What technology is used in vaccines against coronavirus disease 2019?

Introduction

Coronavirus disease-2019 (COVID-19) is a respiratory illness caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus.¹ It was first identified in Wuhan, China in December 2019 and rapidly spread globally, resulting in the World Health Organization (WHO) declaring a pandemic on March 11, 2020.²  As of January 2021, the SARS-CoV-2 virus is still infecting large portions of the global and US populations. This is despite the implementation of preventative measures recommended by authorities including the Centers for Disease Control and Prevention (CDC) and WHO, such as frequent handwashing, wearing a face covering, physical distancing, and screening for COVID-19 in high-risk settings.^3-5

Vaccine development has always been an objective of the global response to COVID-19.⁶ Transmission of SARS-CoV-2 has continued despite preventative measures alone, highlighting the necessity of vaccine development. Prior to development of COVID-19 vaccines, most vaccines on the US market have been produced with several long-utilized technologies; these include live attenuated virus, inactivated virus, and subunits of microorganisms. Now, several COVID-19 vaccines using novel production methods are either in use or in development. Two vaccines using novel mRNA vaccine technology received Emergency Use Authorizations (EUA) from the US Food and Drug Administration (FDA) in December 2020, and are being administered to millions of people.^7,8  Because new technologies used in COVID-19 vaccines may be unfamiliar, this review discusses novel vaccine technologies used in COVID-19 vaccines, with a focus on mRNA technology.

SARS-CoV-2 viral particle

The structure of the SARS-CoV-2 virus underlies its mechanism for host infection and thereby, the targets of vaccine production. The SARS-CoV-2 viral particle is a single-stranded RNA virus with 4 structural proteins, including the spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins.¹ The S protein contains two subunits (S1 and S2), and plays a critical role in viral entry into the cell and initiation of an immune response. The S1 subunit contains a fragment of the spike protein called the receptor binding domain (RBD) that mediates receptor binding to angiotensin converting enzyme 2 (ACE2). After the S1 subunit mediates receptor binding, the S2 subunit mediates membrane fusion, and the SARS-CoV-2 virus enters the host cell.

In addition to the role of host cell entry, the S protein also plays a role in inducing an antibody response.¹ The S protein RBD has the ability to neutralize antibodies and T-cell immune responses. A major antibody response is induced by the S protein RBD, and immunoglobulin G (IgG) and T cells targeting the RBD are detectable in the serum of patients infected with SARS-CoV-2. Due to its role in host cell entry and induction of an immune response, the S protein and the S protein RBD have become key targets for vaccines against COVID-19.

Common vaccine technologies

The technology used by some COVID-19 vaccines differs from that of many other available vaccines. These include live attenuated, inactivated, and subunit vaccine production technologies, which are described below.

Live attenuated vaccines

Live attenuated vaccines contain a weakened form of the virus with reduced virulence, but retain the immunogenic antigens that elicit a strong humoral and cellular response.⁹ Once the live attenuated vaccine enters the body, the immune system induces development of memory cells after one or two doses. Since they contain live viruses, live attenuated vaccines must generally be refrigerated to maintain their activity. Moreover, because of the risk of clinical infection, live attenuated virus generally cannot be used in immunocompromised individuals.¹⁰ Some examples of live attenuated vaccines include those for measles, mumps, and rubella; varicella; zoster; yellow fever; influenza (intranasal); and smallpox.⁹

Inactivated vaccines

Inactivated vaccines use heat, radiation, or chemicals to inactivate the pathogen and generate the antigenic starting materials, which can consist of either the entire virus or bacteria or a fraction of it.⁹ The pathogen is inactivated and can no longer replicate, making this vaccine technology safer than live attenuated vaccines. Inactivated viruses do not require refrigeration, which may be beneficial in distribution. However, the immune response is weaker than what occurs in natural infection and multiple doses of the inactivated vaccine may be required to induce a sufficient immune response. Examples of inactivated vaccines include those for hepatitis A and B, influenza (intramuscular), human papillomavirus, and rabies.

Subunit Vaccines

Subunit vaccines use a component of the microorganism (typically the surface protein subunit, polysaccharide, or toxoids), which induces an immune response.⁹ Once an antigenic subunit is identified, it can be produced and purified using recombinant technology. However, the process of identifying antigenic subunits can be extensive and costly. Examples of subunit vaccines include pneumococcal polysaccharide, meningococcal, and tetanus vaccines.

Novel vaccine technologies

Vaccines against COVID-19 have begun to implement novel and diverse technologies.¹¹ The first of these to be represented by products currently in use is mRNA technology. Vaccines using other technologies are currently under development, including double-stranded DNA (dsDNA), adenovirus-based, and protein vaccines.  Table 1 provides summary information on vaccines against COVID-19 that are currently in use or under development.

mRNA Vaccine Technology

Messenger RNA vaccines utilize the protein production process to induce cells to produce proteins that trigger an immune response to the target pathogen.^1,12 Once the mRNA strand enters the host cell, it provides instructions to make a piece of the SARS-CoV-2 S protein. After the S protein is assembled, the host cell breaks down the mRNA and the S protein is displayed on the cell surface, inducing an immune response. Due to the fragility of mRNA strands, which rapidly undergo enzymatic degradation, mRNA vaccines are being formulated with a coating of lipid nanoparticles that surround strands of mRNA.¹³ This protects the mRNA from degradation and helps facilitate its delivery into host cells.

