Coronavirus disease 2019 (COVID-19) outbreak was first reported in Wuhan, China in December 2019, and was found to be caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel pleomorphic, positive-stranded RNA virus belonging to the Coronaviridae family. Quickly, it has become a global pandemic, infecting more than 176 million people and causing the death of more than 3.8 million individuals, that we are yet to recover from. Thus, an ongoing quest is being carried out for prophylaxis/therapy to prevent the transition from infection into serious forms of COVID-19.
Coronavirus disease 2019 (COVID-19) outbreak was first reported in Wuhan, China in December 2019, and was found to be caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel pleomorphic, positive-stranded RNA virus belonging to the Coronaviridae family. Quickly, it has become a global pandemic, infecting more than 176 million people and causing the death of more than 3.8 million individuals, that we are yet to recover from. Thus, an ongoing quest is being carried out for prophylaxis/therapy to prevent the transition from infection into serious forms of COVID-19 . Though measures like physical distancing, use of masks, frequent sterilization, repurposing of existing drugs, etc. are being undertaken, the development of herd immunity through vaccination seems to be the most instrumental measure.
Many therapeutic strategies which can prove useful in the management of COVID-19 disease are underway, such as blocking the virus from binding cell receptors, preventing synthesis and replication of viral RNA, restoring innate immunity, modulating specific receptors/enzymes of the host, etc. . However, amongst all such strategies to control the pandemic, the role of vaccines in preventing coronavirus (CoV) disease has been regarded as the most promising approach. The viral genome encodes several non-structural and structural proteins which include the spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins, which may play potentially instrumental roles to develop antigenic responses against the virus .
Scientists worldwide are in a race to develop safe and efficacious vaccine candidates against SARS-CoV-2 to curb the pandemic of COVID-19. Overwhelming attention has been paid to the S protein of the virus. The S protein makes up the studs outside the virus and is responsible for viral anchoring onto human cells through interaction with angiotensin-converting enzyme 2 (ACE2) receptors . Hence, a vaccine expressing the S protein should induce a protective immune response without exposure to the whole virus in killed or attenuated form, i.e., the S protein itself is capable enough to act as the target antigen. Newer platforms use only the genetic material coding for S protein. Viral vectors with altered genetic payload (weakened viruses carrying sequences for the antigenic S protein) are also among the frontrunners in the race. Previously none of the adenovirus vectors, DNA vaccines, and mRNA vaccines had been approved by USFDA but the current pandemic has changed the trend. Other candidates in the race for vaccines include protein subunit vaccines and whole virus vaccines, some of which have displayed very promising results.
As of 28 October 2021, 49.10% of the global population has received at least one dose of COVID-19 vaccine, out of which 38.05% have been fully vaccinated . Perturbations have been raised for the vaccines especially regarding their efficacy and the possibility of SARS-CoV-2 reinfection after being vaccinated. Mutation of an RNA virus is a matter of grave concern as it gives rise to newer strains, posing apprehensions that a vaccine developed for one strain might not be effective against a mutated strain. So far, several variants, such as B.1.1.7 (alpha, originated in the UK), B.1.351 (beta, originated in South Africa), P.1 (gamma, originated in Brazil), and B.1.617.2 (delta, originating from India) have been identified as major concerns . These new mutants can spread faster, which raises the question of whether they may reduce the effectiveness of approved vaccines. World Health Organization (WHO) categorized variants C.37 (lambda, originated in Peru) and B.1.621 (mu, originated in Colombia) are of interest in this context . Several other variants (B.1.466.2, B.1.525, B.1.526, B.1.617.1, B.1.619, B.1.620, B.1.630, B.1.1.318, C.36.3, R1, etc.) are still under monitoring . In this review, we provided insights into the epidemiology, mechanism of action, and propensity for reinfection with CoV for the different vaccines administered worldwide.
