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

pharmaceuticals
Review
COVID-19 Vaccines: A Review of the Safety and Efficacy of
Current Clinical Trials
Zhi-Peng Yan 1, *,† , Ming Yang 2,† and 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; [email protected]
* Correspondence: [email protected] (Z.-P.Y.); [email protected] (C.-L.L.);
Tel.: +852-2255-4252 (C.-L.L.); Fax: +852-2816-2863 (C.-L.L.)
† Co-first authors.
Abstract: 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.
Citation: Yan, Z.-P.; Yang, M.; Lai,
C.-L. COVID-19 Vaccines: A Review Keywords: COVID-19; vaccine; safety; efficacy; herd immunity
of the Safety and Efficacy of Current
Clinical Trials. Pharmaceuticals 2021,
14, 406. https://doi.org/10.3390/
ph14050406 1. Introduction
The COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus
Academic Editor: Juan Carlos Saiz 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
Received: 25 March 2021
Organization (WHO) [1].
Accepted: 18 April 2021
The prevention and control of the epidemic in 2020, other than treatment of symp-
Published: 25 April 2021
tomatic patients, has included monitoring of asymptomatic infections, follow-up and
monitoring after cure and discharge, close contact tracking, high-risk population screening,
Publisher’s Note: MDPI stays neutral
and disinfection of the epidemic source, but the only way for the radical control of COVID-
with regard to jurisdictional claims in
19 infections is by effective vaccination. Vaccines stimulate the body to produce specific
published maps and institutional affil-
antibodies, with anamnestic response when the body is exposed to this pathogen again.
iations.
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 immunogenic-
ity profile of each vaccine is also documented (Table 2).
Copyright: © 2021 by the authors.
There are currently two forms of messenger ribonucleic acid (mRNA) vaccines: non-
Licensee MDPI, Basel, Switzerland.
replicating mRNA (NRM) vaccines and self-amplifying mRNA (SAM) vaccines. The
This article is an open access article
constructed mRNA is formulated into a carrier—usually lipid nanoparticles—to protect
distributed under the terms and
them from degradation and promote cellular uptake [2]. After the carrier particles are
conditions of the Creative Commons
Attribution (CC BY) license (https://
ingested into the cell, mRNA is released, which is translated by the ribosome to produce
creativecommons.org/licenses/by/
the target protein (recognizable antigen) [3]. After the target protein is secreted by the cell,
4.0/). it is rec-ognized by the immune system and stimulates an immune response.
Pharmaceuticals 2021, 14, 406. https://doi.org/10.3390/ph14050406 https://www.mdpi.com/journal/pharmaceuticals

