Safety and biocompatibility of injectable vaccine adjuvants composed of thermogelling block copolymer gels

Abstract

Injectable thermogelling polymers have been recently investigated as novel adjuvants and delivery systems for next generation vaccines. As research into natural and synthetic biocompatible polymers progresses, the safety and biocompatibility of these compounds is of paramount importance. We have developed cationic pentablock copolymer (PBC) vaccine adjuvants based on Pluronic F127, a thermogelling triblock copolymer that has been approved by the FDA for multiple applications, and methacrylated poly(diethyl amino)ethyl methacrylate outer blocks. These novel materials have been demonstrated to effectively create an antigen depot, minimally impact antigen stability, and enhance the immune response to antigens (i.e., adjuvanticity) in mice. In this work, we investigated the safety and biocompatibility of the parent triblock Pluronic gels and the cationic PBC gels in mice. Histological analysis showed no injection site reactions and no damage to the liver or kidneys was observed upon administering the block copolymer formulations. However, the subcutaneous injection of a thermogelling Pluronic solution induced increased levels of lipids in the blood, with no further deleterious effects observed from the addition of the cationic outer blocks. This hyperlipidemia resolved within 30 days after the administration of the Pluronic formulation. To mitigate this adverse effect, the vaccine adjuvant formulations were modified by adding poly(vinyl alcohol), which allowed gelation, while reducing the amount of Pluronic in the formulation. This modified formulation abrogated the observed hyperlipidemia and no adverse effects were observed in the serum through biomarker analysis or at the injection site (i.e., inflammation) in comparison to the responses induced by administration of saline or incomplete Freund's adjuvant. These studies provide a foundation to developing these gels as adjuvants for next generation vaccines. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1754–1762, 2019.

Pentablock Copolymer Micelle Nanoadjuvants Enhance Cytosolic Delivery of Antigen and Improve Vaccine Efficacy while Inducing Low Inflammation

“…Rapid glycolytic activity as demonstrated by the TLR agonists in extracellular flux analysis has been reported to contribute to inflammation . In a separate study using cathepsin activity, we have demonstrated that micelles do not induce inflammation at the site of injection . Combined with the glycolytic activity of the micelles demonstrated in this work (Figure ), this suggests that a potential benefit of micelle adjuvants would be to avoid adverse inflammatory reactions.…”

“…In this study, we prepared low concentration PBCs in aqueous solutions to form micelles without gelation that still enhanced antibody responses. This also eliminates any potential inflammatory responses associated with the high polymer concentrations needed to form gels 31 . However, little is known about the mechanism of action of PBC micelle adjuvants; how they interact with innate immune cells; and how these interactions lead to the induction of effective adaptive immunity.…”

Structural Stability and Antigenicity of Universal Equine H3N8 Hemagglutinin Trimer upon Release from Polyanhydride Nanoparticles and Pentablock Copolymer Hydrogels

“…High concentrations of PBCs, like those used in this study, form hydrogels composed of micellar structures. Hydrogels comprised of 4.1 wt% PBC, and 5.9 wt% Pluronic F127 were prepared in PBS (0.05 M, pH 7.2) at 4 °C based on previous safety studies . rH3 3 protein was added to obtain a final concentration of 4 mg/mL in PBS.…”

Vaccine implants: current status and recent advancements

“…Narsimhan and co-workers, developed grafted cationic pentablock copolymers based on Pluronic F127 and poly(diethylaminoethylmethacrylate) (PDEAEM) blocks for sustained vaccine delivery. Following subcutaneous injection, these thermogelling polymers formed safe hydrogel depots in situ without any reactogenicity [73] and stimulated strong antigen-specific antibody responses when hydrogels were loaded with the OVA antigen [74].…”