2. Vaccines Approved for Public Use
Within a year of the emergence of novel CoV, vaccines are being deployed in countries, giving faith to our ability to fight the COVID-19 pandemic. The goal of developing an effective vaccine against CoV has fetched huge investments from multiple governments and non-government agencies across the globe. During Phase I, small groups of people receive the candidates under clinical trial. In Phase II, the scope is expanded, and vaccine candidates are administered to people who have characteristics (such as age and physical health) similar to those for whom the new vaccine is intended. In Phase III, the vaccines are given to thousands of people in a multicentric approach and tested for their efficacy and safety. After approval, post-marketing surveillance continues as the fourth phase. Regulatory authorities continue to ensure safety through regular/periodic monitoring. Currently, we are on the verge of a very critical step of immunization of the majority of the global population through approved vaccine products. To date, all the approved vaccines belong to either of the five types i.e., mRNA vaccine, viral vector vaccine, protein subunit vaccine, inactivated virus, and DNA vaccine (Figure 1).
Figure 1. Distribution of approved vaccines based on vaccine types. Recombinant viral vector vaccines dominate the list followed by inactivated vaccines, mRNA vaccines, protein subunit vaccine and DNA vaccine.
2.1. Vaccines Approved by WHO for Global Application
WHO, in collaboration with other agencies, is aiming to work with vaccine manufacturers to offer low-cost vaccines to countries under the COVAX initiative. So far, WHO has approved six vaccines against COVID-19 (Table 1).
Table 1. A summary table of the vaccines approved by WHO.
(ChAdOx1nCoV-19, AZD1222) (University of Oxford, Oxford, UK)
targeted towards S protein
|Modified Chimpanzee Adenovirus ChAdOx1
||2 doses 8 to 12 weeks apart, i.m.
||2 doses 21 to 28 days apart, i.m.
||Johnson and Johnson (Ad26.COV2.S, Janssen)
||S protein of SARS-CoV-2 WA1/2020 strain
||Recombinant, replication incompetent adenovirus Ad26
||Single dose, i.m.
||2 doses, 4 to 6 weeks apart, i.m.
||Inactivated virus (2019-CoV)
||Inactivated virus +
|2 doses, 3–4 weeks apart, i.m.
||Inactivated virus +
|2 doses, 2–4 weeks apart, i.m.
2.1.1. Pfizer-BioNTech (mRNA Vaccine)
This is the first COVID-19 vaccine granted by WHO on 31 December 2020. This is an mRNA-based vaccine developed collaboratively by three pharmaceutical companies of Germany, USA, and China. The vaccine BNT162b2 is composed of nucleoside-modified mRNA (4284 nucleotides long sequence) encoding a mutated form of the full-length S protein of SARS-CoV-2 delivered in the form of lipid nanoparticles encapsulating the nucleic acid. The vaccine is a suspension for intramuscular injection administered as a series of two doses (0.3 mL each) 21 days apart each dose consisting of 30 μg mRNA vaccine embedded in lipid nanoparticles. Comirnaty in the USA and Pfizer-BioNTech COVID-19 vaccine in Europe contain the same formulation, and thus can be used interchangeably. The mRNA BNT162 codes for the RBD of S protein of SARS-CoV-2 besides including T4 fibritin-derived trimerization domain to elicit an immune response. The RNA sequence consists of a 5′ cap, a 48-base signal peptide, and two proline substitutions, K986P and V987P, allowing the spike to adopt a prefusion-stabilized conformation reducing the membrane fusion ability, increasing expression, and stimulating neutralizing antibodies. The 2P proline substitutions in the S protein were originally developed at the University of Texas at Austin, TX, USA for a vaccine against camel–flu, predominant in the Middle East. WHO recommends a two-dose schedule of BNT162b2 three to four weeks apart. The vaccine BNT162b2 (Comirnaty) has demonstrated 95% efficacy against symptomatic SARS-CoV-2 infection 
. In some countries, BNT162b2 is recommended for minors (≥12 years) also. Lustig and colleagues 
highlighted the requirement of the timely administration of the second dose, particularly in the elderly and immunosuppressed population. An Italian survey on anti-SARS-CoV-2 IgA response in baseline seropositive and seronegative individuals receiving BNT162b2 suggested the possibility of considering delaying/dropping the second dose of the vaccine in baseline seropositive individuals 
