COVID-19 Vaccination: From Interesting Agent to the Patient
1.1. Covid-19 Breakdown and Background
1.2. The Research and History Ortho-Coronavirinae
1.3. Vaccinations Proposed for SARS-CoV-1
- Inactivated SARS-CoV based vaccine: this vaccine expressed several structural proteins such as nucleo-capsid, membranes and spike proteins . These are thought to induce an immune reaction that is capable of stimulating an immune response. The inactivated virus was intended for use as a first-generation vaccine, this is due to the ease of generation of these inactivated viral particles. The next step was the replacement of the inactivated viral vaccine by a second vaccine based around fragments containing neutralizing epitopes that are safer and more efficacious to use. Several reports have shown that SARS-CoV-1 was inactivated with formaldehyde, UV light, and β-propiolactone which can induce virus-neutralizing antibodies in immunized animals [28,29,30].
- S-protein based vaccines: several recombinant based vaccines that have expressed the spike protein in SARS-CoV-1 were assessed in pre-clinical studies . Reports have shown that candidate DNA vaccines encoding the spike protein stimulated an immune response. This led to the study showing that injected mice are protected for SARS-CoV-1. Wang et al. have produced higher titres of neutralizing antibodies and demonstrated that major and minor neutralizing epitopes are located in the S1 and S2 subunits, respectively . Other groups also found neutralizing epitopes in the S2 subunit [33,34]. Bisht et al.  have shown that intranasal or intramuscular inoculations of mice with highly attenuated Modified Vacciniavirus Ankara (MVA) vaccines encoding full-length SARS-CoV-1 S protein. This also produced neutralizing antibodies. Bukreyev et al.  reported that mucosal immunization of African green monkeys with an attenuated parainfluenza virus expressing S protein resulted in the production of neutralizing antibodies and protected animals from infection by challenge with SARS-CoV-1. These data suggest that the S protein can induce neutralizing antibodies and protective responses in immunized animals .
- Vaccines based on fragments containing neutralizing epitopes: fragments that were responsible for the virus binding to receptors within a host cell were targeted. Patients and animals that became infected with SAR-CoV-1 reacted strongly to this type of vaccine. They were immunized and inactivated with a receptor-binding domain (RBD) [29,38]. Absorption of antibodies by RBD showed the capability for removal of most of the neutralizing antibodies, RBD-specific antibodies isolated from these antisera have potent neutralizing activity [38,39]. The immunized mice were protected from SARS-CoV-1. The antibodies purified from the antisera against SARS-CoV-1 significantly inhibited RBD binding to ACE2 [29,38,40,41]. This suggested that RBD contains the major neutralizing epitopes in the S protein and is an ideal SARS vaccine candidate because RBD contains the receptor-binding site, which is critical for virus attachment to the target cell for infection [42,43,44]. Antibodies specific for RBD are expected to block the binding of the virus to the target cell. Therefore, RBD induces higher titers of neutralizing antibodies than those vaccines expressing the full-length S protein [31,32,35,37,43].
1.4. Vaccinations Proposed for MERS-CoV
- Recombinant MERS-CoV: unlike the SARS-CoV-1 vaccine, the MERS-CoV vaccine was constructed based on the recombinant viruses using reverse genetics. This resulted in expressed marker mutations, which allowed for replication-competent, propagation-defective MERS-CoV vaccines .
- Viral-Vector-based MERS vaccine: this is similar to the vector-based SARS vaccine; MERS vaccines can also be constructed using viral vectors that express major MERS-CoV proteins, normally the S protein. Several such MERS vaccine candidates have been developed and/or tested for efficacy in mouse models or camels [46,47,48,49]. Viral vectors expressing full-length S protein of MERS-CoV induced S-specific antibody responses and/or T-cell responses in a mouse model via the intramuscular route, showed effective in vitro neutralization for MERS-CoV infection [47,50]. Additionally, vaccination of mice with an MVA-based full-length S vaccine-elicited MERS-CoV-specific CD8+ T cell response and neutralizing antibodies, protecting mice against MERS-CoV [48,49]. Intra-nasally or intra-muscularly administered MVA-S vaccine-induced mucosal immunity resulted in a significant reduction of excreted infectious viruses and viral RNA transcripts [45,46].
