† These authors contributed equally.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were
first detected in Wuhan, China in December 2019 and resulted in a worldwide
pandemic in 2020. SARS-CoV-2 infections totalled more than 180 million with 3.9
million deaths as of June 24, 2021. Tremendous research efforts have resulted in
the development of at least 64 vaccine candidates that have reached Phase I to
III clinical trials within 14 months. The primary efficacy endpoint for a random
placebo-controlled clinical trial of a COVID-19 vaccine to be approved by US FDA
should confer at least 50% protection against COVID-19. Three COVID-19 vaccines
(BNT162b2, mRNA-1273 and Sputnik V) in clinical Phase III trials have now
achieved
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global public health crisis. The situation is getting worse as many countries are facing the third wave of SARS-CoV-2 infections and as of 24 June 2021, there were over 180 million infections with 3.9 million deaths globally. There is an urgent need to develop a safe and effective vaccine needed to curtail the escalating COVID-19 pandemic. To date, WHO has reported over 237 vaccine candidates in preclinical and clinical trials using various platforms [1]. Many of the vaccine candidates are in Phase I/II clinical trials to evaluate immunogenicity and safety using different vaccine dosages in a small number of healthy volunteers. Some of these vaccine candidates have progressed to Phase III trials to further demonstrate efficacy and safety in larger cohorts of participants. As of May 20, 100 vaccine candidates have entered clinical evaluations and 20 vaccines have progressed to Phase III clinical trials. Several of the forerunners have completed Phase III trials and have been approved for regular use in some countries and emergency use in others.
The pandemic has warranted urgent actions to develop vaccines at warp speed. The mortality rate among individuals with underlying medical conditions and old age is higher than those who are young and healthy [2]. Besides conventional vaccines such as inactivated and recombinant subunit proteins, mRNA vaccines which have never been approved in the history of human vaccinations have now been used to vaccinate millions of people. However, the long-term safety and efficacy in preventing COVID-19 infections are still unclear.
Vaccine development is a rigorous and complex process. Vaccine safety is the
primary goal of COVID-19 vaccine development, which can be evaluated in various
animal models before human clinical trials. The incidence of solicited local and
systemic adverse events as well as the usage of pain medication for 7 days after
each injection, unsolicited adverse reactions for 28 days following each
injection must be taken into account in the safety assessment of vaccine
candidates. Solicited local adverse events included pain, redness, swelling and
induration at the injection site while solicited systemic adverse events included
fever, headache, fatigue, nausea, muscle ache and joint pain. In terms of
severity, adverse events were classified as mild (transient discomfort for
Antibody-dependent enhancement (ADE) and vaccine-associated enhanced respiratory disease (VAERD) are two potential risks related to vaccine-enhanced COVID-19 disease. ADE usually arises when viruses bind to non-neutralizing antibodies which in turn facilitate viruses to enter the host cells via Fc receptors expressed on monocytes. ADE could also occur when antibodies induced by vaccines were insufficient in neutralizing the virus. ADE has been observed in SARS-CoV-1 and MERS-CoV infections where anti-S antibodies were involved in ADE of SARS infections by gaining entry into FcR-expressing cells [4], while a neutralizing antibody (Mersmab 1) targeting the receptor-binding domain (RBD) aided the entry of MERS pseudo-virus via the DPP4 pathway [5]. In view of ADE caused by using the whole S protein or inactivated vaccine of SARS-CoV-1 and MERS-CoV, researchers have removed the potential ADE-promoting epitopes from the S protein by using the RBD as a sub-unit vaccine [6]. Despite the knowledge that ADE was caused by the whole S protein in SARS-CoV-1, the majority of the SARS-CoV-2 vaccine candidates employed the whole S protein as an immunogen. The SARS-CoV-2 receptor-binding domain (RBD) has also been shown to elicit a potent neutralizing response without ADE [7, 8].
VAERD could occurs when Th2 cytokines such as IL-4, IL-5 and IL-13 were overproduced, resulting in excessive mucus production, increased polymorphonuclear leukocytes and eosinophils in lung histopathology [9]. It has been suggested that non-neutralizing antibodies could stimulate Th2 response, leading to the formation of immune complexes which could cause tissue damage [10]. SARS-CoV vaccines based on the inactivated virus or recombinant S or N proteins administered with and without adjuvants in mice, ferrets and non-human primates were reported to induce Th2-mediated immunopathology with eosinophil infiltrations after challenge [11, 12]. In addition, inactivated MERS-CoV vaccine was found to increase infiltrations of eosinophil by promoting the production of Th2 cytokines, resulting in adverse lung pathology in mice [13]. Most of the vaccine candidates that entered Phase III clinical trials were designed to elicit S protein-mediated immune responses. However, earlier studies have shown that whole inactivated virus or the entire S glycoprotein from SARS-CoV-1 were associated with increased respiratory conditions in animal models [12, 14]. Therefore, preventing Th2-biased immunity or eliminating elicitation of poorly neutralizing antibodies would be paramount to ensuring vaccine safety. Immunogenicity data of Th1 vs. Th2 polarization in addition to neutralization antibodies vs total IgG responses in animal models could provide a critical framework for safety assessment and regulatory decisions required to accelerate vaccine development. Characterization of the types of immune responses induced by COVID-19 vaccine candidates in animal challenge studies could be useful to evaluate the possibility of the vaccine in inducing vaccine-associated ERD in humans. FDA has included the requirement to demonstrate the Th1/Th2 ratio of cellular immune responses elicited by vaccine candidates in clinical trials [15].
