Delivery of self-amplifying mRNA vaccines by cationic lipid nanoparticles: the impact of cationic lipid selection

Gustavo Lou, Giulia Anderluzzi, Signe Tandrup Schmidt, Stuart Woods, Simona Gallorini, Michela Brazzoli, Fabiola Giusti, Ilaria Ferlenghi, Russell Johnson, Craig W. Roberts, Derek T. O'Hagan, Barbara C. Baudner, Yvonne Perrie

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Self-amplifying RNA (SAM) represents a versatile tool that can be used to develop potent vaccines, potentially able to elicit strong antigen-specific humoral and cellular-mediated immune responses to virtually any infectious disease. To protect the SAM from degradation and achieve efficient delivery, lipid nanoparticles (LNPs), particularly those based on ionizable amino-lipids, are commonly adopted. Herein, we compared commonly available cationic lipids, which have been broadly used in clinical investigations, as an alternative to ionizable lipids. To this end, a SAM vaccine encoding the rabies virus glycoprotein (RVG) was used. The cationic lipids investigated included 3ß-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol (DC-Chol), dimethyldioctadecylammonium (DDA), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 1,2-dimyristoyl-3-trimethylammonium-propane (DMTAP), 1,2-stearoyl-3-trimethylammonium-propane (DSTAP) and N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium (DOBAQ). Whilst all cationic LNP (cLNP) formulations promoted high association with cells in vitro, those formulations containing the fusogenic lipid 1,2-dioleoyl-sn-3-phosphoethanolamine (DOPE) in combination with DOTAP or DDA were the most efficient at inducing antigen expression. Therefore, DOTAP and DDA formulations were selected for further in vivo studies and were compared to benchmark ionizable LNPs (iLNPs). Biodistribution studies revealed that DDA-cLNPs remained longer at the injection site compared to DOTAP-cLNPs and iLNPs when administered intramuscularly in mice. Both the cLNP formulations and the iLNPs induced strong humoral and cellular-mediated immune responses in mice that were not significantly different at a 1.5 µg SAM dose. In summary, cLNPs based on DOTAP and DDA are an efficient alternative to iLNPs to deliver SAM vaccines.

Original languageEnglish
Pages (from-to)370-379
Number of pages10
JournalJournal of Controlled Release
Volume325
Early online date1 Jul 2020
DOIs
Publication statusPublished - 10 Sep 2020

Keywords

  • self-amplifying RNA
  • lipid nanoparticles
  • microfluidics
  • cellular uptake
  • in vitro potency
  • pharmacokinetics
  • immunogenicity

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