- Nanoparticle-based MERS vaccine: in recent years nanoparticles have been at the forefront of many research projects, this has allowed them to have the potential to develop a MERS vaccine. Nanoparticles containing MERS-CoV full-length S proteins can be prepared and purified from pellets of infected baculovirus insect cells. In the absence of adjuvants, these nanoparticles induced a lower level of MERS-CoV producing antibodies in mice. While in the presence of adjuvants, such as aluminium hydroxide (Alum) or Matrix M1, such antibodies were significantly increased and maintained. Thus, adjuvants are required for MERS nanoparticle vaccines and different adjuvants function differently in promoting the immunogenicity of these vaccines .
- DNA-based MERS vaccine: Like the full-length S gene of SARS-CoV-1, DNA encoding full-length S protein of MERS-CoV is utilized to develop MERS vaccines [31,51]. Indeed, intramuscular injections of mice with a synthetic DNA encoding full-length S proteins of MERS-CoV elicited potent virus-neutralizing antibodies and cellular immune responses, as represented by the secretion of INF-γ, TNF-α, and/or IL-2 cytokines in CD4+ and/or CD8+ T cells, as well as the production of antibodies in immunized camels.
- Subunit MERS vaccines: Protein-based subunit vaccines against MERS-CoV have been developed [52,53,54]. While some are designed on the basis of the full-length S1 proteins , the majority of them are based on viral RBD [53,54,56,57]. These RBD-based vaccines are evaluated for immunogenicity and protective immunity in a number of MERS-CoV mice models. The antigenicity and functionality of these RBD proteins have also been extensively investigated. In general, subunit vaccines might not induce immune responses as strong as those induced by other vaccine types mentioned above. However, the immunogenicity of subunit vaccines could be significantly promoted in the presence of an ideal adjuvant via an appropriate route . In addition, it is also essential to maintain a suitable conformation of the protein antigen in the vaccine, such as the MERS-CoV RBD proteins [53,56]. In terms of safety consideration, subunit vaccines should be accounted as the safest vaccine type. They do not contain viral genetic materials, but only include essential antigens for eliciting protective immune responses, thus excluding the possibility of recovering virulence or inducing adverse reactions [58,59,60].
1.5. Vaccinations Proposed for SARS-CoV-2
2. Drug Research and Development: Promising Analogue to Patient
2.1. Drug Development and Discovery
2.2. Target Identification
- SAR defined;
- Drug ability (preliminary toxicity);
- Synthetic feasibility;
- In-Vitro assessment of drug resistance and efflux potential;
- Evidence of in vivo efficacy of chemical class;
- Pharmacokinetics of chemical entity.
2.3. Lead Optimization
2.4. Formulation and Development Process
2.5. Pre-Clinical Research
2.6. Clinical Research
2.6.1. Phase 0
2.6.2. Phase 1 (Safety and Dosage)
2.6.3. Phase 2 (Efficacy and Side Effects)
2.6.4. Phase 3 (Efficacy and Monitoring of Adverse Reactions)
2.6.5. Phase 4
3. FDA Review
- Proposed labeling;
- Safety updates;
- Drug abuse information;
- Patent information;
- Any data from studies that may have been conducted outside the United States;
- Institutional review board compliance information;
- Directions for use.
- Each member of the board conducts a full review of their section of the application.
- FDA instructors travel to clinical study sites to conduct an inspection of the facilities. The FDA looks for evidence of fabrication, manipulation or withholding of data.
- The project manager assigned will oversee all the individual reviews into a combined action package. The review team recommends a decision and a senior figure will make the final decision.
