INTRODUCTION:

Coronavirus disease 2019 (COVID-19) outbreak started in Wuhan, China when the people started with the symptoms of respiratory disorder. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which can be transmitted through respiratory droplets and human to human transmission. SARS-CoV-2 is a single-stranded RNA virus having a genome of 30 kilobases enclosed with structural proteins, non-structural proteins, and enzymes (1).

The onset of this disease has symptoms like fever, dry cough, fatigue, and difficulty in breathing. The nature of SARS-CoV-2 seems highly contagious as it also can be spread with asymptomatically infected individuals. Currently, a limited number of candidate vaccines have been approved due to the novelty of the virus. According to a report from WHO, as of 26 March 2021, there were around 267 candidate vaccines in development has been recorded and majority of candidate vaccines are still in early-stage in clinical trials. Currently, 25 candidate vaccines have entered Phase III and IV where this phase trial involved a massive number of people to evaluate the safety and efficacy of candidate vaccines (2). The main idea for vaccination is to initiate altered or weakened SARS-CoV-2 antigen to create primary immunity where it is the best and long-lasting solution for controlling the pandemic situation. Still, a few criteria should be considered where the benefits overweigh the drawbacks. For instance, the production of a vaccine should be achieved in a well-timed and efficient way to ensure it is an inexpensive as well as have high clinical response results with possibly low adverse effects on the patients.

Methods:

The study material was conducted through an online literature collection. The literature search was done based on inclusion criteria like articles should be published in English language only, published until April 2021 and have provided relevant information related to the candidate of COVID-19 vaccines. The literature search was conducted through established scientific search engines like Science Direct, PubMed, Google Scholar databases and related scientific platforms by using related keywords and terms. After data has been collected, a standardized Excel spreadsheet was used for data extraction. The spreadsheet was customized for the review process by categorized the details for instance the author, the title, year of publication, publication stage, and other related details. The spreadsheet was used to analyse the proven research articles to meet the specified criteria of data material. The selected research articles were classified for the review process by categorized the matching specified criteria related to studies such as safety and efficacy of candidate vaccines, mechanism of candidate vaccines, relevant clinical data, and studies of candidate vaccines. The review was constructed with the first draft of the report to summarize the important aspects of the research findings that related to the objective, data, and discussion that support research findings.

COVID-19 Vaccine Candidates:

CoronaVac:

CoronoVac is the first inactivated viral vaccine developed by Sinovac. This vaccine is formulated with the presence of aluminium hydroxide as adjuvant and produced by β-propiolactone-activation of the CN2 strain of SARS-CoV-2 of Wuhan strain. Findings from the preclinical study found that CoronaVac has a safe vaccine profile as in the rhesus macaques there was no enhanced infection disease or aggravation of immunopathological and displayed full protection against SARS-CoV-2 threat (3). From the first and second clinical trials in 2020, it showed CoronaVac had tolerable vaccine profile and stimulated humoral immunity against SARS-CoV-2 which they used for emergency use in China and proceed to the next phase that has been conducted in a few countries (4). A preprint of clinical trial in Phase III has been released for clinical trial of CoronaVac in Chile and from the findings, the antibody produced was equivalent to the previous Phase II trial reports in China which over 90% seroconversion. Even though the seroconversion rates are marginally lower in older participants, these outcomes still showed CoronaVac is a promising vaccine candidate as it possessed a protective vaccine profile in elder populations. The vaccine candidate has a safe profile as well as stimulates strong cellular immunity as it is considered enhanced the antibody titres against the S1-RBD along with the neutralising capacities, formed T cell against particular SARS-CoV-2 virus and secreted Th1 cytokines which demonstrated less possibility of enhanced disease following the next infection (5). The data displayed in Phase III studies shown that overall vaccine efficacy was 50.65% after two weeks in two vaccinations. The other clinical trial studies stated the outcome was 83.7% effective in the prevention of severe cases in Brazil and Turkey (6).

BBIBP-CorV:

BBIBP-CorV is developed by Sinopharm along with the Beijing Institute of Biotechnology. This vaccine was engineered by β-propiolactone mediated inactivation which consist of inactivates SARS-CoV-2, strain HB02 in aluminium hydroxide adjuvant. According to past study, the addition of adjuvants aids the secretion of inflammasome-derived IL-1βand IL-18 at a high level which leads to the stimulation of the proinflammatory mechanism of the immune system (7). Based on preclinical studies on non-human primates and other animal models like mice as well as guinea pigs, BBIBP-CorV stimulates the neutralising antibodies titres to a high level and gives the protection against SARS-CoV-2. Besides, BBIBP-CorV gives highly effective shielding against SARS-CoV-2 intratracheal threat in rhesus macaques and there was no antibody-dependent enhancement of infection spotted (8). In first clinical trial (ChiCTR2000032459), the immune response of the vaccine demonstrated the neutralising antibodies stimulated by BBIBP-CorV can neutralize multiple strains which indicate the promising vaccine candidate to provide cross-protection against other SARS-CoV-2 strains. Phase II clinical had different vaccination schedules with two doses of BBIBP-CorV to find out the suitable dose (9). The published findings stated that BBIBP-CorV vaccine at two doses of 4μg vaccine demonstrated favourable to achieve higher neutralising antibody titres than a single dose of either 4μg or 8μg. The outcome indicates that prime-boost vaccination is essential to reach more effective protection of the vaccine against SARS-CoV-2. In clinical study Phase III, it was conducted in multi-country like Argentina (NCT04560881), Bahrain, Jordan, Egypt, and United Arab Emirates (NCT04510207). World Health Organization has made a report on Sinopharm’s vaccine stated that the effectiveness shows 78.1% against COVID-19 in multi-country trial (10).

BBV152:

The developer for BBV152 is Bharat Biotech in India along with the Indian Council of Medical Research. This inactivated whole virus vaccine candidate known as Covaxin which is engineered by β-propiolactone inactivation of novel coronavirus of Indian strain. The presence of adjuvant in the vaccine formula has displayed significantly reduce viral loads in animal models infected with the SARS-CoV-2 virus in preclinical studies (11). In Phase I, healthy participants aged 18 to 55 years had participated in 11 hospitals throughout India and randomly allocated with different formulations (NCT04471519). From findings Ella et al. (2021), there were humoral and cellular immune responses detected in the participants who received the Algel-IMDG-based vaccines and there was a rise in the frequency of CD4+ INF-γ T cells in comparison to BBV152 with Algel which directed to Th1 bias. It was desirable to be biased to Th1 as Th2 would cause enhanced respiratory disease (12). According to the interim findings in clinical trial Phase II (NCT04471519), there was a significant rise in IFN-γ, IL-2, and TNF-α or called Th1-biased cytokines which indicated a strong cellular immune response. The BBV152 has been approved to be used as Emergency Use Authorization in India as the efficacy was displayed as more than 50%. The 6 µg of BBV152 with Algel-IMDG formulation was chosen to proceed to the next Phase III (NCT04641481) (13). In another study, 20 serum samples from the participant in Phase II were used to test against the unclassified cluster or called hcov-19/India/2020Q111 as well as UK-variant strain. The study emphasised the comparable neutralization activity of vaccinated sera against heterologous SARS-CoV-2 strain and UK-variant strain with equal efficiency (14). Based on Bharat Biotech news released, the vaccine demonstrated 81% interim efficacy in the prevention of COVID-19 without prior infection after the second dose (15).

mRNA-1273:

mRNA-1273 is developed by the National Institute of Allergy and Infectious Diseases (NIAID) together with Moderna in Cambridge. The mRNA-1273 was introduced into the host cell as well as uses the transcription and translation mechanism to make the viral antigen which then presented in T cell. Following that, it was identified unswervingly by B lymphocytes which lead to the instigation of an adaptive immune response against the S protein of the SARS-CoV-2 virus directly (16). In non-human primates, the study demonstrated this vaccine candidate is confirmed to stimulate strong S-specific antibodies and neutralising action. The mRNA-1273 produced higher ACE2 binding inhibition and neutralising activity as well as stronger responses of receptor-binding domain and N-terminal domain responses (17). From first clinical trial (NCT04283461) findings, it was demonstrated that this vaccine had an adequate safety and reactogenicity vaccine profile (18). In preliminary report, it was stated that the vaccine candidate produced high levels of receptor binding domain and neutralising antibodies in older adults. Findings from clinical trial II concluded the vaccine candidates elicited strong immune responses and favourable safety profile in all participants. The safety and reactogenicity profile was consistent with the first clinical trial. Generally, the findings provided the support of immunogenicity and safety of mRNA-1273 to be continued for the next phase (19). In clinical trial Phase III (NCT04470427) showed the vaccine profile, regimen and platform was proven to be favourable as there was no unexpected incidence were observed. It was concluded from the findings, the mRNA-1273 displayed 94.1% efficacy in the prevention of COVID-19 disease as well as its severe disease (20).

