Acid-sensitive Polymer Microparticles for Subunit Vaccine Delivery

Download or read book Acid-sensitive Polymer Microparticles for Subunit Vaccine Delivery written by Matthew D. Gallovic and published by . This book was released on 2016 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Vaccines are one of the most significant contributions to modern medicine, as they are credited with such feats as the near or complete eradication of devastating diseases (e.g., polio, smallpox). Despite these successes, more conventional formulations (e.g., live-attenuated pathogens) have critical drawbacks that limit their use to healthy patients. Subunit vaccines are an appealing alternative because they contain safe antigens and can be universally administered. The Food and Drug Administration’s (FDA’s) mid-1980s approval of the first subunit vaccine containing a recombinant protein antigen has fostered our ability to develop new protein-based formulations. However, a common issue with protein antigens continues to be their lack of immunogenicity and structural sensitivity. Compounds known as adjuvants are used to boost the efficacy of protein-based subunit vaccines. Aluminum salts (alum) were the only FDA-approved adjuvants for many years, but they have a poorly-defined mechanism of action and, more importantly, have limited efficacy against many pathogens. A more recent generation of adjuvants known as pathogen-associated molecular patterns (PAMPs) analogs can induce broader immune responses against many pathogens. In 2009, the FDA approved an adjuvant formulation containing alum along with a PAMP analog (monophosphoryl lipid A). This has catalyzed the use of countless other PAMP analog adjuvants, but their widespread application is still limited by factors such as the intracellular location of many of their target receptors. Vehicles such as polymer particles can aid in enhancing antigenicity and adjuvanticity by offering sustained and passive targeted delivery to phagocytic antigen-presenting cells (APCs). However, many traditional polymer particle formulation methods are denaturing to structurally sensitive protein antigens. Furthermore, many of these processes encapsulate proteins and adjuvants inefficiently. In this work, acid-sensitive polymer particles that exploit the acidic endocytic pathway of APCs are developed and used to deliver protein antigens and/or PAMP analog adjuvants to boost the efficacy of subunit vaccines. Particular attention is paid to developing (i) dual-functioning immunostimulatory polymer vehicles that can deliver protein antigens, (ii) mild processes that can efficiently encapsulate both protein antigens and adjuvants, and (iii) polymer particles that can be conjugated with protein antigens post-fabrication.