COVID-19 Vaccine

Figure 1: Electron micrograph of SARS-CoV-2 (Mallapaty, 2020).

The global spread of coronavirus has led to a drastic need for a vaccine. In early January 2020, The World Health Organization (WHO) announced reports of pneumonia due to a novel coronavirus in Wuhan, China (American Journal of Managed Care [AJMC], 2020). By January 31, the WHO declared the spread of coronavirus as a public health emergency (AJMC, 2020). The novel coronavirus was identified as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on February 11, 2020 and the name was chosen due to its genetic similarities to the Severe acute respiratory syndrome coronavirus (SARS-CoV) that caused the SARS outbreak in 2003 (World Health Organization [WHO], 2020).

SARS-CoV-2 is an enveloped positive-sense single-stranded RNA virus that causes coronavirus disease 2019 (COVID-19), a respiratory illness that can lead to systemic infection of other organs and sometimes death (Machhi et al., 2020). On March 11, 2020, COVID-19 was declared a pandemic by the WHO (AJMC, 2020). While the origin of SARS-CoV-2 is not exactly known, it is assumed that it originated from bats (Centers for Disease Control and Prevention [CDC], 2021). This is evident from early infection reports from people who worked in live animal markets (CDC, 2021). SARS-CoV-2 has four structural proteins: the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and envelope (E) protein (Dong et al., 2020). The N protein is involved with packaging the RNA genome and the M and E proteins provide the structure for the envelope (Wu et al., 2020). The S protein is needed for cell entry and contains the S1 and S2 subunits which allow for receptor binding and membrane fusion, respectively (Wu et al., 2020). The S protein is the target of most COVID-19 vaccine candidates due its postfusion conformation which allows the virus to evade host immune responses (Dong et al., 2020).

A COVID-19 vaccine would prevent the infection and spread of SARS-CoV-2. As of January 29, 2021, there are 63 vaccine candidates in clinical trials and 173 in pre-clinical development (WHO, 2021b). There are nine vaccines that have been approved for public use: two RNA vaccines (the Pfizer–BioNTech vaccine and the Moderna vaccine), three inactivated vaccines (Sinopharm BBIBP-CorV vaccine, Bharat Biotech BBV152 vaccine, Sinovac CoronaVac vaccine), three viral vector vaccines (Gamaleya Research Institute Sputnik V vaccine, the Oxford–AstraZeneca vaccine, and CanSino Biologics Ad5-nCoV vaccine), and one protein subunit vaccine (EpiVacCorona vaccine) (Craven, 2021).

A COVID-19 vaccine would prevent the acquirement and spread of SARS-CoV-2. As of January 31, 2021, there have been 103 million cases of COVID-19 and 2.2 million deaths around the world (Worldometer, 2021). 775000 of these cases and 19900 deaths are in Canada (Government of Canada, 2021a). Although people above the age of 70 contribute to 12.5% of the total COVID-19 cases in Canada, they contribute to 89% of COVID-19 deaths (Government of Canada, 2021a). Since vaccines have revolutionized the prevention of communicable diseases, a COVID-19 vaccine would vastly prevent the deaths of the elderly population.

Individuals who are taking immunosuppressive medications due to receiving an organ transplant or having a chronic illness, such as rheumatoid arthritis, are at a higher risk of contracting COVID-19 (Canadian Digestive Health Foundation [CDHF], n.d.). Due to their immunodeficient state, this may mean experiencing more severe acute symptoms and a higher risk of death or long-term symptoms (CDHF, n.d.). They may not be eligible to receive a COVID-19 vaccine; however, herd immunity can be attained if majority of the population is immunized. This would greatly protect immunodeficient individuals from SARS-CoV-2 by preventing the spread of the virus.

