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  • Michael Nguyen

The Heroes of Vaccine Development: Lipid Nanoparticles

Updated: Mar 29

Introduction

Lipid nanoparticles (LNPs) have played a groundbreaking role in the area of vaccines. They provided a versatile and effective mRNA delivery platform that helped accelerate the COVID-19 vaccine development. Presently, LNPs are being explored as carriers for a multitude of different therapeutics, including plasmid DNA, single stranded DNA, siRNA, miRNA, tRNA, Cas9 RNA and much more. This breakthrough significantly accelerated the response to emerging infectious diseases, offering a rapid and adaptable approach to vaccine development. In this article, we at Helix Biotech, Inc. discuss how mRNA-LNPs enabled world governments to expedite the pharmaceutical development process and save lives, as well as their future benefits.


In 2019 and subsequent periods, the rapid spread of COVID-19 and mounting hospitalizations prompted governments around the world to implement safety measures in order to minimize the loss of human lives. These included wide-spread lockdowns or restrictions on movement, social distancing, mandatory face masks in public spaces, heightened sanitary practices, quarantines, travel restrictions, etc. Despite these measures, the threat of COVID-19 remained and necessitated a more lasting solution: a cure or a preventative vaccine solution. Here, we will focus on the latter and begin by discussing what makes mRNA-LNPs such an attractive option.

Figure 1. Masked scientist.


LNPs as Vehicles for mRNA Vaccination

The key innovation lies in the encapsulation of mRNA within LNPs, a process that protects the fragile mRNA molecules from degradation and enhances their stability. mRNA is the key pharmaceutical ingredient as they are short strands of genetic material that can be translated into proteins (in this case viral spike proteins), which can act as a template for antibody generation. However, they cannot be administered alone as they are quickly degraded by host enzymes. LNPs act as protective vehicles, shielding the mRNA during transit through the bloodstream and aiding its entry into target cells. This encapsulation not only ensures the integrity of the genetic material but also enhances the efficiency of cellular uptake, leading to robust immune responses.


The successful clinical application of Onpattro, an siRNA-LNP therapeutic, in 2018 was a milestone for the use of LNP technology [1]. Such a triumph demonstrated their effectiveness and biocompatibility in humans. This also spurred researchers to apply or continue applying this technology to other applications, such as vaccine development. Though the Onpattro LNP formulation was deemed suboptimal for mRNA, new LNP formulations with novel components arose that would prove promising. Pfizer-BioNTech and Moderna employed novel lipid components (e.g. ALC-0315, ALC-0159, and SM-102) which helped provide an adaptable mRNA delivery platform.


Adapting to an Ever Changing Adversary


The adaptability of mRNA and LNPs has been a game-changer in responding to emerging infectious diseases. Traditional vaccine development methods often require a time-consuming process of cultivating and attenuating the pathogen, which can be impractical when facing rapidly evolving threats [2]. In contrast, mRNA vaccines using LNPs can be designed and produced with remarkable speed. The genetic sequence of a new pathogen can be quickly identified, and the corresponding mRNA can be synthesized and formulated into LNPs for rapid deployment.


This versatility was demonstrated during the development of mRNA vaccines for the COVID-19 pandemic. The mRNA-LNP platform allowed scientists to swiftly translate the genetic code of the COVID-19 virus, SARS-CoV-2, into vaccine candidates. The agility of this technology enabled the initiation of clinical trials within months of the virus' emergence. This would result in the unprecedented issuance of the first emergency use authorization (EUA) for the Pfizer-BioNTech COVID-19 Vaccine on December 11th, 2020. A second EUA would be approved for the Moderna COVID-19 vaccine in the following days. These FDA-approved EUAs facilitated mass vaccinations in record time in the USA, subsequently extending to the rest of the world.

Figure 2. Phylogenetic tree of SARS-CoV-2 variants. Credit: Wang et al. 2022.