Pharmaceuticals 2021, 14, 406 2 of 28
Table 1. Summary of vaccine trials.
Population Characteristics of
Title [Reference] Clinical Phase Doses Technology Immunogenicity Safety Profile
the Latest Trial
45 adults in 3 groups: 10 µg, Lipid nanoparticle
30 µg, 100 µg nucleoside-modified mRNA Dose-dependent antibody
BNT162b1 [4–6] 1–2 2 injections, 21 days apart No serious adverse events
12 vaccines: 3 placebo in each vaccine, encoding the spike response
group glycoprotein of SARS-CoV-2
43,448 volunteers aged 16 or Lipid nanoparticle
older in total: (1:1 ratio) 2 injections of 30 µg doses for nucleoside-modified mRNA Similar dose-dependent
BNT162b2 [7,8] 1–3 No serious adverse events
21,720 received vaccines phase 3, 21 days apart vaccine, encoding the spike response as BNT162b
21,728 received placebo glycoprotein of SARS-CoV-2
30,420 adults in total:
Lipid nanoparticle capsule of Similar grade 3 adverse events
(1:1 ratio) 2 injections of 100 µg doses, 100% seroconversion rates by
mRNA-1273 [9–11] 1–3 four lipids, encoding the S-2P in the placebo group (1.3%) and
15,210 received vaccines 28 days apart day 15
antigen. the vaccine group (1.5%)
15,210 received placebo
Chimpanzee Median titre of booster-dose
23,848 adults randomised 1:1 2 injections of 3.5–6.5 × 1010 - 13 serious adverse events
adenovirus-vectored vaccine group is more than 5 times
ChAdOx1 nCoV-19 [12–14] 1–3 ratio to receive ChAdOx1 viral particles per mL, 28 days - None considered related to the
with SARS-CoV-2 spike higher than the single-dose
nCoV-19 or placebo apart vaccine
glycoprotein group.
Replication defective Higher antibody GMT in - 25 grade 3 or above adverse
508 adults randomised 2:1:1 to
Ad5-vectored COVID-19 Ad5-vectored vaccine high-dose group, compared events
1&2 receive vaccine at the dosage of 1 injection
[15–17] expressing the spike with medium and low-dose - All resolved within 3 to 4 days
1 × 1011 , 5 × 1010 , or placebo
glycoprotein of SARS-CoV-2 groups. without medications
Replication of Ad5-vectored
21,977 adults in total: 2 injections of 1011 viral and Ad-26 vectored vaccine
rAd26-S and rAd5-S [18,19] 1–3 16,501 received vaccines particles in 0.5 mL vaccine, expressing the gene for 100% seroconversion rate No serious adverse events
5476 received placebo 21 days apart SARS-CoV-2 full-length
glycoprotein S
30,000 adults in total: Nanoparticle of trimeric
2 injections of 5 mg protein IgG GMT and neutralization
Randomised in 2:1 ratio to full-length SARS-CoV-2 spike
NVX-CoV2373 [20–22] 1–3 with 50 mcg matrix-M responses exceeding No serious adverse events
receive vaccine and saline glycoproteins and Matrix-M1
adjuvant, 21 days apart. convalescent serum
placebo adjuvant
96 adults randomised 1:1:1:1 to Phase 1:
WIV-04 strain inactivated receive low-dose, Isolated from WIV-04 strain 100% seroconversion rates in Mild
1–2 3 injections on day 0, 28 and 56 and cultivated in a Verco cell phase 1 trial and 85.7% in the injection site pain and fever
vaccine [10] medium-dose, high-dose and Phase 2: line, followed by serial phase 2 (23.4%)
aluminium hydroxide, 2 injections on day 0 and 14, or
respectively inactivation
day 0 and 21
192 adults:
18–59 years (96 adults) Phase 1:
≥60 years (96 adults). HB02-strain in Verco cell line, - Higher seroconversion with One grade 3 adverse event:
BBIBP-CorV [11,23] 1–2 2 injections separated 28 days
24 receiving vaccine of 2 µg, with serial inactivation higher dosage (8 µg) by day 14, self-limiting fever (>38.5 ◦ C)
4 µg or 8 µg on day 0 and 28; Phase 2: - Higher neutralizing antibody
and 24 receiving placebo. Single-dose GMT in younger adults
Table 1. Cont.
Population Characteristics of
Title [Reference] Clinical Phase Doses Technology Immunogenicity Safety Profile
the Latest Trial
13,000 adults randomised to -High seroconversion rates: One case of serious
Inactivated vaccine from Vero
receive vaccine or placebo 83% in the 3 µg group, 79% in hypersensitivity with urticaria,
Coronavac [24] 1–3 2 injections, 28 days apart cell line with SARS-CoV-2
(randomisation ratio not the 6 µg group, and 4% in the recovered 3 months after
(CN02 strain)
provided) placebo group medical treatment.
40,000 adults randomised to replication-incompetent
Comparable serious adverse
receive vaccination or placebo 1 injection of 5 × 1010 virus adenovirus serotype 26 (Ad26)
Ad26.COV2.S [25–29] 1–3 100% seroconversion day 57 events in vaccination group
(randomisation ratio not particles vector encoding full-length
and placebo group.
provided) SARS-CoV-2 spike protein
whole-virion inactivated
Comparable local and systemic
380 participants (aged SARS-CoV-2 vaccine 92.9% (95% CI 88.2–96.2)
adverse event profile in the
12–65 years) randomised by 1:1 2 intramuscular injections on formulated with a toll-like seroconversion rate in the 3 µg
BBV152 [30–32] 1–2 3 µg (9.47%) and 6 µg (11.0%)
ratio to receive vaccines of day 0 and day 28 receptor 7/8 agonist molecule group, and 98.3% (95% CI
groups. No reported serious
either 3 µg or 6 µg. (IMDG) adsorbed to alum 95.1–99.6) in the 6 µg group.
adverse events.
(Algel)
Table 2. 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
- 10 µg: 4813 U/mL
-Functional CD4+ and CD8+ responses in all
- 30 µg: 27,873 U/mL Higher GMT compared to convalescent
participants, predominantly Th1 helper
Similar to BNT162b2 - Increase dosage to 100 µg did not increase serum panel
BNT162b1 [4–6] responses.
(actual figure not stated) the IgG GMC. - 10 µg: 1.8-fold
- The mean fraction of RBD-specific T cells
- Lower antigen-binding IgG in participants - 30 µg: 2.8-fold
was higher than convalescent plasma.
≥65 years of age
- 10 µg: 5782 U/mL
Higher GMT compared to convalescent
- 20 µg: 12,464 U/mL
serum panel
BNT162b2 [7,8] 94.6% (95% CI 89.9–97.3) - 30 µg: 9136 U/mL Not assessed
