VIRAL VECTORS AND mRNA-BASED COVID-19 VACCINES: AN OVERVIEW
OSAKUADE, OLUWANIFEMI WILLIAMS
DOKITA Editorial Board Member
The coronavirus disease 2019 (COVID-19) is due to a pathogen named the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This disease, which is now a pandemic, was first noticed in Wuhan, China, as atypical viral pneumonia. Its causative agent eventually identified as a novel coronavirus1. From December 2019 till 4th March 2021, there have been 115 million cases and 2.56 million deaths 2.
The SARS-CoV-2 genome sequence came into being in January 2020, and ever since then, the race to find effective vaccines against the virus has been on 3. It usually takes 10-15 years before vaccine licensure. The fastest-ever vaccine to be licensed was the Ebola vaccine which was developed in just five years 1. However, for COVID-19, the vaccine search was extraordinarily expedited, with vaccines licensed within less than a year 1, 3.
New vaccine technology was also widely put to use in the development of COVID-19 vaccines 1. This new vaccine technology refers to nucleic acid-based vaccines and recombinant viral vectors. Some of the most popular new COVID-19 vaccines like Pfizer and AstraZeneca use this new technology. Traditional viral vaccine technology primarily utilised killed-virus and attenuated live-virus vaccines 4. Vaccines like that exist for COVID-19, but we will focus on the newer technologies in this paper, specifically mRNA vaccines and viral vector-based vaccines.
CLASSIFICATION OF VACCINES
There are three types of vaccines 4:
- Vector vaccines
- Protein subunit vaccines
- Nucleic acid vaccines
- Vector vaccines
This vaccine involves the use of attenuated viruses that are not the SARS-COV-2 virus. These viruses contain some genetic material of SARS-COV-2. The viruses then use this genetic material to build a SARS-COV-2 viral protein. The body recognises the protein as a foreign body, forming T-cells and antibodies against that protein. When the SARS-COV-2 virus later appears in the body, memory cells from the earlier exposure give an instant and powerful immune response4. The category ‘vector vaccines’ broadly accommodates the traditional killed and attenuated live-viruses and the newer recombinant viral vectors.
- Protein subunit vaccines
These consist of harmless proteins obtained from the viral pathogen injected into the body. As a non-self particle, the body forms antibodies and T-cells against this protein. If the virus which bears that protein appears in the future, the body will exhibit an instant immune response 4.
- Nucleic acid-based vaccines
These vaccines come as DNA-based vaccines and mRNA-based vaccines.
a. DNA-based vaccines
These are viral genes or gene fragments encoding immunogenic antigens delivered to the host cell nucleus using DNA plasmids as vectors 1.
b. RNA-based vaccines
These contain mRNA instructions for our cells to produce harmless viral proteins. The immune system forms antibodies and T-cells against this viral protein and the source virus, thus priming the body for defence in the case of any viral infection 4.
IMMUNOGENIC FEATURES OF SARS-COV-2
SARS-COV-2 has four structural proteins 1.
- Spike (S)
- Envelope (E)
- Membrane (M)
- Nucleocapsid (N)
The Spike protein is the most immunogenically relevant of the four 1.
The Spike (S) Protein: The Spike proteins are glycosylated proteins that cover the viral envelope’s surface. They are responsible for viral entry into the cell. This function of spike proteins in SARS-COV-2 is similar to its function in other beta corona viruses like MERS-COV and SARS-COV 5.
This spike protein has two subunits: S1 and S2. S1, also known as, Receptor Binding Domain (RBD), binds to the Angiotensin Converting Enzyme (ACE2) on the host cell membrane. When it binds, the S2 subunit changes its conformation to allow a fusion of the viral envelope and the cell membrane, permitting viral penetration 5.
Because this is how the virus infects the cell, it is the target of many COVID-19 vaccines 1. The vaccinators’ strategy is to form neutralising antibodies against the spike proteins, thus preventing viral entry into cell 5.
VARIOUS COVID-19 VACCINES
1. mRNA Vaccines
Also known as BNT162b2 or Comirnaty, this vaccine was developed by two German and US companies, namely Pfizer and BioNTech7.
Mechanism of Action
BNT162b2 is a lipid nanoparticle-formulated nucleoside-modified mRNA vaccine. The lipid nanoparticle in which the modified mRNA is enclosed dissolves into the host cell’s lipid bilayer, thus facilitating the viral mRNA’s introduction into the cytoplasm where it becomes transcribed. The viral mRNA in the vaccine encodes SARS-COV-2 full-length spike protein. This mRNA, however, is modified by two proline mutations to lock the S-protein in the pre-fusion conformation. This mechanism makes the modified protein mimic the intact virus with which neutralising antibodies must interact 7.
The vaccine requires two doses given intramuscularly with an interval of 21 days in between 8.
The vaccine is 95% effective after two doses. However, two weeks after just one dose, the vaccine is 52% effective against symptomatic COVID-19 9.