The adaptability of LNPs extends beyond their rapid development. The same platform can be readily adjusted to address new variants or emerging infectious threats. For example, the SARS-CoV-2 virus quickly mutated and formed many new variants, which can be viewed in Fig. 2. Some of these variants possessed increased transmissibility, increased pathogenicity or were better at evading immunization attempts via the current vaccines (Tao et al. 2021). Vaccination strategies had to be adjusted to address these emerging variants. Thankfully, the previous mRNA-LNP technologies already in place provided a pathway to quickly refine and update vaccines as needed. This included the development of booster shots or modified vaccines to enhance protection against specific variants and ensure sustained immunity.


Future Developments


At present, mRNA-LNP technology is being explored to combat other viral pathogens, such as the respiratory syncytial virus, the flu, malaria, Marburg virus, and even in some combinatorial multi-vaccine applications. Because viruses have evolved to take advantage of the host expression system, the mRNA sequence can simply be adjusted to the appropriate virus and the expression mechanisms remain similar [4]. This is not the case for bacteria, causing antibacterial therapeutics to lag behind their viral counter-parts. Bacterial pathogens require greater adaptation to the mRNA construct, necessitating different modifications and genetic sequences. For example, several prokaryotic sequence elements, such as the signal sequence, promoters, ribosome binding sites can be replaced by human or other eukaryotic-specific sequences to best utilize the host expression system, and promote translation. These changes have been shown to optimize the effectiveness and safety of these mRNA-LNP therapeutics [4]. In the end, the widespread availability of commercially viable mRNA-LNP drug products is inevitable, given the versatility and advancements in this technology.


Concluding Remarks


In conclusion, LNPs have revolutionized the field of vaccine development, particularly for mRNA-based vaccines. Their role in protecting, delivering, and facilitating the translation of genetic material has allowed for an unprecedentedly rapid response to emerging infectious diseases. The speed and adaptability of mRNA-LNP technology represents a paradigm shift in the way we now approach vaccine development and how humanity responds to global health challenges.


References


  1. Akinc, A., Maier, M. A., Manoharan, M., Fitzgerald, K., Jayaraman, M., Barros, S., Ansell, S., Du, X., Hope, M. J., Madden, T. D., Mui, B. L., Semple, S. C., Tam, Y. K., Ciufolini, M., Witzigmann, D., Kulkarni, J. A., van der Meel, R., & Cullis, P. R. (2019). The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs. Nature Nanotechnology, 14(12), 1084–1087. https://doi.org/10.1038/s41565-019-0591-y

  2. Rando, H. M., Lordan, R., Lee, A. J., Naik, A., Wellhausen, N., Sell, E., Kolla, L., Gitter, A., Greene, C. S., Bansal, V., Barton, J. P., Boca, S. M., Boerckel, J. D., Brueffer, C., Byrd, J. B., Capone, S., Das, S., Dattoli, A. A., Dziak, J. J., … Wellhausen, N. (2023). Application of Traditional Vaccine Development Strategies to SARS-CoV-2. MSystems, 8(2). https://doi.org/10.1128/msystems.00927-22

  3. Tao, K., Tzou, P. L., Nouhin, J., Gupta, R. K., de Oliveira, T., Kosakovsky Pond, S. L., Fera, D., & Shafer, R. W. (2021). The biological and clinical significance of emerging SARS-CoV-2 variants. Nature Reviews Genetics, 22(12), 757–773. https://doi.org/10.1038/s41576-021-00408-x

  4. Kon, E., Levy, Y., Elia, U., Cohen, H., Hazan-Halevy, I., Aftalion, M., Ezra, A., Bar-Haim, E., Naidu, G. S., Diesendruck, Y., Rotem, S., Ad-El, N., Goldsmith, M., Mamroud, E., Peer, D., & Cohen, O. (2023). A single-dose F1-based mRNA-LNP vaccine provides protection against the lethal plague bacterium. Science Advances, 9(10). https://doi.org/10.1126/sciadv.adg1036


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