A study by Huang et al. (2021) observed the long-term symptoms of patients 6 months after being discharged from Jin Yin-tan Hospital in Wuhan, China. Of the 1733 participants in the study, 76% of patients reported at least one symptom 6 months after symptom onset. The most common symptoms were fatigue or muscle weakness (63% of participants) and trouble sleeping (26% of participants). 23% of participants also experienced anxiety or depression (Huang et al., 2021). Additionally, patients who were more severely ill while in hospital had abnormal chest imaging results and impaired pulmonary diffusion (ability of oxygen transfer between the lungs and circulatory system) (Burchardi & Stokke, 1991; Huang et al., 2021). These severely ill patients would require rehabilitation to improve lung function (Huang et al., 2021). A COVID-19 vaccine would prevent the acquirement of SARS-CoV-2 and thus eliminate the risk of long-term symptoms post-recovery.

Figure 2: Canadian unemployment rate from 2020 (Trading Economics, 2020).

In February of 2020 before the rise of the SARS-CoV-2 pandemic, the unemployment rate of Canada was 5.6% (Trading Economics, 2020). This later peaked to 13.7% in May (Trading Economics, 2020) due to closures of non-essential businesses and employees that would be unable to work from home. Due to the reopening of some businesses, such as restaurants and hair salons, the unemployment rate has since decreased to 8.8% in December 2020 (Trading Economics, 2020). However, 1.1 million Canadians are still unemployed (The Daily, 2021). Additionally, the public fear of getting COVID-19 and the reduced customer capacity of businesses has resulted in approximately 5% of small businesses to consider bankruptcy (Tam et al., 2020). This approximates to 415000 jobs lost in the private labour force. This puts strain on the federal government to provide funding to those unable to work. As such, the development of a vaccine would help in creating jobs by allowing businesses to reopen at full capacity and rehire their staff once majority of the population is immunized.

A COVID-19 vaccine would help in creating new jobs. For example, pharmacy chains Walgreens and CVS in the United States were reported to be looking for 35000 workers in December 2020 in order to distribute the vaccine to the public (Buchwald, 2020). The production of a new vaccine requires a large infrastructure that involves research, manufacturing, storage, transportation, distribution, intellectual property, and regulations. Thus, thousands of new workers from different sectors would be required to fill these roles.

Finally, a COVID-19 vaccine would stimulate economic growth. Due to the lack of in-person shopping that is available in Canada, the household disposable income of Canadians has risen by 11% due to income support from the federal government (Arora, 2020). When businesses reopen once again, this disposable income may play a role in boosting the economy.

The purpose of a vaccine is to provide individuals with long-term immunity against a pathogen. When the body first encounters a foreign antigen, a primary immune response is generated. This response involves host cells presenting the antigen to T cells, which are a part of the adaptive immune system. These T cells aid in activating B cells, which generate antibodies against these antigens. These antibodies, alongside T cells, can neutralize antigens and help eliminate the pathogen (The Immunisation Advisory Centre, 2020). A proportion of these immune cells also have memory which allows an existing memory of the antigen to be stored away. Upon repeated exposure to the same pathogen, memory T cells allow an even greater secondary immune response so the infection can be cleared more efficiently (Janeway et al., 2001). In fact, vaccination increases the number of circulating antibodies against a specific antigen and results in a secondary immune response that is 10-100x higher than the primary response (Janeway et al., 2001). The antibodies generated from the secondary response also have greater antigen affinity (Janeway et al., 2001). As such, vaccines take advantage of this memory and mimic a natural infection by exposing individuals to components of the virus to prime an immune system upon repeated exposure to the pathogen.

Currently, there are 4 different types of vaccines being developed for SARS-CoV-2. This includes whole virus, protein subunit, viral vector, and nucleic acid vaccines (Gavi, 2020). Specifically, as of January 26, 2021, there are 15 whole virus, 13 protein subunit, 20 nucleic acid, and 15 viral vector vaccines in development which have reached clinical phases (Gavi, 2020). In all cases, these vaccines trigger an immune response which results in specialized memory cells taking note of specific antigens produced by the virus. This primes the immune system to fight off the virus more effectively and efficiently upon repeated exposure to the pathogen.

Figure 3: Current COVID-19 vaccine types in development (WHO, 2021a).