BNT162b:

The second mRNA-based vaccine is BNT162b or known as Comirnaty. German company BioNTech and pharmaceutical company Pfizer in the United States has registered two types of BNT162b, which are BNT162b1 and BNT162b2 but BNT1262b2 is more favourable. The encoding process of BNT162b2 is it modified two proline mutations to retain prefusion conformation by encoding the prefusion stabilized membrane-anchored full-length spike protein(21). A study was revealed BNT162b had given protection in rhesus macaques against the SARS-CoV-2 virus by preserving the lower respiratory tract from viral RNA as well as no signify of disease enhancement was found. It was reported that single immunisation of both types of BNT162b vaccine was administered during the study of BNT162b immunogenicity in mice model and displayed high dose level-dependent RBD and S1 binding serum IgG titres, which higher especially in BNT162b2. Furthermore, CD4+ T-cells in BNT162b2 produced high frequency in interleukin-2 (IL-2) whereas less in interleukin-4 (IL-4) which demonstrated favourable in Th1 response so, the theoretical risk of enhanced pulmonary condition during the following infection of the virus will be reduced (22). A study was performed to evaluate the vaccine profile of both BNT162b1 and BNT162b2 vaccines which both vaccines had produced identically great dose-dependent neutralising antibody titres against SARS-CoV-2 in the vaccinated subjects but BNT162b2 demonstrated with lower occurrence and severity of systemic reactions than BNT162b1 especially in the elder person group. It was hypothesized by Kondili and companions (2016) that the difference of RNA nucleotide components in both vaccines influenced the immune stimulatory action and reactogenicity profile (23,24). Following this, a clinical trial was performed solely for BNT162b2 vaccine due to less immunogenic reaction among participants in Argentina, Brazil, Germany, Turkey, South Africa, and the United States. BNT162b provided 95% protection and safe against COVID-19 with two-dose injection in the human population. It was concluded two-dose regime should be maintained to reach the maximum of protection against SARS-CoV-2 (25).

Ad5-nCoV-19:

This vaccine candidate is also known as Convidicea and it has been developed by Cansino Biologics with partnerships for instance Beijing Institute of Biotechnology and Academy of Military Medical Sciences. This vaccine candidate utilized the human adenovirus serotype 5 vector (Ad5) which facilitates in sending instruction that coordinates for full-length S protein of SARS-CoV-2 virus. The worrisome part is that Ad5 is one of the major serotypes in the human cell, which could lead to hinder robust immune response against antigen due to widespread pre-existing immunity in the host cell (26). However, a study by Tatsis and Ertl (2004) found that adenovirus-based vectors have been displayed to produce a powerful humoral and cellular immune response in non-human primates and humans after single vaccination (27). From the findings in clinical trial Phase I (NCT04313127, NCT04568811), the vaccine candidate was tolerable in all participants as well as exhibited humoral and T-cell responses promptly in most of the participants (28). There were two studies on Ad5 nCoV-19 vaccine (NCT04341389, NCT04566770) in Phase II vaccine trials and a published study report on the vaccine trial (NCT04341389) has been released. Findings from the report stated that the pre-existing immunity to Ad5 caused lower in particular antibody responses of the receptor-binding domain and neutralising antibody response. It was indicated that the age and pre-existing anti-Ad5 immunity of the subjects would also influence the safety and immunogenicity of the Ad5 nCoV-19 vaccine. Despite the pre-existing immunity problem, it was concluded in this report the vaccine candidate is safe and produces excellent immune responses in most of the subjects after the first vaccination (29). In Phase III clinical trial (NCT04526990), participants received single injection of Ad5 nCoV-19 vaccine that conducted throughout Argentina, Mexico, Pakistan, Russia, and Chile (30). The efficacy of the vaccine demonstrated 65.7% in prevention and 90.98% in terminating severe symptoms based on the interval analysis (31).

AZD1222/ ChAdOx1 nCoV-19:

This vaccine is based on ChAdOx1 chimpanzee adenovirus that has been developed by Astra Zeneca and in collaboration with the University of Oxford. A research found this vaccine comprised of replication-defective chimpanzee adenoviruses, encrypts SARS-CoV-2 full-length spike protein to produce strong spike-specific T-cell responses along with powerful humoral immune responses (32). The clinical trial Phase I (NCT04324606) displayed the antibodies against SARS-CoV-2 spike protein reached in 28 days and continued raised to 56 days in participants who received one dose of ChAdOx1 nCoV-19 while participants received two injections increased higher than one dose (33). Clinical trial Phase II and III were focused in vaccine profile including humoral and cellular immune responses of a single or double dose regimen (34). From findings, the vaccine candidate activated a particular antibody response to the spike glycoprotein and receptor-binding domain (RBD) of the COVID-19 virus after the initial dose in all vaccinees and booster effect was found only in participants who received dose two vaccines. Other than that, the strong humoral and cellular immunity acquired in the older group data supporting a few studies records that when reduce the immune function with age subsequently reduce the immune response to vaccines which is related to pre-existing immunity in this vaccine platform (35). Nonetheless, the outcomes also reliable which ChAdOx1 nCoV-19 vaccine has good immunogenicity against the virus in adults older than 50 years (36). A published study case on analysis of the vaccine profile in Brazil (COV003) and United Kingdom (COV002) showed its efficacy of 70.4% after two doses (37). In March 2021, the administration of the second dose was halted because five individuals had venous thrombosis and thrombocytopenia after vaccination (38). Greinacher and colleagues (2021) had made some investigations and concluded ChAdOx1 nCoV-19 may result in rare progress of immune thrombotic thrombocytopenia interceded by platelet-activating antibodies against platelet factor 4 (PF4) which analytically imitates autoimmune heparin-induced thrombocytopenia (39). Despite that, it was displayed in interim analysis which AZD1222 has an efficacy of 79% in the prevention of symptomatic infection and 100% efficacy against severe condition disease and hospitalization (40).