At the injection site: Pain, redness and swelling. Systemically: Fever, fatigue, headache chills, muscle pain and joint pain. The chance of anaphylaxis is estimated to be 11 cases in a million 8.
During shipping and long-term storage, ultra-cold freezers at -80° to -60°C store BNT162b2. It may be refrigerated between 2°C to 8°C for five days. This vaccine lasts at room temperature for only 6 hours, after which it is discarded 10.
Also known as mRNA-1273, this mRNA vaccine was developed in the US by the National Institute of Allergies and Infectious Diseases (NIAID), the Biomedical Advanced Research and Development Authority (BARDA), and Moderna11.
Mechanism of Action
mRNA-1273, like Pfizer, is a lipid nanoparticle-encapsulated, nucleotide-modified mRNA vaccine that encodes the SARS-COV-2 spike in its pre-fusion conformation 12.
The vaccine requires two doses given intramuscularly with 29 days in between each dose 11.
mRNA-1273 has 94.1% efficacy in preventing symptomatic COVID-19 11.
Injection site: Pain, erythema, tenderness and induration. Systemically: Fatigue, chills, and myalgia. These are usually mild-moderate effects 13.
mRNA-1273 may be refrigerated between 2°C to 8°C for up to 30 days 14.
2. Viral Vector-based Vaccines
Also known as AZD-1222, this vaccine as developed by Oxford University and its affiliated Jenner’s Institute.
Mechanism of Action
AZD-1222 uses a simian adenovirus (ChAdOx1) as the viral vector. This virus contains the entire coding sequence of SARS-COV-2 spike protein. When AZD-1222 is injected into the body, the adenovirus enters the host cells and synthesises the SARS-COV-2 spike protein. This stimulates the immune system to form antibodies and T-cells against the S-protein 15.
AZD-1222 is administered intramuscularly in two doses with four weeks in between 15.
The vaccine has an efficacy of 62.1% after taking both doses. The vaccine’s efficacy after a single first dose is 76%. While it is not clear how long vaccination from a single dose lasts, it is recommended that when the vaccine is in low supply, vaccinating a larger population with a single dose better protects the overall population than vaccinating half that group with the two doses 16.
AZD-1222 can be stored, transported and handled at normal refrigerated conditions (2°C to 8°C)17.
b. Sputnik V
Also known as Gam-COVID-Vac, this vaccine was developed in Russia by the Gamaleya Research Institute of Epidemiology and Microbiology 18.
Mechanism of Action
Gam-COVID-Vac is a heterologous prime-boost viral vector-based vaccine. Being heterologous means that it uses two different adenoviruses as vectors.
Being a prime-booster vaccine means that a second dose of the vaccine is required to optimise the immune response. The two human adenoviruses used here are rAd26-S and rAd5-6. These viruses are modified to bear the spike gene of SARS-COV-2. Two different virus vectors are used to overcome pre-existing immunity in the population against anyone of the viral vectors. Only Gam-COVID-Vac uses this heterologous model of the vaccine. No other approved COVID-19 vaccine does 18, 19.
Two doses are given with 21 days between each dose. One adenovirus vector is injected during the first dose, while the second viral vector is given during the second dose 18.
Gam-COVID-Vac has an efficacy of 91.6% in preventing moderate to severe disease after a single dose. However, after both doses, the vaccine has an efficacy of 100% in preventing moderate to severe disease 19.
Injection site: Pain. Systemically: Hyperthermia, headache, myalgia, and joint pain. Note that these effects are usually mild and transient18.
The vaccine must be stored at -18°C 20.
c. Johnson and Johnson
Also known as Ad26.CoV2.S, this vaccine was developed by Janssen Pharmaceuticals under the firm Johnson and Johnson 21.
Mechanism of Action
This vaccine comprises a genetically modified replication-incompetent adenovirus type 26 (Ad26) vector made to encode the SARS-COV-2 spike protein 21.
A single dose delivered intramuscularly is required 22.
Injection site: Pain and inflammation. Systemically: Possible anaphylaxis, headache, fatigue, nausea, and fever 22.
Twenty-eight days after vaccination, Ad26.CoV2.S has an 85% efficacy in preventing moderate to severe disease in adults 23.
Ad26.CoV2.S should typically be stored at between 2°C to 8°C. The vaccine, however, remains viable in temperatures between 9°C to 25°C for 12 hours 24.
Of All These the Most Optimal…
The factors affecting the excellence of a vaccine include:
- Dosage: Vaccines requiring a single dose will more speedily reach the whole population than those requiring two or more shots 25. They may also be cheaper to manufacture 16.
- Storage temperatures: Vaccines that can be stored at higher temperatures are more feasible in low-resource settings 3.
- Efficacy: The higher the efficacy, the higher the chance of preventing disease in a population 26.
