From influenza to COVID-19: Lipid nanoparticle mRNA vaccines at the frontiers of infectious diseases

Abstract

Vaccination represents the best line of defense against infectious diseases and is crucial in curtailing pandemic spread of emerging pathogens to which a population has limited immunity. In recent years, mRNA vaccines have been proposed as the new frontier in vaccination, owing to their facile and rapid development while providing a safer alternative to traditional vaccine technologies such as live or attenuated viruses. Recent breakthroughs in mRNA vaccination have been through formulation with lipid nanoparticles (LNPs), which provide both protection and enhanced delivery of mRNA vaccines in vivo. In this review, current paradigms and state-of-the-art in mRNA-LNP vaccine development are explored through first highlighting advantages posed by mRNA vaccines, establishing LNPs as a biocompatible delivery system, and finally exploring the use of mRNA-LNP vaccines in vivo against infectious disease towards translation to the clinic. Furthermore, we highlight the progress of mRNA-LNP vaccine candidates against COVID-19 currently in clinical trials, with the current status and approval timelines, before discussing their future outlook and challenges that need to be overcome towards establishing mRNA-LNPs as next-generation vaccines. STATEMENT OF SIGNIFICANCE: With the recent success of mRNA vaccines developed by Moderna and BioNTech/Pfizer against COVID-19, mRNA technology and lipid nanoparticles (LNP) have never received more attention. This manuscript timely reviews the most advanced mRNA-LNP vaccines that have just been approved for emergency use and are in clinical trials, with a focus on the remarkable development of several COVID-19 vaccines, faster than any other vaccine in history. We aim to give a comprehensive introduction of mRNA and LNP technology to the field of biomaterials science and increase accessibility to readers with a new interest in mRNA-LNP vaccines. We also highlight current limitations and future outlook of the mRNA vaccine technology that need further efforts of biomaterials scientists to address.

Keywords: COVID-19; Lipid nanoparticles; Vaccines; mRNA.

Graphical abstract

Fig. 1

Scheme of induced immune response following mRNA vaccination. Dendritic cell (DC) maturation upon (ds) mRNA sensing by TLRs (adjuvant effect of mRNA) and subsequent Type I interferon (INF) production [[79], [80], [81]]. Type I INF initiates the transcription of interferon-stimulated genes (ISGs) involved in the DC maturation process, but also activates antiviral enzymes that promote mRNA degradation and inhibit antigen expression (innate immune response) [24]. The mature DC can express the antigenic proteins and present them on MHC class I and class II to CD8⁺ (cytotoxic) and CD4⁺(helper) T cells respectively (adaptive immune response) [82]. Secreted antigen can be presented through the MHC II pathway to T helper cells and B cells, to generate memory B cells and plasma cells that can engender antigen-specific immune defenses and antibody production resulting in a durable protection [83,84]. Figure created using BioRender.com.

Fig. 2

Structure of a typical lipid nanoparticle formulation. The cartoon scheme (left) highlights key components of a lipid nanoparticle with payload and how they contribute to its structure and function (above, right). A representative cryogenic transmission electron micrograph of LNPs with an mRNA cargo is shown on the bottom right, adapted with permission from Richner et al. 2017 [97].

Fig. 3

Lipid nanoparticle formation utilizing a microfluidic platform with a staggered herringbone micromixer (SHM). Within the microfluidic channels, the SHM allows the aqueous phase (containing the nucleic acids, e.g. mRNA, under an acidic pH) and the water-miscible organic phase (containing the lipids and cholesterol) to proceed from laminar flow (pre-SHM) through several cycles of chaotic mixing until complete mixing of the phases has occurred (cycle 15). This process facilitates the complexation of cationic/ionizable lipids (dark pink) with the nucleic acids and the formation of micelles and early particle structures formed by the lipid mix, typically consisting of a cationic/ionizable lipid, a helper lipid (orange), cholesterol (brown), and a PEG-lipid (light pink), and eventually mRNA-encapsulated lipid nanoparticles.

Fig. 4

Chemical structures of the cationic lipid subtypes developed for utilization in lipid nanoparticle formulations for nucleic acid delivery. DOTMA, DOTAP, DODMA and DODAP represent the first generation of cationic and ionizable cationic lipids to be utilized in LNP formulations. Next generation lipids include the lipidoid C12-200 , invented by Drs. Anderson, Langer and colleagues and licensed by Alnylam, Moderna's SM-102, formerly known as 'Lipid H' , and ALC-0315 from Acuitas Therapeutics. Ionizable cationic lipids optimized for LNP formation and delivery include DLin-DMA , DLin-KC2-DMA and DLin-MC3-DMA , all patented by Arbutus Biopharma. ALC-0315 from Acuitas and SM-102 from Moderna are the lipids utilized in the SARS-CoV-2 vaccines BNT162b2, from BioNTech and Pfizer, and mRNA-1273, from Moderna, respectively.

Fig. 5

Structure of the lymph node and localization of foreign agents. Materials enter the lymph node after draining from the injection site into the afferent lymphatics and pass around the subcapsular sinus (SCS), which provides a rapid pathway for fluid to exit the lymph node via the efferent lymphatics. T cells and B cells are localized within the interior paracortical and cortical regions of the node; access to these regions by vaccine candidates is required to generate a potent immune response. Passage of materials across the SCS can occur via conduits in a reticular network that drains from the main lymphatic sinuses, though these channels are very narrow, spanning only 3–5 nm in diameter [180,181]. Certain nanomaterials may be able to enter the conduits through gaps between barrier cells; others, while trapped at the barrier, may be able to release a cargo (e.g. small molecule), which can freely diffuse across the SCS and into the cortex [182]. Soluble antigen <70 kDa may also access the lymph node interior, whereas larger macromolecules cannot [180,181,183].

Fig. 6

Overview of lipid nanoparticle design and administration strategies for targeting the lymphatic system. Manipulating the physicochemical properties of LNPs, including size and surface charge, can either direct them to the lymphatics or promote their uptake by cells at the injection site, where i.m. is the most frequently used route of administration. Adjusting LNP formulation by tuning the level of PEGylation can promote access to the lymphatics; similarly, decoration of the particle surface with targeting agents can facilitate localization to antigen-presenting cells and/or specific cell types in the lymph node. Figure created using BioRender.com.

Fig. 7

Importance of administration route in tissue localization, translation efficacy and duration of mRNA-LNPs. Mice were injected with mRNA-LNPs expressing firefly luciferase by the intradermal (i.d.), intramuscular (i.m.), subcutaneous (s.c.), intravenous (i.v.), intraperitoneal (i.p.) or intratracheal (i.t.) routes. Administration by i.v. and i.p. resulted in a high level of localization to the liver, with some residual activity at the injection site (around the eyes and abdomen, respectively); similar distribution was observed with i.t. and i.m. injection, though with significant bioluminescent signal in the lungs and muscles; for i.m., this was detectable for up to eight days post-injection. LNPs injected via the s.c. and i.d. routes resulted in translation solely at the injection site, but bioluminescence could be detected up to six (s.c.) to ten (i.t.) days. Reproduced with permission from Pardi et al. 2015 [232].