Vaccines fundamentally activate the immune system of an individual to prepare for possible infection by a virus, so the immune response mounted would be enhanced. To study their usefulness, the vaccine candidates would have to be assessed for their immunogenicity and safety in clinical trials. Immunogenicity is the ability of an antigen present in a vaccine to elicit measurable immune responses. The adaptive immune responses were activated after viral uptake and antigen processing by antigen-presenting cells. B cells are activated by the antigens through the B cell receptor (BCR). B cells are assisted by activated T follicular helper cells (Tfh) to differentiate into plasma cells which can then produce specific antibodies against the antigen. Humoral immune responses to SARS-CoV-2 were mainly mediated by antibodies that were directed to the spike glycoprotein and the nucleocapsid protein. However, neutralizing antibodies are targeted mainly at the SARS-CoV-2 spike protein [16]. Neutralizing antibodies should be effectively preventing viruses from entering host cells to limit the infection and they also play an important protective role to prevent re-infection.
By contrast, the cellular immune response is mediated by T cells. Cytotoxic and
helper T cells are known to play a crucial role in adaptive immune responses by
clearing the virus-infected cells [17]. CD8+ T cells activated by peptide
antigens presented on MHC I differentiate into the cytolytic T cells, whereas
CD4+ T cells activated by peptide antigens presented on MHC II further enhances
CD8+ T cell responses. T-helper 1 (Th1), T-helper 2 (Th2), T-helper 17 (Th17)
and regulatory T cells (Treg) are effector subtypes of activated CD4+ T helper
cells that play important roles in mediating immune response through the release
of various cytokines. Th1 cells secrete IFN-
The advantages and disadvantages of SARS-CoV-2 vaccine candidates are presented in Table 1. The safety of the SARS-CoV-2 vaccine candidates and their immunogenicity in eliciting neutralizing antibodies will be presented in Table 2 (Ref. [32, 33, 34, 26, 35, 3, 27, 36, 28, 37, 38, 39, 29, 40, 30, 31]). The findings on T cell responses and cytokine profiles elicited by SARS-CoV-2 vaccine candidates are addressed in Table 3 (Ref. [26, 27, 28, 41, 29, 30, 31]). The emergence of SARS-CoV-2 variants and their impacts on the efficacies of current vaccines against SARSCo-V-2 are discussed.
Vaccine platforms | Inactivated Vaccine | mRNA vaccine | Adenovirus vector vaccine | Recombinant S protein | ||||||
Manufacturers | Sinopharm | Sinopharm | Sinovac | Moderna | Pfizer Biontech | CanSino | Oxford University/AstraZeneca | Gamaleya | Janssen/Johnson & Johnson | Novavax |
China | China | China | USA | USA/Germany | China | UK | Russia | USA | USA | |
Vaccine candidates | BBIBP-Corv | New Crown COVID-19 | CoronaVac | mRNA-1273 | BNT162b2 | Ad5-nCoV | ChAdOx1 nCoV-19 | Sputnik V | Ad26.COV2.S | NVX-CoV2373 |
Adjuvant | Aluminum hydroxide | Aluminum hydroxide | aluminum hydroxide | Lipid nanoparticles | Lipid nanoparticles | No adjuvant | No adjuvant | No adjuvant | No adjuvant | Matrix-M1 |
Storage temperature | 2–8 |
2–8 |
2–8 |
−20 |
−70 |
2–8 |
2–8 |
−18 |
2–8 |
2–8 |
Efficacy | N/A | N/A | 50.4% | 94.1% | 95% | N/A | 70% | 91.6% | 66% | 89.3% |
Emergency use approval | China | Not reported | China | US, Canada, Europe and UK | UK, Canada, US and Europe | China | UK, Argentina, India, Mexico, Brazil, Europe and Canada | Russia and Mexico | US (Paused 13 April), Canada and Europe | Not reported |
Advantages | Safe because the virus is killed. Easy for transport and storage. | Easy and quick to design. Large scale production. Safe as no infectious virus handling is required. Can induce humoral and cellular responses. | Replication-defective vector viruses tend to elicit stronger immune responses than killed viruses. Can induce humoral and cellular responses with a single dose with Ad5-nCoV and Ad26.COV2.S. | Focus on the most immunogenic S protein of the virus for protection. Incapable of causing infections. | ||||||
Disadvantages | Significant risk due to growth of large volume of live viruses before inactivation. The inactivation process may affect antigen immunogenicity. Some inactivated vaccines were shown to increase severity of disease. Adjuvants are required. Multiple doses are needed every 12 months. | There are no licensed mRNA vaccines. mRNA vaccines exhibit instability due to liposome and require storage at −20 |
Pre-existing immunity against viral vector can attenuate immune responses. Some candidates require storage at −20 |
Adjuvant may need to boost long-term immunity. |
Vaccine candidates | Clinical trials | No. of subjects | Route | No. of doses | Schedule (Days) | Dosage | Immunogenicity (GMT NtAb) | Safety | References |