Considering the conditions stated above, we conclude that the most optimal vaccine is the most convenient blend of those three factors. That is the vaccine we should choose.
- Silveira MM, Marcal G, Moreira SG, and Mendonca M. DNA vaccine against COVID-19: perspectives and challenges. Elsevier. 2020.
- WHO Coronavirus Disease [COVID-19] Dashboard. Available from: https://covid19.who.intl/. [Accessed 4th March 2021.]
- Cennimo DJ – COVID-19 vaccines. Medscape. Available from: emedicine.medscape.com/article/2500139-overviewa1. [Accessed 17th February 2021.]
- Understanding how COVID-19 Vaccines Work. Available from: https://www.cdc.com.gov/coronavirus/. [Accessed 16th February.]
- Arashkia A, Jalivand S, et al. Severe acute respiratory syndrome coronavirus-2 spike [s] protein based viral vaccine candidates: State of the art and future prospects. Wiley-Blackwell. 2020.
- Yuan H, Yang C, Xu C, Xu W, and Liu S. Structural and functional properties of SARS-COV-2 spike protein: potential antivirus drug development for COVID-19. APS. 2020.
- Walsh EE, Frenck RW, Gruber WC, et al. Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates. NEJM. 2020.
- US National Library of Medicine. Study to describe the safety, tolerability, immunogenicity and efficacy of RNA vaccine candidates against COVID-19 in healthy individuals. Available at: clinicaltrials.gov/ct2/show/NCT04368728. [Accessed 4th March 2021.]
- Polock FP, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. National Library of Medicine. 2020.
- Pfizer-BioNTech COVID-19 vaccine Storage and Handling Summary. Available from: www.cdc.gov/vaccines/covid-19/info-b-product/pfizer/index. [Accessed 16th February 2021.]
- Baden LR, Hana M, Sahly E, Rouphael NG, Robets PC, et al. Efficacy and safety of the mRNA-1273 SARS-COV-2 vaccine. NEJM. 2020.
- Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, et al. an mRNA vaccine against SARS-COV-2; preliminary report. NEJM. 2020.
- Anderson EJ, Rouphael NG, Widge AT, Jackson LA, et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults, NEJM. 2020.
- Moderna COVID-19 Vaccine Storage and Handling Summary. 2020.
- Hung IF, Poland GA. Single-dose Oxford-AstraZeneca COVID-19 vaccine followed by a 12week booster. Lancet. 2021.
- Voyssey M, Clemens SA, Madhi SA, Weckx LY, Folegatti PM, Aley PK. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 [Azd 1222] vaccine; a pooled analysis of four randomized trials. Lancet. 2021.
- AstraZeneca COVID-19 vaccine authorized for emergency supply in the UK. Available at: www.astrazeneca.com/media-centre/press-releases/2020/astrazenecas-covid-19-vaccine-authorised-in-uk.html. [Accessed 20th February 2021.]
- Logunov DV, Dolzhikova IV, Gintsburg AL, et al. Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccines in two formulations: two open, non-randomisd phase 1/2 studies from Russia. Lancet. 2021.
- Logunov DY, Dolzhikova IV, Schcheblyakov DV, Tukhvatulin AI, Zubova OV, Dzharuttaeva AS, et al. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomized controlled phase 3 trial in Russia. Lancet. 2021.
- Russia to freeze dry coronavirus vaccine to avoid distribution challenges. Available at: https://www.themoscowtimes.com/2020/11/17/russia-to-freeze-dry-coronavirus-vaccine-to-avoid-distribtion-challenges-reuters-a72065. [Accessed 6th March 2021.]
- Janssen Investigational COVID-19 Vaccine: Interim analysis of Phase 3 clinical data released. Available at: https://www.nih,govt/news-events/news-releases/janssen-investigational-covid-19-vaccine-interim-analysis-phase-3-clinical-data-released. [Accessed 6th March 2021.]
- Fact Sheet for Recipients and Caregivers. 2021.
- Johnson & Johnson. Johnson & Johnson COVID-19 vaccine authorized by US FDA for emergency use – first single-shot vaccine in fight against global pandemic. Available at: https://www.jnj.com/johnson-johnson-covid-19-vaccine-authorized-by-u-s-fda-for-emergency-usefirst-single-shot-vaccine-in-fight-against-global-pandemic. [Accessed 3rd March 2021.]
- Fact Sheet for Healthcare Providers Administering Vaccines [vaccination providers.] 2021.
- Lewis T – should we change COVID vaccine dose to reach more people? What the data say. Scientific American. Available from: https://www.scientificamerican.com/article/should-we-change-covid-vavvine-doses-to-reach-more-people-what-the-data-say1/. [Accessed 6th March 2021.]
- Carl Zimmer – 2 companies say their vaccines are 25% effective. What does that mean? New York Times. Available at: https://www.nytimes.com/2020/11/20/health/covid-vaccine-95-effective.html. [Accessed 6th March 2021.]