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.
9. BBIBP-CorV
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.
Funding
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.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Figure and Tables
Enlarge this image.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.
Summary of vaccine trials.
| Title [Reference] | Clinical Phase | Population Characteristics of the Latest Trial | Doses | Technology | Immunogenicity | Safety Profile |
|---|---|---|---|---|---|---|
| BNT162b1 [4,5,6] | 1–2 | 45 adults in 3 groups: 10 μg, 30 μg, 100 μg |
2 injections, 21 days apart | Lipid nanoparticle nucleoside-modified mRNA vaccine, encoding the spike glycoprotein of SARS-CoV-2 | Dose-dependent antibody response | No serious adverse events |
| BNT162b2 [7,8] | 1–3 | 43,448 volunteers aged 16 or older in total: (1:1 ratio) |
2 injections of 30 μg doses for phase 3, 21 days apart | Lipid nanoparticle nucleoside-modified mRNA vaccine, encoding the spike glycoprotein of SARS-CoV-2 | Similar dose-dependent response as BNT162b | No serious adverse events |
| mRNA-1273 [9,10,11] | 1–3 | 30,420 adults in total: |
2 injections of 100 μg doses, 28 days apart | Lipid nanoparticle capsule of four lipids, encoding the S-2P antigen. | 100% seroconversion rates by day 15 | Similar grade 3 adverse events in the placebo group (1.3%) and the vaccine group (1.5%) |
| ChAdOx1 nCoV-19 [12,13,14] | 1–3 | 23,848 adults randomised 1:1 ratio to receive ChAdOx1 nCoV-19 or placebo | 2 injections of 3.5–6.5 × 1010 viral particles per mL, 28 days apart | Chimpanzee adenovirus-vectored vaccine with SARS-CoV-2 spike glycoprotein | Median titre of booster-dose group is more than 5 times higher than the single-dose group. | - 13 serious adverse events |
| Ad5-vectored COVID-19 [15,16,17] | 1 & 2 | 508 adults randomised 2:1:1 to receive vaccine at the dosage of 1 × 1011, 5 × 1010, or placebo | 1 injection | Replication defective Ad5-vectored vaccine expressing the spike glycoprotein of SARS-CoV-2 | Higher antibody GMT in high-dose group, compared with medium and low-dose groups. | - 25 grade 3 or above adverse events |
| rAd26-S and rAd5-S [18,19] | 1–3 | 21,977 adults in total: |
2 injections of 1011 viral particles in 0.5 mL vaccine, 21 days apart | Replication of Ad5-vectored and Ad-26 vectored vaccine expressing the gene for SARS-CoV-2 full-length glycoprotein S | 100% seroconversion rate | No serious adverse events |
| NVX-CoV2373 [20,21,22] | 1–3 | 30,000 adults in total: |
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 adjuvant | IgG GMT and neutralization responses exceeding convalescent serum | No serious adverse events |
| WIV-04 strain inactivated vaccine [10] | 1–2 | 96 adults randomised 1:1:1:1 to receive low-dose, medium-dose, high-dose and aluminium hydroxide, respectively | Phase 1: |
Isolated from WIV-04 strain and cultivated in a Verco cell line, followed by serial inactivation | 100% seroconversion rates in phase 1 trial and 85.7% in the phase 2 | Mild |
| Phase 2: |
||||||
| BBIBP-CorV [11,23] | 1–2 | 192 adults: |
Phase 1: |
HB02-strain in Verco cell line, with serial inactivation | - Higher seroconversion with higher dosage (8 μg) by day 14, |
One grade 3 adverse event: self-limiting fever (>38.5 °C) |
| Phase 2: |
||||||
| Coronavac [24] | 1–3 | 13,000 adults randomised to receive vaccine or placebo |
2 injections, 28 days apart | Inactivated 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 group | One case of serious hypersensitivity with urticaria, recovered 3 months after medical treatment. |
| Ad26.COV2.S [25,26,27,28,29] | 1–3 | 40,000 adults randomised to receive vaccination or placebo (randomisation ratio not provided) | 1 injection of 5 × 1010 virus particles | replication-incompetent adenovirus serotype 26 (Ad26) vector encoding full-length SARS-CoV-2 spike protein | 100% seroconversion day 57 | Comparable serious adverse events in vaccination group and placebo group. |
| BBV152 [30,31,32] | 1–2 | 380 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 28 | whole-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. |
Efficacy and other immune responses of vaccines after completion of vaccinations.