. However, further detailed study is required to conclude anything regarding this concern. In a press release dated 8 July 2021, Pfizer-BioNTech has ignited the possibility of a third booster dose of the vaccine 
. In line with most of the pre-existing vaccines, the efficacy of BNT162b2 has been found to decrease with the increasing age of the recipient 
2.1.2. Astrazeneca/University of Oxford (Viral Vector Vaccine)
The vaccine prepared by Oxford-AstraZeneca is available in the market as Covishield or Vaxzevria. In February 2021, WHO recommended the use of this vaccine for all adults. It is currently approved in more than 130 countries. It is a monovalent vaccine that consists of a chimpanzee adenovirus DNA vector i.e., a recombinant and replication-deficient (ChAdOx1) vector, and encodes the S glycoprotein of SARS-CoV-2 
. The non-replicating viral vector vaccine is currently designated as AZD1222. L-Histidine analogs are also present in the formulation. The vaccine expresses SARS-CoV-2 S immunogen in a trimeric pre-fusion conformation; to stabilize the expressed S-protein in the pre-fusion conformation the code sequence was not modified in the pre-fusion conformation 
. Two separate doses of 0.5 mL each are provided in the ChAdOx1nCoV-19 vaccination course. After the first dose, the second dose should be given after 4–12 weeks 
. Persons who receive the first dose of this vaccine should receive the second vaccine dose to complete the course of vaccination. Each dose of this vaccine consists of more than 2.5 × 108
infectious units of ChAdOx1-S 
. The vaccine is given in the form of suspension for injection through intramuscular injection. According to a review of findings on the dosing interval of the ChAdOx1nCoV-19 vaccine, it has been found that the most important factor for vaccine efficacy is the dosing interval, and not the dosing level 
. This is consistent with previous research which supports greater effectiveness over a longer period of time in other vaccines such as those for influenza and Ebola 
. After a gap of 12 or more weeks between the first and second dose, the study found that vaccine efficacy reached 82.4% (95% CI 62.7% to 91.7%). The efficacy was only 54.9% when the two doses were given less than six weeks apart 
According to a report published in British Medical Journal, after a study of 2000 healthy and young volunteer workers, the rollout of Oxford-AstraZeneca COVID-19 vaccine in South Africa was stopped, reporting that it did not protect from mild and moderate disease owing to the new variant (501Y.V2) that emerged there 
. In a cohort study in the UK, both BNT162b2 and ChAdOx1nCoV-19 have been found to demonstrate comparable efficacies against the B.1.1.7 variant of SARS-CoV-2 
2.1.3. Johnson and Johnson (Viral Vector Vaccine)
Janssen is a non-replicating viral vector vaccine (Ad26.COV2.S) to fight the menace of COVID-19. Ad26.COV2.S is a recombinant, replication-incompetent adenovirus serotype 26 vector encoding a full-length, stabilized S protein of SARS-CoV-2 WA1/2020 strain. It uses the same systems AdVac and PER.C6 earlier successfully used for developing the Ebola vaccine by the same sponsor company. The vaccine is recommended as a single intramuscular injection of 0.5 mL to adults delivering 5 × 1010
viral particles. Due to insufficient data on vaccine co-administration, a minimum gap of 14 days is recommended with any other kind of vaccination for other disorders. According to an update by WHO on 25 June 2021, Ad26.COV2.S is safe and effective at protecting people from extremely serious risks of COVID-19, including death, hospitalization, and severe disease. 28 days after inoculation Ad26.CoV2.S displayed an efficacy of 85.4% against severe disease and 93.1% against hospitalization 
. A single dose of Ad26.COV2.S demonstrated the efficacy of 66.9% against symptomatic moderate and severe SARS-CoV-2 infection in clinical trials 
. In search of design elements for CoV S protein, replacing Ad26 vector encoding a membrane-bound stabilized S protein with a wild-type signal peptide (Ad26.COV2.S) elicited potent neutralizing humoral immunity and cellular immunity that was polarized towards Th1 IFN-γ in mice 
. In a comparative study by Mukhopadhyay and colleagues, Ad26.COV2.S ranked second to the rapid elicitation of immunogenicity and protective efficiency in non-human primates among six vaccine candidates based on data available until October 2020 
