(635g) Pulmonary Persistence of Intranasally Administered Polyanhydride Nanovaccines

Polyanhydrides are a class of degradable biomaterials that are suitable for the encapsulation and delivery of subunit vaccines. Nanoparticles comprised of sebacic acid (SA), 1,6-bis-(p-carboxyphenoxy)hexane (CPH), 1,8-bis-(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG), and their copolymers have shown the ability to sustain the release and enhanced internalization of fragile protein antigens. Polyanhydride nanovaccines have also demonstrated immunomodulatory capabilities, and more recently, full protection against a lethal bacterial challenge of Yersinia pestis was demonstrated 42 weeks post-vaccination using a single intranasal dose.

Intranasal vaccination is an advantageous strategy to induce both systemic and mucosal immunity while avoiding antigen degradation in the first pass metabolism and increasing bioavailability via the large adsorptive surface area. However, it has been shown that soluble antigen alone delivered intranasally does not induce a protective immune response, and therefore, requires the use of adjuvants. Previously, we have demonstrated the favorable deposition, distribution, and persistence of antigen delivered with polyanhydride nanovaccines at early time points after administration, which enhances internalization by antigen presenting cells (APCs) such as macrophages and dendritic cells. While the initial interactions between antigen-loaded nanoparticles and APCs are important in laying a foundation for vaccine efficacy, we hypothesize that the persistence of antigen released from polyanhydride nanoparticles plays a central/key role in the continual recruitment of APCs and the development of high antibody titers with increased avidity. In this work, we followed the persistence of intranasally administered antigen-containing polyanhydride nanoparticles over nine weeks. Utilizing live animal imaging, high throughput microscopy, and flow cytometry, we studied the impact of particle chemistry on the creation of a tunable erosion profile to control antigen release and persistence. Our results demonstrate the impact of persistent antigen encapsulated into polyanhydride nanoparticles on APC interactions in comparison with that of monophosphoryl lipid A (MPLA), and provide new insights into the underlying mechanisms behind the induction of high titer and highly avid antibody upon intranasal administration of nanovaccines.

S.H. and K.A.R. contributed equally to the design and performance of this work.