mRNA Vaccines: A Look at What's to Come

Supplements, August 2021 Immunization Supplement,

Whereas traditional vaccines have used live or inactivated pathogens to elicit an immune response, mRNA is responsible for cellular processes, building structures, and more.

The unprecedented impact of the COVID-19 global pandemic has necessitated a rapid evolution of scientific and medical knowledge to thwart the spread of the disease. At the time of writing (July 26, 2021), more than 196 million confirmed cases have been identified globally, including over 4 million deaths; in the United States, this includes more than 34 million confirmed cases and over 611,000 deaths.1 Parts of the world are seeing an ebbing in new infections and deaths and an easing of certain restrictions, largely due to advances in immunology and the advent and availability of vaccines against SARS-CoV-2, the virus that causes COVID-19.

As of late July 2021, it is estimated more than 4 billion vaccine doses have been administered globally with more than 35.6 million doses of vaccine currently being administered each day. More than 397 million doses of vaccines against COVID-19 have been administered to Americans, with more than 163 million Americans fully immunized against the disease.2 Although there are a number of novel vaccine technologies and delivery platforms seem to have been developed at a seemingly fever pace, resulting in skepticism and hesitancy in some, the messenger ribonucleic acid (mRNA) vaccines, the first to receive Emergency Use Authorization (EUA) by the FDA, represent the culmination of years of scientific development and basic science and translational research.3,4

As shown in Figure 1,5 whereas traditional vaccines have used live or inactivated pathogens to elicit an immune response, mRNA is responsible for cellular processes, building structures, regulating functions, and building structural components. In simplest terms, the mRNA vaccine technology works to trigger an immune response by instructing cells to make a protein—or piece of a protein—after administration.3,5 The immune response results in antibody production and resultant protection against the virus or pathogen upon exposure. Important facts about mRNA vaccines from the CDC are available in Table 1.3

A Brief History of mRNA Technology

Although individuals expressing vaccine hesitancy may describe the seemingly "rushed" or rapid development of the technology utilized by the mRNA vaccines against COVID-19, the evolution of mRNA technology and the advancement of mRNA science has been at least 3 decades in development (Figure 2).6-13

The interest in therapeutic use of mRNA technology in vaccination dates to the late 1980s, with the demonstration of liposomal nanoparticle-encapsulated mRNA being able to be successfully introduced into cells. By the early 1990s, mRNA injections into mice demonstrated that this technique could be used to synthesize proteins in vivo; research on elucidating the pharmacology and impact on inducing cellular and humoral immune responses through the early 2000s ensued.14,15 To-date, over twenty mRNA-based immunotherapies have entered clinical trials as solid tumor treatments for individuals with cancer.16

mRNA Technology and the Future of Vaccine Manufacturing

Since mRNA may be obtained from DNA of the target pathogen using regular laboratory materials and processes, mRNA vaccines are relatively inexpensive to manufacture, albeit there are significant costs for procuring manufacturing materials and in the vaccine distribution process.10 mRNA is fragile; the ultra-cold storage necessary to preserve the efficacy of such a vaccine may be cost-prohibitive and limit the location where vaccine may be distributed. Another key advantage of mRNA vaccine technology relative to traditional vaccines is that these vaccines take much less time to produce. Traditional live or inactivated viral vaccine manufacturing is a long process, necessitating at least 4 to 6 weeks of fermentation; on the contrary, mRNA vaccines can be ready within weeks of the identification of the genome of the target pathogen and synthesized in the laboratory in minutes, a desirable characteristic during an outbreak of a communicable disease.17

It has been postulated—and perhaps now demonstrated—that mRNA may be useful for creating a variety of vaccines and treatment in a shorter time and at a lower cost than traditional medicines.

Impact of mRNA Technology on the Development of Novel Vaccines

The impact of the advent and success of the mRNA vaccines in providing a robust immune response against SARS-CoV-2 suggests this platform may represent a "game-changing" impact on the world of immunology and vaccine development. Future mRNA vaccine technology may allow for 1 vaccine to provide protection for multiple diseases, thus decreasing the number of immunizations necessary to ensure protection against common vaccine-preventable diseases. Prior to the COVID-19 pandemic, several mRNA vaccines were already undergoing clinical development for the treatment of conditions where vaccine development had not previously been successful: notably, against HIV-1, Zika virus, and rabies virus.3 Influenza virus mRNA vaccines are also in development, whereas clinical utility of this technology for the development of vaccines against other bacterial or parasitic pathogens remains in the preclinical stages.9 Beyond vaccines, cancer research has used mRNA to trigger the immune system to target specific cancer cells. Immunotherapy, against both infectious pathogens and malignant cells, represent key prospective uses of the mRNA vaccine platform.10

Pharmacists should be aware that mRNA vaccine and therapeutics technologies will continue to mature with the increased scientific interest and funding this area of pharmaceutical development has received considering the vaccine response during the global COVID-19 pandemic. Despite the rapid development and availability of this technology in the midst of the COVID-19 pandemic, the advent and demonstrated clinical safety and efficacy of the mRNA vaccines developed against SARS-CoV-2 are likely to result in long-lasting and monumental changes to the vaccine development process and to open up the possibility of novel therapeutic agents for the treatment and prevention of a wide swath of conditions to which a robust preventative strategy had not previously existed. The availability of effective vaccines against COVID-19, including 2 mRNA platform vaccines, represents a critical turning point in the global race against SARS-CoV-2. The future potential for mRNA vaccine development against a myriad of conditions remains promising.