. During preclinical developments, Ad26.COV2.S was found to protect Rhesus macaques
monkeys from SARS-CoV-2 after single immunization 
. Recently, a G614 spike SARS-CoV-2 virus variant Syrian hamster model has proven the success of Ad26.COV2.S in preventing COVID-19 and associated LRT infections 
. A second dose of the vaccine to Syrian hamsters was found to be beneficial for the G614 spike SARS-CoV-2 variant with optimum immunogenicity without vaccine-associated enhanced respiratory diseases. Low dose Ad26.COV2.S has been demonstrated to impart protection of SARS-CoV-2 in Rhesus macaques 
2.1.4. Moderna (mRNA Vaccine)
This vaccine is an mRNA vaccine (mRNA-1273). The vaccine comprises lipid nanoparticle-encapsulated, nucleoside-modified mRNA encoding the stabilized prefusion S glycoprotein S-2P of SARS-CoV-2 
. The mRNA encodes S protein in such a way that when the vaccine is injected, immune cells process the mRNA, and the subsequent proteins would be marked for destruction 
. The dosage regimen includes two doses of 0.5 mL (100 μg lipid nanoparticle encapsulated mRNA) each to be administered through the intramuscular route 28–42 days apart. The vaccine is about 94.1% effective against COVID-19, starting 14 days after the first dose 
. Storage at −20 °C is recommended for the long term; however, after thawing it is stable at cold conditions for up to 30 days thus making it very suitable for widespread community use 
. Corbett et al. noticed robust SARS-Co-2 neutralizing activity with mRNA-1273 in non-human primates without any pathogenic change in the respiratory system 
. It has been observed that mRNA-1273 induces both potent neutralizing antibodies and CD8+ T cell responses for protection against SARS-CoV-2 infection in the lungs and noses of mice without imparting any immunopathological manifestation 
. In addition to that, a high pseudovirus neutralizing antibody response was noticed in mice expressing a mutated form of the S protein, D614G 
2.1.5. Sinopharm (Inactivated Virus Vaccine)
This is an inactivated novel CoV (19-nCoV-CDC-Tan-HBO2 strain, optimal replication, highest virus yield in Vero cell) vaccine (BBIBP-CorV/verocell) developed in China against SARS-CoV-2 to stimulate the immune system. β-propionolactone bonded with the genes of virus in such a manner that the virus cannot replicate, but its S proteins remain intact. Two doses (3–4 weeks apart) of 0.5 mL (6.5 U inactivated SARS-CoV-2 antigen + 0.225 mg aluminium hydroxide adjuvant) through intramuscular route have been recommended by WHO. Vaccine efficacy was found to be 79% against both symptomatic COVID-19 infection (14th day onwards after second dose) and COVID-19-associated hospitalization 
. Phase III clinical trial data (NCT04984408) are insufficient to determine vaccine efficacy against persons with comorbidities 
. It can be stored under cold temperature conditions making it suitable for widespread community use. Sinopharm, CoronaVac, and Covaxin use similar technologies to prepare inactivated virus vaccines against COVID-19 
. During animal experiments, 2 doses (2 μg each) of BBIBP-CorV successfully induced high titer values of neutralizing antibodies against SARS-CoV-2 in mice, rats, guinea pigs, rabbits, Cynomolgus monkeys, and Rhesus monkeys 
2.1.6. Sinovac Biotech (Inactivated Virus Vaccine)
CoronaVac (formerly PiCoVacc) is an inactivated virus (formalin treated) vaccine using alum as an adjuvant, developed by Sinovac Biotech, Beijing, China. CoronaVac is recommended in 2 doses of 0.5 mL (600 SU SARS-CoV-2 antigen) each intramuscular injection 2–4 weeks apart. CoronaVac has been claimed to be 51% effective against symptomatic COVID-19 infection and 100% effective against severe COVID-19 infection and hospitalization, according to a phase III clinical trial in Brazil, from day 14 onwards after the second dose 
. In a phase I/II study in China involving 144 and 600 participants, respectively, in phase I and phase II between 16 April 2020 and 5 May 2020, 3 μg dose had been recommended for further trials based on safety, immunogenicity, and production capacity 
. Pain at the injection site is the most reported adverse effect post-vaccination. Though it is recommended for the adult population, only limited safety data for individuals ≥60 years is currently available. WHO granted an emergency use listing for CoronaVac on 1 June 2021.