Compared with other vaccine production technologies, the use of mRNA technology presents various advantages. For example, use of a non-infectious element (mRNA) is proposed to translate to lower risk of clinical infection.^1,12 Additionally, because mRNA vaccines use a DNA template and readily available materials, mRNA vaccines can be rapidly developed with shorter manufacturing times and a lower manufacturing cost. Nonetheless, their lack of use may present disadvantages, such as the current lack of long-term safety and efficacy data.

dsDNA

Double-stranded DNA (dsDNA) vaccines utilize a process in which a target antigen sequence is inserted in a plasmid vector backbone.^9,12 The plasmid enters the host cell, integrates into its DNA, and is then transcribed and translated to produce antigenic proteins. For COVID-19 vaccine development, the antigen sequence for the full-length S protein is inserted in a plasmid vector backbone and surrounded by liposomes and biodegradable polymeric nanoparticles to assist with delivery into host cells.

An advantage associated with dsDNA technology includes stability and a longer shelf-life.^1,9,12 Similar to mRNA vaccines, additional advantages include the ability to induce both humoral and cellular immune responses, and the ability to easily scale up production to large quantities. Also like mRNA vaccines, disadvantages of dsDNA vaccines include an unknown long-term safety and efficacy profile.

Adenovirus

Adenovirus-based vaccines utilize a process of inserting genes into adenovirus vectors.¹² When the vector infects or transduces host cells, antigens are then presented during the immune response to induce immunity.⁹ Adenovirus vectors are generally considered harmless and will not cause infection. For COVID-19 vaccine development, the adenovirus vectors include human adenovirus serotype 5 (the most commonly used adenovirus vector), rare-serotype human adenoviruses, or adenoviruses that infect chimpanzees.¹² The gene inserted into these various adenoviruses encodes for the full-length S protein.

The main advantages associated with the adenovirus-based vaccine technology is that it is safe and has potent immunogenicity.^1,12  Additionally, because DNA is less fragile than mRNA and the adenovirus provides a protective coat, adenovirus-based vaccines may have fewer requirements for cold storage to maintain potency.¹⁴

Rapid uptake of mRNA vaccine technology

As of January 2021, the US FDA has allowed the use of two mRNA-based vaccines under EUA for the prevention of COVID-19; these are the Pfizer-BioNTech and Moderna vaccines.^7,8 Historically, the vaccine development and testing process can take approximately 12 to 18 months.¹⁵ For the mRNA COVID-19 vaccines, however, development took approximately 10 months from the time the genetic sequence of SARS-CoV-2 was published to the time the first vaccine received EUA. The shortened timeline is mostly attributable to the fact that once researchers know the sequence of the viral particle, mRNA encoding for the protein of interest is very easy to synthesize.

Uncertainties with mRNA vaccine technology

The most important criteria in the development of vaccines are safety and efficacy. While both mRNA-based COVID-19 vaccines have demonstrated promising short-term efficacy and safety, currently, neither is supported by long-term data. The first publications of results of these trials reported results after median follow-up times of approximately 60 days.^16,17 Nonetheless, short-term results are generally favorable, as information provided in the FDA EUAs indicates that both vaccines have similar safety profiles.^7,8 Both vaccines frequently cause local and systemic adverse events, particularly after their second doses, but rare serious adverse events have been infrequent.^16,17

Other potential adverse events of mRNA vaccines have been theorized based on the pathophysiology of the SARS-CoV-2 virus. Previous vaccine development for SARS-CoV-2 and Middle East respiratory syndrome (MERS)-CoV have raised concerns of pulmonary immunopathology related to cytokine release and eosinophil infiltration.¹ Additionally, studies in animal models identified that S protein-specific IgG resulted in lung injury because of alteration in the ability to resolve inflammation. To date, however, these events have not been reflected in the prescribing information for either available COVID-19 vaccine.^18,19

Safety monitoring programs for COVID-19 vaccines

The FDA has strict standards and rigorously evaluates vaccines for safety and efficacy.²⁰ For both mRNA-based vaccines, all safety data from phase 1 and 2 studies and some safety data for phase 3 studies were evaluated. For an EUA request, FDA expects submissions to include phase 3 data with a median follow-up of at least 2 months after the full vaccination regimen. The safety database is also expected to include over 3,000 vaccinated recipients who have been followed for serious adverse events and adverse events of special interest for at least 1 month after the completion of the full vaccination regimen. Ongoing safety evaluations will rely on various systems, including the Vaccine Adverse Event Reporting System, the Vaccine Safety Datalink, the Biologics Effectiveness and Safety Initiative, and Medicare claims data.