| Title [Reference] | Protective Efficacy | Antigen-Specific IgG GMT Level | Neutralizing Antibody Responses | Cellular Responses |
|---|---|---|---|---|
| BNT162b1 [4,5,6] | Similar to BNT162b2 |
- 10 μg: 4813 U/mL |
Higher GMT compared to convalescent serum panel |
-Functional CD4+ and CD8+ responses in all participants, predominantly Th1 helper responses. |
| BNT162b2 [7,8] | 94.6% (95% CI 89.9–97.3) | - 10 μg: 5782 U/mL |
Higher GMT compared to convalescent serum panel |
Not assessed |
| mRNA1273 [9,10,11] | 94.1% (95% CI 89.3–96.8; p < 0.001) | - 25 μg: 299,751 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. |
| ChadOx1 nCoV-19 [12,13,14] | Overall: |
- Antigen-specific antibody peaked at day 28 with 157 GMEU |
91% and 100% participants achieved PRNT80 responses in one-dose and booster-dose groups, respectively. | - The median SFCs PBPMC in the standard-dose groups: |
| Ad5-vectored COVID-19 [15,16,17] | Not available at the time of writing | - High-dose: 1445.8 (95% CI 935.5–2234.5); |
- High-dose: |
- The mean SFCs PMPMC: |
| 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-Lyo | 100% 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 |
| NVX-CoV2373 [20,21,22] | 89.3% (95% CI 75.2–95.4) against B.1.1.7 UK variant, |
- GMEU increase by 8 (15,319 units in “5 μg + M1” and 20,429 units in “25 μg + M1”). |
GMFRs 5 times greater with adjuvant (5.2 times in “5 μg + M1” and 6.3 times in “25 μg + M1”). |
Stimulated Th1 phenotype response with increased IFN-γ, IL-2 and TNF- α. |
| WIV-04 strain inactivated vaccine [10] | Not available at the time of writing. | - Low-dose: 415 (95% CI 288–597); |
Neutralizing antibody levels increased significantly 14 days after the second dose, and the third dose | Not 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: |
-In age group 18–59 years, neutralizing antibody GMT were: |
Not assessed |
| Coronavac [24] | Brazil: |
3 μg: 27.6 (95% CI 22.7–33.5) |
3 μg: 5.6 (95% CI 3.6–8.7); |
The average IFN-γ positive spot-forming cells per 100,000 cells were: |
| Ad26.COV2.S [25,26,27,28,29] | Overall: |
- Ranged from 2432 U/mL to 5729 U/mL. |
- The GMT of neutralizing antibody ranged from 242 to 449. |
Stronger CD4+ cells response recorded in younger adults: |
| BBV152 [30,31,32] | Not reported | - 3 μg: 100.9 (95% CI 74.1–137.4) |
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 3Progress of existing 86 vaccines candidates in clinical trial as at 6th April 2021.