18–55 years: 1.7–4.6 times
- Lower antigen-binding IgG for ≥65 years of
≥65 years: 1.1–2.2 times
age
- 25 µg: 299,751 U/mL - The 25 µg, 100 µg groups elicited CD4+ T
Neutralizing PRNT80 generally at or above
mRNA1273 [9–11] 94.1% (95% CI 89.3–96.8; p < 0.001) - 100 µg: 782,719 U/mL cell responses to Th1 cytokines.
the value of convalescent serum
- 250 µg: 1,192,154 U/mL - Minimal Th2 response
Overall:
- The median SFCs PBPMC in the
70.4% - Antigen-specific antibody peaked at day 28
standard-dose groups:
(95% CI 54.8–80.6) with 157 GMEU
18–55 years: 1187;
2-standard dose: - Antigen specific IgG on day 28 decreased 91% and 100% participants achieved PRNT80
56–69 years: 797
ChadOx1 nCoV-19 [12–14] 62.1% with increasing age: responses in one-dose and booster-dose
≥70 years: 977
(95% CI 41.0–75.7) 18–55 years: 6439 U/mL; groups, respectively.
No significant increase of PBPMC after the
Low dose + standard dose: 56–69 years: 4553 U/mL; and ≥70 years: 3565
booster vaccination (p = 0.46 from paired
90.0% U/mL
Student’s t test of day 28 vs. day 42)
(95% CI 67.4–97.0)
Table 2. Cont.
- The mean SFCs PMPMC:
- High-dose:
Low-dose:
34.0 (95% CI 22.6–50.1);
- High-dose: 1445.8 (95% CI 935.5–2234.5); 20.8 (95%CI 12.7–34.0);
- Medium-dose:
- Medium-dose: 806 (95% CI 528.2–1229.9) Medium-dose:
16.2 (95% CI 10.4–25.2);
- Low-dose: 615.8 (95% CI 405.4–935.5) 40.8 (95% CI 27.6–60.3) and
Ad5-vectored COVID-19 [15–17] Not available at the time of writing - Low-dose:
- Seroconversions of 97%, 94% and 100% in High-dose:
14.5 (95% CI 9.6–12.8))
the low-dose, medium-dose and high-dose 58.0 (95% CI 39.1–85.9)
- 4-fold increase of anti-RBD IgG in 50%, 50%
groups, respectively. T-cell responses in the high-dose group
and 75% in the high-dose, medium-dose and
significantly higher than the low-dose group
low-dose groups, respectively.
(p < 0.001)
- 100% increased formation of CD4+ and
CD8+ cells, and increased IFN-γ
- Median cell proliferation:
100% neutralizing antibody with GMT 49.25
SARS-CoV-2 S1 subunit-specific IgG GMT In frozen formulation:
and 45.95 by using Gam-COVID-Vac and
rAd26-S and rAd5-S [18,19] 91.6% (95% CI 85.6–95.2) was 53,006 with Gam-COVID-Vac and 51,200 CD4+ : + 2.5%
51,200 with Gam-COVID-Vac-Lyo,
with Gam-COVID-Vac-Lyo CD8+ : +1.3%
respectively.
In lyophilised formulation:
CD4+ : +1.3%
CD8+ : +1.1%
GMFRs 5 times greater with adjuvant
89.3% (95% CI 75.2–95.4) against B.1.1.7 UK - GMEU increase by 8 (15,319 units in “5 µg + (5.2 times in “5 µg + M1” and 6.3 times in “25 Stimulated Th1 phenotype response with
variant, M1” and 20,429 units in “25 µg + M1”). µg + M1”). increased IFN-γ, IL-2 and TNF- α.
NVX-CoV2373 [20–22]
49.4% (95% CI 6.1–72.8) against B.1.351 South - GMEU level higher than in convalescent Second dose with adjuvant resulted in GMT Minimal Th2 responses as measured by IL-5
Africa variant. serum after second dose levels 4 times greater than those in and IL-13 cytokines.
symptomatic infections.
- Low-dose: 415 (95% CI 288–597); Neutralizing antibody levels increased
WIV-04 strain inactivated vaccine [10] Not available at the time of writing. - Medium-dose: 349 (95% CI 258–472); significantly 14 days after the second dose, Not assessed
- High-dose: 311 (95% CI 229–422) and the third dose
In the 4 µg trial by 14 days after the second
dose, the GMTs were:
-In age group 18–59 years, neutralizing
- 279.2 (95% CI 192.6–404.7) against 35C;
antibody GMT were:
- 234.8 (95% CI 122.2–450.8) against 56Y;
2 µg: 22.6 (95% CI 18.9–27.0);
- 181.0 (95% CI 105.9–309.5) against 834Y;
4 µg: 29.3 (95% CI 23.8–36.0);
- 304.4 (95% CI 202.1–485.6) against HN97;
8 µg: 36.7 (95% CI 29.8–45.2)
BBIBP-CorV [11,23] Not available at the time of writing. - 117.4 (95% CI 61.1–225.4) against F13; Not assessed
-In the age group ≥60 years, neutralizing
- 193.3 (95% CI 141.4–264.0) against HB01;
antibody GMT were:
- 210.7 (95% CI 120.3–369.1) against BJ01,
2 µg: 13.4 (95% CI 9.4–19.0);
- 146.8 (95% CI 93.8–230.0) against CQ01;
4 µg: 18.9 (95% CI 13.4–26.6);
- 218.5 (95% CI 125.3–380.8) against QD01;
8 µg: 23.7 (95% CI 19.0–29.6)
- 394.8 (95% CI 256.5–607.6) against passage
7 virus.
Table 2. Cont.
Brazil:
symptomatic prevention:
50.4%
- mild cases prevention:
78% The average IFN-γ positive spot-forming
Severe cases prevention: 3 µg: 27.6 (95% CI 22.7–33.5) 3 µg: 5.6 (95% CI 3.6–8.7); cells per 100,000 cells were:
Coronavac [24] 100% 6 µg: 34.5 (95% CI 28.5–41.8) 6 µg: 7.7 (95% CI 5.2–11.5); 3 µg group: 7.4 (95% CI 3.9–11.1);
Turkey: Placebo: 2.3 (95% CI 2.0–2.5) Placebo: 2.0 (95% CI 2.0–2.0) 6 µg group: 3.9 (95% CI 1.0–6.7);
83.5% Placebo: 1.5 (95% CI 0.2–2.9)
(confidence interval not reported)
Indonesia:
65.3%.
(confidence interval not reported)
- The GMT of neutralizing antibody ranged
Overall: - Ranged from 2432 U/mL to 5729 U/mL. Stronger CD4+ cells response recorded in
from 242 to 449.
66.9% (95% CI 59.0–73.4) - The booster immunization on day 57 younger adults:
Ad26.COV2.S [25–29] - The booster immunization on day 57
≥60 years old increased binding antibody titres 2.56-fold 18–55 years:76 to 83%
increased neutralizing antibody titres by a
76.3% (95% CI, 61.6–86.0) (range 1.58–3.04). ≥65 years: 60 to 67%
mean of 4.62-fold (range: 3.56–5.68).
The neutralizing IgG GMTs at day 56 were
- 3 µg: 100.9 (95% CI 74.1–137.4) Strongly biased to a Th1 cell response at day
10,413.9 (95% CI 9142.4–11,862.2) in the 3 µg
BBV152 [30–32] Not reported - 6 µg: 197.0 (95% CI 155.6–249.4) 42. Th2 response were detected at minimal
group; and 9541.6 (95% CI 8245.9–11,041.0) in
(p = 0.0041) level.
the 6 µg group at day 56.
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.
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.
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
