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COVID-19 Vaccines: A Review of the Safety and Efficacy of Current Clinical Trials

Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong 999077, China
Department of Ophthalmology, The University of Hong Kong, Hong Kong 999077, China
Authors to whom correspondence should be addressed.
Co-first authors.
Pharmaceuticals 2021, 14(5), 406;
Submission received: 25 March 2021 / Revised: 12 April 2021 / Accepted: 18 April 2021 / Published: 25 April 2021
(This article belongs to the Special Issue Current Trends in RNA Virus Vaccines)


Various strategies have been designed to contain the COVID-19 pandemic. Among them, vaccine development is high on the agenda in spite of the unknown duration of the protection time. Various vaccines have been under clinical trials with promising results in different countries. The protective efficacy and the short-term and long-term side effects of the vaccines are of major concern. Therefore, comparing the protective efficacy and risks of vaccination is essential for the global control of COVID-19 through herd immunity. This study reviews the most recent data of 12 vaccines to evaluate their efficacy, safety profile and usage in various populations.

Graphical Abstract

1. Introduction

The COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Up till February 2021 it had infected more than 110 million patients, causing 2.4 million deaths worldwide, according to data recorded by the World Health Organization (WHO) [1].
The prevention and control of the epidemic in 2020, other than treatment of symptomatic patients, has included monitoring of asymptomatic infections, follow-up and monitoring after cure and discharge, close contact tracking, high-risk population screening, and disinfection of the epidemic source, but the only way for the radical control of COVID-19 infections is by effective vaccination. Vaccines stimulate the body to produce specific antibodies, with anamnestic response when the body is exposed to this pathogen again.
During 2020, there has been extensive research to look into the use of vaccinations to prevent further transmission of SARS-CoV-2. Globally, several prospective vaccines have been produced and used by the public (Table 1). The protective efficacy and immunogenicity profile of each vaccine is also documented (Table 2).
There are currently two forms of messenger ribonucleic acid (mRNA) vaccines: non-replicating mRNA (NRM) vaccines and self-amplifying mRNA (SAM) vaccines. The constructed mRNA is formulated into a carrier—usually lipid nanoparticles—to protect them from degradation and promote cellular uptake [2]. After the carrier particles are ingested into the cell, mRNA is released, which is translated by the ribosome to produce the target protein (recognizable antigen) [3]. After the target protein is secreted by the cell, it is rec-ognized by the immune system and stimulates an immune response.
DNA vaccines, also known as nucleic acid vaccines or genetic vaccines, have also been studied. DNA vaccines are eukaryotic expression plasmid DNA (sometimes also RNA) that encode immunogens or immu-nogens4. It can enter animals through a certain route, and be transcribed and translated after being taken up by host cells. The antigen protein can stimulate the body to produce two kinds of non-specific and specific immune responses, thereby playing a role in immune protection [33,34]. The production process of mRNA is not complicated. The difficulty lies in the fact that mRNA is prone to folding and failure in the absence of protection [35]. Therefore, there is the shortcoming of extremely poor stability. It is questionable whether unstable mRNA is safe for the human body [36]. The comparison between DNA and RNA vaccines is shown in Figure 1.
As of 10 April 2021, the top five countries with vaccination programs are the United States (6.129 million), China (4.052 million), the European Union (2.66 million), the United Kingdom (1.82 million) and India (1.084 million) [37]. Although the implementation of vaccination is one of the important factors to achieve global herd immunity, there is no consensus concerning the superiority of one vaccine over the others in terms of protective efficacy and safety profile, even thigh previous reviews have commented on some of the vaccines [38,39].
To date, there are 86 vaccines under development in clinical phase trials. They are developed with different methods such as protein subunits, inactivated virus, DNA-based vaccine, RNA-based vaccine, viral vectors, and live-attenuated viruses. (see Table 3) [40]. However, many of them are currently in preclinical or phase 1 trials, or without publishing on academic journals at the time of writing. The inclusion criteria of this review are: (1) vaccines that has at least finished their phase 2 clinical trials; and (2) the clinical data of the trial has been published in academic journals and accessible on databases (PubMed, Embase, MedLine, Cochrane) at the time of writing. Exclusion criteria includes: (1) vaccines that are on preclinical phases at the time of writing. (2) vaccines that have not gone through at least phase 2 trials 3) vaccines that have phase 2 trials but have not published their data in academic journals nor accessible on databases (PubMed, Embase, Medline, Cochrane).
This study reviews 12 vaccines in production to evaluate their protective efficacy, safety profile and usage in high risk populations such as children, elderly and patients with co-morbidities.

2. BiONTech (BNT162b1 and BNT162b2)

The BiONTech trials focus on two candidates: BNT162b1 and BNT162b2. Both vaccines are lipid-based, nucleoside-modified mRNA vaccines that encode the trimerized receptor-binder (RBD) of the spike glycoprotein SARS-CoV-2. The RBD-IgG concentrations and SARS-CoV-2 neutralizing titres were measured after complete course of the vaccines. In the trial of BNT162b112, serum IgG geometric mean concentra-tion (GMC) of the recipient after first dose was comparable to the convalescent sera of COVID-19 patient. The trial showed a strong, dose-dependent vaccine-induced antibody response: the GMC of vaccine recipients is 8 times and 42 times the convalescent sera in the 10 μg and 30 μg group, respectively. A further increase to 100 μg showed no additional elevation of RBD IgG concentration, compared with 10 μg and 30 μg trials [4,5].
BNT162b1 induced functional CD4+ and CD8+ T cell responses in almost all recipients: 95.2% participants mounted RBD-specific CD4+ T cell responses. There is a positive correlation between RBD-binding IgG and SARS-CoV-2 neutralizing antibody titres [6]. Severe adverse events, such as grade 3 decrease of lymphocyte count and grade 2 neutropenia, were manageable. No clinical deteriorations were observed.
The overall serological responses of BNT162b2 and BNT162b1 were similar [7]: Phase 2/3 trial showed they conferred 94.6% (95% CI 89.7–97.3) protection against COVID-19 in persons older than 16 years of age [8]. Double dose vaccination further boosts the immune response in both younger and older adults, while the response was weaker in participants 65 to 85 years old. Exploration of dose elevations of vaccinations in the elderly should be conducted in future research.
Serious adverse events such as death from arteriosclerosis and cardiac arrest, paroxysmal ventricular arrhythmia were recorded. However, cardiovascular events occurred similarly in the placebo group, with two deaths due to haemorrhagic stroke and myocardial infarction, and two with unknown causes. It is uncertain whether the vaccine increases cardiovascular risk.
COVID-19 infections is associated with a higher inflammatory burden that can induce vascular inflammation, myocarditis and cardiac arrhythmias [17]. Vaccinations for other acute respiratory virus infection show the possibility of a transient increase in the risk of vascular events [18]. Some studies showed a 10-fold increase of acute myocardial infarction admission within the seven days for of testing positive for influenza B, and a 5-fold increase of risk with influenza A [41,42,43]. Another study suggests that binding of SARS-CoV-2 to ACE2 can cause acute myocardial and lung injury through the alteration in ACE2 signaling pathways [44]. The effect of vaccinations for patients with pre-existing cardiovascular diseases have to be further elucidated.

