Novel dry powder formulations of aluminum salt-adjuvanted vaccines for intranasal administration

Date

2017-12-07

Authors

Thakkar, Sachin

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Abstract

Many currently licensed and commercially available human vaccines contain insoluble aluminum salts as vaccine adjuvants. The primary particles of aluminum (oxy)hydroxide and aluminum (hydroxy)phosphate are in the nanometer-scale. However, when dispersed in an aqueous solution, the primary particles aggregate to form larger microparticles of 1-20 μm. A major limitation with these vaccines is that they must not be exposed to freezing temperatures during transport or storage such that the liquid vaccine freezes, because slow freezing causes irreversible coagulation that damages the vaccines (e.g., loss of efficacy). Therefore, vaccines that contain aluminum salts as adjuvants are formulated as liquid suspensions and are required to be kept in a cold chain (2-8o C) during transport and storage. Formulating vaccines adjuvanted with aluminum salts into dry powder that can be readily reconstituted before injection could address this limitation. Spray freeze-drying of vaccines with low concentrations of aluminum salts and high concentrations of trehalose alone, or a mixture of sugars and amino acids, as excipients can convert vaccines containing aluminum salts into dry powder, but fails to preserve the particle size and/or immunogenicity of the vaccines. In this dissertation, using ovalbumin as a model antigen adsorbed onto aluminum (oxy)hydroxide or aluminum (hydroxy)phosphate, a commercially available tetanus toxoid vaccine adjuvanted with potassium aluminum sulfate, a human hepatitis B vaccine adjuvanted with aluminum (oxy)hydroxide, and a human papillomavirus vaccine adjuvanted with aluminum hydroxyphosphate sulfate, it was showed that vaccines containing a relatively high concentration of aluminum salts (up to ~1%, w/v, of aluminum hydroxide) can be converted into a dry powder by thin-film freeze-drying by using low levels of trehalose (i.e., as low as 2% w/v) as an excipient. Importantly, the thin-film freeze-drying process did not cause particle aggregation, nor decreased the immunogenicity of the vaccines upon reconstitution. Moreover, we showed that the immunogenicity of thin-film freeze-dried OVA-adsorbed Alhydrogel® vaccine powder was not significantly changed after it was exposed for an extended period of time in temperatures as high as 40o C or subjected to repeated slow freezing-and-thawing. Nasal vaccination using a dry powder vaccine formulation represents an attractive, non-invasive delivery with better storage stability and provides added protection at mucosal surfaces. In this dissertation, we also demonstrate the feasibility of nasal immunization using the dry powder formulation of insoluble aluminum salt adjuvanted vaccines and a novel intranasal (IN) delivery technology. Special emphasis was put on the characterization of the formulation that can be realistically used in humans by a nasal dry powder delivery device. The dry powder vaccine elicited a significant serum antibody response in rats compared to that of liquid vaccine administered via subcutaneous injection or IN route. Significant mucosal specific IgA responses were also observed solely after IN delivery. In addition, in vitro nasal deposition study using nasal casts of adult humans using a novel nasal dry powder device shows that out of the total recovered powder developed showed that out of the recovered powder (~60%), about 90% stayed in the nose. This study demonstrates for the first time to our best knowledge the generation of potent systemic and mucosal immune responses using the dry powder form of an aluminum salt-adjuvanted vaccine and suggests dry powder vaccine formulations are a promising approach for mucosal vaccination targeting the nasal mucosa. Thin-film freeze-drying is a viable platform technology to produce dry powders of vaccines that contain aluminum salts. It is expected that immunization programs can potentially benefit by integrating thin-film freeze-drying into vaccine preparations

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