Inactivated vaccine (BBIBP-CorV) | Phase I | 192 (18–59 years) | I.M | 2 | Days-0, 28 | 2 µg | (Day-42) 87.7 | Fever was reported in less than 10% of participants. All adverse reactions were mild. No severe adverse reaction was reported within 28 days post-vaccination in all groups. | [32] |
4 µg | 211.2 | ||||||||
8 µg | 228.7 | ||||||||
Phase I | ( |
I.M | 2 | Days-0, 28 | 2 µg | (Day-42) 80.7 | |||
4 µg | 131.5 | ||||||||
8 µg | 170.8 | ||||||||
Phase II | 448 (18–59 years) | I.M | 2 | Days-0,14 | 4 µg | (Day-28) 169.5 | Adverse effects reported were mild or moderate. Fever in less than 4% of participants in each dosage group. | ||
Days-0, 21 | 4 µg | 282.7 | |||||||
Days-0, 28 | 4 µg | 218.0 | |||||||
I.M | 1 | Day-0 | 8 µg | (Day-28) 14.7 | |||||
Inactivated vaccine (New Crown COVID-19) | Phase I | 96 (18–59 years) | I.M | 3 | Days-0, 28, 56 | 2.5 µg | (Day-70) 316 | All adverse reactions were mild (grade 1 or 2), mainly injection site pain and fever. No other adverse reactions were reported within 28 days post-vaccination. | [33] |
5 µg | 206 | ||||||||
10 µg | 297 | ||||||||
Phase II | 224 (18–59 years) | I.M | 2 | Days-0, 14 | 5 µg | (Day-28) 121 | |||
Days-0, 21 | 5 µg | (Day-35) 247 | |||||||
Inactivated vaccine (CoronaVac) | Phase I | 144 (18–59 years) | I.M | 2 | Days-0, 14 | 3 µg | (Day-42) 5.4 | Most adverse reactions were mild (grade 1). The most commonly reported symptom was pain at the injection site. No serious adverse events were noted within 28 days of vaccination. | [34] |
6 µg | 15.2 | ||||||||
Days-0, 28 | 3 µg | (Day-56) 19.0 | |||||||
6 µg | 29.6 | ||||||||
Phase II | 600 (18–59 years) | I.M | 2 | Days-0, 14 | 3 µg | (Day-42) 23.8 | |||
6 µg | 30.1 | ||||||||
I.M | 2 | Days-0, 28 | 3 µg | (Day-56) 44.1 | |||||
6 µg | 65.4 | ||||||||
LNP-mRNA (mRNA-1273) | Phase I | 45 (18–55 years) | I.M | 2 | Days-0, 28 | 25 µg | (Day-43) 112.3 | No stage 4 adverse effects were reported. Myalgia, fatigue, headache, chills and pain at the injection site occurred in more than half the participants in all groups. Adverse events were more frequent after the second dose and more prominent in the highest dose group. | [26] |
100 µg | 343.8 | ||||||||
250 µg | 332.2 | ||||||||
Phase I | 40 (56–70 years) | I.M | 2 | Days-0, 28 | 25 µg | Adverse events were mild or moderate in elderly. No serious adverse events were reported. | |||
100 µg | (Day-43) 402 | [35] | |||||||
( |
I.M | 2 | Days-0, 28 | 25 µg | |||||
100 µg | (Day-43) 317 | ||||||||
Phase III | 30,420 ( |
I.M | 2 | Days-0, 28 | 100 µg | N/A | Soreness at the injection site after the first dose. Fatigue, myalgia, arthralgia, headache, pain. Redness at the injection site after the second dose was common among the younger than elderly. | [3] | |
LNP-mRNA (BNT162b2) | Phase I | 195 (18–55 years) | I.M | 2 | Days-0, 21 | 10 µg | (Day-35) 97 | The adverse event primarily pain at the injection site in younger. Injection-site pain was reported by 92% after the first dose and by 75% after the second dose in the elderly. Fatigue, headache, chills, muscle pain, and joint pain were reported in small numbers of younger recipients, but no severe systemic events were reported in the elderly. | [27] |
20 µg | 292 | ||||||||
30 µg | 163 | ||||||||
Phase I | (65–85 years) | I.M | 2 | Days-0, 21 | 10 µg | (Day-35) 111 | |||
20 µg | 81 | ||||||||
30 µg | 206 | ||||||||
Phase III | 43,448 ( |
I.M | 2 | Days-0, 21 | 30 µg | N/A | Serious adverse events were low. Shoulder injury related to vaccine administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia and right leg paresthesia were reported among BNT162b2 recipients. Two BNT162b2 recipients died (one from arteriosclerosis, one from cardiac arrest), as did four placebo recipients (two from unknown causes, one from hemorrhagic stroke, and one from myocardial infarction. | [36] | |
Adenovirus type 5 vectored vaccine (Ad5-nCoV) | Phase I | 108 (18–60 years) | I.M | 1 | Day-0 | 5 |
(Day-28) 14.5 | Pain at injection site was reported in 54% vaccine recipients. Fever, Fatigue, headache and muscle pain were common. Most adverse reactions that were reported in all dose groups were mild or moderate in severity. Severe fever along with fatigue, dyspnoea, muscle and joint pain were reported in less than 10% of participants. | [28] |
1 |
16.2 | ||||||||
1.5 |
34 | ||||||||
Phase II | 508 (≥18 years) | I.M | 1 | Day-0 | 5 |
(Day-28) 19.5 | [37] | ||
1 |
18.3 | ||||||||
Chimpanzee adenovirus vectored vaccine ChAdOx1 nCoV-19 (AZD1222) | Phase I/II | 1077 (18–55 years) | I.M | 2 | Days-0, 28 | 5 |
(Day-28) 218 | Pain, fever, chills, muscle ache, headache, and malaise were common in the ChAdOx1 nCoV-19 group. | [38] |
Phase III | 23,848 ( |
I.M | 2 | Days-0, 28 | 5 |