3. Moderna (mRNA1273)

mRNA1273 is manufactured by Moderna. It encodes stabilized prefusion S-2P antigen, consisting of the SARS-CoV-2 glycoprotein with a transmembrane anchor and an intact S1-S2 cleavage site [9]. A preliminary report showed the binding antibody IgG GMT to S-2P increased after vaccinations, with 100% serocon-version rates by day 15. Dose-response relationship was observed with higher dosage eliciting stronger IgG GMT. Both low dose (25 μg) and medium dose (100 μg) elicited CD4+ T cell responses by expression of Th1 cytokines.
The phase 1 clinical trial showed a dose-response relationship [45]. It also elicited a strong CD4+ cytokine response involving Th1 helper T cells. The higher dosage (100 μg) was chosen for phase 3 clinical trials. Robust neutralizing activity to the 614G variant was observed for the 100 μg dose, regardless of the patients’ age.
The phase 3 clinical trial showed 94.1% (95% CI 89.3–96.8; p < 0.001) protective efficacy in preventing COVID-19 illness [10]. The vaccine efficacy to prevent COVID-19 was consistent across subgroups stratified by age (18 to <65 years of age and ≥65 years), presence of risk for severe COVID-19, sex, and race and ethnic groups. The frequency of grade 3 adverse events in the placebo group (1.3%) was similar to that in the vaccine group (1.5%).

4. ChadOx1 nCoV-19 (AZD1222)

ChadOx1 nCoV-19 consists of replication-deficient simian adenovirus vector ChAdOx1, containing the full-length structural surface glycoprotein of SARS-CoV-2, with a tissue plasminogen activator leader sequence [12]. It expresses a codon-optimised coding sequence for the spike protein. Upon vaccination, antibodies against SARS-CoV-2 spike protein peaked by day 28 and remained elevated up to day 56 in participants receiving 1 dose. The median titre of the booster-dose group was more than five times higher than the single-dose group. Paracetamol was used to reduce local regional side effects such as fever and myalgia. Prophylactic paracetamol was prescribed in certain participants, but serological response was independent of prophylactic paracetamol prescription.
ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults, and it provides similar immunogenicity across all age groups after a booster dose [13]. Serological response was independent of dosage and age after booster, with the IgG level being consistently higher than those without booster vaccinations. Median IgG titres peaked by day 42 in most groups who received two-dose vaccinations. A higher vaccine efficacy was observed when the participants first received a low-dose followed by a stand-ard-dose (90%, 95% CI 67.4–97.0, p = 0.01), compared with two standard-dose recipients (62.1%, 95% CI 41.0–75.7) [24].
In terms of safety profile, 13 serious adverse events occurred but none was considered related to either study vaccine as assessed by the investigators [13]. There was a reported case of hemolytic anemia and three cases of transverse myelitis. The independent neurological committee considered two of them were unlikely to be related to vaccination, and one of them was an idiopathic, short segment spinal cord demyelination [14].
Phase 3 trials are being performed in the United Kingdom, Brazil and the United States of America to assess the protective efficacy and safety [13].
Various thromboembolic events were reported after participants have received ChadOx1 nCoV-19 (AZD122) vaccinations. One of the reasons may be related to post-vaccination immune-mediated thrombo-cytopenia [46]. In a report including 28 patients after receiving AZD122 with thromboembolic events, all of them were tested positive for anti-platelet factor 4(PF4)-heparin antibodies, which clinically mimics auto-immune heparin-induced thrombocytopenia [47]. This was similarly observed in another study where five participants with thromboembolic events (100%) tested positive with high level of IgG anti-PF4-polyanion complexes, measured by enzyme linked immunoassay (ELISA) [48]. The adverse reaction may be related to the adenovirus-platelet-leukocyte complexes formed after vaccination, which are taken up by the liver by interaction [28] with membrane-associated heparan sulphate proteoglycan (MAHSP) [49,50]. MAHSP acts as a receptor for viral entry. Heparin can lead to dose-dependent inhibition of this reaction, leading to induction of anti-PF4/heparin antibodies [51]. Subsequently, heparin-induced thrombocytopenia and thrombophilia was observed in patients after receiving AZD122 vaccination.

5. Convidecia (Adenovirus Type-5 Vectored COVID-19 Vaccine)

Adenovirus type-5 (AD-5) vectored COVID-19 vaccine is a replication of defective Ad5-vectored vaccine expressing the spike glycoprotein SARS-CoV-2 [15]. It clones an optimized full-length spike gene based on Wuhan-Hu-1 with the tissue plasminogen activator signal peptide gene into an E1 and E3 deleted Ad-5 vector, and constructed the Ad-5 vectored COVID-19 vaccines using the Admax system. The vaccine demonstrated a dose-response relationship at day 28 after vaccination: the T-cell responses in the high dose group were significantly higher than that in the low-dose group (p < 0.0010), but not significant compared with that in the middle group. TNF-α expression from CD4+ T cells was significantly lower in the low dose group than in the high dose (p < 0.0001) and middle dose groups (p = 0.0032). TNF-α expression from CD8+ T cells was higher in the high-dose group than that in both the middle dose group (p = 0.016) and the low-dose group (p < 0.0001).
The phase two trial showed a higher dosage correlates with a higher seroconversion rate and higher GMTs of neutralizing antibody responses to pseudovirus [16]. The seroconversion rate in high-dose group was 59% (95% CI 52–65) and 47% (95% CI 39–56). The GMT were 61.4 (95% CI 53.0–71.0) in the high-dose group and 55.3 (95% CI 45.3–67.5) in the low dose group. Stratified analysis based on age showed older adults (>55 years) were associated with lower antibody responses in both dose groups post-vaccinations. A total of 25 grade 3 or above adverse events were documented, but they were self-limiting and resolved within 3 to 4 days without medications.
Phase 3 trial are being performed globally, with 40,000 participants. It is expected to be completed by January 2022 [17].

6. Gam-COVID-Vac (Recombinant Adenovirus Type 26 and Recombinant Adenovirus Type 5 Vaccine)

rAd26-S and rAD5-S are vaccines made by Russian manufacturer which carry the gene for SARS-CoV-2 full-length glycoprotein S. Phase 1/2 studies showed both rAd26-S and rAD5-S formulations were safe and well tolerated [18]. Patients receiving combined rAD26-S and rAD5-S were associated with a higher se-roconversion rate (100%) and neutralising antibody GMT (49.25) on day 28 [19]. Combined regimen was better than individual rAD26-S or rAD5-S injection. Increased CD4+ T cells, CD8+ T cells and IFN- γ secre-tion were observed in all vaccine recipients. No serious adverse events were reported.
The phase 3 study showed a protective efficacy of 91.6% (95% CI 85.6–95.2) against COVID-19 [19]. Immunogenicity was significantly higher in the vaccination arm: The RBD-specific IgG was detected in 98% participant samples, with a GMT of 8996 (95% CI 7610–10,635) and a seroconversion rate of 98.25%. Conversely, the RBD-specific IgG was detected in 15% participant samples with a GMT of 30.55 (95% CI 20.18–46.26) and a seroconversion rate of 14.91% (p < 0.0001 vs. the vaccination arm). Neutralising antibody follows a similar trend too: with GMT of 44.5 (95% CI 31.8–62.2) and seroconversion rate of 95.83% in the vaccination arm; compared with GMT of 1.6 (95% CI 1.12–2.19) and 7.14% seroconversion rate.

7. Covovax (NVAX-CoV2373)

NVAX-CoV2373 is a recombinant SARS-CoV-2 nanoparticle vaccine composed of trimeric full-length sARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant. The phase 1 study showed two-dose 5 μg regimen with adjuvant induced IgG GMT and neutralization responses that exceeded convalescent serum from most symptomatic COVID-19 patients [20]. The immunological outcomes in 5 μg and 25 μg vaccination groups were comparable. Second vaccinations with adjuvant resulted in GMT level four times greater than the convalescent plasma in symptomatic patients. Adjuvant regimens induced polyfunctional CD4+ T-cell responses that were reflected in IFN-γ, TNF-α and IL-2 production on spike protein stimulation. No serious adverse events were reported. Interim analysis showed the vaccine achieved protective efficacy of 86% against UK variant and 60% against South Africa variant [21]. The phase 3 trial showed a protective efficacy of 89.3% (95% CI 75.2–95.4) against B.1.1.7 UK variant, but only 49.4% (95% CI 6.1–72.8) against B.1.351 variant [22].

