Preclinical development of lyophilized self-replicating RNA vaccines for COVID-19 and malaria with improved long-term thermostability.

Autor: Gulati GK; HDT Bio, 1150 Eastlake Ave E Suite 200A, Seattle, WA 98109, USA. Electronic address: gaurav.gulati@hdt.bio., Simpson AC; HDT Bio, 1150 Eastlake Ave E Suite 200A, Seattle, WA 98109, USA., MacMillen Z; MalarVx, Inc, 1551 Eastlake Ave E, Suite 100, Seattle, WA 98102, USA., Krieger K; HDT Bio, 1150 Eastlake Ave E Suite 200A, Seattle, WA 98109, USA., Sharma S; HDT Bio, 1150 Eastlake Ave E Suite 200A, Seattle, WA 98109, USA., Erasmus JH; HDT Bio, 1150 Eastlake Ave E Suite 200A, Seattle, WA 98109, USA., Reed SG; HDT Bio, 1150 Eastlake Ave E Suite 200A, Seattle, WA 98109, USA., Davie JW; MalarVx, Inc, 1551 Eastlake Ave E, Suite 100, Seattle, WA 98102, USA., Avril M; MalarVx, Inc, 1551 Eastlake Ave E, Suite 100, Seattle, WA 98102, USA., Khandhar AP; HDT Bio, 1150 Eastlake Ave E Suite 200A, Seattle, WA 98109, USA. Electronic address: amit.khandhar@hdt.bio.
Jazyk: angličtina
Zdroj: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2024 Nov 17; Vol. 377, pp. 81-92. Date of Electronic Publication: 2024 Nov 17.
DOI: 10.1016/j.jconrel.2024.11.023
Abstrakt: Messenger RNA (mRNA) vaccines against COVID-19 have demonstrated high efficacy and rapid deployment capability to target emerging infectious diseases. However, the need for ultra-low temperature storage made the distribution of LNP/mRNA vaccines to regions with limited resources impractical. This study explores the use of lyophilization to enhance the stability of self-replicating mRNA (repRNA) vaccines, allowing for their storage at non-freezing temperatures such as 2-8 °C or room temperature (25 °C). We lyophilized repRNA molecules complexed to a novel cationic emulsion delivery system, LION™, with different sugar-based lyoprotectants to identify candidates that provided the best vaccine integrity and effectiveness after being thermally stressed. For screening, we used repRNA encoding the reporter protein secreted embryonic alkaline phosphatase (SEAP) and for proof-of-concept, we used repRNA vaccines encoding SARS-CoV-2 full-length spike (WA-1 isolate) or full-length surface protein circumsporozoite (CS) of Plasmodium yoelii (Py). We found that lyophilization of LION/repRNA with sucrose provided the best colloidal stability, preserved in vitro expression, and induced equivalent antigen-specific antibody responses in mice compared to freshly prepared liquid LION/repRNA. Furthermore, lyophilized vaccines were stable for at least one week at 25 °C and at least one year at 2-8 °C. The cumulative analysis of stability-determining physicochemical data, in vitro potency, and in vivo immunogenicity in mice enabled the selection of a lead lyophilized composition containing 10 % w/v sucrose as the lyoprotectant. The data presented here provide a foundation for the clinical evaluation of next-generation thermostable repRNA vaccines that will enable more equitable vaccine access globally.
Competing Interests: Declaration of competing interest AK, AS, JE, SR are co-inventors on patent applications related to the LION materials described in this work. GG, AS, KK, SS, SR, and AK have equity interests in HDT Bio. MA, ZM and JD have equity interests in MalarVx, Inc.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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