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http://hdl.handle.net/11375/28367
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DC Field | Value | Language |
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dc.contributor.advisor | Thompson, Michael | - |
dc.contributor.advisor | Cranston, Emily | - |
dc.contributor.author | Singh, Varsha | - |
dc.date.accessioned | 2023-03-20T13:04:35Z | - |
dc.date.available | 2023-03-20T13:04:35Z | - |
dc.date.issued | 2023 | - |
dc.identifier.uri | http://hdl.handle.net/11375/28367 | - |
dc.description.abstract | Pulmonary immunization via inhalation of aerosolized vaccines offers enhanced immunity against respiratory diseases, in addition to the ability to mitigate cold-chain requirements. Achieving ideal particle size and consistent aerosolization of vaccine powders to achieve efficient lung deposition is challenging. In contrast to respiratory delivery of non-biological pharmaceuticals, there is no well characterized formulation platform readily adaptable to incorporating sensitive biologics like viruses and viral vectors. This work focuses on improving the aerosolization and bioactivity of spray dried vaccines to achieve the end goal of effective immunization via inhalation. The biologics studied in this work were human serotype 5 adenovirus (AdHu5) and Influenza H1N1 PR8 (influenza). First, eight amino acids, known to improve the dispersibility, were screened for improving aerosolization of adenovirus containing mannitol/dextran (control) powder. However, no amino acid significantly improved the aerosolization performance compared to the control, but the presence of amino acids was found to decrease the viral activity in dry powders. To understand the effect of amino acid concentration on aerosolization and underlying negative effects on adenovirus activity, L-leucine was chosen for further investigation due to its comparable aerosol performance to the control. While a high concentration of L-leucine (>50% (w/w)) improved the aerosolization significantly, it was found to cause aggregation of adenoviruses in liquid formulation prior to spray drying. Further, the factors underlying the activity losses of adenovirus in spray dried powders were explored. It was found that the presence of internal solid air interface within the microstructure of the dry particles are important indicators of activity losses in spray dried formulations. This work provides a deeper understanding of the previously unexplored causes of viral activity losses in liquid formulation (negative effects of amino acids on viruses) and dry particles (inactivation of viruses at solid air interfaces). Finally, a thermally stable dry powder vaccine platform with high aerosolization was developed for influenza vaccine and was tested for immunogenicity in mice. The work outlined the challenges associated with dry powder administration in murine models for preclinical studies and used a custom made dosator device. The final dry powder vaccine platform developed for influenza virus showed high aerosolization (>40% FPF) and elicited efficient immune response in mice. The dry powder formulation platform developed in this work can be explored for other vaccines. The knowledge gained from this work offers a major step forward in the development of marketable dry powder vaccines for inhalation. | en_US |
dc.language.iso | en | en_US |
dc.subject | spray drying, viral vectors, dry powder vaccines, aerosolization, inhalation, pulmonary delivery | en_US |
dc.title | Improving aerosolization and potency of a thermally stable spray dried vaccine platform for inhalation delivery | en_US |
dc.type | Thesis | en_US |
dc.contributor.department | Chemical Engineering | en_US |
dc.description.degreetype | Thesis | en_US |
dc.description.degree | Candidate in Philosophy | en_US |
dc.description.layabstract | Vaccine delivery by inhalation promises efficient protection from respiratory diseases like tuberculosis and influenza. Compared to injectable vaccines, inhalable dry powder vaccines offer several advantages: (1) ease of administration, (2) enhanced immunity, and (3) the ability to exhibit stability at high temperatures mitigating the need for refrigeration during storage and transport. However, achieving flowability of powder particles for reaching deep in the lungs is challenging, among other critical factors like maintaining the activity of the virus in dry vaccine powders. In this work, tuberculosis (TB) or flu virus containing powders were produced by spray drying, a process that rapidly converts a solution into dry powder. The solution components were screened and chosen to achieve high powder flowability and minimize viral activity loss during the process. Most importantly, the final powders developed in this work were suitable for inhalation and retained sufficient activity for immunization. The reported dry formulation platforms can be extended to other vaccines. The inhalation delivery of such dry powder vaccines can be a game changer in vaccine supply, providing better opportunities for stockpiling and mass vaccination, particularly in a pandemic setting. | en_US |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Singh_Varsha_2023 February_PhD.pdf | Varsha Singh_PhD Thesis | 4.73 MB | Adobe PDF | View/Open |
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