8. WIV04-Strain Inactivated SARS-CoV-2 Vaccine

The WIV-04 strain inactivated SARS-CoV-2 vaccine is designed by the Wuhan Institute of Biological Products Co Ltd. The WIV-04 strain was isolated and cultivated in a Verco cell line for propagation, and the supernatant of the infected cells was inactivated by β-propiolactone. Interim analysis of two randomised controlled trials showed a seroconversion rate of 100% in phase 1 trial and 85.7% in the phase 2 trial [10]. A lower-dosage injection was associated with a higher GMT of neutralizing antibody at day 14 after the third injection, compared with other dosage groups. Injection schedule on day 0 and 21 confer a higher GMT, compared with the schedule of day 0 and 14. Most patients started to generate antibody response after the second injection, and remained at high level 14 days after the third injection. The most common adverse reactions were injection site pain and fever, which were mild and self-limiting. The phase 3 study data was not available at the time of writing.


BBIBP-CorV is developed by the Beijing Institute of Biological Products. It is an inactivated vaccine developed from the strain 19nCoV-CDC-Tan-HB02 (HB02) [11]. The HB02 strain was purified and passaged in Vero cell lines to generate vaccine production by using a novel carrier in a basket reactor. In the phase 1 trial, a higher dosage (8 μg) was associated with a higher seroconversion rate by day 14, while seroconversion rates reached 100% in all three dosage cohorts on day 28. By day 28, the neutralizing antibody GMT was significantly higher in the high-dose group than the low-dose group (2 μg), with no significant difference between medium-dose (4 μg) and high-dose. Younger adults were associated with higher neutralizing anti-body GMT, compared with older adults (>60 years).
The phase 2 trial showed the immunization schedule of 4 μg on day 0 and 21 was associated with the highest neutralizing antibody GMT (282.7, 95% CI 221.2–361.4), compared with other immunization schedules. One grade 3 or above adverse event was documented due to self-limiting grade 3 fever (>38.5 °C).
A phase 3 study is currently underway in Abu Dhabi with 15,000 participants: 5000 participants receiving placebo, another 5000 receiving BBIBP-CorV, and the remaining 5000 receiving another inactivated vaccine manufacturer by Sinopharm [23].

10. Coronavac Vaccine

Coronavac is developed by Sinovac Life Sciences (Beijing China) as an inactivated vaccine created from Vero cells that have been inoculated with SARS-CoV-2 (CN02 strain) [24]. The phase 1 trial showed seroconversion rates of 88% and 100% and 8% in the 3 μg, 6 μg and placebo groups on day 28, respectively. The neutralising antibody GMT were 465.8 (95% CI 288.1–753.1), 1395.9 (95% CI, 955.2–2039.7) and 89.8 (95%CI 76.1–105.9) in the three groups, respectively. Higher dosage was associated with a better immunogenicity.
The phase 2 immunization schedule trial showed receiving vaccination on day 0 and 14 resulted in the most promising outcomes: seroconversion rates were 97%, 100% and 0% in the 3 μg, 6 μg and placebo groups on day 28, respectively. The neutralising antibody GMT were 44.1 (95% CI 37.2–52.2), 65.4 (95% CI 56.4–75.9) and 2.0 (95% CI 2.0–2.1) in the three groups, respectively. One case of serious adverse events related to acute hypersensitivity with presentation of urticaria 48 h after the first dose. It was managed with chlorphenamine and dexamethasone, and recovered within 3 days.
The phase 3 study data has not been published in medical journals. An online search of the phase 3 study in Brazil showed a 50.4% protective efficacy in preventing symptomatic infections, 78% protective efficacy in preventing mild cases requiring treatment and 100% prevention of severe cases [52]. Phase 3 studies in Turkey and Indonesia showed a protective efficacy of 83.5% and 65.3%, respectively [53,54].

11. Ad26.COV2.S

Ad26.COV2.S is developed by Johnson & Johnson. It is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike protein. Early animal studies showed promising efficacy with low-dose single-shot vaccination [25,26]. In the phase 1 clinical trial, binding and neutralizing antibodies were detected in 100% of vaccine recipients by 57 days after single vaccinations [27]. The geometric mean titres (GMT) of spike-specific binding antibodies and neutralizing antibodies ranged from 2432–5729 and 242–449, respectively. A booster immunization on day 57 increased binding antibody titres and neutralizing antibody titres by a mean of 2.56-fold (range 1.58–3.04) and 4.62-fold (range: 3.56–5.68), respectively. An interim study showed the titres remain stable until at least day 71 [28]. Strong immune responses were recorded as CD4+ T cells were detected in 76 to 83% of the young patients (aged 18–55 years), and 60 to 67% in older patients (aged greater than 65). Phase 3 data showed a 66.9% (95% CI 59.0–73.4) protective efficacy across all participant age groups, and 76.3% (95% CI, 61.6–86.0) in participants older than 60 years old [29]. In preventing severe or critical COVID-19, Ad26.COV2.S was associated with 76.7% efficacy at 14 days, and 85.4% at 28 days. Adverse reactions were recorded such as thromboembolic events (15 in vaccination arm and 10 in placebo arm) and tinnitus (6 vs. 0).
Subgroup analysis based on region showed a higher vaccine efficacy in N. America, compared with South Africa and Latin America. The protective efficacies were 74.4% (95% CI 65.0–81.6) at 14 days and 72.0% (95% CI 58.2–81.7) at 28 days; compared with 52.0% (95% CI 30.3–67.4) at day 14 and 64% (95% CI 41.2–87.7) in South Africa. The protective efficacies in Latin America were 64.7% (95% CI 54.1–73.0) and 61.0% (95% CI 46.9–71.8), respectively. This may be related to the difference in the prevalence of mutant strain of SARS-CoV-2 in different regions.

12. Covaxin (BBV 152)

BBV 152 is a whole-viron inactivated SARS-CoV-2 vaccine formulated with a toll-like receptor 7/8 agonist molecule (IMDG) adsorbed to alum (Algel) [30]. It is developed by Bharat Biotech from an isolated NIV-2020-770 strain of a patient with COVID-19 sequenced in India. Previous animal studies showed acceptable safety profiles, humoral and cell-mediated responses [31]. Phase 2 trials showed a good reactogenicity, safety profile, and enhanced humoral and cell-mediated immune responses when participants received a higher dose (6 μg) of Algel-IMDG formulation [32]. In the phase 2 trial, the GMT at day 56 was significantly higher in the 6 μg group (197.0, 95% CI 155.6–249.4) compared with the 3 μg group (100.9, 95% CI 74.7–137.4, p = 0.0041). Seroconversion rates were 92.9% (95% CI 88.2–96.2) in the 3 μg group, and 98.3% (95% CI 95.1–99.6) in the 6 μg group. The Algel-IMDG formulation elicited T-cell responses biased to a Th1 phenotype at day 42, with no significant difference in causing local or systemic adverse reactions between the 3 μg and the 6 μg groups. No serious adverse events were reported in the study. Protective efficacy was not reported.

