Adjuvant-carrying targeted Synthetic Vaccine Particles (tSVP™) augment the immune response to encapsulated antigen and exhibit strong local immune activation without inducing systemic cytokine release (75.3)

Abstract

Abstract Augmentation of immunogenicity can be achieved by particulate delivery of an antigen and also by its co-administration with an adjuvant. However, many adjuvants initiate strong systemic inflammatory reactions resulting in safety concerns. Here we show that co-delivery of an antigen encapsulated into synthetic polymer nanoparticles with TLR7/8 or TLR9 agonists results in a strong elevation of immune responses which does not involve systemic production of inflammatory cytokines. In contrast, antigen admixed with free TLR7/8 agonist leads to lower immunogenicity and to rapid induction of serum cytokines associated with toxicity and immune suppression (e.g., TNF-α and IL-6 levels are 50-200 times higher upon injection of free than of encapsulated TLR7/8 agonist). Conversely, local immune stimulation as seen by cellular infiltration of draining lymph nodes and by intranodal cytokine production was much more pronounced and persisted longer if particle-encapsulated TLR agonists were used. Moreover, particle encapsulation permitted the efficient utilization of immunostimulatory CpG sequences with an enzyme-labile phosphodiester backbone which are known to rapidly degrade in vivo. The strong local immune activation in lymph nodes which resulted in a marked augmentation of immunogenicity was achieved using a modular self-assembling polymer nanoparticle platform and was equally efficient whether antigen and adjuvant were encapsulated in a single particle or in two separate particles.