Whole virus vaccines come in two different forms, which are live attenuated and inactivated. Live attenuated vaccines contain a weakened form of the virus (Shin et al., 2020). Although the virus is not harmful, it is still able to replicate within the body. Inactivated vaccines, on the other hand, have their genetic material removed by heat or chemicals (Shin et al., 2020). This prevents the virus from infecting host cells or replicating within the body. As such, inactivated vaccines are generally safer than live attenuated vaccines because live attenuated vaccines run a small risk of triggering the disease in rare cases (Gavi, 2020). Triggering of the disease can occur upon a small chance the virus reverts to its pathogenic form (Shin et al., 2020). Although inactivated vaccines are safer, they also trigger a weaker immune response compared to live attenuated vaccines and may require multiple doses and adjuvants (Gavi, 2020). Despite these few shortcomings, whole virus vaccines are a very well-established technology and can trigger a strong immune response that involves B and T cell activation (Gavi, 2020). This thereby makes it a plausible vaccine candidate.

Protein subunit vaccines use pieces of the pathogen rather than the whole virus to trigger an immune response (Gavi, 2020). These pieces of the pathogen are recognized as foreign antigens by the body and are therefore able to stimulate an immune response that involves the activation of T cells and antibody production by B cells (Gavi, 2020). In the specific case of SARS-CoV-2, the full-length spike protein or its S1/S2 subunits are used as antigens to stimulate an immune response (Shin et al., 2020). Since protein subunit vaccines only contain pieces of the pathogen, they are unable to infect cells and potentially cause disease. Therefore, protein subunit vaccines are generally safe and are also a well-established technology (Gavi, 2020). However, these vaccines generate a weaker immune response compared to other vaccines and may require booster shots and adjuvants (Gavi, 2020).

Viral vector vaccines contain a viral vector that delivers genetic information to host cells by infecting them (Shin et al., 2020). The host cell machinery is then used to transcribe and translate this genetic information to produce a desired antigen (Gavi, 2020). Once translated, the antigen is presented on the surface of the host cell, which immune cells can detect to start an immune response (Gavi, 2020). There are two types of viral vector vaccines, which include replicating and non-replicating viral vectors. Replicating viral vector vaccines can produce new viral particles with each cell infected compared to non-replicating vectors which can only produce the vaccine antigen (Gavi, 2020). The current viral vector vaccines being developed for SARS-CoV-2 are non-replicating and are therefore safer and non-pathogenic (Gavi, 2020). Like whole virus vaccines, viral vector vaccines are a well-established technology and can trigger a strong immune response that involves B and T cell activation (Gavi, 2020). However, viral vector vaccines may have reduced effectiveness due to anti-vector immunity. This can occur if an individual has previously been exposed to the viral vector, which can trigger an immune response against the vector (Shin et al., 2020). Therefore, an immune response must be elicited within a single dose (van Riel & de Wit, 2020). Otherwise, a different viral vector will need to be produced if a second dose of the vaccine is required for full immunity (Gavi, 2020).

Nucleic acid vaccines use genetic material such as RNA or DNA to provide cells with instructions on how to produce the antigen (Gavi, 2020). Rather than using a viral vector, the genetic material is introduced into host cells by attachment to molecules or through a device called a “gene gun” (Gavi, 2020). Like viral vector vaccines, host cell machinery is used to transcribe and translate this genetic information to produce the antigen upon delivery of viral genetic information into host cells (Gavi, 2020). These antigens are then presented on the surface of host cells which in turn stimulates an immune response. These vaccines do not contain any live components and are therefore very safe (Gavi, 2020). They can also be easily modified and produced which makes them helpful in facing new viruses or variants (van Riel & de Wit, 2020). Nucleic acid vaccines are also able to trigger a strong immune response involving B and T cell activation (Gavi, 2020). However, this technology is relatively new and may be very temperature sensitive (Gavi, 2020). In addition, the long-term health effects of nucleic acid vaccines are yet to be discovered (Dong et al., 2020). Despite the technology being fairly new, mRNA vaccines are currently the most popular type of vaccines being developed for SARS-CoV-2.