13. Challenges

In view of the surging infections and promising efficacy in clinical trials of vaccines (Table 2), many countries have advocated vaccination programs for their citizens. However, questions have been raised concerning the efficacy against new variant strains. Experience in Manaus (Brazil) showed secondary immunity alone was not sufficient to arrest transmission [55], possibly due to new variant strains. The B.1.1.7 of the UK and South African 501Y.V2 variants are shown to cause alterations to the spike protein, which may affect immune recognition of antibodies derived from existing vaccines [56]. Further clinical trials are required to test for the efficacy of existing vaccines against mutant variants.
Another problem is the duration of the protective efficacy. It is likely that at least yearly boosters are necessary. Seasonal modification to annual vaccines to arrest the transmission of previous strains may also be considered. It is also doubtful whether circulating neutralizing antibody is protective against COVID-19 infection as animal studies showed robust viral infective activities in nasal turbinate. Reinfection is still potentially possible [57].
Also with the expansion of the vaccination programs in the general population, the relationship of certain side effects, such as the thrombotic events occurring after receiving ChadOx1 nCoV-19, with the vaccines has to be further determined.
The pathological correlation between incidence of cardiovascular adverse events and vaccination with in-activated or live-attenuated virus has to be elucidated. SARS-CoV-2 infection is associated with systemic inflammatory response causing cytokine releases and cytokine storm, resulting in vasculopathy and its complications [58]. Likewise, influenzae carries similar pathogenesis as SARS-CoV-2. However, the experience of influenzae vaccinations (inactivated virus) shows that vaccinations reduced major cardiovascular events significantly, and has become part of the routine care of patients with chronic cardiovascular conditions [59]. COVID-19 vaccinations do not follow the typical trend of influenzae. In general, attenuated patho-gens have the very rare potential to revert to its pathogenic form [60]. Further studies is required to determine whether vaccines with inactivated SARS-CoV-2 can reduce or induce cardiovascular events.
Diabetic patients are associated with a higher risk of inflammatory response and coagulopathy during an infection episode [61]. Close monitoring of inflammatory markers, tight glycemic controls and lifestyle modifications are recommended for diabetic COVID-19 care [62]. Acute complications after vaccinations can be monitored by measurement of prognostic inflammatory markers, such as serum ferritin, lactate dehydrogenase, C-reactive protein (CRP), erythrocyte sedimentation rate, D-dimer level, cardiac troponin and N-terminal pro-brain-type natriuretic peptide (NT-proBNP) [63,64,65,66]. These markers have close associations with the prognosis of COVID-19 infections. However, the interval and duration of monitoring has to be further studied. The relation between thrombotic events and vaccine using as adenovirus vector has been discussed in a previous section.

14. Conclusions

The COVID-19 vaccines in clinical trials have all shown promising immunogenicity with varying degree of protective efficacy, and an acceptable safety profile. A second dose immunization gives more robust immune response in all vaccines. The immunological outcome in the elderly is poorer than in the younger recipients. Further exploration on immunization schedule is required, such as more frequent vaccinations or higher dosage in each injection. Grade 3 or above side effects are not common in the clinical trials to date.

Author Contributions

Literature search, study designs, figures, data collections, data analysis, data interpretation and manuscript writing were done by Z.-P.Y., M.Y. and C.-L.L., Z.-P.Y. and M.Y. contributed equally to this work. All authors have read and agreed to the published version of the manuscript.


The authors did not receive funding for this project.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data generated during and/or analysed during the current study are available on electronic databases (PubMed, Embase, Medline, Google Scholar, Cochrane). All data generated or analysed during this study are included in this published article.

Conflicts of Interest

The authors Zhipeng Yan, Ming Yang and Ching-Lung Lai declare there is no conflict of interest.