| Number | Vaccine Platform | Type of Candidate VACCINE | Usage | Developer | Clinical Status | Phase Trials Registration No. |
|---|---|---|---|---|---|---|
| 1 | Inactivated virus | CoronaVac; SARS-CoV-2 vaccine (inactivated) | 2 doses |
Sinovac Research and Development Co., Ltd. | Phase 4 | Phase ½: |
| Phase 3: |
||||||
| Phase 4: |
||||||
| 2 | Inactivated virus | Inactivated SARS-CoV-2 vaccine (Vero cell) | 2 doses |
Sinopharm + China National Biotec Group Co + Wuhan Institute of Biological Products | Phase 3 | Phase ½: |
| Phase 3: |
||||||
| 3 | Inactivated virus | Inactivated SARS-CoV-2 vaccine (Vero cell), vaccine name BBIBP-CorV | 2 doses |
Sinopharm + China National Biotec Group Co + Beijing Institute of Biological Products | Phase 3 | Phase 1/2: |
| Phase 3: |
||||||
| 4 | Viral vector (Non-replicating) | ChAdOx1-S—(AZD1222) (Covishield) | 2 doses |
AstraZeneca + University of Oxford | Phase 4 | Phase 1: |
| Phase 1/2: |
||||||
| Phase 2 |
||||||
| Phase 3: |
||||||
| Phase 4: |
||||||
| 5 | Viral vector (Non-replicating) | Recombinant novel coronavirus vaccine (Adenovirus type 5 vector) | 1 dose |
CanSino Biological Inc./Beijing Institute of Biotechnology | Phase 3 | Phase 1: |
| Phase 1/2: |
||||||
| Phase 2: |
||||||
| Phase 3: |
||||||
| 6 | Viral vector (Non-replicating) | Gam-COVID-Vac Adeno-based (rAd26-S + rAd5-S) | 2 doses |
Gamaleya Research Institute; Health Ministry of the Russian Federation | Phase 3 | Phase 1/2: |
| Phase 2: |
||||||
| Phase 2/3: |
||||||
| Phase 3: |
||||||
| 7 | Viral vector (Non-replicating) | Ad26.COV2.S | 1–2 doses |
Janssen Pharmaceutical | Phase 3 | Phase 1: |
| Phase 1/2: |
||||||
| Phase 2: |
||||||
| Phase 3: |
||||||
| 8 | Protein subunit | SARS-CoV-2 rS/Matrix M1-Adjuvant (Full length recombinant SARS CoV-2 glycoprotein nanoparticle vaccine adjuvanted with Matrix M) | 2 doses |
Novavax | Phase 3 | Phase 1/2: |
| Phase 2: |
||||||
| Phase 3: |
||||||
| 9 | RNA based vaccine | mRNA -1273 |
2 doses |
Moderna + National Institute of Allergy and Infectious Diseases (NIAID) | Phase 4 | Phase 1: |
| Phase 1/2: |
||||||
| Phase 2: |
||||||
| Phase 2/3: |
||||||
| Phase 3: |
||||||
| Phase 4: |
||||||
| 10 | RNA based vaccine | BNT162b2 | 2 doses |
Pfizer/BioNTech + Fosun Pharma | Phase 4 | Phase 1: |
| Phase 1/2: |
||||||
| Phase 2: |
||||||
| Phase 2/3: |
||||||
| Phase 3: |
||||||
| Phase 4: |
||||||
| 11 | Protein subunit | Recombinant SARS-CoV-2 vaccine (CHO Cell) | 2–3 doses |
Anhui Zhifei Longcom Biopharmaceutical + Institute of Microbiology, Chinese Academy of Sciences | Phase 3 | Phase 1: |
| Phase 1/2: |
||||||
| Phase 2: |
||||||
| Phase 3: |
||||||
| 12 | RNA based vaccine | CVnCoV Vaccine | 2 doses |
CureVac AG | Phase 3 | Phase 1: |
| Phase 2: |
||||||
| Phase 2/3: |
||||||
| Phase 3: |
||||||
| 13 | Inactivated virus | SARS-CoV-2 vaccine (Vero cells) | 2 doses |
Institute of Medical Biology + Chinese Academy of Medical Sciences | Phase 3 | Phase 1/2: |
| Phase 3: |
||||||
| 14 | Inactivated virus | QazCovid-in®—COVID-19 inactivated vaccine | 2 doses |
