Conjugation of Mannans to Enhance the Potency of Liposome Nanoparticles for the Delivery of RNA Vaccines

Abstract

Recent approval of mRNA vaccines to combat COVID-19 have highlighted the potential of this platform. Lipid nanoparticles (LNP) is the delivery vehicle of choice for mRNA as they prevent its enzymatic degradation by encapsulation. We have recently shown that surface exposition of mannose, incorporated in LNPs as stable cholesterol-amine conjugate, enhances the potency of self-amplifying RNA (SAM) replicon vaccines through augmented uptake by antigen presenting cells (APCs). Here, we generated a new set of LNPs whose surface was modified with mannans of different length (from mono to tetrasaccharide), in order to study the effect on antibody response of model SAM replicon encoding for the respiratory syncytial virus fusion F protein. Furthermore, the impact of the mannosylated liposomal delivery through intradermal as well as intramuscular routes was investigated. The vaccine priming response showed to improve consistently with increase in the chain length of mannoses; however, the booster dose response plateaued above the length of disaccharide. An increase in levels of IgG1 and IgG2a was observed for mannnosylated lipid nanoparticles (MLNPs) as compared to LNPs. This work confirms the potential of mannosylated SAM LNPs for both intramuscular and intradermal delivery, and highlights a disaccharide length as sufficient to ensure improved immunogenicity compared to the un-glycosylated delivery system.

Lipid-Based Nanoparticles for Delivery of Vaccine Adjuvants and Antigens: Toward Multicomponent Vaccines

“…185,186 Mannose receptor-mediated targeting has already been studied for DNA and RNA delivery in antitumor immunotherapy, 187 in the formulation of an HIV DNA vaccine, 188 and also for the delivery of self-amplifying mRNA (SAM) vaccines. 143,189 Mannose-coated particles were obtained by modifying the zwitterionic lipid components, 188 polyethylene glycol (PEG), 190,191 via ester bonds with cholesterol 187 or via conjugation to cholesterol amine. 143 Although mannose is already sufficient to trigger the DC-SIGN receptor and favor uptake from DC, we have recently observed that balance between oligomannose length and amount of PEG used for liposome stabilization (see next paragraph) can be exploited to further enhance the immunogenicity of SAM vaccines.…”

“…143 Although mannose is already sufficient to trigger the DC-SIGN receptor and favor uptake from DC, we have recently observed that balance between oligomannose length and amount of PEG used for liposome stabilization (see next paragraph) can be exploited to further enhance the immunogenicity of SAM vaccines. 189 These mannosylated liposomes hold the promise to be suitable for the development of skin delivery systems. Wamhoff et al described the design of liposome formulations covered with a glycomimetic ligand for the lectin receptor Langerin, to selectively target Langerhans cells, for the development of novel vaccination strategies.…”

“…Mannose receptor-mediated targeting has already been studied for DNA and RNA delivery in antitumor immunotherapy, in the formulation of an HIV DNA vaccine, and also for the delivery of self-amplifying mRNA (SAM) vaccines. , Mannose-coated particles were obtained by modifying the zwitterionic lipid components, polyethylene glycol (PEG), , via ester bonds with cholesterol or via conjugation to cholesterol amine …”

The Potential of Nanomedicine to Unlock the Limitless Applications of mRNA

“…For instance, Ziller et al published results on how EPC/DOPC/DOTAP LPX could be further modified to achieve controlled-release effects [104]. Furthermore, similarly to that which Goswami et al [80,81] studied for LNPs, and as previously commented in Section 2.1.1, the development of mannosylation strategies through the incorporation of mannose-modified lipids has also been proposed for LPX for specific targeting to macrophages, achieving positive results in the induction of a stimulatory immune response upon mice vaccination [113,114].…”

“…routes [80]. Authors further investigated how the length of this LNP-surface decoration may influence antibody response, observing that vaccine priming response was improved with a higher chain length [81].…”