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Figure 1. Schematic graph of the comparison between DNA and mRNA vaccine in terms of mechanisms. DNA vaccine is a circle DNA which contains the spike gene of SARS-CoV-2. After electroporation, cell membrane permeation will be increased, allowing DNA enter into cytoplasm thereby reaching to the nuclear. Subsequently, DNA will be translated into mRNA, which will be further translated into SARS-CoV-2 spike proteins and express on cell membrane. Nanoparticle-encapsulated mRNA encoding SARS-CoV-2 antigen will be integrated into cytoplasm. The spike mRNA utilizes ribosome and bases to translate spike proteins, which express on the cell membrane. The membrane spike protein will be recognized by antigen presenting cell (APC) thereby activating immune reaction.
Figure 1. Schematic graph of the comparison between DNA and mRNA vaccine in terms of mechanisms. DNA vaccine is a circle DNA which contains the spike gene of SARS-CoV-2. After electroporation, cell membrane permeation will be increased, allowing DNA enter into cytoplasm thereby reaching to the nuclear. Subsequently, DNA will be translated into mRNA, which will be further translated into SARS-CoV-2 spike proteins and express on cell membrane. Nanoparticle-encapsulated mRNA encoding SARS-CoV-2 antigen will be integrated into cytoplasm. The spike mRNA utilizes ribosome and bases to translate spike proteins, which express on the cell membrane. The membrane spike protein will be recognized by antigen presenting cell (APC) thereby activating immune reaction.
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Table 1. Summary of vaccine trials.
Table 1. Summary of vaccine trials.
Title [Reference]Clinical PhasePopulation Characteristics of the Latest TrialDosesTechnologyImmunogenicitySafety Profile
BNT162b1 [4,5,6]1–245 adults in 3 groups: 10 μg, 30 μg, 100 μg
12 vaccines: 3 placebo in each group
2 injections, 21 days apartLipid nanoparticle nucleoside-modified mRNA vaccine, encoding the spike glycoprotein of SARS-CoV-2Dose-dependent antibody responseNo serious adverse events
BNT162b2 [7,8]1–343,448 volunteers aged 16 or older in total: (1:1 ratio)
21,720 received vaccines
21,728 received placebo
2 injections of 30 μg doses for phase 3, 21 days apartLipid nanoparticle nucleoside-modified mRNA vaccine, encoding the spike glycoprotein of SARS-CoV-2Similar dose-dependent response as BNT162bNo serious adverse events
mRNA-1273 [9,10,11]1–330,420 adults in total:
(1:1 ratio)
15,210 received vaccines
15,210 received placebo
2 injections of 100 μg doses, 28 days apartLipid nanoparticle capsule of four lipids, encoding the S-2P antigen.100% seroconversion rates by day 15Similar grade 3 adverse events in the placebo group (1.3%) and the vaccine group (1.5%)
ChAdOx1 nCoV-19 [12,13,14]1–323,848 adults randomised 1:1 ratio to receive ChAdOx1 nCoV-19 or placebo2 injections of 3.5–6.5 × 1010 viral particles per mL, 28 days apart Chimpanzee adenovirus-vectored vaccine with SARS-CoV-2 spike glycoproteinMedian titre of booster-dose group is more than 5 times higher than the single-dose group.- 13 serious adverse events
- None considered related to the vaccine
Ad5-vectored COVID-19 [15,16,17]1 & 2508 adults randomised 2:1:1 to receive vaccine at the dosage of 1 × 1011, 5 × 1010, or placebo1 injectionReplication defective Ad5-vectored vaccine expressing the spike glycoprotein of SARS-CoV-2Higher antibody GMT in high-dose group, compared with medium and low-dose groups.- 25 grade 3 or above adverse events
- All resolved within 3 to 4 days without medications
rAd26-S and rAd5-S [18,19]1–321,977 adults in total:
16,501 received vaccines
5476 received placebo
2 injections of 1011 viral particles in 0.5 mL vaccine, 21 days apartReplication of Ad5-vectored and Ad-26 vectored vaccine expressing the gene for SARS-CoV-2 full-length glycoprotein S100% seroconversion rateNo serious adverse events
NVX-CoV2373 [20,21,22]1–330,000 adults in total:
Randomised in 2:1 ratio to receive vaccine and saline placebo
2 injections of 5 mg protein with 50 mcg matrix-M adjuvant, 21 days apart.Nanoparticle of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvantIgG GMT and neutralization responses exceeding convalescent serumNo serious adverse events
WIV-04 strain inactivated vaccine [10]1–296 adults randomised 1:1:1:1 to receive low-dose, medium-dose, high-dose and aluminium hydroxide, respectivelyPhase 1:
3 injections on day 0, 28 and 56
Isolated from WIV-04 strain and cultivated in a Verco cell line, followed by serial inactivation100% seroconversion rates in phase 1 trial and 85.7% in the phase 2Mild
injection site pain and fever (23.4%)
Phase 2:
2 injections on day 0 and 14, or day 0 and 21
BBIBP-CorV [11,23]1–2192 adults:
18–59 years (96 adults)
≥60 years (96 adults).
24 receiving vaccine of 2 μg, 4 μg or 8 μg on day 0 and 28; and 24 receiving placebo.
Phase 1:
2 injections separated 28 days
HB02-strain in Verco cell line, with serial inactivation- Higher seroconversion with higher dosage (8 μg) by day 14,
- Higher neutralizing antibody GMT in younger adults
One grade 3 adverse event: self-limiting fever (>38.5 °C)
Phase 2:
Coronavac [24]1–313,000 adults randomised to receive vaccine or placebo
(randomisation ratio not provided)
2 injections, 28 days apartInactivated vaccine from Vero cell line with SARS-CoV-2 (CN02 strain)-High seroconversion rates: 83% in the 3 μg group, 79% in the 6 μg group, and 4% in the placebo groupOne case of serious hypersensitivity with urticaria, recovered 3 months after medical treatment.
Ad26.COV2.S [25,26,27,28,29]1–340,000 adults randomised to receive vaccination or placebo (randomisation ratio not provided)1 injection of 5 × 1010 virus particlesreplication-incompetent adenovirus serotype 26 (Ad26) vector encoding full-length SARS-CoV-2 spike protein100% seroconversion day 57Comparable serious adverse events in vaccination group and placebo group.
BBV152 [30,31,32]1–2380 participants (aged 12–65 years) randomised by 1:1 ratio to receive vaccines of either 3 μg or 6 μg.2 intramuscular injections on day 0 and day 28whole-virion inactivated SARS-CoV-2 vaccine formulated with a toll-like receptor 7/8 agonist molecule (IMDG) adsorbed to alum (Algel)92.9% (95% CI 88.2–96.2) seroconversion rate in the 3 μg group, and 98.3% (95% CI 95.1–99.6) in the 6 μg group.Comparable local and systemic adverse event profile in the 3 μg (9.47%) and 6 μg (11.0%) groups. No reported serious adverse events.
Table 2. Efficacy and other immune responses of vaccines after completion of vaccinations.
Table 2. Efficacy and other immune responses of vaccines after completion of vaccinations.
Title [Reference]Protective EfficacyAntigen-Specific IgG GMT LevelNeutralizing Antibody ResponsesCellular Responses
BNT162b1 [4,5,6]Similar to BNT162b2
(actual figure not stated)
- 10 μg: 4813 U/mL
- 30 μg: 27,873 U/mL
- Increase dosage to 100 μg did not increase the IgG GMC.
- Lower antigen-binding IgG in participants ≥65 years of age