Pharmaceuticals 2021, 14, 406 and failure in the absence of protection [35]. Therefore, there is the shortcoming
7 of 28of ex-
tremely 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.
Figure1.1.Schematic
Figure Schematic graph
graph of of
thethe comparison
comparison between
between DNA DNA
and and
mRNAmRNA vaccine
vaccine in terms
in terms of mech-
of mecha-
anisms. DNA vaccine is a circle DNA which contains the spike gene of SARS-CoV-2.
nisms. DNA vaccine is a circle DNA which contains the spike gene of SARS-CoV-2. After electro-
After electro-
poration, cell membrane permeation will be increased, allowing DNA enter into cytoplasm
poration, cell membrane permeation will be increased, allowing DNA enter into cytoplasm thereby
thereby reaching to the nuclear. Subsequently, DNA will be translated into mRNA, which will be
reaching to the nuclear. Subsequently, DNA will be translated into mRNA, which will be further
further translated into SARS-CoV-2 spike proteins and express on cell membrane. Nanoparticle-
translated into SARS-CoV-2 spike proteins and express on cell membrane. Nanoparticle-encapsulated
encapsulated mRNA encoding SARS-CoV-2 antigen will be integrated into cytoplasm. The spike
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.
Table 3. Progress 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.
Phase 12 :
NCT04383574
NCT04352608
NCT04551547
Phase 3:
NCT04456595
NCT04508075
NCT04582344
CoronaVac; SARS-CoV-2 2 doses Sinovac Research and NCT04617483
1 Inactivated virus (day 0 + 14) Phase 4
vaccine (inactivated) Development Co., Ltd. NCT04651790
Intramuscular NCT04800133
Phase 4:
NCT04756830
NCT04747821
NCT04775069
NCT04789356
NCT04754698
NCT04801888
Phase 12 :
ChiCTR2000031809
2 doses Sinopharm + China National Phase 3:
Inactivated SARS-CoV-2
2 Inactivated virus (day 0 + 21) Biotec Group Co + Wuhan Phase 3 ChiCTR2000034780
vaccine (Vero cell)
Intramuscular Institute of Biological Products ChiCTR2000039000
NCT04510207
NCT04612972
Phase 1/2:
Inactivated SARS-CoV-2 2 doses Sinopharm + China National ChiCTR2000032459
3 Inactivated virus vaccine (Vero cell), vaccine (day 0 + 21) Biotec Group Co + Beijing Phase 3 Phase 3:
name BBIBP-CorV Intramuscular Institute of Biological Products NCT04560881
NCT04510207
Phase 1:
PACTR202005681895696
Phase 1/2:
PACTR202006922165132
NCT04568031
ChAdOx1-S—(AZD1222) 2 doses NCT04444674
Viral vector (Non-replicating) AstraZeneca + University of
4 (day 0 + 28) Phase 4 NCT04324606
(Covishield) Oxford
ISRCTN15638344
NCT04760730
Phase 2
NCT04686773
ISRCTN69254139
Table 3. Cont.
Phase 3:
ISRCTN89951424
NCT04516746
NCT04540393
ChAdOx1-S—(AZD1222) 2 doses NCT04536051
Viral vector (Non-replicating) AstraZeneca + University of
4 (day 0 + 28) Phase 4 EUCTR2020–005226-28-DE
(Covishield) Oxford
Phase 4:
NCT04760132
NCT04775069
Phase 1:
ChiCTR2000030906
NCT04313127
NCT04568811
NCT04552366
Phase 1/2:
Recombinant novel 1 dose NCT04398147
CanSino Biological Inc./Beijing
5 Viral vector (Non-replicating) coronavirus vaccine Day 0 Phase 3 Phase 2:
Institute of Biotechnology
(Adenovirus type 5 vector) Intramuscular ChiCTR2000031781
NCT04566770
NCT04341389
Phase 3:
NCT04526990
NCT04540419
Phase 1/2:
NCT04436471
NCT04437875
NCT04713488
NCT04760730
Phase 2:
2 doses Gamaleya Research Institute; NCT04587219
Gam-COVID-Vac Adeno-based Phase 2/3:
6 Viral vector (Non-replicating) (day 0 + 21) Health Ministry of the Russian Phase 3
(rAd26-S + rAd5-S) NCT04640233
Intramuscular Federation
Phase 3:
NCT04530396
NCT04564716
NCT04642339
NCT04656613
NCT04741061
Table 3. Cont.
Phase 1:
NCT04509947
Phase 1/2:
NCT04436276
1–2 doses Phase 2:
7 Viral vector (Non-replicating) Ad26.COV2.S Day 0 or Day 0+ Day 56 Janssen Pharmaceutical Phase 3 EUCTR2020-002584-63-DE
NCT04765384
Phase 3:
NCT04505722
NCT04614948
Phase 1/2:
SARS-CoV-2 rS/Matrix NCT04368988
M1-Adjuvant (Full length Phase 2:
recombinant SARS CoV-2 2 doses
NCT04533399
8 Protein subunit (day 0 + 21) Novavax Phase 3
glycoprotein nanoparticle Phase 3:
vaccine adjuvanted with Intramuscular
NCT04611802
Matrix M) EUCTR2020-004123-16-GB
NCT04583995
Phase 1:
NCT04283461
NCT04813796
Phase 1/2:
NCT04677660
NCT04712110
Phase 2:
NCT04405076
NCT04761822
2 doses Moderna + National Institute
mRNA -1273 Phase 2/3:
9 RNA based vaccine (day 0 + 28) of Allergy and Infectious Phase 4
mRNA-1283 NCT04649151
Intramuscular Diseases (NIAID)
NCT04796896
Phase 3:
NCT04470427
NCT04811664
NCT04805125
NCT04806113
Phase 4:
NCT04760132
NCT04792567
Table 3. Cont.
Phase 1:
NCT04523571
ChiCTR2000034825
NCT04816643
Phase 1/2:
NCT04588480
NCT04380701
NCT04537949
EUCTR2020-003267-26-DE
Phase 2:
NCT04649021
NCT04761822
2 doses
Pfizer/BioNTech + Fosun Phase 2/3:
10 (day 0 + 21) Phase 4
RNA based vaccine BNT162b2 Pharma NCT04754594
Intramuscular
Phase 3:
NCT04368728
NCT04713553
NCT04800133
NCT04805125
NCT04816669
Phase 4:
NCT04760132
EUCTR2021-000412-28-BE
EUCTR2021-000412-28-BE
NCT04780659
NCT04775069
Phase 1:
NCT04445194
ChiCTR2000035691
NCT04636333
Anhui Zhifei Longcom Phase 1/2:
Recombinant SARS-CoV-2 2–3 doses Biopharmaceutical + Institute
11 Protein subunit Day 0 + 28 or Day 0 + 28 + 56 Phase 3 NCT04550351
vaccine (CHO Cell) of Microbiology, Chinese NCT04813562
Intramuscular Academy of Sciences Phase 2:
NCT04466085
Phase 3:
NCT04646590
Phase 1:
NCT04449276
Phase 2:
2 doses NCT04515147
12 RNA based vaccine CVnCoV Vaccine Day 0 + Day 28 CureVac AG Phase 3 PER-054-20
Intramuscular Phase 2/3:
NCT04652102
Phase 3:
NCT04674189
Table 3. Cont.
Phase 1/2:
SARS-CoV-2 vaccine (Vero 2 doses Institute of Medical Biology + NCT04470609
13 Inactivated virus Day 0 + Day 28 Chinese Academy of Medical Phase 3 NCT04412538
cells)
Intramuscular Sciences Phase 3:
NCT04659239
2 doses Research Institute for Biological Phase 12 :