Research Institute for Biological Safety Problems, Rep of Kazakhstan | Phase 3 | Phase ½: |
| Phase 3: |
||||||
| 15 | DNA based vaccine | INO-4800 + electroporation | 2 doses |
Inovio Pharmaceuticals + International Vaccine Institute + Advaccine (Suzhou) Biopharmaceutical Co., Ltd. | Phase 2/3 | Phase 1: |
| Phase 1/2: |
||||||
| Phase 2: |
||||||
| Phase 2/3: |
||||||
| 16 | DNA based vaccine | AG0301-COVID19 | 2 doses |
AnGes + Takara Bio + Osaka University | Phase 2/3 | Phase 1/2: |
| Phase 2/3: |
||||||
| 17 | DNA based vaccine | nCov vaccine | 3 doses |
Zydus Cadila | Phase 3 | Phase 1/2: |
| Phase 3: |
||||||
| 18 | DNA based vaccine | GX-19N | 2 doses |
Genexine Consortium | Phase ½ | Phase 1/2: |
| 19 | Inactivated virus | Whole-Virion Inactivated SARS-CoV-2 Vaccine (BBV152) | 2 doses |
Bharat Biotech International Limited | Phase 3 | Phase 1/2: |
| Phase 3: |
||||||
| 20 | Protein subunit | KBP-COVID-19 (RBD-based) | 2 doses |
Kentucky Bioprocessing Inc. | Phase 1/2 | Phase 1/2: |
| 21 | Protein subunit | VAT00002: SARS-CoV-2 S protein with adjuvant | 2 doses |
Sanofi Pasteur + GSK | Phase 3 | Phase 1/2: |
| Phase 2: |
||||||
| Phase 3: |
||||||
| 22 | RNA based vaccine | ARCT-021 | 2 doses |
Arcturus Therapeutics | Phase 2 | Phase 1/2: |
| Phase 2: |
||||||
| 23 | Virus like particle | RBD SARS-CoV-2 HBsAg VLP vaccine | 2 doses |
Serum Institute of India + Accelagen Pty + SpyBiotech | Phase 1/2 | Phase 1/2: |
| 24 | Inactivated virus | Inactivated SARS-CoV-2 vaccine (Vero cell) | 2–3 doses |
Beijing Minhai Biotechnology Co | Phase 2 | Phase 1: |
| Phase 2: |
||||||
| 25 | Viral vector (Non-replicating) | GRAd-COV2 (Replication defective Simian Adenovirus (GRAd) encoding S) | 1 dose |
ReiThera + Leukocare + Univercells | Phase 2/3 | Phase 1: |
| Phase 2/3: |
||||||
| 26 | Viral vector (Non-replicating) | VXA-CoV2-1 Ad5 adjuvanted Oral Vaccine platform | 2 doses |
Vaxart | Phase 1 | Phase 1: |
| 27 | Viral vector (Non-replicating) | MVA-SARS-2-S | 2 doses |
University of Munich (Ludwig-Maximilians) | Phase 1 | Phase 1: |
| 28 | Protein subunit | SCB-2019 + AS03 or CpG 1018 adjuvant plus Alum adjuvant (Native like Trimeric subunit Spike Protein vaccine) | 2 doses |
Clover Biopharmaceuticals Inc./GSK/Dynavax | Phase 2/3 | Phase 1: |
| Phase 2/3: |
||||||
| 29 | Protein subunit | COVAX-19® Recombinant spike protein + adjuvant | 2 doses |
Vaxine Pty Ltd. | Phase 1 | Phase 1: |
| 30 | Protein subunit | MVC-COV1901 (S-2P protein + CpG 1018) | 2 doses |
Medigen Vaccine Biologics + Dynavax + National Institute of Allergy and Infectious Diseases (NIAID) | Phase 2 | Phase 1: |
| Phase 2: |
||||||
| 31 | Protein subunit | FINLAY-FR1 anti-SARS-CoV-2 Vaccine (RBD + adjuvant) | 2 doses |
Instituto Finlay de Vacunas | Phase 1/2 | Phase 1: |
| Phase 1/2: |
||||||
| 32 | Protein subunit | FINLAY-FR-2 anti-SARS-CoV-2 Vaccine (RBD chemically conjugated to tetanus toxoid plus adjuvant) | 2 doses |
Instituto Finlay de Vacunas | Phase 3 | Phase 1: |
| Phase 2: |
||||||
| Phase 3: |
||||||