Higher GMT compared to convalescent serum panel
- 10 μg: 1.8-fold
- 30 μg: 2.8-fold
-Functional CD4+ and CD8+ responses in all participants, predominantly Th1 helper responses.
- The mean fraction of RBD-specific T cells was higher than convalescent plasma.
BNT162b2 [7,8]94.6% (95% CI 89.9–97.3)- 10 μg: 5782 U/mL
- 20 μg: 12,464 U/mL
- 30 μg: 9136 U/mL
- Lower antigen-binding IgG for ≥65 years of age
Higher GMT compared to convalescent serum panel
18–55 years: 1.7–4.6 times
≥65 years: 1.1–2.2 times
Not assessed
mRNA1273 [9,10,11]94.1% (95% CI 89.3–96.8; p < 0.001)- 25 μg: 299,751 U/mL
- 100 μg: 782,719 U/mL
- 250 μg: 1,192,154 U/mL
Neutralizing PRNT80 generally at or above the value of convalescent serum - The 25 μg, 100 μg groups elicited CD4+ T cell responses to Th1 cytokines.
- Minimal Th2 response
ChadOx1 nCoV-19 [12,13,14]Overall:
(95% CI 54.8–80.6)
2-standard dose:
(95% CI 41.0–75.7)
Low dose + standard dose:
(95% CI 67.4–97.0)
- Antigen-specific antibody peaked at day 28 with 157 GMEU
- Antigen specific IgG on day 28 decreased with increasing age:
18–55 years: 6439 U/mL;
56–69 years: 4553 U/mL; and ≥70 years: 3565 U/mL
91% and 100% participants achieved PRNT80 responses in one-dose and booster-dose groups, respectively.- The median SFCs PBPMC in the standard-dose groups:
18–55 years: 1187;
56–69 years: 797
≥70 years: 977
No significant increase of PBPMC after the booster vaccination (p = 0.46 from paired Student’s t test of day 28 vs. day 42)
Ad5-vectored COVID-19 [15,16,17]Not available at the time of writing- High-dose: 1445.8 (95% CI 935.5–2234.5);
- Medium-dose: 806 (95% CI 528.2–1229.9)
- Low-dose: 615.8 (95% CI 405.4–935.5)
- Seroconversions of 97%, 94% and 100% in the low-dose, medium-dose and high-dose groups, respectively.
- High-dose:
34.0 (95% CI 22.6–50.1);
- Medium-dose:
16.2 (95% CI 10.4–25.2);
- Low-dose:
14.5 (95% CI 9.6–12.8))
- 4-fold increase of anti-RBD IgG in 50%, 50% and 75% in the high-dose, medium-dose and low-dose groups, respectively.
- The mean SFCs PMPMC:
20.8 (95%CI 12.7–34.0);
40.8 (95% CI 27.6–60.3) and
58.0 (95% CI 39.1–85.9)
T-cell responses in the high-dose group significantly higher than the low-dose group (p < 0.001)
rAd26-S and rAd5-S [18,19]91.6% (95% CI 85.6–95.2)SARS-CoV-2 S1 subunit-specific IgG GMT was 53,006 with Gam-COVID-Vac and 51,200 with Gam-COVID-Vac-Lyo100% neutralizing antibody with GMT 49.25 and 45.95 by using Gam-COVID-Vac and 51,200 with Gam-COVID-Vac-Lyo, respectively.- 100% increased formation of CD4+ and CD8+ cells, and increased IFN-γ
- Median cell proliferation:
In frozen formulation:
CD4+: + 2.5%
CD8+: +1.3%
In lyophilised formulation:
CD4+: +1.3%
CD8+: +1.1%
NVX-CoV2373 [20,21,22]89.3% (95% CI 75.2–95.4) against B.1.1.7 UK variant,
49.4% (95% CI 6.1–72.8) against B.1.351 South Africa variant.
- GMEU increase by 8 (15,319 units in “5 μg + M1” and 20,429 units in “25 μg + M1”).
- GMEU level higher than in convalescent serum after second dose
GMFRs 5 times greater with adjuvant (5.2 times in “5 μg + M1” and 6.3 times in “25 μg + M1”).
Second dose with adjuvant resulted in GMT levels 4 times greater than those in symptomatic infections.
Stimulated Th1 phenotype response with increased IFN-γ, IL-2 and TNF- α.
Minimal Th2 responses as measured by IL-5 and IL-13 cytokines.
WIV-04 strain inactivated vaccine [10]Not available at the time of writing.- Low-dose: 415 (95% CI 288–597);
- Medium-dose: 349 (95% CI 258–472);
- High-dose: 311 (95% CI 229–422)
Neutralizing antibody levels increased significantly 14 days after the second dose, and the third doseNot assessed
BBIBP-CorV [11,23]Not available at the time of writing.In the 4 μg trial by 14 days after the second dose, the GMTs were:
- 279.2 (95% CI 192.6–404.7) against 35C;
- 234.8 (95% CI 122.2–450.8) against 56Y;
- 181.0 (95% CI 105.9–309.5) against 834Y;
- 304.4 (95% CI 202.1–485.6) against HN97;
- 117.4 (95% CI 61.1–225.4) against F13;
- 193.3 (95% CI 141.4–264.0) against HB01;
- 210.7 (95% CI 120.3–369.1) against BJ01,
- 146.8 (95% CI 93.8–230.0) against CQ01;
- 218.5 (95% CI 125.3–380.8) against QD01;
- 394.8 (95% CI 256.5–607.6) against passage 7 virus.
-In age group 18–59 years, neutralizing antibody GMT were:
2 μg: 22.6 (95% CI 18.9–27.0);
4 μg: 29.3 (95% CI 23.8–36.0);
8 μg: 36.7 (95% CI 29.8–45.2)
-In the age group ≥60 years, neutralizing antibody GMT were:
2 μg: 13.4 (95% CI 9.4–19.0);
4 μg: 18.9 (95% CI 13.4–26.6);
8 μg: 23.7 (95% CI 19.0–29.6)
Not assessed
Coronavac [24]Brazil:
symptomatic prevention:
- mild cases prevention:
Severe cases prevention:
(confidence interval not reported)
(confidence interval not reported)
3 μg: 27.6 (95% CI 22.7–33.5)
6 μg: 34.5 (95% CI 28.5–41.8)
Placebo: 2.3 (95% CI 2.0–2.5)
3 μg: 5.6 (95% CI 3.6–8.7);
6 μg: 7.7 (95% CI 5.2–11.5);
Placebo: 2.0 (95% CI 2.0–2.0)
The average IFN-γ positive spot-forming cells per 100,000 cells were:
3 μg group: 7.4 (95% CI 3.9–11.1);
6 μg group: 3.9 (95% CI 1.0–6.7);
Placebo: 1.5 (95% CI 0.2–2.9)
Ad26.COV2.S [25,26,27,28,29]Overall:
66.9% (95% CI 59.0–73.4)
≥60 years old
76.3% (95% CI, 61.6–86.0)
- Ranged from 2432 U/mL to 5729 U/mL.
- The booster immunization on day 57 increased binding antibody titres 2.56-fold (range 1.58–3.04).
- The GMT of neutralizing antibody ranged from 242 to 449.
- The booster immunization on day 57 increased neutralizing antibody titres by a mean of 4.62-fold (range: 3.56–5.68).
Stronger CD4+ cells response recorded in younger adults:
18–55 years:76 to 83%
≥65 years: 60 to 67%
BBV152 [30,31,32]Not reported- 3 μg: 100.9 (95% CI 74.1–137.4)
- 6 μg: 197.0 (95% CI 155.6–249.4)
(p = 0.0041)
The neutralizing IgG GMTs at day 56 were 10,413.9 (95% CI 9142.4–11,862.2) in the 3 μg group; and 9541.6 (95% CI 8245.9–11,041.0) in the 6 μg group at day 56.Strongly biased to a Th1 cell response at day 42. Th2 response were detected at minimal level.
GMC: Geometric Mean Concentration (U/mL); GMT: Geometric Mean Titre (U/mL); GMEU: Geometric Mean ELISA units (U/mL); GMFR: Geometric Mean Fold Rises (Times); RBD: Receptor-Binding Domain; PMPMC: Per Million Peripheral Mononuclear cells; PRNT80: Plaque Reduction Neutralizing Testing assay with detectable 80% live-virus neutralization.
Table 3. Progress of existing 86 vaccines candidates in clinical trial as at 6th April 2021.
Table 3. Progress of existing 86 vaccines candidates in clinical trial as at 6th April 2021.
NumberVaccine PlatformType of Candidate VACCINEUsageDeveloperClinical StatusPhase Trials Registration No.
1Inactivated virusCoronaVac; SARS-CoV-2 vaccine (inactivated)2 doses
(day 0 + 14)
Sinovac Research and Development Co., Ltd.Phase 4Phase ½:
Phase 3:
Phase 4:
2Inactivated virusInactivated SARS-CoV-2 vaccine (Vero cell)2 doses
(day 0 + 21)
Sinopharm + China National Biotec Group Co + Wuhan Institute of Biological ProductsPhase 3Phase ½:
Phase 3:
3Inactivated virusInactivated SARS-CoV-2 vaccine (Vero cell), vaccine name BBIBP-CorV2 doses
(day 0 + 21)
Sinopharm + China National Biotec Group Co + Beijing Institute of Biological ProductsPhase 3Phase 1/2:
Phase 3:
4Viral vector (Non-replicating)ChAdOx1-S—(AZD1222) (Covishield)2 doses
(day 0 + 28)
AstraZeneca + University of OxfordPhase 4Phase 1:
Phase 1/2:
Phase 2
Phase 3:
Phase 4:
5Viral vector (Non-replicating)Recombinant novel coronavirus vaccine (Adenovirus type 5 vector)1 dose
Day 0
CanSino Biological Inc./Beijing Institute of BiotechnologyPhase 3Phase 1:
Phase 1/2:
Phase 2:
Phase 3:
6Viral vector (Non-replicating)Gam-COVID-Vac Adeno-based (rAd26-S + rAd5-S)2 doses
(day 0 + 21)
Gamaleya Research Institute; Health Ministry of the Russian FederationPhase 3Phase 1/2:
Phase 2:
Phase 2/3:
Phase 3:
7Viral vector (Non-replicating)Ad26.COV2.S1–2 doses
Day 0 or Day 0+ Day 56
Janssen PharmaceuticalPhase 3Phase 1:
Phase 1/2:
Phase 2:
Phase 3:
8Protein subunitSARS-CoV-2 rS/Matrix M1-Adjuvant (Full length recombinant SARS CoV-2 glycoprotein nanoparticle vaccine adjuvanted with Matrix M)2 doses
(day 0 + 21)
NovavaxPhase 3Phase 1/2:
Phase 2:
Phase 3:
9RNA based vaccinemRNA -1273
2 doses
(day 0 + 28)
Moderna + National Institute of Allergy and Infectious Diseases (NIAID)Phase 4Phase 1:
Phase 1/2:
Phase 2:
Phase 2/3:
Phase 3:
Phase 4:
10RNA based vaccineBNT162b22 doses
(day 0 + 21)
Pfizer/BioNTech + Fosun PharmaPhase 4Phase 1:
Phase 1/2:
Phase 2:
Phase 2/3:
Phase 3:
Phase 4:
11Protein subunitRecombinant SARS-CoV-2 vaccine (CHO Cell)2–3 doses
Day 0 + 28 or Day 0 + 28 + 56
Anhui Zhifei Longcom Biopharmaceutical + Institute of Microbiology, Chinese Academy of SciencesPhase 3Phase 1:
Phase 1/2:
Phase 2:
Phase 3:
12RNA based vaccineCVnCoV Vaccine2 doses
Day 0 + Day 28
CureVac AGPhase 3Phase 1:
Phase 2:
Phase 2/3:
Phase 3:
13Inactivated virusSARS-CoV-2 vaccine (Vero cells)2 doses
Day 0 + Day 28
Institute of Medical Biology + Chinese Academy of Medical SciencesPhase 3Phase 1/2:
Phase 3:
14Inactivated virusQazCovid-in®—COVID-19 inactivated vaccine2 doses
Day 0 + Day 21
Research Institute for Biological Safety Problems, Rep of KazakhstanPhase 3Phase ½:
Phase 3:
15DNA based vaccineINO-4800 + electroporation2 doses
Day 0 + Day 28
Inovio Pharmaceuticals + International Vaccine Institute + Advaccine (Suzhou) Biopharmaceutical Co., Ltd.Phase 2/3Phase 1:
Phase 1/2:
Phase 2:
Phase 2/3:
16DNA based vaccineAG0301-COVID192 doses
Day 0 + Day 14
AnGes + Takara Bio + Osaka UniversityPhase 2/3Phase 1/2:
Phase 2/3:
17DNA based vaccinenCov vaccine3 doses
Day 0 + Day 28 + Day 56
Zydus CadilaPhase 3Phase 1/2:
Phase 3:
18DNA based vaccineGX-19N2 doses
Day 0 + Day 28
Genexine ConsortiumPhase ½Phase 1/2:
19Inactivated virusWhole-Virion Inactivated SARS-CoV-2 Vaccine (BBV152)2 doses
Day 0 + Day 14
Bharat Biotech International LimitedPhase 3Phase 1/2:
Phase 3:
NCT04641481; CTRI/2020/11/028976
20Protein subunitKBP-COVID-19 (RBD-based)2 doses
Day 0 + Day 21
Kentucky Bioprocessing Inc.Phase 1/2Phase 1/2:
21Protein subunitVAT00002: SARS-CoV-2 S protein with adjuvant2 doses
Day 0 + Day 21
Sanofi Pasteur + GSKPhase 3Phase 1/2:
Phase 2:
Phase 3:
22RNA based vaccineARCT-0212 doses
Day 0 + Day 21
Arcturus TherapeuticsPhase 2Phase 1/2:
Phase 2:
23Virus like particleRBD SARS-CoV-2 HBsAg VLP vaccine2 doses
Day 0 + Day 28
Serum Institute of India + Accelagen Pty + SpyBiotechPhase 1/2Phase 1/2:
24Inactivated virusInactivated SARS-CoV-2 vaccine (Vero cell)2–3 doses
Detailed schedule not specified
Beijing Minhai Biotechnology CoPhase 2Phase 1:
Phase 2:
25Viral vector (Non-replicating)GRAd-COV2 (Replication defective Simian Adenovirus (GRAd) encoding S)1 dose
Day 0
ReiThera + Leukocare + UnivercellsPhase 2/3Phase 1:
Phase 2/3:
26Viral vector (Non-replicating)VXA-CoV2-1 Ad5 adjuvanted Oral Vaccine platform2 doses
Day 0 + Day 28
VaxartPhase 1Phase 1:
27Viral vector (Non-replicating)MVA-SARS-2-S2 doses
Day 0 + Day 28
University of Munich (Ludwig-Maximilians)Phase 1Phase 1:
28Protein subunitSCB-2019 + AS03 or CpG 1018 adjuvant plus Alum adjuvant (Native like Trimeric subunit Spike Protein vaccine)2 doses
Day 0 + Day 21
Clover Biopharmaceuticals Inc./GSK/DynavaxPhase 2/3Phase 1:
Phase 2/3:
29Protein subunitCOVAX-19® Recombinant spike protein + adjuvant2 doses
Day 0 + Day 21
Vaxine Pty Ltd.Phase 1Phase 1:
30Protein subunitMVC-COV1901 (S-2P protein + CpG 1018)2 doses
Day 0 + Day 28
Medigen Vaccine Biologics + Dynavax + National Institute of Allergy and Infectious Diseases (NIAID)Phase 2Phase 1:
Phase 2:
31Protein subunitFINLAY-FR1 anti-SARS-CoV-2 Vaccine (RBD + adjuvant)2 doses
Day 0 + Day 28
Instituto Finlay de VacunasPhase 1/2Phase 1:
Phase 1/2:
32Protein subunitFINLAY-FR-2 anti-SARS-CoV-2 Vaccine (RBD chemically conjugated to tetanus toxoid plus adjuvant)2 doses
Day 0 + Day 28
Instituto Finlay de VacunasPhase 3Phase 1:
Phase 2:
Phase 3:
33Protein subunitEpiVacCorona (EpiVacCorona vaccine based on peptide antigens for the prevention of COVID-19)2 doses
Day 0 + Day 21
Federal Budgetary Research Institution State Research Center of Virology and Biotechnology “Vector”Phase 3Phase 1/2:
Phase 3:
34Protein subunitRBD (baculovirus production expressed in Sf9 cells) Recombinant SARS-CoV-2 vaccine (Sf9 Cell)2 doses
Day 0 + Day 21
West China Hospital + Sichuan UniversityPhase 2Phase 1:
Phase 2:
35Protein subunitIMP CoVac-1 (SARS-CoV-2 HLA-DR peptides)1 dose
Day 0
University Hospital TuebingenPhase 1NCT04546841
36Protein subunitUB-612 (Multitope peptide based S1-RBD-protein based vaccine)2 doses
Day 0 + Day 28
COVAXX + United Biomedical IncPhase 2/3Phase 1:
Phase 2:
Phase 2/3:
37Viral vector (Replicating)DelNS1-2019-nCoV-RBD-OPT1 (Intranasal flu-based-RBD)2 doses
Day 0 + Day 28
University of Hong Kong, Xiamen University and Beijing Wantai Biological PharmacyPhase 2Phase 1:
Phase 2:
38RNA based vaccineLNP-nCoVsaRNA2 doses
Day 0 + Day 28
Imperial College LondonPhase 1Phase 1:
39RNA based vaccineSARS-CoV-2 mRNA vaccine (ARCoV)2 doses
Day 0 + Day 28
Academy of Military Science (AMS), Walvax Biotechnology and Suzhou Abogen BiosciencesPhase 2Phase 1:
Phase 2:
40Virus like particleCoronavirus-Like Particle COVID-19 (CoVLP)2 doses
Day 0 + Day 21
Medicago Inc.Phase 2/3Phase 1:
Phase 2:
Phase 2/3:
41Viral vector (Replicating) + APCCovid-19/aAPC vaccine. The Covid-19/aAPC vaccine is prepared by applying lentivirus modification with immune modulatory genes and the viral minigenes to the artificial antigen presenting cells (aAPCs).3 doses
Day 0 + Day 14 + Day 28
Shenzhen Geno-Immune Medical InstitutePhase 1Phase 1:
42Viral vector (Non-replicating) + APCLV-SMENP-DC vaccine. Dendritic cells are modified with lentivirus vectors expressing Covid-19 minigene SMENP and immune modulatory genes. CTLs are activated by LV-DC presenting Covid-19 specific antigens.1 dose
Day 0
Shenzhen Geno-Immune Medical InstitutePhase 1/2Phase 1/2:
43Protein subunitAdimrSC-2f (Recombinant RBD +/− Aluminium)No detailAdimmune CorporationPhase 1Phase 1:
44DNA based vaccineCovigenix VAX-001—DNA vaccines + proteo-lipid vehicle (PLV) formulation2 doses
Day 0 + Day 14
Entos Pharmaceuticals Inc.Phase 1NCT04591184
45DNA based vaccineCORVax—Spike (S) Protein Plasmid DNA Vaccine2 doses