N/A | Serious adverse events occurred in 168 participants, 79 of whom received ChAdOx1 nCoV-19. | ||
2.5 |
[39] | ||||||||
Adenovirus vectored vaccine (Sputnik V) | Phase I | 38 (18–60 years) | I.M | 1 | Day-0 | 1 |
N/A | Asthenia, myalgia, arthralgia, fever, headache and pain at injection site were reported in a portion of vaccinated participants. Most adverse events were mild and no serious adverse events were detected. | [29] |
Phase II | 38 (18–60 years) | I.M | 2 | Days 0, 21 | 1 |
(Day-42) 49.25 | |||
Phase III | 21,977 ( |
I.M | 2 | Days 0, 21 | 1 |
N/A | No Grade 4 adverse events reported. Most reported adverse events were grade 1. The most common severe events reported were pain at the injection site, fever, fatigue and headache. Four deaths were reported during the study but no related to vaccine. | [40] | |
Adenovirus vectored vaccine (Ad26.COV2. S) | Phase I/IIa | 805 (18–55 years) | I.M | 1 | Day-0 | 5 |
(Day-29) 224 | Most solicited systemic adverse events were mild in both younger and elderly, mainly injection site pain, fever, headache and myalgia. Five serious adverse events occurred but unrelated to vaccine. | [30] |
1 |
215 | ||||||||
5 |
(Day-57) 310 | ||||||||
1 |
370 | ||||||||
( |
I.M | 1 | Day-0 | 5 |
(Day-29) 277 | ||||
1 |
212 | ||||||||
(18–55 years) | I.M | 2 | Day-0, 56 | 5 |
(Day-71) 827 | ||||
1 |
1266 | ||||||||
S-Protein Subunit (NVX-CoV2373) | Phase I | 131 (18–55 years) | I.M | 2 | Days-0, 21 | 5 µg + Matrix M1 | (Day 35) 3906 | Adverse events and reactogenicity were mild in the majority of participants. Most common severe systemic events were joint pain and fatigue. 8 of 131 participants had severe systemic events. | [31] |
25 µg + Matrix M1 | 3305 | ||||||||
N/A denotes no data available; I.M denotes intramuscular administration; VP denotes viral particles. |
Vaccine candidates | T cell responses | Th1 cytokines | Th2 cytokines | References |
Inactivated vaccine (BBIBP-CorV) | N/A | N/A | N/A | N/A |
Inactivated vaccine (New Crown COVID-19) | N/A | N/A | N/A | N/A |
Inactivated vaccine (CoronaVac) | N/A | N/A | N/A | N/A |
LNP-mRNA (mRNA-1273) | Good CD4+ T cells | IFN- |
Minimal IL-4, IL-13 | [26] |
Low levels of CD8+ T cells | ||||
LNP-mRNA (BNT162b2) | Good CD4+ and CD8+ T cells | IFN- |
Minimal IL-4 | [27] |
Adenovirus type 5 vectored vaccine (Ad5-nCoV) | Detected CD4+ and CD8+ T cells | IFN- |
N/A | [28] |
Chimpanzee adenovirus vectored vaccine | Detected CD4+ and CD8+ T cells | IFN- |
Minimal IL-4, IL-5, IL-13 | [41] |
ChAdOx1 nCoV-19 (AZD1222) | ||||
Adenovirus vectored vaccine (Sputnik V) | Detected CD4+ and CD8+ T cells | IFN- |
N/A | [29] |
Adenovirus vectored vaccine (Ad26.COV2. S) | Detected CD4+ and CD8+ T cells | IFN- |
Minimal IL-4, IL-13 | [30] |
S-Protein Subunit (NVX-CoV2373) | Detected CD4+ T cells | IFN- |
Minimal IL-5, IL-13 | [31] |
N/A denotes no data available. |
The inactivated vaccine platform is the most common vaccine platform used in vaccinology. Many infectious diseases have already been eradicated using inactivated vaccines and it would be desirable to utilize the much tried and tested platform for developing a safe SARS-CoV-2 vaccine. The inactivated vaccine, BBIBP-Corv, developed by Chinese pharmaceutical company Sinopharm, was produced from the 19nCoV-CDC-Tan-HB (02) (HB02) strain derived from the throat swab of a covid-19 patient [42]. It showed high homology with many SARS-CoV-2 strains and therefore displayed a high level of phylogenetic relationships with strains within the SARS-CoV-2 population [32]. The logic behind the development of this vaccine is that inactivated vaccine platforms already had a good track record to provide immune protection against respiratory diseases [43]. Research has been going at an accelerated pace due to the scale of the pandemic, leading to changes from typical human trial protocols as Phase I and II trials were reportedly conducted in parallel [9].
The results of both Phase I (n = 192) and II (n = 448) trials showed that the
BBIBP-CorV vaccine was safe and well-tolerated at 4
Good immunogenicity of the vaccine was demonstrated as the vaccine could induce
rapid humoral responses and 100% seroconversion was evident in both cohorts by
day 42. The two-dose immunizations with 4
Due to the lack of clinical data for children and adolescents, studies on the effects of the vaccine in these groups are currently on-going [42]. Phase III trials officially began in July 2020 in China as well as in countries such as Argentina (NCT04560881) and the UAE (ChiCTR2000034780). Phase III trials were expected to conclude by late 2021 to provide further information on the dosages and immunization schedules as well as safety and immunogenicity. The World Health Organization (WHO) has granted emergency approval for BBIBP-Corv on May 7, 2021 [44].