An updated analysis using data following their availability revealed a low risk of anaphylaxis with both currently available mRNA COVID-19 vaccines.²¹ Between December 14, 2020 and January 18, 2021, using data from over 17 million total doses of both products, the CDC identified 47 cases of anaphylaxis following the Pfizer-BioNTech vaccine and 19 following the Moderna vaccine, resulting in rates of 4.7 and 2.5 cases per million doses administered, respectively. Nonetheless, pharmacists should remain cognizant that EUA is a mechanism to provide availability of these products during public health emergencies, and both mRNA vaccines currently remain unapproved. Therefore, continued vigilance to stay abreast of the evolving knowledge of their efficacy and safety will be required.

Conclusion

Since the beginning of the coronavirus pandemic, development of safe and effective vaccines has been a major goal. The first two approved COVID-19 vaccines utilize novel mRNA-based technology, and have demonstrated impressive short-term efficacy and safety. Additional technologies are being utilized in development of other COVID-19 vaccines, including dsDNA and adenovirus vaccines. Given these rapid changes and global vaccination efforts, familiarity with the underlying technologies and characteristics of the various vaccines against COVID-19 will be important for pharmacists.

References

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2. World Health Organization. Archived: WHO timeline – COVID-19. World Health Organization. Updated April 27, 2020. Accessed January 17, 2021. https://www.who.int/news/item/27-04-2020-who-timeline—covid-19
3. Centers for Disease Control and Prevention. Coronavirus disease 2019: How to protect yourself and others. Centers for Disease Control and Prevention. Accessed January 17, 2021. https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention-H.pdf
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5. World Health Organization. Coronavirus disease (COVID-19) advice for the public. World Health Organization. Updated January 6, 2021. Accessed January 21, 2021. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public
6. World Health Organization. COVID-19 vaccines. World Health Organization. Accessed January 21, 2021. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/covid-19-vaccines
7. US Food and Drug Administration. Moderna COVID-19 vaccine. US Food and Drug Administration. Updated January 6, 2021. Accessed January 17, 2021. https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/moderna-covid-19-vaccine
8. US Food and Drug Administration. Pfizer-BioNTech COVID-19 vaccine. US Food and Drug Administration. Updated January 12, 2021. Accessed January 17, 2021. https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/pfizer-biontech-covid-19-vaccine
9. Tinoco R, Crowe JE. Immune Globulins and Vaccines. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 13th ed. McGraw-Hill Education; 2017. Accessed February 18, 2021. accesspharmacy.mhmedical.com/content.aspx?aid=1162539971
10. Center for Disease Control and Prevention. Altered immunocompetence. Center for Disease Control and Prevention. Updated February 4, 2021. Accessed February 18, 2021. https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html
11. Corum J, Zimmer C. How nine Covid-19 vaccines work. New York Times. Updated January 21, 2021. Accessed January 21, 2021. https://www.nytimes.com/interactive/2021/health/how-covid-19-vaccines-work.html
12. Wang Y, Xing M, Zhou D. Coronavirus disease-19 vaccine development utilizing promising technology. Curr Opin HIV AIDS. 2020;15(6):351-358. doi:10.1097/coh.0000000000000648
13. Anonymous. Nanomedicine and the COVID-19 vaccines. Nat Nanotechnol. 2020;15:963. doi:10.1038/s41565-020-00820-0
14. Corum J, Zimmer C. How the Oxford-AstraZeneca vaccine works. New York Times. Updated February 3, 2021. Accessed February 18, 2021. https://www.nytimes.com/interactive/2020/health/oxford-astrazeneca-covid-19-vaccine.html
15. Trafton A. Explained: why RNA vaccines for covid-19 raced to the front of the pack. MIT News. Updated December 11, 2020. Accessed January 21, 2021. https://news.mit.edu/2020/rna-vaccines-explained-covid-19-1211
16. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021;384(5):403-416. doi:10.1056/NEJMoa2035389
17. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577
18. Pfizer-Biontech COVID-19 vaccine – bnt162b2 injection. Package insert. Pfizer-BioNTech; 2020.
19. Moderna COVID-19 Vaccine – cx-024414 injection. Package insert. Moderna US; 2020.
20. US Food and Drug Administration. Emergency use authorization for vaccines explained. US Food and Drug Administration. Updated November 11, 2020. Accessed January 21, 2021. https://www.fda.gov/vaccines-blood-biologics/vaccines/emergency-use-authorization-vaccines-explained
21. Shimabukuro TT, Cole M, Su JR. Reports of Anaphylaxis After Receipt of mRNA COVID-19 Vaccines in the US—December 14, 2020-January 18, 2021. JAMA. 2021. doi:10.1001/jama.2021.1967

Prepared by:

Christina Wilkins, PharmD Candidate Class of 2021
University of Illinois at Chicago College of Pharmacy

Reviewed by:

Ryan Rodriguez, PharmD, BCPS
Clinical Associate Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

March 2021

The information presented is current as of February 12, 2021.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.