mRNA Vaccines Against SARS‐CoV‐2 Variants Delivered by Lipid Nanoparticles Based on Novel Ionizable Lipids

Abstract

SARS‐CoV‐2 variants are now still challenging all the approved vaccines, including mRNA vaccines. There is an urgent need to develop new generation mRNA vaccines with more powerful efficacy and better safety against SARS‐CoV‐2 variants. In this study, a new set of ionizable lipids named 4N4T are constructed and applied to form novel lipid nanoparticles called 4N4T‐LNPs. Leading 4N4T‐LNPs exhibit much higher mRNA translation efficiency than the approved SM‐102‐LNPs. To test the effectiveness of the novel delivery system, the DS mRNA encoding the full‐length S protein of the SARS‐CoV‐2 variant is synthesized and loaded in 4N4T‐LNPs. The obtained 4N4T‐DS mRNA vaccines successfully trigger robust and durable humoral immune responses against SARS‐CoV‐2 and its variants including Delta and Omicron. Importantly, the novel vaccines have higher RBD‐specific IgG titers and neutralizing antibody titers than SM‐102‐based DS mRNA vaccine. Besides, for the first time, the types of mRNA vaccine‐induced neutralizing antibodies are found to be influenced by the chemical structure of ionizable lipids. 4N4T‐DS mRNA vaccines also induce strong Th1‐skewed T cell responses and have good safety. This work provides a novel vehicle for mRNA delivery that is more effective than the approved LNPs and shows its application in vaccines against SARS‐CoV‐2 variants.

Splenic-targeting biomimetic nanovaccine for elevating protective immunity against virus infection

“…6 G, the elevated level of IgG in serum was observed when mice immunized with CMR-PLGA/p54 NVs. Alternatively, the ratio of IgG2a to IgG1 is a marker for Th1 and Th2 immune responses [ 52 ]. As shown in Fig.…”

Manganese-coordinated mRNA vaccines with enhanced mRNA expression and immunogenicity induce robust immune responses against SARS-CoV-2 variants

“…S1). The formulation of LNPs containing IC8 had been optimized in our previous study, so as to show good transfection in mRNA delivery ( 32 ). Therefore, we prepared IC8 LNPs loading luciferase mRNA (IC8@Luc) and IC8/Mn LNPs loading Luc mRNA (IC8/Mn@Luc) (containing a different mass ratio of Mn to mRNA) using a microfluidic device ( Fig.…”

“…We previously found that the ionizable lipid in LNPs notably influenced the mRNA expression. The ionizable lipids with multiple tertiary amino nitrogen atoms, compared to the ones with one nitrogen atom like mRNA-1273, could remarkably enhance the immunogenicity of mRNA vaccines ( 32 ).…”

A novel heterologous receptor-binding domain dodecamer universal mRNA vaccine against SARS-CoV-2 variants

“…In particular, lipid nanoparticles (LNPs) have been shown to enable efficient and safe mRNA delivery, and have been successfully used to treat SARS-CoV-2 infections through the delivery of mRNA (such as SM-102 and ALC-0315 LNPs for mRNA-1273 and BNT162b2) 22 , 27 . Ionizable lipids, one of the key components of LNPs, are critical to enhancing the delivery efficiency and therapeutic efficacy of mRNA vaccines 27 , 28 , 29 , 30 . Ionized lipids provide a positive charge to ensure maximum encapsulation of negatively charged mRNAs into LNPs through electrostatic interactions and help mRNAs cross cellular barriers 25 .…”

“…The rational design of ionizable lipids has great potential to initiate more potently protective immunity of mRNA-LNP vaccines 31 , 32 . We designed a new set of multi-charged ionizable lipids (MIC1-MIC6) and found significant increases in the transfection and expression efficiency of mRNA 30 .…”