Scale-Up of a Thermostable Spray Dried Tuberculosis Vaccine Candidate and Development of a Thermostable Dry Powder COVID Vaccine Candidate

Vaccines are an important tool for maintaining global health and preventing widespread disease. Many vaccines are liquid presentations that must be kept frozen until use, which are then thawed and administered via parenteral injection. While this approach has been successful, challenges are still faced in several aspects, which can be avoided through conversion to a dry powder vaccine. First, the liquid vaccine presentations are generally reliant on the cold chain for distribution, which can cause logistical challenges in general transportation of vaccines, but especially in exposure to potentially harsh conditions encountered in the last mile of distribution. This may be avoided through glass stabilization in an amorphous powder form, such that the powder would be resilient enough to withstand exposure to room temperature conditions for long term, and higher temperature conditions over a shorter term without degradation of either the powder’s physical stability, or its encapsulated components. Second, liquid presentations of vaccines are normally given through parenteral injection, which both requires trained professionals to administer, and can pose risks for needlestick injuries and transfer of bloodborne illnesses if incidents occur during administration. Conversion to dry powder platforms can allow easier routes of administration, including pulmonary administration via dry powder inhalers (DPIs) or pressurized metered dose inhalers (pMDIs), or nasal administration via dry powder nasal spray devices, while preserving the ability to reconstitute and inject as a liquid presentation if needed. Both intranasal and pulmonary delivery provides more direct exposure of the vaccine components to mucous membranes, potentially conferring better mucosal immune responses than the systemic immune responses provoked via parenteral injection of vaccines. Third, creating a general dry powder platform for stabilization of different vaccine antigen and adjuvant systems may be useful for stockpiling for pandemic preparedness, in the case where many vaccines would need to be distributed rapidly. Using a dry powder platform could allow many doses of stabilized adjuvant system to be kept at room temperature conditions for an extended period of time, to which different antigens could be added for a more rapid response when faced with a pandemic situation. This thesis presents the engineering of stable dry powder platforms for vaccine candidates suitable for either pulmonary or nasal delivery. It includes both in silico modelling of spray drying processes to manufacture the dry powder platforms, as well as in vitro techniques to measure the powders’ initial performance and performance on stability when exposed to various temperature conditions. Chapter 2 is a publication in the International Journal of Pharmaceutics: Aisenstat, M., McCollum, J., Ordoubadi, M., Wang, H., Minootan, Z., Gerhardt, A., Martin, A. R., Fox, C. B., Vehring, R.: Scale-up of a Low-temperature Spray-drying Process for a Tuberculosis Vaccine Candidate using Lab-scale Equipment. International Journal of Pharmaceutics, 674, 125456, 2025. The publication outlines the scale-up process for an adjuvanted subunit tuberculosis (TB) vaccine. The paper also highlights initial physical and chemical performance results, demonstrating the success of the scale-up optimization process Chapter 3 discusses the stability results of the scaled-up TB vaccine powder produced in the publication from Chapter 2. This chapter both goes into more depth about how the powder stability holds up when exposed to temperature conditions ranging from -20 °C to 50°C for up to 19.5 months of exposure. This chapter also explores the use of different administration devices, including a DPI for pulmonary delivery, a nasal dry powder delivery device for nasal delivery, and the feasibility of using pMDIs for this application, via a study of the powder’s colloidal stability when suspended in several propellant samples. Chapter 4 is a paper submitted for publication, which discusses the design, spray drying, and accelerated stability results of a COVID-19 vaccine using both a different antigen and adjuvant system compared to the TB vaccine in previous chapters. This publication explores several different formulations at two temperature conditions.