| 33 | Protein subunit | EpiVacCorona (EpiVacCorona vaccine based on peptide antigens for the prevention of COVID-19) | 2 doses |
Federal Budgetary Research Institution State Research Center of Virology and Biotechnology “Vector” | Phase 3 | Phase 1/2: |
| Phase 3: |
||||||
| 34 | Protein subunit | RBD (baculovirus production expressed in Sf9 cells) Recombinant SARS-CoV-2 vaccine (Sf9 Cell) | 2 doses |
West China Hospital + Sichuan University | Phase 2 | Phase 1: |
| Phase 2: |
||||||
| 35 | Protein subunit | IMP CoVac-1 (SARS-CoV-2 HLA-DR peptides) | 1 dose |
University Hospital Tuebingen | Phase 1 | NCT04546841 |
| 36 | Protein subunit | UB-612 (Multitope peptide based S1-RBD-protein based vaccine) | 2 doses |
COVAXX + United Biomedical Inc | Phase 2/3 | Phase 1: |
| Phase 2: |
||||||
| Phase 2/3: |
||||||
| 37 | Viral vector (Replicating) | DelNS1-2019-nCoV-RBD-OPT1 (Intranasal flu-based-RBD) | 2 doses |
University of Hong Kong, Xiamen University and Beijing Wantai Biological Pharmacy | Phase 2 | Phase 1: |
| Phase 2: |
||||||
| 38 | RNA based vaccine | LNP-nCoVsaRNA | 2 doses |
Imperial College London | Phase 1 | Phase 1: |
| 39 | RNA based vaccine | SARS-CoV-2 mRNA vaccine (ARCoV) | 2 doses |
Academy of Military Science (AMS), Walvax Biotechnology and Suzhou Abogen Biosciences | Phase 2 | Phase 1: |
| Phase 2: |
||||||
| 40 | Virus like particle | Coronavirus-Like Particle COVID-19 (CoVLP) | 2 doses |
Medicago Inc. | Phase 2/3 | Phase 1: |
| Phase 2: |
||||||
| Phase 2/3: |
||||||
| 41 | Viral vector (Replicating) + APC | Covid-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 |
Shenzhen Geno-Immune Medical Institute | Phase 1 | Phase 1: |
| 42 | Viral vector (Non-replicating) + APC | LV-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 |
Shenzhen Geno-Immune Medical Institute | Phase 1/2 | Phase 1/2: |
| 43 | Protein subunit | AdimrSC-2f (Recombinant RBD +/− Aluminium) | No detail | Adimmune Corporation | Phase 1 | Phase 1: |
| 44 | DNA based vaccine | Covigenix VAX-001—DNA vaccines + proteo-lipid vehicle (PLV) formulation | 2 doses |
Entos Pharmaceuticals Inc. | Phase 1 | NCT04591184 |
| 45 | DNA based vaccine | CORVax—Spike (S) Protein Plasmid DNA Vaccine | 2 doses |
Providence Health & Services | Phase 1 | Phase 1: |
| 46 | RNA based vaccine | ChulaCov19 mRNA vaccine | 2 doses |
Chulalongkorn University | Phase 1 | Phase 1: |
| 47 | DNA based vaccine | bacTRL-Spike oral DNA vaccine | 1 dose |
Symvivo Corporation | Phase 1 | NCT04334980 |
| 48 | Viral Vector (Non-replicating) | Human Adenovirus type 5: hAd5 S + N vaccine (S-fusion + N-ETSD) E2b-deleted Adeno | 1–2 doses |
Immunity Bio.Inc | Phase 1 | Phase 1: |
| 49 | Viral vector (Non-replicating) | COH04S1 (MVA-SARS-2-S)—Modified vaccinia ankara (sMVA) platform + synthetic SARS-CoV-2 | 2 doses |
City of Hope Medical Center + National Cancer Institute | Phase 1 | Phase 1: |
| 50 | Viral vector (Replicating) | rVSV-SARS-CoV-2-S Vaccine | 1 dose |
Israel Institute for Biological Research | Phase 1/2 | Phase 1/2: |