New Crown COVID-19 is an inactivated vaccine produced by Sinopharm. The
SARS-CoV-2 virus (WIV04 strain; GenBank accession number MN996528) was cultivated
in Vero cells and it was inactivated with
CoronaVac was developed by Sinovac Life Sciences Co., Ltd (Beijing, China) and
is an inactivated SARS-CoV-2 vaccine with aluminum hydroxide as an adjuvant. The
SARS-CoV-2 virus was propagated in Vero cells and harvested viruses were
inactivated by
For the inactivated SARS-CoV-2 vaccine, CoronaVac, 744 healthy participants aged 18–59 years in Phase I/II trials were included to evaluate immunogenicity, safety and tolerance. The trials were randomized, double-blind and placebo-controlled, with established safety and immunogenic assessment criteria.
No significant differences in the incidence of adverse reactions was reported
among the three groups of participants receiving a low dose of 3
Phase II trials showed increased immune responses when compared to Phase I with
over 90% seroconversions for the participants receiving the 3
Four Phase III trials are ongoing in Brazil (NCT04456595), Indonesia (NCT04508075), Turkey (NCT04582344) and Chile (NCT04651790). Interim results released by Sinovac showed that initial vaccine efficacy was at 78% but variable efficacies were reported for the Phase III trials in the three countries. Vaccine efficacy at 91.25% was reported in Turkey and 65.3% in Indonesia but Brazil reported a reduced efficacy at only 50.4% [46].
mRNA vaccines provide flexibility in the design and expression of viral antigens that are similar to those expressed during natural infections. The mRNA vaccine platform has the potential to facilitate rapid vaccine development in response to emerging pathogens. mRNA vaccine comprises a mRNA strand coding for a target antigen which is translated in the cytoplasm of the host cell [47]. mRNA-1273 is a vaccine that carries mRNA of the full-length spike protein encapsulated in lipid nanoparticles and is developed by Moderna and National Institute of Allergy and Infectious Diseases (NIAID). It encodes the SARS-CoV-2 spike protein antigen which is a stable prefusion SARS-CoV-2 glycoprotein with intact S1 and S2 cleavage sites. S-2P is stabilized by two consecutive proline substitutions at amino acids 986 and 987, which are located at the top of the central helix in the S2 subunit [48].
In the Phase I dose-escalation clinical trial, 15 participants (18–55 years of
age) were administered with two doses of either 25
The clinical trials of mRNA-1273 were expanded to include 40 older adults (56 to
70 years or
Four mRNA-based vaccine candidates, BNT162a1, BNT162b1, BNT162b2 and BNT162c2
representing two different antigens: RBD or full-length spike (with 2 proline
mutations) were developed by of Pfizer and BioNTech (Germany). BNT162a1 is an
uridine-containing mRNA encoding the RBD while BNT162c2 is self-amplifying mRNA
carrying a modified spike protein [49]. BNT162b1 and BNT162b2 are both
nucleoside-modified RNAs formulated in lipid nanoparticles. BNT162b2 encoded the
stabilized prefusion SARSCoV-2 full-length spike protein, modified by 2 proline
mutations (P2 S) which locked it in the prefusion conformation whilst BNT162b1
encoded the RBD [48, 50]. The safety and immunogenicity of three different doses
(10
BNT162b2 was reported to have milder severity of systemic reactions (fatigue,
headache, chills, muscle ache, and joint pain) than BNT162b1, particularly in
older adults [27]. Therefore, the BNT162b2 vaccine candidate was chosen to
progress to the Phase II/III study at 30
Ad5-nCoV is a recombinant adenovirus serotype type 5 vectored vaccine encoding the full-length SARS-CoV-2 WT spike protein. It was developed by CanSino Biologics Inc., China.
Healthy adults (n = 108) aged 18 to 60 years were enrolled in a Phase I clinical
trial and they received a single dose of vaccine consisting of either 5
A chimpanzee adenovirus vectored vaccine ChAdOx1 nCoV-19 (AZD1222) encoding the spike protein of SARS-CoV-2 was developed by inserting a codon-optimized S protein gene in a replication-defective vector ChAdOx1 [53] The vaccine was the culminating efforts between academia (Oxford University) and industrial collaboration (AstraZeneca).
A Phase I/II trial enrolled 1077 healthy volunteers (aged 18–55 years) and
participants were immunized with either a single dose or with two doses
consisting of 5
Two vectors, adenovirus type 26 (Ad26) and adenovirus type 5 (Ad5), were used to construct the Gam-COVID vaccine (Sputnik V) carrying the genes for the SARS-CoV-2 full-length glycoprotein S. Both recombinant vaccines (rAd26-S and rAd5-S) were developed by Gamaleya Research Institute of Epidemiology and Microbiology (Moscow, Russia).
In Phase I study, the safety and immunogenicity of the Gam-COVID vaccine were
evaluated in nine volunteers who received the vaccine intramuscularly on day 0,
with either one dose of rAd26-S or one dose of rAd5-S and they were monitored for
28 days. In Phase II study, 20 volunteers were primed with rAd26-S, followed with
booster vaccinations with one dose of rAd5-S on day 21. Both frozen and
lyophilized vaccine formulations were safe, well-tolerated and elicited
RBD-specific IgG as well as neutralizing antibodies. Side effects were mild to
moderate (injection site pain, fever, headache, myalgia) but no serious adverse
events were reported [29]. On day 42, neutralizing antibody responses were
detected in all 40 participants in the Phase II trial with GMT levels of 49.25
elicited by the frozen formulation compared to 45.95 with the lyophilized
formulation. A seroconversion rate of 100% was achieved after the second dose.
