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http://hdl.handle.net/11375/27560
Title: | Improving Thermal Stability and Intratracheal Delivery of Viral-Vectored Dry Powder Vaccines |
Authors: | Manser, Myla |
Advisor: | Thompson, Michael Cranston, Emily |
Department: | Chemical Engineering |
Keywords: | Dry Powder Vaccines;Thermal Stabilty;Inhalation;Spray Drying |
Publication Date: | 2022 |
Abstract: | As the global public health community continues to strive for more equitable vaccine access, thermal instability of liquid vaccines continues to be a significant challenge due to strict cold-chain temperature requirements. Dry powder vaccines offer a favourable alternative, with the ability to retain vaccine efficacy at ambient temperature conditions. In the form of dry powder, vaccines against respiratory diseases can also be administered via inhalation for targeted delivery to the lung tissue. A processing technique known as spray drying is particularly promising for the development of thermally stable and inhalable dry powder vaccines, offering a method of continuous and scalable production. Spray drying is widely used in the pharmaceutical industry and can effectively encapsulate and immobilize labile biologics, like adenoviral vectors, within a glassy carbohydrate matrix to help retain biologic function. However, pulmonary delivery of a thermally stable, viral vectored dry powder vaccine has yet to be demonstrated. This thesis focuses on improving the formulation of a carbohydrate excipient blend of mannitol and dextran encapsulating a human serotype 5 adenovirus (AdHu5), with the goal of producing an inhalable vaccine with sufficient viral potency for in vivo murine testing. First, the impact of cryoprotective agents used for frozen storage of the stock adenovirus was investigated with respect to viral activity retention, thermal stability and inhalation properties of the dry powder after spray drying. Trehalose was considered a preferred cryoprotective agent, compared to glycerol traditionally used for adenoviral cryo-storage, allowing for the preparation of a high potency viral dry powder with 1.5 log loss of viral titre after processing and thermal aging. Further investigation of the dextran mass ratio and dextran molecular weight used within the excipient blend revealed that incorporating mannitol in a 1:3 ratio with 500 kDa dextran can further improve viral activity to achieve 0.8 log loss of viral titre after aging. Through controlled drying dynamics, this formulation led to improved activity retention and thermal stability, in addition to desirable aerosolization properties for pulmonary delivery. Using this optimized formulation, custom-made intratracheal dosator devices were evaluated for pulmonary powder delivery in mice. The method of powder loading in the device was found to be a significant factor of device performance in vivo when determining if the critical powder mass dosage could be delivered. Successful intratracheal delivery of the AdHu5-vectored dry powder was achieved with a pipette-tip loading dosator and led to a strong bioactive response. Overall, this work indicates the feasibility of murine pulmonary delivery and immunological testing of a thermally stable, adenoviral-vectored vaccine in dry powder form. |
Description: | This work focuses on the development of a spray dried adenoviral vector for its application as a thermally stable and inhalable vaccine against tuberculosis. |
URI: | http://hdl.handle.net/11375/27560 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Manser_Myla_M_2022May_MASc.pdf | 2.91 MB | Adobe PDF | View/Open |
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