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The role of nanoparticle format and route of administration on self-amplifying mRNA vaccine potency
Giulia Anderluzzi1, Gustavo Lou1, Stuart Woods2
1Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral St., Glasgow G4 0RE, Scotland, UK; GSK, Siena, Italy.
Abstract:
The efficacy of RNA-based vaccines has been recently demonstrated, leading to the use of mRNA-based COVID-19 vaccines. The application of self-amplifying mRNA within these formulations may offer further enhancement to these vaccines, as self-amplifying mRNA replicons enable longer expression kinetics and more potent immune responses compared to non-amplifying mRNAs. To investigate the impact of administration route on RNA-vaccine potency, we investigated the immunogenicity of a self-amplifying mRNA encoding the rabies virus glycoprotein encapsulated in different nanoparticle platforms (solid lipid nanoparticles (SLNs), polymeric nanoparticles (PNPs) and lipid nanoparticles (LNPs)). These were administered via three different routes: intramuscular, intradermal and intranasal. Our studies in a mouse model show that the immunogenicity of our 4 different saRNA vaccine formulations after intramuscular or intradermal administration was initially comparable; however, ionizable LNPs gave higher long-term IgG responses. The clearance of all 4 of the nanoparticle formulations from the intramuscular or intradermal administration site was similar. In contrast, immune responses generated after intranasal was low and coupled with rapid clearance for the administration site, irrespective of the formulation. These results demonstrate that both the administration route and delivery system format dictate self-amplifying RNA vaccine efficacy.
Insights
Self-amplifying RNA (saRNA) vaccine efficacy depends on delivery. Intramuscular or intradermal routes with lipid nanoparticles showed superior long-term immune responses compared to intranasal delivery.
Area of Science:
- Vaccinology
- Nanotechnology
- Immunology
Background:
- Messenger RNA (mRNA) vaccines have shown efficacy, particularly for COVID-19.
- Self-amplifying mRNA (saRNA) offers potential advantages over non-amplifying mRNA, including prolonged expression and enhanced immune responses.
- Investigating nanoparticle delivery systems and administration routes is crucial for optimizing saRNA vaccine potency.
Purpose of the Study:
- To evaluate the immunogenicity of saRNA vaccines encoding rabies virus glycoprotein.
- To compare the impact of different nanoparticle formulations (SLNs, PNPs, LNPs) on vaccine efficacy.
- To assess the influence of administration route (intramuscular, intradermal, intranasal) on saRNA vaccine performance.
Main Methods:
- Encapsulation of saRNA encoding rabies virus glycoprotein into solid lipid nanoparticles (SLNs), polymeric nanoparticles (PNPs), and lipid nanoparticles (LNPs).
- Administration of the four saRNA vaccine formulations (including ionizable LNPs) via intramuscular, intradermal, and intranasal routes in a mouse model.
- Assessment of immune responses, specifically long-term IgG levels, and clearance rates from administration sites.
Main Results:
- Intramuscular and intradermal administration of saRNA vaccines yielded initially comparable immunogenicity across formulations.
- Ionizable lipid nanoparticles (LNPs) demonstrated superior long-term IgG responses after intramuscular or intradermal delivery.
- Intranasal administration resulted in low immune responses and rapid clearance, regardless of the nanoparticle formulation used.
Conclusions:
- Both the administration route and the nanoparticle delivery system significantly influence the efficacy of self-amplifying RNA vaccines.
- Lipid nanoparticle formulations delivered intramuscularly or intradermally are promising for achieving robust and sustained immune responses.
- Intranasal delivery of saRNA vaccines requires further optimization to overcome limitations in immunogenicity and retention.