| 51 | Viral vector (Replicating) + APC | Dendritic cell vaccine AV-COVID-19. A vaccine consisting of autologous dendritic cells loaded with antigens from SARS-CoV-2, with or without GM-CSF | 1 dose |
Aivita Biomedical, Inc. National Institute of Health Research and Development, Ministry of Health Republic of Indonesia | Phase 1/2 | Phase 1: |
| Phase 1/2: |
||||||
| 52 | Live attenuated virus | COVI-VAC | 1–2 doses |
Codagenix/Serum Institute of India | Phase 1 | Phase 1: |
| 53 | Protein subunit | CIGB-669 (RBD + AgnHB) | 3 doses |
Center for Genetic Engineering and Biotechnology (CIGB) | Phase 1/2 | Phase 1/2: |
| 54 | Protein subunit | CIGB-66 (RBD + aluminium hydroxide) | 3 doses |
Center for Genetic Engineering and Biotechnology (CIGB) | Phase 3 | Phase 1/2: |
| Phase 3 |
||||||
| 55 | Inactivated Virus | VLA2001 | 2 doses |
Valneva, National Institute for Health Research, United Kingdom | Phase 1/2 | Phase 1/2: |
| 56 | Protein subunit | BECOV2 | 2 doses |
Biological E. Limited | Phase 1/2 | Phase 1/2: |
| 57 | Viral vector (Replicating) | AdCLD-CoV19 (adenovirus vector) | 1 dose |
Cellid Co., Ltd. | Phase 1/2 | Phase 1/2: |
| 58 | DNA based vaccine | GLS-5310 | 2 doses |
GeneOne Life Science, Inc. | Phase 1/2 | Phase 1/2: |
| 59 | Protein subunit | Recombinant Sars-CoV-2 Spike protein, Aluminum adjuvanted | 2 doses |
Nanogen Pharmaceutical Biotechnology | Phase 1/2 | Phase 1/2: |
| 60 | Protein subunit | Recombinant protein vaccine S-268019 (using Baculovirus expression vector system) | 2 doses |
Shionogi | Phase 1/2 | Phase 1/2: |
| 61 | Viral vector (Non-replicating) | AdCOVID, Adenovirus-based platform expresses the receptor-binding domain (RBD) of the Sars-Cov-2 spike protein | 1 doses |
Altimmune, Inc. | Phase 1 | Phase 1: |
| 62 | Protein subunit | SARS-CoV-2-RBD-Fc fusion protein | Dosage and Schedule not specified |
University Medical Center Groningen + Akston Biosciences Inc. | Phase 1/2 | Phase 1/2: |
| 63 | Inactivated Virus | ERUCOV-VAC, inactivated virus | 2 doses |
Erciyes University | Phase 2 | Phase 1: |
| Phase 2: |
||||||
| 64 | Protein subunit | COVAC-1 and COVAC-2 sub-unit vaccine (spike protein) + SWE adjuvant | 2 doses |
University of Saskatchewan | Phase 1/2 | Phase 1/2: |
| 65 | Protein subunit | GBP510, a recombinant surface protein vaccine with adjuvant AS03 (aluminium hydroxide) | 2 doses |
SK Biosciences Co. Ltd. and CEPI | Phase 1/2 | Phase 1/2: |
| 66 | Protein subunit | Razi Cov Pars, recombinant spike protein | 3 doses |
Razi Vaccine and Serum Research Institute | Phase 1 | Phase 1: |
| 67 | Inactivated Virus | COVID-19 inactivated vaccine | 2 doses |
Shifa Pharmed Industrial Co | Phase 2/3 | Phase 1: |
| 68 | Protein subunit | MF59 adjuvanted SARS-CoV-2 Sclamp vaccine | 2 doses |
The University of Queensland | Phase 1 | Phase 1: |
| 69 | DNA based vaccine | COVIGEN | 2 doses |
University of Sydney, Bionet Co., Ltd. Technovalia | Phase 1 | Phase 1: |
| 70 | DNA based vaccine | COVID-eVax, a candidate plasmid DNA vaccine of the Spike protein | No detailed dosage schedule |