Self-amplifying RNA (saRNA) vaccines are a specific subtype of nucleic acid vaccines. These types of vaccines differ from traditional RNA vaccines due to their ability to self-replicate (Zhang et al., 2019). This is done by encoding an alphaviral RNA dependent RNA polymerase (RdRp) and a gene of interest into the mRNA so that it can replicate within the cytoplasm of a host cell and produce a desired antigen (Zhang et al., 2019). Once inside the cell, the RdRp is translated by the host's ribosome and will be used to synthesize genomic RNA for self-amplification and a subgenomic RNA to produce antigens (Creative Biolabs, n.d.). These antigens will then be processed by the cell and presented on its surface so that the antigen can be recognized by the immune system. Naked saRNA can be electroporated into cells (McKay et al., 2020) but encapsulating them in a lipid nanoparticle (Dong et al., 2020; McKay et al., 2020) is the currently preferred mode of transport due to its low cost and ability to prevent RNA degradation (Zhang et al., 2019). In comparison to traditional RNA vaccines, saRNA vaccines have a prolonged half-life (Shin et al., 2020) and require a lower dose (van Riel & de Wit, 2020). They can also be mass produced (van Riel & de Wit, 2020) and have the advantage of eliciting a strong immune response from creating its own adjuvants in the form of double stranded RNA and other replication intermediates (Pardi et al., 2018). However, saRNA vaccines still have low stability even when encapsulated in a lipid nanoparticle, they require multiple doses for an adequate immune response (van Riel & de Wit, 2020), and they have a slower immune response compared to traditional RNA vaccines (Zhang et al., 2019).

mRNA vaccines have emerged as a leading contender in the fight against COVID-19. In Canada, as of January 2021, the only two vaccines approved for emergency-use against COVID-19 are mRNA-based. They include Pfizer-BioNTech’s COVID-19 vaccine BNT162b2, and Moderna’s COVID-19 vaccine mRNA-1273 (Government of Canada, 2021b). Unlike traditional vaccines that utilize a weakened pathogen or antigens, mRNA vaccines deliver the mRNA of the antigen of interest to the host cells (Pardi et al., 2018). More specifically, the mRNA encodes for the spike protein or the receptor binding domain of the spike protein from SARS-CoV-2 (L. Jackson et al., 2020; Mulligan et al., 2020).

Figure 4: Activation of cell-mediated immunity and antibody-mediated immunity upon mRNA vaccination (Li, 2020).

The vaccines contain antigen-specific mRNA that is encapsulated in a lipid nanoparticle and is delivered via intramuscular injection into the deltoid muscle (Pardi et al., 2018). The lipid nanoparticle fuses with the cell membrane of host cells through endocytosis and the mRNA enters the host cell cytosol. Upon delivery of mRNA to the host cells, ribosomes in the cytosol will translate the mRNA into the antigen it encodes for (Pardi et al., 2018).

Moderna’s COVID-19 vaccine results in the translation of the spike protein while Pfizer-BioNTech’s COVID-19 vaccine results in the translation of the receptor binding domain (RBD) of the spike protein (L. Jackson et al., 2020; Mulligan et al., 2020). The antigen is complexed with Major Histocompatibility Complex (MHC) Class I or MHC Class II proteins and is then expressed on the host cell surface (Schlake et al., 2012). Cell surface expression of the antigen complex triggers a cell-mediated and antibody-mediated immune response (Pardi et al., 2018). The resulting immune responses behave in the same manner as traditional vaccines. The goal of this vaccine is to generate antibodies and long-term memory to prevent future infection of SARS-CoV-2.

