mRNA vaccines played a crucial role in navigating through the COVID-19 pandemic. These vaccines employ laboratory-created mRNA to prompt an immune response by instructing cells on coding a protein within the human body (Understanding How COVID-19 Vaccines Work, 2023). This immune response generates antibodies, safeguarding against further illness. Beyond the pandemic, these vaccines have the potential to reshape the therapeutics field, addressing rare and complex diseases once deemed unrehabilitatable. The intricacies of this technology make it a compelling subject for life science students to comprehend.
The initial mRNA flu vaccine underwent mouse testing in the 1990s, followed by the first human trials for mRNA vaccines targeting rabies in 2013. Overcoming challenges related to the rapid degradation of mRNA within the body, particularly before delivering its message to translate into the required protein, was a significant hurdle. The first mRNA vaccines, designed to combat the deadly Ebola virus, utilized fatty envelopes. However, since the virus was limited to certain African countries, global commercial development was limited (“The Long History of mRNA Vaccines,” 2021). The breakthrough in addressing the "message delivery" issue came with advancements in nanotechnology, employing lipid nanoparticles that enter cells, allowing mRNA to be coded into protein.
Various formats, including Lipid nanoparticles, Polymers, Peptides, Free mRNA solutions, and Ex vivo through dendritic cells, have been employed to deliver mRNA vaccines. Co-delivery of multiple RNAs in some instances has shown synergistic effects, boosting immunity. mRNA vaccines encode three main types of proteins: antigens, neutralizing antibodies (which induce specific immune responses), and proteins with immunostimulatory activity (boosting adaptive and innate immunity) (Zeng et al., 2020). Advancements in formulation technology now include a continuous-flow microfluidic device, ensuring reproducible production of nanoparticles at various scales with controllable sizes.
mRNA instructs cells in the body to create specific proteins that play essential roles within our bodies. This process utilizes our biological processes to potentially treat diseases and prevent infections (MRNA Technology: What It Is and How It Works, n.d.). In the in vivo system, the mRNA vaccine mimics a viral infection, employing the host cell protein machinery to convert mRNA into a defined antigen, eliciting a robust immune response. The mRNA activity initiates in the cytosol, translating into the target protein, undergoing post-translational modifications, and ultimately being presented to the immune system (Mirtaleb et al., 2023).
Addressing the COVID-19 pandemic involved implementing and developing various vaccine technologies, such as protein-based vaccines, inactivated vaccines, viral vector vaccines, and RNA vaccines. The mRNA vaccine by Pfizer/BioNTech and Moderna, the first of its kind in the market with FDA approval, utilized Lipid nanoparticles (LNPs) crucial for effective mRNA protection and transport to cells. LNPs, an early version being liposomes, serve as a versatile nanomedicine delivery platform approved for drugs and applied to medical practice. The vaccine nanoparticles measured 80-100 nm in size and contained approximately 100 mRNA molecules per lipid nanoparticle (Tenchov et al., 2021).
The efficacy of the COVID-19 mRNA vaccine was directly tested in clinical trials without pre-clinical studies due to the urgent need to combat the virus and the associated deaths. The accelerated timeline resulted from global collaboration among scientists, sharing gene sequences, simultaneously executing multiple phases of clinical trials, conducting safety and dose execution trials concurrently, and risking manufacturing products before approval. This differs from the typical thorough analysis of variables and factors before moving on to the next step, followed by manufacturing post-approval by various regulatory institutions.
mRNA vaccines replace conventional vaccines due to their safety, efficacy, potency, and cost-effective manufacturing. These vaccines can address emerging pandemic infectious diseases, providing safe and long-lasting immune responses in both animal models and humans in clinical and pre-clinical trials. Polymers and lipid-based carriers used as delivery mechanisms offer safety, stability, higher transfection efficiency, and lower expenses. Looking ahead, mRNA vaccines hold the potential to be formulated for diseases like cancer and autoimmune diseases. Despite the benefits, challenges such as instability at high temperatures make packaging and transportation challenging, resulting in lower safety compared to inactivated vaccines and lower efficiency than DNA vaccines. Further insights, improvements, and optimizations are necessary for the future formulation of mRNA vaccines to optimize drug functioning in treating rare diseases.
References:
[1] Mirtaleb, M. S., Falak, R., Heshmatnia, J., Bakhshandeh, B., Taheri, R. A., Soleimanjahi, H., & Emameh, R. Z. (2023). An insight overview of COVID-19 mRNA vaccines: Advantages, pharmacology, mechanism of action, and prospective considerations. International Immunopharmacology, 117, 109934.
https://doi.org/10.1016/j.intimp.2023.109934
[2] MRNA technology: What it is and how it works. (n.d.). https://www.pfizer.com/science/innovation/mrna-technology#:~:text=How%20is%20mRNA%20revolutionizing%20the,treat%20diseases%20and%20prevent%20infections.
[3] Tenchov, R., Bird, R. E., Curtze, A., & Zhou, Q. (2021). Lipid Nanoparticles─From liposomes to mRNA Vaccine delivery, a landscape of research diversity and advancement. ACS Nano, 15(11), 16982–17015.
[6https://doi.org/10.1021/acsnano.1c04996
[4] The long history of mRNA vaccines. (2021, October 7). Johns Hopkins Bloomberg School of Public Health.
https://publichealth.jhu.edu/2021/the-long-history-of-mrna-vaccines
[5] Understanding how COVID-19 vaccines work. (2023, September 22). Centers for Disease Control and Prevention.
https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/how-they-work.html#:~:text=Instead%2C%20mRNA%20vaccines%20use%20mRNA,that%20germ%20in%20the%20future.
[6] Zeng, C., Zhang, C., Walker, P., & Dong, Y. (2020). Formulation and delivery technologies for mRNA vaccines. In Current Topics in Microbiology and Immunology (pp. 71–110). https://doi.org/10.1007/82_2020_217