2.2. Vaccines Approved Regionally
Many countries have approved one or more vaccines based on outcomes. Some have been approved by WHO later. Still, some vaccines are there, which have succeeded to satisfy the regulatory bodies of a few countries but are yet to obtain global acceptance.
2.2.1. Sputnik V (Viral Vector Vaccine)
Sputnik V (Formerly, Gam-COVID-Vac) is a recombinant adenovirus vaccine rAd26 and rAd5 developed in Russia. This adenovirus vaccine is the World’s first registered combination vector vaccine against COVID-19, the ‘V’ standing for ‘Victory’ over COVID-19. Based on phase I and phase II clinical trial data only, it was approved for use in Russia in August 2020. According to an interim analysis published later, the efficacy of Sputnik V is 91.6% 
. It is to be administered through intramuscular injection in two doses, first dose rAd26 and after 21 days, second dose rAd5. Novel CoV gene encoding S protein is integrated with viral vector DNA. Thus, unmodified full-length S protein generates an antigenic response in the host. A cold chain of subzero temperature is not required for storage of the lyophilized powder which paves the way for easier community use. Sputnik Light is a single dose of rAd26 to be used as a third booster dose if needed after at least six months. Adenovirus 26 and adenovirus 5 are used as vectors for the expression of SARS-CoV-2 S protein. The heterologous recombinant adenovirus approach with two varying serotypes aims to overcome any pre-existing adenovirus immunity 
. Initially, Sputnik V has faced lots of criticism for unseemly haste with low transparency, but the outcome and interim analysis reports published in the Lancet have attempted to do away with the allegations of non-transparency 
. The Gamaleya Research Institute (Moscow, Russia) claimed that Sputnik V is more than 90% effective against the B.1.617.2 variant of CoV 
2.2.2. EpiVacCorona (Protein Subunit Vaccine)
EpivacVacCorona is a peptide vaccine developed in Russia. The vaccine comprises three synthetic peptides mimicking viral S protein. These peptides are conjugated to a carrier protein, a fusion product of viral nucleocapsid protein, and a bacterial maltose-binding site protein. The viral portion of the chimeric protein is responsible for immunization, aluminium hydroxide serves as an adjuvant. It is to be injected in two doses 21 to 28 days apart through the intramuscular route. Currently, it is approved for emergency use in Russia, Belarus, and Turkmenistan. Immunogenicity and protectivity of the peptide candidate were assessed in a preclinical study 
. EpiVacCorona was administered in two doses (260 μg each) 14 days apart to hamsters, ferrets, African green monkeys, and Rhesus macaques
monkeys. The vaccine was 100% successful to generate virus-specific antibodies in animals. In hamsters, dose-dependent immunogenicity was observed along with prevention from pneumonia, in ferrets, EpiVacCorona speeded up clearance of CoV from the upper respiratory tract (URT); COVID-associated pneumonia was prevented in non-human primates. Two clinical trials (NCT04780035 and NCT04527575) aiming to assess the tolerability, safety, immunogenicity, prevention efficacy, and reactogenicity of EpiVacCorona comprising of 3000 and 100 volunteers, respectively, are yet to post the results 
. Currently, the vaccine has been approved in Russia, Turkmenistan, and Belarus.