14 Inactivated virus QazCovid-in® —COVID-19 Phase 3 NCT04530357
Day 0 + Day 21 Safety Problems, Rep of
inactivated vaccine Phase 3:
Intramuscular Kazakhstan
NCT04691908
Phase 1:
NCT04336410
Inovio Pharmaceuticals + ChiCTR2000038152
2 doses International Vaccine Institute + Phase 1/2:
15 DNA based vaccine INO-4800 + electroporation Day 0 + Day 28 Phase 2/3 NCT04447781
Advaccine (Suzhou)
Intradermal Biopharmaceutical Co., Ltd. Phase 2:
ChiCTR2000040146
Phase 2/3:
NCT04642638
Phase 1/2:
NCT04463472
2 doses AnGes + Takara Bio + Osaka NCT04527081
16 DNA based vaccine AG0301-COVID19 Day 0 + Day 14 Phase 2/3 jRCT2051200085
University
Intramuscular Phase 2/3:
NCT04655625
Phase 1/2:
3 doses CTRI/2020/07/026352
17 DNA based vaccine nCov vaccine Day 0 + Day 28 + Day 56 Zydus Cadila Phase 3 CTRI/2021/03/032051
Intradermal Phase 3:
CTRI/2020/07/026352
2 doses Phase 1/2:
18 DNA based vaccine GX-19N Day 0 + Day 28 Genexine Consortium 1 NCT04445389
Phase 2
Phase 1/2:
NCT04471519
Whole-Virion Inactivated 2 doses
Bharat Biotech International CTRI/2020/07/026300
19 Inactivated virus Day 0 + Day 14 Phase 3
SARS-CoV-2 Vaccine (BBV152) Limited CTRI/2020/09/027674
Intramuscular
Phase 3:
NCT04641481; CTRI/2020/11/028976
2 doses
Phase 1/2:
20 Protein subunit KBP-COVID-19 (RBD-based) Day 0 + Day 21 Kentucky Bioprocessing Inc. Phase 1/2
NCT04473690
Intramuscular
Table 3. Cont.
Phase 1/2:
2 doses NCT04537208
VAT00002: SARS-CoV-2 S Phase 2:
21 Protein subunit protein with adjuvant Day 0 + Day 21 Sanofi Pasteur + GSK Phase 3
Phase 3:
PACTR202011523101903
Phase 1/2:
2 doses NCT04480957
22 RNA based vaccine ARCT-021 Day 0 + Day 21 Arcturus Therapeutics Phase 2 Phase 2:
NCT04728347
2 doses Phase 1/2:
RBD SARS-CoV-2 HBsAg VLP Serum Institute of India +
23 Virus like particle Day 0 + Day 28 Phase 1/2 ACTRN12620000817943
vaccine Accelagen Pty + SpyBiotech
Intramuscular ACTRN12620001308987
Phase 1:
Inactivated SARS-CoV-2 2–3 doses
Beijing Minhai Biotechnology NCT04758273
24 Inactivated virus Detailed schedule not specified Phase 2
vaccine (Vero cell) Co Phase 2:
Intramuscular
NCT04756323
GRAd-COV2 (Replication Phase 1:

1 dose
Viral vector (Non-replicating) ReiThera + Leukocare + NCT04528641
25 defective Simian Adenovirus Day 0 Phase 2/3
Univercells Phase 2/3:
(GRAd) encoding S) Intramuscular
NCT04791423
2 doses
VXA-CoV2-1 Ad5 adjuvanted Phase 1:
26 Viral vector (Non-replicating) Day 0 + Day 28 Vaxart Phase 1
Oral Vaccine platform NCT04563702
Intramuscular
2 doses
University of Munich Phase 1:
27 Viral vector (Non-replicating) MVA-SARS-2-S Day 0 + Day 28 Phase 1
(Ludwig-Maximilians) NCT04569383
Intramuscular
SCB-2019 + AS03 or CpG 1018 Phase 1:

2 doses Clover Biopharmaceuticals
adjuvant plus Alum adjuvant Phase 2/3 NCT04405908
28 Protein subunit Day 0 + Day 21 Inc./GSK/Dynavax
(Native like Trimeric subunit Phase 2/3:
Intramuscular
Spike Protein vaccine) NCT04672395
2 doses
COVAX-19® Recombinant Phase 1:
29 Protein subunit Day 0 + Day 21 Vaxine Pty Ltd. Phase 1
spike protein + adjuvant NCT04453852
Intramuscular
Medigen Vaccine Biologics + Phase 1:

MVC-COV1901 (S-2P protein + 2 doses
Dynavax + National Institute of NCT04487210
30 Protein subunit CpG 1018) Day 0 + Day 28 Phase 2
Allergy and Infectious Diseases Phase 2:
Intramuscular
(NIAID) NCT04695652
Table 3. Cont.
Phase 1:
FINLAY-FR1 anti-SARS-CoV-2 2 doses
Instituto Finlay de Vacunas Phase 1/2 RPCEC00000338
31 Protein subunit Vaccine (RBD + adjuvant) Day 0 + Day 28
Phase 1/2:
Intramuscular
RPCEC00000332
Phase 1:
FINLAY-FR-2 anti-SARS-CoV-2 RPCEC00000340
Vaccine (RBD chemically 2 doses Phase 2:
32 Protein subunit Day 0 + Day 28 Instituto Finlay de Vacunas Phase 3 RPCEC00000347
conjugated to tetanus toxoid
plus adjuvant) Intramuscular Phase 3:
RPCEC00000354
EpiVacCorona (EpiVacCorona 2 doses Federal Budgetary Research Phase 1/2:

Protein subunit vaccine based on peptide Day 0 + Day 21 Institution State Research NCT04527575
33 Phase 3
antigens for the prevention of Intramuscular Center of Virology and Phase 3:
COVID-19) Biotechnology “Vector” NCT04780035
Phase 1:
ChiCTR2000037518
RBD (baculovirus production
2 doses West China Hospital + Sichuan NCT04530656
expressed in Sf9 cells)
34 Protein subunit Day 0 + Day 21 University Phase 2 Phase 2:
Recombinant SARS-CoV-2
Intramuscular ChiCTR2000039994
vaccine (Sf9 Cell)
NCT04640402
NCT04718467
1 dose
IMP CoVac-1 (SARS-CoV-2
35 Protein subunit Day 0 University Hospital Tuebingen Phase 1 NCT04546841
HLA-DR peptides)
Subcutaneous
Phase 1:
NCT04545749
UB-612 (Multitope peptide 2 doses
COVAXX + United Biomedical Phase 2:
36 Protein subunit based S1-RBD-protein based Day 0 + Day 28 Phase 2/3
Inc NCT04773067
vaccine) Intramuscular Phase 2/3:
NCT04683224
Phase 1:
2 doses University of Hong Kong, ChiCTR2000037782
DelNS1-2019-nCoV-RBD-OPT1
37 Viral vector (Replicating) Day 0 + Day 28 Xiamen University and Beijing Phase 2 NCT04809389
(Intranasal flu-based-RBD)
Intranasal Wantai Biological Pharmacy Phase 2:
ChiCTR2000039715
2 doses
Phase 1:
38 RNA based vaccine LNP-nCoVsaRNA Day 0 + Day 28 Imperial College London Phase 1
ISRCTN17072692
Intranasal
Phase 1:
2 doses Academy of Military Science ChiCTR2000034112
SARS-CoV-2 mRNA vaccine
39 RNA based vaccine Day 0 + Day 28 (AMS), Walvax Biotechnology Phase 2 ChiCTR2000039212
(ARCoV)
Intranasal and Suzhou Abogen Phase 2:
Biosciences ChiCTR2100041855
Table 3. Cont.
Phase 1:
NCT04450004
Coronavirus-Like Particle 2 doses
Virus like particle Medicago Inc. Phase 2/3 Phase 2:
40 Day 0 + Day 21
COVID-19 (CoVLP) NCT04662697
Intranasal
Phase 2/3:
NCT04636697
Covid-19/aAPC vaccine. The
Covid-19/aAPC vaccine is
prepared by applying lentivirus
3 doses
Viral vector (Replicating) + modification with immune Shenzhen Geno-Immune Phase 1:
41 Day 0 + Day 14 + Day 28 Phase 1
APC modulatory genes and the viral Medical Institute NCT04299724
Subcutaneous
minigenes to the artificial
antigen presenting cells
(aAPCs).
LV-SMENP-DC vaccine.
Dendritic cells are modified
with lentivirus vectors
1 dose
Viral vector (Non-replicating) + expressing Covid-19 minigene Shenzhen Geno-Immune Phase 1/2:
42 Day 0 Phase 1/2
APC SMENP and immune Medical Institute NCT04276896
Subcutaneous
modulatory genes. CTLs are
activated by LV-DC presenting
Covid-19 specific antigens.
AdimrSC-2f (Recombinant Phase 1:
43 Protein subunit No detail Adimmune Corporation Phase 1
RBD +/− Aluminium) NCT04522089
Covigenix VAX-001—DNA 2 doses
44 DNA based vaccine vaccines + proteo-lipid vehicle Day 0 + Day 14 Entos Pharmaceuticals Inc. Phase 1 NCT04591184
(PLV) formulation Intramuscular
2 doses
CORVax—Spike (S) Protein Phase 1:
45 DNA based vaccine Day 0 + Day 14 Providence Health & Services Phase 1
Plasmid DNA Vaccine NCT04627675
Intradermal
2 doses
Phase 1:
46 RNA based vaccine ChulaCov19 mRNA vaccine Day 0 + Day 21 Chulalongkorn University Phase 1
NCT04566276
Intramuscular
1 dose
bacTRL-Spike oral DNA
47 DNA based vaccine Day 0 Symvivo Corporation Phase 1 NCT04334980
vaccine
Oral
Human Adenovirus type 5: 1–2 doses Phase 1:
48 Viral Vector (Non-replicating) hAd5 S + N vaccine (S-fusion + Day 0 + day 21 Immunity Bio.Inc Phase 1 NCT04591717
N-ETSD) E2b-deleted Adeno Subcutaneous or Oral NCT04710303
COH04S1
(MVA-SARS-2-S)—Modified 2 doses
City of Hope Medical Center + Phase 1:
49 Viral vector (Non-replicating) vaccinia ankara (sMVA) Day 0 + Day 28 Phase 1
National Cancer Institute NCT04639466
platform + synthetic Intramuscular
SARS-CoV-2
Table 3. Cont.
1 dose
Israel Institute for Biological Phase 1/2:
50 Viral vector (Replicating) rVSV-SARS-CoV-2-S Vaccine Day 0 Phase 1/2
Research NCT04608305
Intramuscular
Dendritic cell vaccine Phase 1:
AV-COVID-19. A vaccine Aivita Biomedical, Inc. NCT04690387
consisting of autologous 1 dose National Institute of Health
Viral vector (Replicating) + Day 0 Phase 1/2 NCT04685603
51 dendritic cells loaded with Research and Development,
APC Intramuscular
antigens from SARS-CoV-2, Ministry of Health Republic of Phase 1/2:
with or without GM-CSF Indonesia NCT04386252
1–2 doses
Codagenix/Serum Institute of Phase 1:
52 Live attenuated virus COVI-VAC Day 0 or Day 0 + 28 Phase 1
India NCT04619628
Intranasal
3 doses
Day 0 + 14 + 28 or Day 0 + 28 + Center for Genetic Engineering Phase 1/2:
53 Protein subunit CIGB-669 (RBD + AgnHB) Phase 1/2
56 and Biotechnology (CIGB) RPCEC00000345
Intranasal
3 doses Phase 1/2:

CIGB-66 (RBD + aluminium Center for Genetic Engineering
54 Protein subunit Day 0 + 14 + 28 or Day 0 + 28 + Phase 3 RPCEC00000346
hydroxide) and Biotechnology (CIGB)
56 Phase 3
Intranasal RPCEC00000359
2 doses Valneva, National Institute for
Phase 1/2:
55 Inactivated Virus VLA2001 Day 0 + Day 21 Health Research, United Phase 1/2
NCT04671017
Intramuscular Kingdom
2 doses
Phase 1/2:
56 Protein subunit BECOV2 Day 0 + Day 28 Biological E. Limited Phase 1/2
CTRI/2020/11/029032
Intramuscular
1 dose
AdCLD-CoV19 (adenovirus Phase 1/2:
57 Viral vector (Replicating) Day 0 Cellid Co., Ltd. Phase 1/2
vector) NCT04666012
Intramuscular
2 doses
Day 0 + Day 56 or Day 0 + Day Phase 1/2:
58 DNA based vaccine GLS-5310 GeneOne Life Science, Inc. Phase 1/2
84 NCT04673149
Intradermal
2 doses
Recombinant Sars-CoV-2 Spike Nanogen Pharmaceutical Phase 1/2:
59 Protein subunit Day 0 + 21 Phase 1/2
protein, Aluminum adjuvanted Biotechnology NCT04683484
Intramuscular
Recombinant protein vaccine 2 doses
Phase 1/2:
60 Protein subunit S-268019 (using Baculovirus Day 0 + 21 Shionogi Phase 1/2
jRCT2051200092
expression vector system) Intramuscular
AdCOVID, Adenovirus-based
1 doses
platform expresses the Phase 1:
61 Viral vector (Non-replicating) Day 0 Altimmune, Inc. Phase 1
receptor-binding domain (RBD) NCT04679909
Intranasal
of the Sars-Cov-2 spike protein
Table 3. Cont.
Dosage and Schedule not University Medical Center
SARS-CoV-2-RBD-Fc fusion Phase 1/2:
62 Protein subunit specified Groningen + Akston Phase 1/2
protein NCT04681092
Subcutaneous or intramuscular Biosciences Inc.
2 doses Phase 1:
ERUCOV-VAC, inactivated Erciyes University NCT04691947
63 Inactivated Virus Day 0 + 21 Phase 2
virus Phase 2:
Intramuscular
NCT04824391
COVAC-1 and COVAC-2 2 doses
Phase 1/2:
64 Protein subunit sub-unit vaccine (spike protein) Day 0 + 28 University of Saskatchewan Phase 1/2
NCT04702178
+ SWE adjuvant Intramuscular
GBP510, a recombinant surface 2 doses Phase 1/2:
SK Biosciences Co. Ltd. and
65 Protein subunit protein vaccine with adjuvant Day 0 + 28 Phase 1/2 NCT04742738
CEPI
AS03 (aluminium hydroxide) Intramuscular NCT04750343
3 doses
Razi Cov Pars, recombinant Razi Vaccine and Serum Phase 1:
66 Protein subunit Day 0 + 21 + 51 Phase 1
spike protein Research Institute IRCT20201214049709N1
Intramuscular and intranasal
2 doses Phase 1:
67 Inactivated Virus COVID-19 inactivated vaccine Day 0 + 14 Shifa Pharmed Industrial Co Phase 2/3 IRCT20201202049567N1
Intramuscular IRCT20201202049567N2
2 doses
MF59 adjuvanted SARS-CoV-2 Phase 1:
68 Protein subunit Day 0 + 28 The University of Queensland Phase 1
Sclamp vaccine NCT04495933
Intramuscular
2 doses
University of Sydney, Bionet Phase 1:
69 DNA based vaccine COVIGEN Day 0 + 28 Phase 1
Co., Ltd. Technovalia NCT04742842
Intramuscular or intradermal
COVID-eVax, a candidate Phase 1/2:
No detailed dosage schedule
70 DNA based vaccine plasmid DNA vaccine of the Takis + Rottapharm Biotech Phase 1/2 NCT04788459
Intramuscular
Spike protein EUCTR2020-003734-20-IT
1 dose
BBV154, Adenoviral vector Bharat Biotech International Phase 1:
71 Viral vector (Non-replicating) Day 0 Phase 1
COVID-19 vaccine Limited NCT04751682
Intramuscular
2 doses
PTX-COVID19-B, mRNA Phase 1:
72 RNA based vaccine Day 0 + 28 Providence Therapeutics Phase 1
vaccine NCT04765436
Intramuscular
NDV-HXP-S, Newcastle Mahidol University; The
disease virus (NDV) vector 2 doses Government Pharmaceutical
Phase 1/2:
73 Viral vector (Replicating) expressing the spike protein of Day 0 + 28 Organization (GPO); Icahn Phase 1/2
NCT04764422
SARS-CoV-2, with or without Intramuscular School of Medicine at Mount
the adjuvant CpG 1018 Sinai
Table 3. Cont.
CoV2 SAM (LNP) vaccine. A
2 doses
self-amplifying mRNA (SAM) Phase 1:
74 RNA based vaccine Day 0 + 28 GlaxoSmithKline Phase 1
lipid nanoparticle (LNP) NCT04758962
Intramuscular
platform + Spike antigen
VBI-2902a. An enveloped
virus-like particle (eVLP) of 2 doses
75 Virus like particle SARS-CoV-2 spike (S) Day 0 + 28 VBI Vaccines Inc. Phase 1/2 NCT04773665
glycoprotein and aluminum Intramuscular
phosphate adjuvant.
SK SARS-CoV-2 recombinant
2 doses
surface antigen protein subunit Phase 1:
76 Protein subunit Day 0 + 28 SK Bioscience Co., Ltd. Phase 1
(NBP2001) + adjuvanted with NCT04760743
Intramuscular
alum.
Chimpanzee Adenovirus
2–3 doses
serotype 68 (ChAd) and
Day 0 +14 + 28 or Day 0 + 28 +
self-amplifying mRNA (SAM) Phase 1:
77 Viral vector (Non-replicating) 56 or Gritstone Oncology Phase 1
vectors expressing spike alone, NCT04776317
Day 0 + 112
or spike plus additional
Intramuscular
SARS-CoV-2 T cell epitopes.
mRNA-1273.351. A lipid
nanoparticle
(LNP)-encapsulated
3 doses Moderna + National Institute
mRNA-based vaccine that Phase 1:
78 RNA based vaccine Day 0 + 28 + 56 of Allergy and Infectious Phase 1
encodes for a full-length, NCT04785144
Intramuscular Diseases (NIAID)
prefusion stabilized S protein of
the SARS-CoV-2 B.1.351
variant.
SpFN (spike ferritin
nanoparticle) uses spike 3 doses
Walter Reed Army Institute of Phase 1:
79 Protein subunit proteins with a liposomal Day 0 + 28 + 120 Phase 1
Research (WRAIR) NCT04784767
formulation QS21 (ALFQ) Intramuscular
adjuvant.
EuCorVac-19; A spike protein
2 doses
using the recombinant protein POP Biotechnologies and Phase 1/2:
80 Protein subunit Day 0 + 21 Phase 1/2
technology and with an EuBiologics Co.,Ltd NCT04783311
Intramuscular
adjuvant.
2 doses
Inactivated SARS-CoV-2 Organization of Defensive Phase 1:
81 Inactivated virus Day 0 + 21 Phase 1
vaccine FAKHRAVAC (MIVAC) Innovation and Research IRCT20210206050259N1
Intramuscular
MV-014-212, a live attenuated 2 doses
Phase 1:
82 Live attenuated virus vaccine that expresses the spike Day 0 + 35 Meissa Vaccines, Inc. Phase 1
NCT04798001
(S) protein of SARS-CoV-2 Intranasal
Table 3. Cont.
2 doses
MRT5500, an mRNA vaccine Sanofi Pasteur and Translate Phase 1/2:
83 RNA based vaccine Day 0 + 21 Phase 1/2
candidate Bio NCT04798027
Intramuscular
1 doses The Scientific and
Phase 1:
84 Virus like particle SARS-CoV-2 VLP Vaccine Day 0 Technological Research Council Phase 1
NCT04818281
Subcutaneous of Turkey
ReCOV: Recombinant
2 doses
two-component spike and RBD Phase 1:
85 Protein subunit Day 0 + 21 Jiangsu Rec-Biotechnology Phase 1
protein COVID-19 vaccine NCT04818801
Intramuscular
(CHO cell).
2 doses
Phase 1/2:
86 RNA based vaccine DS-5670a, mRNA vaccine Day 0 + 21 Daiichi Sankyo Co., Ltd. Phase 1/2
NCT04821674
Intramuscular
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 corre-
lation 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, parox-
ysmal 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 [41–43]. 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 ChA-
dOx1, 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 neuro-
logical 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 Cha-
dOx1 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 partici-
pants 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 vac-
cination, 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 sero-
conversion 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 neutral-
ization 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 poly-
functional 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 analy-
sis 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 serocon-
version 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 asso-
ciated 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 vac-
cine 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 symp-
tomatic 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 anti-
bodies 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 crit-
ical 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 trans-
mission [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 vacci-
nations (inactivated virus) shows that vaccinations reduced major cardiovascular events
significantly, and has become part of the routine care of patients with chronic cardiovascu-
lar 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) [63–66]. 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.
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COVID-19 Vaccines: A Review of The Safety and Efficacy of Current Clinical Trials

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

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pharmaceuticals

Pharmaceuticals 2021, 14, 406. https://doi.org/10.3390/ph14050406 https://www.mdpi.com/journal/pharmaceuticals

Table 1. Summary of vaccine trials.

2 doses Research Institute for Biological Phase 12 :

GRAd-COV2 (Replication Phase 1:

SCB-2019 + AS03 or CpG 1018 Phase 1:

Medigen Vaccine Biologics + Phase 1:

EpiVacCorona (EpiVacCorona 2 doses Federal Budgetary Research Phase 1/2:

3 doses Phase 1/2:

2. BiONTech (BNT162b1 and BNT162b2)

4. ChadOx1 nCoV-19 (AZD1222)

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

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

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

10. Coronavac Vaccine

of 2.56-fold (range 1.58–3.04) and 4.62-fold (range: 3.56–5.68), respectively. An interim

12. Covaxin (BBV 152)

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