4. FDA Approval
5. FDA Post Market Drug Safety Monitoring
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
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|Vaccine Candidate, Developers||Technology Used||Current Phase||Completed Phase (Findings)||Clinical Trial Sites|
University of Oxford, AstraZeneca 
|Modified chimp adenovirus vector (ChAdOx1)||Phase III (30,000)|
Interventional; randomized, placebo-controlled study for efficacy, safety, and immunogenicity. Brazil (5000) International enrolment of the Phase III trial was paused on 8 September 2020, due to an adverse neurological event in one participant, but resumed on 12 September in the UK. On 23 October, AstraZeneca said it will resume the trial in the US
|Phase I-II (543)|
Spike-specific antibodies at day 28; neutralizing antibodies after a booster dose at day 56. Adverse effects: pain at the injection site, headache, fever, chills, muscle ache, malaise in more than 60% of participants; paracetamol allowed for some participants to increase tolerability
|20 in the UK, São Paulo|
CanSinoBIO, Beijing Institute of Biotechnology of the Academy of Military Medical Sciences 
|Recombinant adenovirus type 5 vector||Phase III (40,000)|
global multi-center, randomized, double-blind, placebo-controlled to evaluate efficacy, safety and immunogenicity in Mexico, Pakistan, Russia, Saudi Arabia
|Phase II (508)|
Neutralizing antibody and T cell responses. Adverse effects: moderate over 7 days: 74% had fever, pain, fatigue
|China and Pakistan|
BioNTech, Fosun Pharma, Pfizer 
|mRNA||Phase III (30,000)|
|Phase I-II (45)|
Strong RBD-binding IgG and neutralizing antibody response peaked 7 days after a booster dose, robust CD4+ and CD8+ T cell responses, undetermined durability. Adverse effects: dose-dependent and moderate including pain at the injection site, fatigue, headache, chills, muscle and joint pain, fever
|62 in the USA and Germany|
|Inactivated SARS-CoV-2||Phase III (33,620)|
Double-blind, randomized, placebo-controlled to evaluate efficacy and safety in Brazil (15,000); Chile (3000); Indonesia (1620); Turkey (13,000)
Brazil paused Phase III trials on November 10 after the suicide of a volunteer in the trials before resuming them on November 11.
|Phase II (600)|
Preprint. Immunogenicity eliciting 92% seroconversion at lower dose; Adverse effects: mild in severity, pain at injection site
|2 in China; 22 in Brazil; Bandung, Indonesia|
Moderna, NIAID, BARDA 
|Lipid nanoparticle dispersion containing mRNA||Phase III (30,000)|
Interventional; randomized, placebo-controlled study for efficacy, safety, and immunogenicity
|Phase I (45)|
Dose-dependent neutralizing antibody response on two-dose schedule; undetermined durability. Adverse effects: fever, fatigue, headache, muscle ache, and pain at the injection site
|89 sites in the USA|
Janssen Pharmaceuticals (Johnson and Johnson), BIDMC 
|Non-replicating viral vector||Phase III (60,000)|
Randomized, double-blinded, placebo-controlled
Temporarily paused on 13 October 2020, due to an unexplained illness in a participant. Johnson and Johnson announced, on 23 October, that they are preparing to resume the trial in the US.
|Phase I-II (1045) Preprint. Seroconversion for S antibodies over 95%. Adverse effects: injection site pain, fatigue, headache and myalgia||291 in US, Argentina, Brazil, Chile, Colombia, Mexico, Peru, Philippines, South Africa and Ukraine|
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Daou, A. COVID-19 Vaccination: From Interesting Agent to the Patient. Vaccines 2021, 9, 120. https://doi.org/10.3390/vaccines9020120
Daou A. COVID-19 Vaccination: From Interesting Agent to the Patient. Vaccines. 2021; 9(2):120. https://doi.org/10.3390/vaccines9020120Chicago/Turabian Style
Daou, Anis. 2021. "COVID-19 Vaccination: From Interesting Agent to the Patient" Vaccines 9, no. 2: 120. https://doi.org/10.3390/vaccines9020120