The antibody responses in vaccinated volunteers were significantly higher than
antibody levels observed in convalescent SARS-CoV-2 patients. CD4+ and CD8+ T
cell responses occurred in 100% of participants within 28 days of vaccination
and increased IFN-
A Phase III trial of Sputnik V vaccine was conducted in Russia involving 21,977 participants aged 18 years or older. A majority of the participants (16,501) were vaccinated with two doses of Sputnik V vaccine while the placebo group only comprised 4476 participants. Interim analysis of Phase III trial showed 91.6% efficacy against COVID-19 and good tolerability was reported in a large cohort (NCT04530396) [40]. The Gam-COVID-Vac (Sputnik V) vaccine became the first coronavirus vaccine approved for use in Russia after its registration on August 11, 2020, ahead of completion of Phase III trials.
Ad26.COV2.S is a replication-deficient recombinant adenovirus type 26 vector expressing the stabilized full-length pre-fusion spike (S) protein of SARS-CoV-2 and was developed by Janssen Pharmaceutical company of the Johnson and Johnson (J&J) group.
Phase I/IIa randomized, double-blinded, placebo-controlled clinical study was
conducted to assess the safety, reactogenicity and immunogenicity of the
Ad26.COV2.S vaccine in adults 18–55 years (n = 402) and those
Vaccine safety and reactogenicity were evaluated in both younger (aged 18–55)
and elderly cohorts (
Novavax NVX-CoV2373 vaccine is a recombinant SARS-CoV-2 subunit vaccine containing the full-length spike (S) glycoprotein stabilized in the prefusion conformation and Matrix-M1 adjuvant.
A phase 1/2 randomized, placebo-controlled trial for NVX-CoV2373 was conducted
with 131 healthy adults (18–59 years of age) to evaluate the safety and
immunogenicity of the rSARS-CoV-2 nanoparticle vaccine. Participants (n = 83)
were administered with 2 doses at 5
The two dose regiments of 5
Overall, individuals inoculated with the first dose of NVX-CoV2373 with
Matrix-M1 adjuvant achieved neutralizing antibody levels similar to SARS-CoV-2
symptomatic patients. A second dose boosted the immunity conferred, causing the
GMEU levels to rise to similar levels as convalescent sera from patients
hospitalized with SARS-COV-2. Additionally, the dose sparing effect of Matrix-M1
was demonstrated based on similar neutralizing antibody levels in both groups
receiving the 5
After the first vaccination, reactogenicity in the majority of the participants
was mild or absent. The most common severe symptoms reported were headache,
fatigue and malaise [31]. Press release from the UK Phase III trial on 28th
January 2021 reported an efficacy of 89.3% in over 20,000 participants (18–84
years of age with 27% over the age of 65%) (NCT04611802). As it is stable at 2
The emergence and rapid spread of the SARS-CoV-2 virus have fast-tracked the process of vaccine development. As of May 2021, vaccines such as BNT162b2 mRNA vaccine, mRNA-1273 vaccine, adenovirus vectored vaccine ChAdOx1 nCov-19 (AZD1222) and an inactivated vaccine CoronaVac from Sinovac have been granted emergency use authorization from WHO and respective government authorities worldwide. FDA has approved the use of BNT162b2, mRNA-1273 and Ad26.COV2.S but not ChAdOx1 nCoV-19 (AZD1222), although the latter has been authorized for use by European Medicines Agency (EMA).
Immune responses vary with different vaccine platforms. mRNA, inactivated and subunit protein-based vaccines were reported to require two doses to achieve protection efficacy while adenovirus vectored vaccines such as the Ad5-nCoV and Ad26.COV2.S vaccines have been shown to evoke sufficient immune responses after a single dose of vaccination.
The spike (S) protein of SARS-CoV has been shown to play a crucial role in viral attachment and entry into host cells. The RBD in the SARS-CoV-2 spike protein was evaluated to be immunodominant and accounted for 90% of neutralizing activities [57]. Functional neutralizing antibodies specific for SARS-CoV-2 are important for viral neutralization and clearance. The lack of standardized GMT values to compare different efficacy studies and the use of different immunoassays by different vaccine developers as well as differences in dosages and schedules of administration, make it difficult to compare the efficacy of SARS-CoV-2 vaccine candidates that were in Phase III clinical trials. NVX-CoV2373 S protein vaccine was reported to elicit the highest neutralizing antibody titers, followed by the Ad26.COV2.S vaccine and the mRNA-1273 vaccine. The ChAdOx1 nCoV-19 (AZD1222) vaccine, BNT162b2 mRNA vaccine, BBIBP-CorV and New Crown inactivated vaccines produced neutralizing antibodies in the medium range. Lower neutralizing antibody GMTs were reported for the Sputnik V, CoronaVac and Ad5-nCoV.S vaccines. The less immunogenic vaccines might still elicit sufficient immunity to confer protection, but the protective role of antibody-mediated humoral responses against SARS-CoV-2 is still unknown as the correlates of protection have not been established [58]. Ibarrondo et al. [59] (2020) reported that there was a rapid decay of anti-SARS-CoV-2 antibodies within 2–4 months post-infection in mild COVID-19 patients. The mRNA-based Moderna vaccine was shown to elicit antibodies that lasted for at least 6 months [60]. Thus, vaccination might promote persistence of humoral response for a longer period compared to natural infection. However, the persistence of SARS-CoV-2 neutralizing antibodies after vaccination with other vaccine candidates is still unknown. The levels of humoral response required to confer protection are unknown as the concentrations of neutralizing antibodies have not been shown to correlate with COVID-19 severity. Strong neutralizing antibody responses have been reported in patients with severe COVID-19 infection and low antibody responses were observed in asymptomatic or patients with mild infection [61]. Thus, current knowledge suggested that in addition to humoral responses, cellular immune responses could play an important role in preventing SARS-CoV-2 infection. Studies of neutralizing antibody titers, memory B and T cells to SARS-CoV-2 will be important for understanding the durability and types of protective immunity against SARS-CoV-2 infection.
