Evaluation of Biocompatibility of Novel Block Copolymer Gels/Micelles As Potential Vaccine Adjuvants

Evaluation of biocompatibility of novel block copolymer gels/micelles as potential vaccine adjuvants

Justin R. Adams¹, Sujata Senapati¹, Michael J. Wannemuehler², Balaji Narasimhan¹, Surya Mallapragada¹

¹Chemical & Biological Engineering; ²Veterinary Microbiology and Preventive Medicine;

Iowa State University, Ames, IA

In addition to being delivery systems for antigens, an ideal adjuvant should be able to modulate an effective innate immune response and enhance the induction of long-lasting immunity. Adjuvant platforms may also allow for fewer doses required and less invasive routes of vaccine administration. Even after decades of research, presently only a few vaccine adjuvants, such as, alum and oil in water emulsion, are approved for safe human usage. However, vaccines adjuvanted with these compounds have long been associated with inflammation at the injection site. Therefore, it is essential to discard the practice of using off-the-shelf adjuvants for vaccines and move towards the design and implementation of novel vaccine adjuvants. Biocompatible polymers have been recently investigated as novel adjuvants and delivery systems for next generation vaccines. However, as research into new polymeric adjuvants progresses, the safety of these compounds is of great concern. There is a need to balance the immunomodulatory properties of vaccine adjuvants with the desire to improve patient compliance by avoiding adverse reactions such as pain, redness, and swelling (i.e., reactogenicity) at the site of administration.

Amphiphilic block copolymers have been used for applications in gene therapy and drug delivery in vivo. Our research group has previously synthesized cationic pentablock copolymers following a new method of catalysis for atom transfer radical polymerization (ATRP), which significantly reduces in vitro cellular toxicity of the polymer. These pentablock copolymers are composed of FDA approved Pluronic F127 and pendant amine groups of poly(2-diethylaminoethylmethacrylate) with reversible micelle and gel formation capabilities in response to external stimuli such as temperature and/or pH. In the micellar phase, these pentablock copolymer can act as a cargo hold for various protein payloads allowing for sustained release of the antigen.

In this work, we investigate the safety and biocompatibility of the pentablock copolymer gels/micelles in a murine model. This study included serum and urine analysis, assessment of inflammation at the injection site, proinflammatory cytokine analysis, and histopathological analysis. Mice were subcutaneously immunized with micelle/gel formulations and were compared to separate groups of mice treated with saline or incomplete FreundÕs adjuvant (IFA).  For the urinalysis, little to no statistical difference in the quantity of creatinine in urine of mice administered with the pentablock copolymer formulations was observed when compared to the saline alone group. The histopathological studies of the administration site tissue, kidney, and liver showed no adverse reactions. Using a live animal imager, local inflammation was assessed and was shown to be markedly less inflammatory post-administration of the block copolymer when compared to IFA.

Combined with previous studies demonstrating the induction of robust humoral immunity in mice, the results of this study highlight the safety and adjuvanticity of the pentablock copolymer micelle/gel vaccine delivery platform.