2.2.3. Bharat Biotech (Inactivated Virus Vaccine)
BBV152 (Covaxin) is a completely ineffective SARS-CoV-2 viral particle that contains the RNA surrounded by a protein shell, but the genetic material is chemically modified so that it cannot replicate 
. The vaccine consists of one of the two different adjuvants and a single inactivated whole SARS-CoV-2 virion. The adjuvant is either an aluminum hydroxide gel (Algel) or a novel TLR7/8 agonist (imidazoquinolinone) adsorbed Algel 
. A separate T-helper-cell 1 (Th1) antibody response with increased levels of SARS-CoV-2-specific IFN-γ and CD4 cells was further induced by the formulation containing the TLR7/8 agonist 
. The dosing regimen of Covaxin consists of two doses (6 μg whole virion inactivated antigen of NIV 2020-770 strain + adjuvant in each dose) given at a 28 days interval 
. Components of Covaxin include BBV152A, BBV152B, and BBV152C. In a study, immunogenicity of this inactivated virus vaccine formulated with both the adjuvants was determined in rabbits, mice, and rats using three concentrations (3, 6, and 9 μg) 
. The results show that BBV152 formulations produce significantly high antigen binding and neutralizing antibody titers at concentrations of 3 and 6 μg in all three species irrespective of adjuvants. Moreover, the vaccine maintains excellent safety profiles at 6 μg 
2.2.4. Cansino Biologics (Viral Vector Vaccine)
Convidicea (Ad5-nCoV), also known as PakVac is a recombinant vaccine against COVID-19 using adenovirus type 5 vector encoding SARS-CoV-2 S protein. Ad5-nCoV is based on replication-defective adenovirus type 5 as the vector to express the S protein of SARS-CoV-2. The vaccine has displayed an efficacy of 65.7% against moderate symptoms of COVID-19 and 91% efficacy to protect from severe disease 
. Comfortable storage conditions of 2-8oC and single dosing requirements make it a potentially popular vaccine candidate. During preclinical studies, Ad5-nCOV single dose was found to protect BALB/c mice completely from URT and LRT infection by mouse-adapted SARS-CoV-2 and to protect ferrets from URT infection by SARS-CoV-2 wild variant 
. A single-dose regimen comprising of 0.5 mL intramuscular solution (≥4 × 1010
viral particles) makes it a more convenient option than multidose alternatives. Currently, it is authorized for emergency use in 10 countries.
2.2.5. Zydus Cadila (Plasmid-DNA Vaccine)
The DNA plasmid-based COVID-19 vaccine, ZyCoV-D is the world’s first DNA vaccine to get the regulatory nod for use. It has been authorized for emergency use in India by CDSCO on 20 August 2021 for people aged ≥12 years. This is also the first needle-free vaccine (Tropis Pharma-jet-based delivery platform) approved globally. In an indigenous collaborative venture by Cadila Healthcare and Biotechnology Industry Research Assistance Council, India, the vaccine comprises a plasmid vector carrying genetic material encoding the S protein of SARS-CoV-2 to interfere with viral entry through membrane protein. The recombinant plasmid acts as a vector to carry the genetic material coding for S1 protein of CoV into the cell to generate an immune response 
. The plasmid enters the host cell nucleus as an episome without integrating into host DNA. Intradermal administration of three doses (0.2 mL each) is recommended on day 0, day 28, and day 56.
Plasmid DNA comes with the inherent advantage of elimination of possibility of vector-based immunity. On interim analysis of phase III trial data, Cadila Healthcare (Ahmedabad, India) announced the efficacy of ZyCoV-D to be 66.6% against symptomatic COVID-19 and 100.0% against moderate to severe disease 
. Manufacturers have also claimed that the vaccine is useful for individuals >12 years, making it an option for adolescents of India. The plasmid constructs have been transformed into Escherichia coli
to boost production 
. The immunogenic potential has been evaluated in mice, guinea pigs, and rabbits at different doses intradermally, while preclinical toxicology was studied in rats and rabbits 
. ZyCoV-D, in preclinical studies induced neutralizing antibody response along with Th-1 response and elevated interferon-γ levels. Yadav et al. evaluated the immunogenicity and protective efficacy of ZyCoV-D formulations at varying doses in Rhesus macaques 
. The vaccine at 2 mg dose successfully induced S1 specific IgG and neutralizing antibody titers, which increased gradually on the viral challenge for up to 2 weeks protecting from lung disease. Evaluation of nasal swab, throat swab, and bronchoalveolar fluid also confirmed viral clearance. Enhanced proliferation of lymphocytes and production of IL-5 and IL-6 were also evidenced. The signal peptide produced from plasmid genetic material includes RBD for ACE2 receptor to hinder viral entry into the host cell during future infections