The spike protein is the antigen used in most of the current SARS-CoV2 vaccines.
However, spike protein is subjected to a relatively high rate of mutations. The
vaccines focusing on the spike protein might not be effective or have reduced
protection against SARS-CoV-2 variants such as B.1.1.7 and B.1.351 that carried
spike (S)-protein mutations [62]. CD4+ T cell responses have been reported to be
mostly directed against the S, M, and N proteins and partially against nsp3,
nsp4, and ORF8 whilst CD8+ T cell responses were directed against immunogenic
peptides not only from the S protein but also from M, and partially from the
nsp3, nsp6 and ORF3a [63]. Peng et al. [64] (2020) identified six
immunodominant T cell epitopes (3 from S protein, 2 from M protein and 1 from N
protein) which were recognized by sera from UK COVID-19 convalescent patients.
Thus, the conserved regions from M and N proteins can be included as target
antigens in future vaccines to stimulate the response of effector T cells against
emerging SARS-CoV-2 variants. With the exception of inactivated vaccines, all
vaccines currently in Phase III have shown the ability to elicit potent Th1
responses. It is characterized by the secretions of IFN-
Nainu et al. [65] (2020) reported that reinfection with SARS-CoV-2 is
possible in humans and most of the reinfection cases were reported from China.
Recent vaccine breakthrough infections with SARS-CoV-2 variants were also
reported in two patients who were fully vaccinated with BNT162b2 or mRNA-1273 at
least 2 weeks prior to re-infection in the USA [66]. The total CD4+ and CD8+
T-cells were found to be substantially reduced in COVID-19 patients, particularly
those who needed intensive care. The percentages of PD-1+CD8+, CD4+ T-cells and
Tim-3+CD4+ T-cells in ICU patients with COVID-19 disease were significantly
higher, implying that SARS-CoV-2 could lead to dysfunctional of T cells in
COVID-19 patients [67]. Moreover, decreased quantity or quality of B cells or
memory T cells might also dampen the immune responses in patients with
reinfections. Patients with lymphopenia could lead to suboptimal production of
neutralizing antibodies and reduced functional activities of effector T cells,
leading to increased susceptibility to SARS-CoV-2 reinfection. In addition,
elevated levels of pro-inflammatory cytokines might contribute to lymphocyte
killing in COVID-19 patients [68]. Increased pro-inflammatory cytokine levels
such as IL-6, IL-10, and TNF-
In contrast to inactivated vaccines, only the cellular immune responses for BNT162b2, mRNA-1273, Ad5-nCoV, ChAdOx1 nCoV-19 (AZD1222), Sputnik V, Ad26.COV2.S and NVX-CoV2373 have been characterized. T cell immunity might contribute to longer-term immunogenicity against SARS-CoV-2 instead of the neutralizing antibodies which were determined for the current COVID-19 vaccines. Together with the emergence of SARS-CoV-2 variants, this might necessitate the search for highly conserved B and T cell epitopes to be incorporated into a “universal vaccine” which can confer broad protection over a longer-term. The “universal vaccine” could be used as a pre-pandemic vaccine to prevent re-infection by variants or infection from other coronavirus strains capable of causing pandemics in the future.
The inactivated vaccine CoronaVac, New Crown COVID-19 and NVX-CoV2373 are the
only vaccines that have not been assessed for their efficacy and safety in the
elderly
As currently approved COVID-19 vaccines contain no live viruses, the risk of COVID-19 vaccine is low in pregnant and lactating women. CDC has indicated no significant differences in safety profiles postvaccination in pregnant versus non-pregnant women from 16 to 54 years old who receive mRNA vaccines [72]. Both Moderna mRNA-1273 and Pfizer BNT162b2 vaccines generated similar immunogenicity and reactogenicity profiles in pregnant and lactating women which were comparable to non-pregnant women. The antibodies produced by the mRNA vaccine were present in infant cord blood and breastmilk samples, suggesting that vaccination could confer robust maternal and neonatal humoral immunity [73]. Cross-reactive antibody and T cell responses were evaluated against SARS-CoV-2 B.1.1.7 and B.1.351 variants post-vaccination. The neutralizing antibody titers in nonpregnant, pregnant, and lactating women were reduced against the B.1.1.7 variant (3.5-fold) and B.1.351 variant (6-fold) when compared to the SARS-CoV-2-USA-WA1/2020 Wuhan strain [74].