Vaccination hesitancy has resulted from the novelty of the mRNA vaccines developed for COVID-19 (Dror et al., 2020). The mRNA vaccines developed by Pfizer-BioNTech and Moderna are the first of their kind to be used commercially. Although these specific vaccines are novel, mRNA vaccine technology has been studied for several years. Three main issues were encountered in the past which made the vaccines difficult to implement until now. Firstly, there was a need for an effective delivery system. Secondly, the stability of mRNA had to be improved. Thirdly, the immunogenic nature of mRNA needed to be addressed (Pardi et al., 2018). Addressing these issues have allowed for mRNA vaccines to be used for COVID-19.

First, there was a need for an effective delivery system. When researchers attempted to deliver naked mRNA as a vaccine in the 1990's, they quickly realized it would be ineffective as mRNA would degrade too quickly upon entering the host which prevented it from eliciting a strong enough immune response (Pardi et al., 2018). Both Pfizer-BioNTech and Moderna addressed this issue by encapsulating the mRNA in a lipid nanoparticle (N. Jackson et al., 2020; Mulligan et al., 2020). This nanoparticle protects the mRNA until it merges with the host cell membrane and deposits the mRNA into the cytosol of the cell (Pardi et al., 2018). Thus, an effective delivery system was implemented.

Second, mRNA is highly unstable by nature so researchers needed to make improvements to its stability (Pardi et al., 2018). While the lipid nanoparticle mentioned previously ensures some stability, further modifications had to be made. Both Pfizer-BioNTech and Moderna addressed this issue through the addition of a 3’ and 5’ untranslated region flanking the antigen mRNA sequence as well as a 5’ cap and extended 3’ polyadenylated tail (N. Jackson et al., 2020; Mulligan et al., 2020). These steps significantly improved the stability of the mRNA vaccine, allowing for increased translation and therefore, a stronger immune response. Additionally, both Pfizer-BioNTech and Moderna’s COVID-19 vaccines must be stored at -70°C and -20°C (Boyd, 2020), respectively, to limit the activity of extracellular RNases which would degrade the mRNA (Government of Canada, 2021b; Pardi et al., 2018).

The third hurdle to overcome was the need to modulate the immunogenicity of mRNA. mRNA is inherently immunogenic (Pardi et al., 2018). This property is useful for eliciting an immune response; however, an extremely immunogenic response shuts down the translation of mRNA in the cell. Effective translation is needed in order to produce enough antigen to elicit a strong immune response (Pardi et al., 2018). Highly immunogenic double stranded RNA contaminants are generated during in vitro mRNA preparations (Pardi et al., 2018). Therefore, vaccines are purified several times during the manufacturing process to remove contaminants which will lead to a dampened immune response (Pardi et al., 2018). Additionally, the immune response can be further dampened through the addition of modified nucleosides to prevent specific immune receptors from being activated (Pardi et al., 2018). Pfizer-BioNTech and Moderna employed this technique by incorporating 1-methyl-pseudouridine in their mRNA sequence (Corbett et al., 2020; Mulligan et al., 2020).

mRNA vaccines offer several advantages over traditional vaccine types. Its major advantages are related to its safety and production. The safety of the vaccine can be attributed to the fact that it is mRNA-based. Since there are no infectious particles involved in the production or delivery of the vaccine, there is no risk of infection directly resulting from vaccination (Mathew et al., 2020). Additionally, mRNA is translated in the cytosol of the cells so there is no risk of integration into the host genome unlike DNA-based vaccines (Mathew et al., 2020). Since infectious particles, like the virus itself, are not involved in the manufacturing of this vaccine, production time and costs are significantly reduced (Mathew et al., 2020). Enzymes and reagents required for the in vitro synthesis of mRNA and the manufacturing of the vaccine are commercially available (Pardi, Hogan, Porter, & Weissman, 2018). Additionally, due to recent advancements in sequencing technology, obtaining the mRNA sequence of viruses has become a quicker process (Pardi, Hogan, Porter, & Weissman, 2018). Pfizer-BioNTech and Moderna were able to produce mRNA vaccines for COVID-19 in record-breaking time due to advancements such as these.

