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Manufacturing and Characterization of Potent mRNA Lipid Nanoparticle Vaccines at Multiple Scales

Award Number: R01FD007457
ORGANIZATION: FOOD AND DRUG ADMINISTRATION
OPDIV: FDA
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Manufacturing and Characterization of Potent mRNA Lipid Nanoparticle Vaccines at Multiple Scales - PROJECT SUMMARY mRNA vaccines have received emergency authorization approval for Covid-19 and are under development for several other infectious diseases. The mRNA-encoded immunogen in these vaccines is delivered inside a lipid nanoparticle (LNP) that comprises four lipids, the most important being the ionizable lipid that is responsible for releasing the mRNA from intracellular endosomes through protonation of amine groups that interact with the endosomal membrane. Clinical studies showed these vaccines are highly efficacious with over 94% of patients protected from SARS-CoV-2 infection. Although the successful development of mRNA LNP vaccines for SARS- Cov-2 constitutes a major breakthrough for a novel medical modality, it has also highlighted several unanswered questions surrounding this platform that require urgent investigation including : 1) What are the critical features of mRNA LNP manufacturing that need to be respected to create potent systems ? 2) What is functional consequence of truncated mRNA transcripts produced by in vitro translation (IVT) or by degradation and how can they be minimized through IVT optimization ? 3) What causes degradation of mRNA LNPs during manufacturing and storage and how can this be measured and minimized ? We recently discovered a new process to rationally design ionizable lipids for increased potency. We also discovered a novel manufacturing process to assemble the mRNA LNP such that the same lipid and mRNA components produce a much more efficient and potent delivery system. This allows more of the mRNA in the LNP to be translated thereby reducing dose and reactogenicity and increasing the number of people that can be vaccinated with the same quantity of vaccine. We have initiated studies to characterize and understand mRNA LNP stability that can affect the quality and performance of these vaccines. In this proposal we will perform studies to further the understanding of how mRNA LNPs are assembled and manufactured at different manufacturing scales from laboratory scale to commercial scale. The lack of public information in this area is a major impediment to improving and broadening the use of this new vaccine modality. We will also illuminate the presence and importance of the heterogeneity of different transcripts in the mRNA drug substance and how that heterogeneity could impact product performance. And finally, the stability of mRNA LNPs during manufacturing and storage will be studied to understand the degradation mechanisms causing loss of bioactivity and structural integrity of the mRNA and lipids, how to measure these properties, and develop formulations that have extended stability profiles compared to current products.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	GEORGE MASON UNIVERSITY	4400 UNIVERSITY DR	FAIRFAX	VA	22030	FAIRFAX CITY	USA	Food and Drug Administration Research	000	3	7/8/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $498,828 )
2023	2023	GEORGE MASON UNIVERSITY	4400 UNIVERSITY DR	FAIRFAX	VA	22030	FAIRFAX CITY	USA	Food and Drug Administration Research	002	3	9/8/2023	NON-COMPETING CONTINUATION	$498,828
2023	2022	GEORGE MASON UNIVERSITY	4400 UNIVERSITY DR	FAIRFAX	VA	22030	FAIRFAX CITY	USA	Food and Drug Administration Research	000	2	3/30/2023	NON-COMPETING CONTINUATION	$0
2023	2021	GEORGE MASON UNIVERSITY	4400 UNIVERSITY DR	FAIRFAX	VA	22030	FAIRFAX CITY	USA	Food and Drug Administration Research	001	1	5/8/2023	NEW	$0
														Subtotal = $498,828

Issue Date FY: 2022 ( Subtotal = $491,446 )
2022	2022	GEORGE MASON UNIVERSITY	4400 UNIVERSITY DR	FAIRFAX	VA	22030	FAIRFAX CITY	USA	Food and Drug Administration Research	001	2	9/1/2022	NON-COMPETING CONTINUATION	$491,446
2022	2021	GEORGE MASON UNIVERSITY	4400 UNIVERSITY DR	FAIRFAX	VA	22030	FAIRFAX CITY	USA	Food and Drug Administration Research	000	1	4/20/2022	NEW	$0
														Subtotal = $491,446

Issue Date FY: 2021 ( Subtotal = $498,998 )
2021	2021	GEORGE MASON UNIVERSITY	4400 UNIVERSITY DR	FAIRFAX	VA	22030	FAIRFAX CITY	USA	Food and Drug Administration Research	000	1	9/21/2021	NEW	$498,998
														Subtotal = $498,998

Grand Total All Awards = $1,489,272

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Manufacturing and Characterization of Potent mRNA Lipid Nanoparticle Vaccines at Multiple Scales

Award Number: R01FD007457

ORGANIZATION: FOOD AND DRUG ADMINISTRATION

OPDIV: FDA

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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