A Cationic Nanoemulsion for the Delivery of Next-generation RNA Vaccines
Open accessAbstract
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.
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Self-amplifying mRNA vaccines benefited from formulation with lipid nanoparticles or cationic nanoemulsion and were able to induce protective antibody titers.
“Studies with self-amplifying mRNA vaccines investigated the effect of different formulations such as lipid-nanoparticles (LNP)10 or cationic nanoemulsion (CNE)11 on the immunogenicity of mRNA vaccines. Self-amplifying vaccines benefited from formulation with LNP or CNE and were able to induce protective antibody titers.”
From Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines (2017) · cites this paper as [11]
Non-replicating mRNA did not induce any detectable antibody titers even when formulated with cationic nanoemulsion.
“In contrast, non-replicating mRNA did not induce any detectable antibody titers even when formulated with CNE.”
From Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines (2017) · cites this paper as [11]
Cationic squalene emulsions can be applicable for mRNA delivery.
“Finally, cationic squalene emulsions can be applicable for mRNA delivery.336,337”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [336]
Several preclinical studies have delivered mRNA vaccines encoding HIV proteins using multiple delivery vehicles, but they have had varied success.
“Several preclinical studies have delivered mRNA vaccines encoding HIV proteins using multiple delivery vehicles, including cationic nanoemulsions109,161, DOTAP/DOPE liposomes162, polymers84,163,164 and ionizable LNPs165,166, but they have had varied success.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [109]
Novel antigens are necessary to effectively target HIV in addition to potent delivery vehicles.
“These studies suggest that novel antigens are necessary to effectively target HIV in addition to potent delivery vehicles.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [109]
In preclinical studies, mRNA vaccines encoding either the native RSV F protein or the stabilized prefusion conformation were successfully delivered using cationic nanoemulsions and lipid nanoparticles without any observed instances of VAED.
“In preclinical studies, mRNA vaccines encoding either the native RSV F protein or the stabilized prefusion conformation were successfully delivered using cationic nanoemulsions109 and LNPs179,180 without any observed instances of VAED.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [109]
Lipid nanoparticle-mRNA vaccines have been tested against other viruses in animal models, including human immunodeficiency virus, Powassan virus, Venezuelan equine encephalitis virus, dengue virus and Ebola virus.
“Furthermore, lipid nanoparticle–mRNA vaccines have been tested against other viruses in animal models, including human immunodeficiency virus28,144,181,190, Powassan virus195, Venezuelan equine encephalitis virus196, dengue virus73 and Ebola virus197.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [28]
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References 46 · Cited by 338
- Authors
- Brito, L. A., Chan, M., Shaw, C. A., Hekele, A., Carsillo, T., Schaefer, M., Archer, J., Seubert, A., Otten, G. R., Beard, C. W., Dey, A. K., Lilja, A., Valiante, N. M., Mason, P. W., Mandl, C. W., Barnett, S. W., Dormitzer, P. R., Ulmer, J. B., Singh, M., O'Hagan, D. T., & Geall, A. J.
- Affiliations
- Novartis (Italy) (IT)
- Corresponding author
- Geall, Andrew J
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 22
- Issue
- 12
- Pages
- 2118-2129
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC4429691
- OpenAlex
- W1994674548
- Cited by
- 338
- References
- 46
- Citations by year
- 2026: 15 · 2025: 28 · 2024: 35 · 2023: 37 · 2022: 51 · 2021: 52 · 2020: 28 · 2019: 23 · 2018: 20 · 2017: 16 · 2016: 16 · 2015: 10 · 2014: 7
- FWCI
- 6.70
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Defense Advanced Research Projects Agency (HR0011-12-3-001)
- University of California, Davis
- National Institute of Biological Resources
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Keywords
- cationic nanoemulsions, self-amplifying mRNA vaccine, mRNA vaccine delivery, MF59 adjuvant, nucleic acid-based vaccines, immunogenicity, muscle protein expression
- MeSH terms
- Animals, Cations, Emulsions, Female, Immunity, Cellular, Macaca mulatta, Mice, Inbred BALB C, Rabbits, RNA, Messenger, RNA, Viral, Drug Delivery Systems, Vaccines, DNA, Mice, Rats
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