title: A cationic nanoemulsion for the delivery of next-generation RNA vaccines.
abstract: Nucleic acid-based vaccines such as viral vectors, plasmid DNA, and mRNA are being developed as a means to address a number of unmet medical needs that current vaccine technologies have been unable to address. Here, we describe a cationic nanoemulsion (CNE) delivery system developed to deliver a self-amplifying mRNA vaccine. This nonviral delivery system is based on Novartis's proprietary adjuvant MF59, which has an established clinical safety profile and is well tolerated in children, adults, and the elderly. We show that nonviral delivery of a 9 kb self-amplifying mRNA elicits potent immune responses in mice, rats, rabbits, and nonhuman primates comparable to a viral delivery technology, and demonstrate that, relatively low doses (75 µg) induce antibody and T-cell responses in primates. We also show the CNE-delivered self-amplifying mRNA enhances the local immune environment through recruitment of immune cells similar to an MF59 adjuvanted subunit vaccine. Lastly, we show that the site of protein expression within the muscle and magnitude of protein expression is similar to a viral vector. Given the demonstration that self-amplifying mRNA delivered using a CNE is well tolerated and immunogenic in a variety of animal models, we are optimistic about the prospects for this technology.
authors.affiliation: Novartis Vaccines, Cambridge, Massachusetts, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Brito
authors.affiliation: Novartis Vaccines, Cambridge, Massachusetts, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Chan
authors.affiliation: Novartis Vaccines, Cambridge, Massachusetts, USA.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Shaw
authors.affiliation: Novartis Vaccines, Holly Springs, North Carolina, USA.
authors.forename: Armin
authors.initials: A
authors.lastname: Hekele
authors.affiliation: Novartis Vaccines, Cambridge, Massachusetts, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Carsillo
authors.affiliation: Novartis Vaccines, Cambridge, Massachusetts, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Schaefer
authors.affiliation: Novartis Vaccines, Cambridge, Massachusetts, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Archer
authors.affiliation: Novartis Vaccines, Siena, Italy.
authors.forename: Anja
authors.initials: A
authors.lastname: Seubert
authors.affiliation: Novartis Vaccines, Cambridge, Massachusetts, USA.
authors.forename: Gillis R
authors.initials: GR
authors.lastname: Otten
authors.affiliation: Novartis Vaccines, Holly Springs, North Carolina, USA.
authors.forename: Clayton W
authors.initials: CW
authors.lastname: Beard
authors.affiliation: Novartis Vaccines, Holly Springs, North Carolina, USA.
authors.forename: Antu K
authors.initials: AK
authors.lastname: Dey
authors.affiliation: Novartis Vaccines, Cambridge, Massachusetts, USA; Current address: Hookipa Biotech AG, Helmut-Qualtinger-Gasse 2, Vienna, Austria.
authors.forename: Anders
authors.initials: A
authors.lastname: Lilja
authors.affiliation: Novartis Vaccines, Cambridge, Massachusetts, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Valiante
authors.affiliation: Novartis Vaccines, Cambridge, Massachusetts, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Mason
authors.affiliation: Novartis Vaccines, Cambridge, Massachusetts, USA.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Mandl
authors.affiliation: Novartis Vaccines, Cambridge, Massachusetts, USA.
authors.forename: Susan W
authors.initials: SW
authors.lastname: Barnett
authors.affiliation: Novartis Vaccines, Cambridge, Massachusetts, USA.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Dormitzer
authors.affiliation: Novartis Vaccines, Cambridge, Massachusetts, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Ulmer
authors.affiliation: Novartis Vaccines, Holly Springs, North Carolina, USA.
authors.forename: Manmohan
authors.initials: M
authors.lastname: Singh
authors.affiliation: Novartis Vaccines, Cambridge, Massachusetts, USA.
authors.forename: Derek T
authors.initials: DT
authors.lastname: O'Hagan
authors.affiliation: Novartis Vaccines, Cambridge, Massachusetts, USA. Electronic address: Andrew.Geall@novartis.com.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Geall
mesh_terms: D000818:Animals; D002412:Cations; D016503:Drug Delivery Systems / Q000379:methods*; D004655:Emulsions / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D007111:Immunity, Cellular; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000276:immunology*; D012367:RNA, Viral / Q000276:immunology*; D011817:Rabbits; D051381:Rats; D019444:Vaccines, DNA / Q000008:administration & dosage*
chemical_list: D002412:Cations; D004655:Emulsions; D012333:RNA, Messenger; D012367:RNA, Viral; D019444:Vaccines, DNA