligands 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 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 mucosal vaccines for treatment of infectious diseases caused by novel and existing mucosal pathogens thus improving public health, while our findings will also shed light on the underlying mechanisms of innate immunity.