(156k) Development of Multi-Adjuvant Systems for Vaccines Against Infectious Diseases

The ability to elicit potent humoral and cellular immune responses is a key element required for the development of efficacious prophylactic and therapeutic vaccine formulations. For vaccines against intracellular pathogens, the induction of a balanced, long-lived, and potent CD4⁺ and CD8⁺ T cell activation and proliferation is critical, combined with robust antibody responses. One strategy is to activate innate immunity and proinflammatory responses through Toll-like receptor-independent cytosolic pathways. Importantly, engagement of these mechanisms has demonstrated its ability to provide protection against bacterial challenge, and several small molecules have been evaluated in preclinical and clinical studies as vaccine adjuvants against infectious diseases.

Small molecules can bind to cytoplasmic receptors triggering signaling cascades that activate innate immunity. Despite their potential as adjuvants, small molecules have some limitations that need to be overcome. For example, there may be low exposure in target tissues due to their size and charge, and are prone to enzymatic biodegradation; with some off-target toxicities. In order to address these challenges, the use of drug delivery systems is being explored.

In this work, three different polymeric nanoparticle platforms were evaluated for small molecule delivery and for their capability to act synergistically as co-adjuvants and elicit robust immune responses. In these studies, nanoparticles based on natural and synthetic polymers were fabricated using water/oil/water and oil/water emulsions. Particle characterization was performed using dynamic light scattering, scanning electron microscopy, and zeta potential measurements that confirmed the size, morphology, and charge of the resulting nanoparticles. Small molecule compounds were loaded into each of the platforms, and their loading and release efficiency were determined using liquid chromatography. Finally, these systems were evaluated using in vivo murine models following parenteral administration to assess their ability to induce cytokine secretion, antibody and cell-mediated immunity. The results obtained demonstrate the potential of polymeric particulate systems as dual delivery and co-adjuvant platforms for the development of small molecule-adjuvanted prophylactic and therapeutic vaccines.