Takis + Rottapharm Biotech | Phase 1/2 | Phase 1/2: |
| 71 | Viral vector (Non-replicating) | BBV154, Adenoviral vector COVID-19 vaccine | 1 dose |
Bharat Biotech International Limited | Phase 1 | Phase 1: |
| 72 | RNA based vaccine | PTX-COVID19-B, mRNA vaccine | 2 doses |
Providence Therapeutics | Phase 1 | Phase 1: |
| 73 | Viral vector (Replicating) | NDV-HXP-S, Newcastle disease virus (NDV) vector expressing the spike protein of SARS-CoV-2, with or without the adjuvant CpG 1018 | 2 doses |
Mahidol University; The Government Pharmaceutical Organization (GPO); Icahn School of Medicine at Mount Sinai | Phase 1/2 | Phase 1/2: |
| 74 | RNA based vaccine | CoV2 SAM (LNP) vaccine. A self-amplifying mRNA (SAM) lipid nanoparticle (LNP) platform + Spike antigen | 2 doses |
GlaxoSmithKline | Phase 1 | Phase 1: |
| 75 | Virus like particle | VBI-2902a. An enveloped virus-like particle (eVLP) of SARS-CoV-2 spike (S) glycoprotein and aluminum phosphate adjuvant. | 2 doses |
VBI Vaccines Inc. | Phase 1/2 | NCT04773665 |
| 76 | Protein subunit | SK SARS-CoV-2 recombinant surface antigen protein subunit (NBP2001) + adjuvanted with alum. | 2 doses |
SK Bioscience Co., Ltd. | Phase 1 | Phase 1: |
| 77 | Viral 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 |
Gritstone Oncology | Phase 1 | Phase 1: |
| 78 | RNA based vaccine | mRNA-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 |
Moderna + National Institute of Allergy and Infectious Diseases (NIAID) | Phase 1 | Phase 1: |
| 79 | Protein subunit | SpFN (spike ferritin nanoparticle) uses spike proteins with a liposomal formulation QS21 (ALFQ) adjuvant. | 3 doses |
Walter Reed Army Institute of Research (WRAIR) | Phase 1 | Phase 1: |
| 80 | Protein subunit | EuCorVac-19; A spike protein using the recombinant protein technology and with an adjuvant. | 2 doses |
POP Biotechnologies and EuBiologics Co.,Ltd | Phase 1/2 | Phase 1/2: |
| 81 | Inactivated virus | Inactivated SARS-CoV-2 vaccine FAKHRAVAC (MIVAC) | 2 doses |
Organization of Defensive Innovation and Research | Phase 1 | Phase 1: |
| 82 | Live attenuated virus | MV-014-212, a live attenuated vaccine that expresses the spike (S) protein of SARS-CoV-2 | 2 doses |
Meissa Vaccines, Inc. | Phase 1 | Phase 1: |
| 83 | RNA based vaccine | MRT5500, an mRNA vaccine candidate | 2 doses |
Sanofi Pasteur and Translate Bio | Phase 1/2 | Phase 1/2: |
| 84 | Virus like particle | SARS-CoV-2 VLP Vaccine | 1 doses |
The Scientific and Technological Research Council of Turkey | Phase 1 | Phase 1: |
| 85 | Protein subunit | ReCOV: Recombinant two-component spike and RBD protein COVID-19 vaccine (CHO cell). | 2 doses |
Jiangsu Rec-Biotechnology | Phase 1 | Phase 1: |
| 86 | RNA based vaccine | DS-5670a, mRNA vaccine | 2 doses |
Daiichi Sankyo Co., Ltd. | Phase 1/2 | Phase 1/2: |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
Details
; Yang, Ming 2
; Ching-Lung Lai 1 1 Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong 999077, China
2 Department of Ophthalmology, The University of Hong Kong, Hong Kong 999077, China;