Pfizer BNT162b2 vaccine was shown to have lower vaccine effectiveness for those with chronic comorbidities including high blood pressure, COPD, immunosuppression and type-2 diabetes [75, 76]. It is known that comorbidities are risk factors for severe COVID-19 outcomes. As a preventive measure, COVID-19 vaccination is most needed for those more vulnerable individuals which could reduce the mortality rate of those with underlying diseases. Antibody responses were markedly diminished after the first immunization in cancer patients but often improve after the second vaccination of BNT162b2 [77]. A recent study found that 90% of cancer patients exhibited sufficient antibody response to two doses of the BNT162b2 vaccination, despite having significantly lower antibody titers than healthy controls [78]. These observations supported vaccinations would reduce the likelihood of severe COVID-19 in cancer patients. The reactogenicity, antibody enhancement effects (ADE), VAERD, protection conferred by neutralizing antibodies and T cells will need to be monitored over a longer-term period of more than 2 years after vaccination in Phase IV trials. ChAdOx1 nCoV-19 (AZD1222) vaccine was associated with blood clots including rare cases of cerebral venous sinus thrombosis (CVST) and disseminated intravascular coagulation (DIC). European Medicines Agency (EMA) concluded that ChAdOx1 nCoV-19 (AZD1222) vaccine is safe as the overall risk of these blood clots is extremely rare with 25 cases in 20 million who received the vaccine in the United Kingdom [79]. Despite adverse effects, the risk of COVID-19 infections were higher than the danger posed by blood clots, hence it is still acceptable as an effective vaccine in many countries.
In view of the emergence of new SARS-CoV-2 variants, the immunogenicity and efficacy of the current vaccines that have been approved for emergency use will need to be further evaluated against these newly evolved variants. Convalescent plasma showed no significant changes in neutralizing activities against B.1.1.7 but the reduction against B.1.351 was significant [62]. Sera from vaccinated individuals with BNT162b2 had approximately two-third lower neutralizing activities against the B.1.351 variant compared to the Wuhan SARS-CoV-2 isolate [80]. Neutralizing activity elicited by mRNA-1273 vaccine against the spike protein of B.1.351 variants was reported to be 6-fold lower than the original Wuhan-Hu-1 strain [81]. However, the antibodies might still provide sufficient protection against COVID-19. Decreased efficacy of NVX-CoV2373, Ad26.COV2.S and ChAdOx1 nCoV-19 (AZD1222) vaccines against B.1.351 had also been reported. Novavax NVX-CoV2373 vaccine efficacy was 89.3% against the UK variant but was only 60% effective against the South African variant [56]. Ad26.COV2.S vaccine was 66% effective in Latin America and only achieved 57% efficacy in South Africa [82]. The efficacy of ChAdOx1 nCoV-19 (AZD1222) was 70% in the UK and Brazil but was reported to be only 22% against mild to moderate COVID-19 infections in South Africa [83]. Pfizer BNT162b2 and ChAdOx1 nCoV-19 (AZD1222) vaccine was found to be highly effective against Indian variant B.1.617.2 at 88% and 60%, respectively [84]. Neutralizing activity in the ChAdOx1 nCoV-19 (AZD1222) vaccine-elicited serum was 9-fold lower against the B.1.351 variant than the UK strain [85]. Since the current vaccines have been reported to have lower efficacies against the South Africa variants (B.1.351 lineage) [62], there may be a need to construct new vaccines which include novel mRNA or proteins (recombinant protein subunit) of new variants as boosters in subsequent vaccinations.
Real-world evidence is provided by the usage and post-market safety or adverse events being reported for current vaccines. This data can be generated from a large cohort of participants in Phase IV clinical trials and is expected to strengthen the evidence gathered relating to the efficacy of a vaccine. The study of approximately 99% of Scotland’s population (5.4 million people) provided reassurance that the Oxford-AstraZeneca ChAdOx1 nCoV-19 (AZD1222) and Pfizer BNT162b2 vaccines could significantly reduce COVID-19 hospitalizations and fatalities among the elderly after the first dose [86]. Real-world evidence reported that the incidence of COVID-19 was dramatically lowered in individuals who were fully vaccinated with the Pfizer BNT162b2 vaccine. The likelihood of contracting and developing COVID-19 was 44 times more for individuals who were not vaccinated while the chances of mortality were likely to be 29 times more than vaccinated individuals. This confirmed the higher level of effective protection with BNT162b2 vaccine. BNT162b2 and ChAdOx1 nCoV-19 (AZD1222) vaccines had demonstrated 91% and 88% reduction, respectively in hospitalizations after the first dose based on 1.33 million COVID-19 vaccinations administered in Scotland, UK. The use of ChAdOx1 nCoV-19 (AZD1222) was supported in older individuals as the majority of those receiving this vaccine were over 80 years old and the effects of the vaccine were observed to be comparable across all age groups [87].
Some of the current vaccines have demonstrated
In addition to safety and efficacy, other factors including cost of production,
ease of distribution, storage stability and long-term immunity should be
monitored. All the vaccines currently in Phase III evaluations were administered
intramuscularly. However, several intranasal vaccine formulations which can be
easily administered are currently being investigated [90, 91] and would be
beneficial as mucosal immunity is known to offer the first line of defense
against the virus. The secretion of mucosal IgA in the upper respiratory tract
during initial contact with the SARS-CoV-2 virus could contribute to early
protection against COVID-19 infection. Several of the vaccine candidates are
facing distribution problems, especially in underdeveloped and developing
countries as they have to be stored at ultra-cold temperatures. The BNT162b2 mRNA
vaccine requires storage at –70
HXL, AAAY, and SDJ wrote the manuscript. HXL prepared the tables. MA reviewed the manuscript and acquired funding for the article processing charge. SP reviewed and edited the manuscript. CLP supervised, edited and reviewed the manuscript.
Not applicable.
We would like to thank the Director General of Health Malaysia for his permission to publish this article.
This study was funded by Individual Research Grants 2021 (GRTIN-IRG-15-2021 and GRTIN-IRG-51-2021) to Chit Laa Poh and Hui Xuan Lim from the Centre for Virus and Vaccine Research (CVVR), School of Medical and Life Sciences, Sunway University.
The authors declare no conflict of interest.