Cited by 48RNA Interference and Gene DeliveryImmunotherapy and Immune ResponsesAdvanced Drug Delivery Systems

Effects of cationic adjuvant formulation particle type, fluidity and immunomodulators on delivery and immunogenicity of saRNA

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Blakney, Anna K., McKay, Paul F., Christensen, Dennis, Yus, Bárbara Ibarzo, Aldon, Yoann, Follmann, Frank, Shattock, Robin J.·2019·Journal of Controlled Release

Abstract

Self-amplifying RNA (saRNA) is well suited as a vaccine platform against chlamydia, as it is relatively affordable and scalable, has been shown to induce immunity against multivalent antigens, and can result in protein expression for up to 60 days. Cationic adjuvant formulations (CAFs) have been previously investigated as an adjuvant for protein subunit vaccines; here we optimize the CAFs for delivery of saRNA in vivo and observe the immunogenicity profile in the context of both cellular and humoral immunity against the major outer membrane protein (MOMP) of Chlamydia trachomatis. We tested both liposomal and emulsion based CAFs with solid and fluid phase lipids, with or without the TLR agonists R848 and 3M-052, for in vitro transfection efficiency and cytotoxicity. We then optimized the RNA/delivery system ratio for in vivo delivery using saRNA coding for firefly luciferase (fLuc) as a reporter protein in vivo. We observed that while the fluid phase liposome formulations showed the highest in vitro transfection efficiency, the fluid and solid phase liposomes had equivalent luciferase expression in vivo. Incorporation of R848 or 3M-052 into the formulation was not observed to affect the delivery efficiency of saRNA either in vitro or in vivo. MOMP-encoding saRNA complexed with CAFs resulted in both MOMP-specific cellular and humoral immunity, and while there was a slight enhancement of IFN-γ+ T-cell responses when R848 was incorporated into the formulation, the self-adjuvanting effects of RNA appeared to dominate the immune response. These studies establish that CAFs are efficient delivery vehicles for saRNA both for in vitro transfections and in vivo immunogenicity and generate cellular and humoral responses that are proportionate to protein expression.

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Crossref · 10.1016/j.jconrel.2019.04.043

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Authors
Blakney, A. K., McKay, P. F., Christensen, D., Yus, B. I., Aldon, Y., Follmann, F., & Shattock, R. J.
Affiliations
  • Imperial College London (GB)
  • Statens Serum Institut (DK)
Corresponding author
Shattock, Robin J.
Venue
Journal of Controlled Release
Publisher
Elsevier BV
Published
2019-06
Volume
304
Pages
65-74
ISSN
0168-3659 (ISSN-L)
OpenAlex
W2944452880
Cited by
48
References
45
Citations by year
2026: 3 · 2025: 8 · 2024: 10 · 2023: 2 · 2022: 6 · 2021: 7 · 2020: 11 · 2019: 1
FWCI
2.06
Type
journal article
Language
en
Open access
Locations
  • Journal of Controlled Release (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion, cc-by-nc-nd)
Funders
  • EPSRC
  • European Commission (280873)
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 › Advanced Drug Delivery Systems
Keywords
self-amplifying RNA, Chlamydia trachomatis, major outer membrane protein, liposomes, emulsions, lipid phase, TLR agonists, R848, immunogenicity, humoral and cellular immune response, IFN-γ T cell response, firefly luciferase reporter
MeSH terms
Immunogenicity, Vaccine, Adjuvants, Immunologic, Animals, Bacterial Vaccines, Cations, Chlamydia Infections, Chlamydia trachomatis, Female, Heterocyclic Compounds, 3-Ring, Imidazoles, Immunity, Cellular, Immunologic Factors, Liposomes, Mice, Inbred BALB C, RNA, Stearic Acids, Transfection, Mice, Immunity, Humoral

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