The disadvantages of mRNA vaccines are largely related to its novelty. Although the technology itself is not new, the commercial use of mRNA vaccines only began with Pfizer-BioNTech and Moderna’s mRNA COVID-19 vaccines. Certain details still remain unanswered, such as the length of long-term immunity and the long-term health effects of the vaccine (Mathew et al., 2020). These factors are expected to be answered in due time. Additionally, although improvements have been made to the stability of mRNA, both mRNA COVID-19 vaccines have to be stored at below freezing temperatures to limit RNase activity and remain effective (N. Jackson et al., 2020; Mulligan et al., 2020). This poses logistical challenges in the transportation and storage of these vaccines, particularly in developing countries.

The emergence of mRNA vaccines has provided hope in the fight against COVID-19. The reported efficacy of Pfizer-BioNTech and Moderna’s mRNA vaccines thus far (95% and 94.1%, respectively) are promising signs of the potential of mRNA vaccines in future vaccine development (N. Jackson et al., 2020; Mulligan et al., 2020).

The surface of SARS-CoV-2 is covered by multiple spike proteins. Each spike protein forms a trimer (Wu et al., 2020) and the collection of these proteins on the virus' enveloped gives it the appearance of a corona, from which the name coronavirus is derived (Tyrrell & Fielder, 2002). These spike proteins are the first proteins to come in contact with host cells for further fusion and infection (Wu et al., 2020).

Figure 5：Structure of SARS-CoV-2 viral particle. The spike proteins are located on the surface of the viral envelope. This gives the virus the appearance of a corona (Orpheus FX, 2020).

Figure 6: The fusion peptide forms a bridge between the viral envelope and the cell membrane. It then refolds to shorten the distance between the two surfaces and induces membrane fusion (Borkotoky et al., 2021).

The spike protein of SARS-CoV-2 is 1273 amino acids in size (Huang et al., 2020) and it mainly composed of 2 subunits: the S1 subunit and the S2 subunit (Borkotoky et al., 2021). The S1 subunit is the receptor binding domain that specifically targets angiotensin-converting enzyme 2 (ACE2) on host cells and the S2 subunit functions to trigger the membrane fusion between the cell membrane and the viral envelope (Borkotoky et al., 2021). At the pre-fusion conformational state, the spike protein is at its closed status and the receptor binding domain does not reach out to its target. Upon interaction, the closed status will be opened and then the S1 subunit will be activated and interact with ACE2. This allows the virus to be anchored to the cell membrane during the membrane fusion step (Borkotoky et al., 2021).

For the membrane fusion to occur, the S1/S2 subunits undergo a furin cleavage (Xia et al., 2020). Then the S2 subunit, which is critical for membrane fusion, undergoes a major helical rearrangement (Borkotoky et al., 2021). Receptor binding by S1 is followed by exposure to a fusion peptide in the S2 domain which integrates into the host membrane and forms a structure called a fusion bridge (Borkotoky et al., 2021). This is followed by a refolding of the spike protein that brings the cell membrane and viral envelope closer together and initiate membrane fusion (Huang et al., 2020). Thus, SARS-CoV-2 is able to enter into cells that have the ACE2 receptor.

The spike protein takes up the most important role of viral infection as it allows for cell entry. Therefore, a vaccine targeting the spike protein would be a practical and efficient consideration for COVID-19 treatment.

In conclusion, there is a clear need for the development of a safe and effective vaccine against SARS-CoV-2. The implications of COVID-19 have reached beyond just health related issues but have also impacted the global economy. The development of a vaccine would not only provide protection to vulnerable populations but it would also provide opportunities for job creation and economic growth. Currently there are 4 different types of vaccines being developed for SARS-CoV-2. These include whole cell, protein subunit, viral vector, and nucleic acid vaccines. Most vaccines being developed target the spike protein of the virus, which is required for entry into host cells. Of these vaccines, mRNA vaccines are the leading candidates in the context of a global pandemic as they are quick and easy to produce. Therefore, an mRNA vaccine targeting the spike protein of SARS-CoV-2 would be considered an effective approach to managing the global spread of COVID-19.

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