Mary Barna Bridgeman, PharmD, BCPS, BCGP, FASCP, is a clinical professor at Ernest Mario School of Pharmacy at Rutgers University in Piscataway, New Jersey, and an internal medicine clinical pharmacist at Robert Wood Johnson University Hospital, also in New Jersey.

REFERENCES

1. Coronavirus Resource Center. Johns Hopkins University & Medicine. Updated July 29, 2021. Accessed July 29, 2021. https://coronavirus.jhu.edu/

2. Coronavirus (COVID-19) vaccinations. Our World in Data. Updated July 29, 2021. Accessed July 29, 2021. https://ourworldindata.org/covidvaccinations?country=USA

3. Understanding mRNA COVID-19 vaccines. CDC. Updated March 4, 2021. Accessed July 8, 2021. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/mrna.html

4. Garde, D. The story of mRNA: how a once-dismissed idea became a leading technology in the Covid vaccine race. Stat News. November 10, 2020. Accessed July 8, 2021. https://www.statnews.com/2020/11/10/the-story-ofmrna-how-a-once-dismissed-idea-became-a-leading-technology-in-thecovid-vaccine-race/

5. How mRNA COVID-19 vaccines work. CDC. Accessed July 8, 2021. https://www.cdc.gov/coronavirus/2019-ncov/downloads/vaccines/COVID-19-mRNA-infographic_G_508.pdf

6. COVID data tracker. CDC. Updated July 28, 2021. Accessed July 29, 2021. https://covid.cdc.gov/covid-data-tracker/#vaccinations

7. Pfizer and Biontech conclude phase 3 study of COVID-19 vaccine candidate, meeting all primary efficacy endpoints. Pfizer. November 18, 2020. Accessed July 27, 2020. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-conclude-phase-3-studycovid-19-vaccine

8. Moderna’s COVID-19 vaccine candidate meets its primary efficacy endpoint in the first interim analysis of the phase 3 COVE study. Moderna. November 16, 2020. Accessed July 27, 2020. https://investors.modernatx.com/newsreleases/news-release-details/modernas-covid-19-vaccinecandidate-meets-its-primary-efficacy

9. Safety, Tolerability, and Immunogenicity of mRNA-1325 in Healthy Adult Subjects. ClinicalTrials.gov. Updated December 9, 2019. Accessed July 28, 2021. https://clinicaltrials.gov/ct2/show/NCT03014089

10. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines — a new era in vaccinology. Nat Rev Drug Discov. 2018;17:261-279. doi:10.1038/nrd.2017.243

11. Infographic: the history of mRNA vaccines. Canadian Institute of Health Research. Updated April 28, 2021. Accessed July 26, 2021. https://cihr-irsc.gc.ca/e/52484.html

12. The long road to mRNA vaccines. Canadian Institutes of Health Research. Updated April 28, 2021. Accessed July 26, 2021. https://cihr-irsc.gc.ca/e/52424.html

13. mRNA vaccine tech translates into promising COVID-19 vaccines. StartUS Insights. Accessed July 8, 2021. https://www.startus-insights.com/innovators-guide/mrna-vaccine-tech-translates-into-promising-covid-19-vaccines/

14. Verbeke R, Lentacker I, De Smedt SC, Dewitte H. Three decades of messenger RNA vaccine development. Nano Today. 2019;28:100766. doi:10.1016/j.nantod.2019.100766

15. Boyle P. mRNA technology promises to revolutionize future vaccines and treatments for cancer, infectious diseases. Association of American Medical Colleges. March 29, 2021. Accessed July 8, 2021. https://www.aamc.org/news-insights/mrna-technology-promises-revolutionize-futurevaccines-and-treatments-cancer-infectious-diseases

16. Miao L, Zhang Y, Huang L. mRNA vaccine for cancer immunotherapy. Mol Cancer. 2021;20:41. doi:10.1186/s12943-021-01335-5

17. Verga, D. mRNA and the future of vaccine manufacturing. PATH. February 10, 2021. Accessed July 8, 2021. https://www.path.org/articles/mrna-andfuture-vaccine-manufacturing/