Day 0 + Day 14
Providence Health & ServicesPhase 1Phase 1:
46RNA based vaccineChulaCov19 mRNA vaccine2 doses
Day 0 + Day 21
Chulalongkorn UniversityPhase 1Phase 1:
47DNA based vaccinebacTRL-Spike oral DNA vaccine1 dose
Day 0
Symvivo CorporationPhase 1NCT04334980
48Viral Vector (Non-replicating)Human Adenovirus type 5: hAd5 S + N vaccine (S-fusion + N-ETSD) E2b-deleted Adeno1–2 doses
Day 0 + day 21
Subcutaneous or Oral
Immunity Bio.IncPhase 1Phase 1:
49Viral vector (Non-replicating)COH04S1 (MVA-SARS-2-S)—Modified vaccinia ankara (sMVA) platform + synthetic SARS-CoV-22 doses
Day 0 + Day 28
City of Hope Medical Center + National Cancer InstitutePhase 1Phase 1:
50Viral vector (Replicating)rVSV-SARS-CoV-2-S Vaccine1 dose
Day 0
Israel Institute for Biological ResearchPhase 1/2Phase 1/2:
51Viral vector (Replicating) + APCDendritic cell vaccine AV-COVID-19. A vaccine consisting of autologous dendritic cells loaded with antigens from SARS-CoV-2, with or without GM-CSF1 dose
Day 0
Aivita Biomedical, Inc. National Institute of Health Research and Development, Ministry of Health Republic of IndonesiaPhase 1/2Phase 1:
Phase 1/2:
52Live attenuated virusCOVI-VAC1–2 doses
Day 0 or Day 0 + 28
Codagenix/Serum Institute of IndiaPhase 1Phase 1:
53Protein subunitCIGB-669 (RBD + AgnHB)3 doses
Day 0 + 14 + 28 or Day 0 + 28 + 56
Center for Genetic Engineering and Biotechnology (CIGB)Phase 1/2Phase 1/2:
54Protein subunitCIGB-66 (RBD + aluminium hydroxide)3 doses
Day 0 + 14 + 28 or Day 0 + 28 + 56
Center for Genetic Engineering and Biotechnology (CIGB)Phase 3Phase 1/2:
Phase 3
55Inactivated VirusVLA20012 doses
Day 0 + Day 21
Valneva, National Institute for Health Research, United KingdomPhase 1/2Phase 1/2:
56Protein subunitBECOV22 doses
Day 0 + Day 28
Biological E. LimitedPhase 1/2Phase 1/2:
57Viral vector (Replicating)AdCLD-CoV19 (adenovirus vector)1 dose
Day 0
Cellid Co., Ltd.Phase 1/2Phase 1/2:
58DNA based vaccineGLS-53102 doses
Day 0 + Day 56 or Day 0 + Day 84
GeneOne Life Science, Inc.Phase 1/2Phase 1/2:
59Protein subunitRecombinant Sars-CoV-2 Spike protein, Aluminum adjuvanted2 doses
Day 0 + 21
Nanogen Pharmaceutical BiotechnologyPhase 1/2Phase 1/2:
60Protein subunitRecombinant protein vaccine S-268019 (using Baculovirus expression vector system)2 doses
Day 0 + 21
ShionogiPhase 1/2Phase 1/2:
61Viral vector (Non-replicating)AdCOVID, Adenovirus-based platform expresses the receptor-binding domain (RBD) of the Sars-Cov-2 spike protein1 doses
Day 0
Altimmune, Inc.Phase 1Phase 1:
62Protein subunitSARS-CoV-2-RBD-Fc fusion proteinDosage and Schedule not specified
Subcutaneous or intramuscular
University Medical Center Groningen + Akston Biosciences Inc.Phase 1/2Phase 1/2:
63Inactivated VirusERUCOV-VAC, inactivated virus2 doses
Day 0 + 21
Erciyes UniversityPhase 2Phase 1:
Phase 2:
64Protein subunitCOVAC-1 and COVAC-2 sub-unit vaccine (spike protein) + SWE adjuvant2 doses
Day 0 + 28
University of SaskatchewanPhase 1/2Phase 1/2:
65Protein subunitGBP510, a recombinant surface protein vaccine with adjuvant AS03 (aluminium hydroxide)2 doses
Day 0 + 28
SK Biosciences Co. Ltd. and CEPIPhase 1/2Phase 1/2:
66Protein subunitRazi Cov Pars, recombinant spike protein3 doses
Day 0 + 21 + 51
Intramuscular and intranasal
Razi Vaccine and Serum Research InstitutePhase 1Phase 1:
67Inactivated VirusCOVID-19 inactivated vaccine2 doses
Day 0 + 14
Shifa Pharmed Industrial CoPhase 2/3Phase 1:
68Protein subunitMF59 adjuvanted SARS-CoV-2 Sclamp vaccine2 doses
Day 0 + 28
The University of QueenslandPhase 1Phase 1:
69DNA based vaccineCOVIGEN2 doses
Day 0 + 28
Intramuscular or intradermal
University of Sydney, Bionet Co., Ltd. TechnovaliaPhase 1Phase 1:
70DNA based vaccineCOVID-eVax, a candidate plasmid DNA vaccine of the Spike proteinNo detailed dosage schedule
Takis + Rottapharm BiotechPhase 1/2Phase 1/2:
71Viral vector (Non-replicating)BBV154, Adenoviral vector COVID-19 vaccine1 dose
Day 0
Bharat Biotech International LimitedPhase 1Phase 1:
72RNA based vaccinePTX-COVID19-B, mRNA vaccine2 doses
Day 0 + 28
Providence TherapeuticsPhase 1Phase 1:
73Viral vector (Replicating)NDV-HXP-S, Newcastle disease virus (NDV) vector expressing the spike protein of SARS-CoV-2, with or without the adjuvant CpG 10182 doses
Day 0 + 28
Mahidol University; The Government Pharmaceutical Organization (GPO); Icahn School of Medicine at Mount SinaiPhase 1/2Phase 1/2:
74RNA based vaccineCoV2 SAM (LNP) vaccine. A self-amplifying mRNA (SAM) lipid nanoparticle (LNP) platform + Spike antigen2 doses
Day 0 + 28
GlaxoSmithKlinePhase 1Phase 1:
75Virus like particleVBI-2902a. An enveloped virus-like particle (eVLP) of SARS-CoV-2 spike (S) glycoprotein and aluminum phosphate adjuvant.2 doses
Day 0 + 28
VBI Vaccines Inc.Phase 1/2NCT04773665
76Protein subunitSK SARS-CoV-2 recombinant surface antigen protein subunit (NBP2001) + adjuvanted with alum.2 doses
Day 0 + 28
SK Bioscience Co., Ltd.Phase 1Phase 1:
77Viral vector (Non-replicating)Chimpanzee Adenovirus serotype 68 (ChAd) and self-amplifying mRNA (SAM) vectors expressing spike alone, or spike plus additional SARS-CoV-2 T cell epitopes.2–3 doses
Day 0 +14 + 28 or Day 0 + 28 + 56 or
Day 0 + 112
Gritstone OncologyPhase 1Phase 1:
78RNA based vaccinemRNA-1273.351. A lipid nanoparticle (LNP)-encapsulated mRNA-based vaccine that encodes for a full-length, prefusion stabilized S protein of the SARS-CoV-2 B.1.351 variant.3 doses
Day 0 + 28 + 56
Moderna + National Institute of Allergy and Infectious Diseases (NIAID)Phase 1Phase 1:
79Protein subunitSpFN (spike ferritin nanoparticle) uses spike proteins with a liposomal formulation QS21 (ALFQ) adjuvant.3 doses
Day 0 + 28 + 120
Walter Reed Army Institute of Research (WRAIR)Phase 1Phase 1:
80Protein subunitEuCorVac-19; A spike protein using the recombinant protein technology and with an adjuvant.2 doses
Day 0 + 21
POP Biotechnologies and EuBiologics Co.,LtdPhase 1/2Phase 1/2:
81Inactivated virusInactivated SARS-CoV-2 vaccine FAKHRAVAC (MIVAC)2 doses
Day 0 + 21
Organization of Defensive Innovation and ResearchPhase 1Phase 1:
82Live attenuated virusMV-014-212, a live attenuated vaccine that expresses the spike (S) protein of SARS-CoV-22 doses
Day 0 + 35
Meissa Vaccines, Inc.Phase 1Phase 1:
83RNA based vaccineMRT5500, an mRNA vaccine candidate2 doses
Day 0 + 21
Sanofi Pasteur and Translate BioPhase 1/2Phase 1/2:
84Virus like particleSARS-CoV-2 VLP Vaccine1 doses
Day 0
The Scientific and Technological Research Council of TurkeyPhase 1Phase 1:
85Protein subunitReCOV: Recombinant two-component spike and RBD protein COVID-19 vaccine (CHO cell).2 doses
Day 0 + 21
Jiangsu Rec-BiotechnologyPhase 1Phase 1:
86RNA based vaccineDS-5670a, mRNA vaccine2 doses
Day 0 + 21
Daiichi Sankyo Co., Ltd.Phase 1/2Phase 1/2:
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Yan, Z.-P.; Yang, M.; Lai, C.-L. COVID-19 Vaccines: A Review of the Safety and Efficacy of Current Clinical Trials. Pharmaceuticals 2021, 14, 406.

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