Ad26.CoV2-S/ JNJ-78436735:

This candidate vaccine has been developed by Janssen Pharmaceuticals Companies by using Ad26 vector where it targets the full length of S protein along with 2 proline substitution and 2 mutations at furin cleavage site (41). Rather than using the Ad5 serotype, the reason to choose the Ad26 serotype is due to low chances of exposure in pre-existing immunity against the vectors. Based on research by Mercado and colleagues (2020), the data from their research showed a single vaccination of Ad26 vector-based vaccines for COVID-19 virus produced powerful neutralising antibodies titres and support full or near-complete protection against COVID-19 virus challenge in rhesus macaques. This Ad26 vector encoding the prefusion stabilized S immunogen (S.PP) vaccine that produced Th-1 biased T cell responses which give animals with sub-protective neutralising antibodies titres and did not exhibit superior viral replication or clinical disease (42). Clinical trial Phase I and II (NCT04614948), was to compare between single-dose and two-dose regimens. The CD8+ T-cell displayed a strong immune response along with the CD4+ T cell detected in most of the participants (43). Ad26.COV2.S vaccine (NCT04505722) trial involved adults in Argentina, Brazil, Chile, United States, South Africa, Colombia, and Mexico. The efficacy was found to have 85% effective against COVID-19 and 77% against severe cases by vaccinated with single dose of Ad26.COV2.S vaccine (44). There was one incidence reported a patient with a case of cerebral venous sinus thrombosis along with thrombocytopenia after vaccinated. Even the component of Ad26.COV2.S vaccine and ChadOx1 nCoV-19 are different, both of them have similar cases happened and it has been described with a report by Muir and colleagues (2021) where this case might have related with adenovirus vector vaccine (45).

Sputnik V/Gam-COVID-Vac:

Sputnik V or known as Gam-COVID-Vac is a non-replicating vaccine that has been developed by Gamaleya Research Institute in Moscow, Acellena Contract Drug Research and Development along with the Health Ministry of the Russian Federation. At first, this vaccine has created controversial news as the approval was premature. It has been approved by the Russian Government instantaneously even before it started in Phase III trials and has no published outcome on previous early-stage trials. Despite everything, the phase III trial demonstrated a persistent defence effect in the participants. This vaccine used other techniques to enhance effectiveness by using heterologous recombinants of adenovirus 5 and adenovirus 26 vectors in expressing the spike protein of the SARS-CoV-2 virus. This is because adenoviral vectors might minimize the promotion of immune responses against vector constituents and production in response to attenuated antigen, so using two different vectors give potential robust and immune responses in a long period as well as it does not influence pre-existing immunity (46). Commonly, after vaccinated with an adenoviral vector, immune response would develop in target antigen and also vector protein which this protein would cause the case of pre-existing immunity. However, in the analysis of clinical trial Phase I and II, the development of humoral immunity to the S protein of the virus in vaccinees was not affected even though there was a development of neutralising antibodies after vaccination with rAd26 and rAd5. Furthermore, the serum sample of vaccinees displayed that the neutralising antibodies to rAd26 did not neutralize rAd5. So, utilization of heterologous prime-boost vaccination is one of the valuable strategies to surmount the formation of immunity to the viral vector part due to rAd26-S as priming and rAd5-s as boosting features. Findings found that both rAd26 and rAd5 vector-based vaccine has a good safety profile, well-tolerated and produced strong humoral as well as cellular immunity in participants (47). Based on Logunov and companions (2021), the outcome in clonical trial Phase III demonstrated the efficacy of vaccine candidate was 91.6% and well-tolerated in a large group.

INO-4800:

This most promising DNA vaccine candidate has been developed by INOVIO Pharmaceuticals that was created to enhance the sequence of S protein in the COVID-19 virus. This candidate vaccine distributes the boosted plasmids straight into the host by using INOVIO’s proprietary smart device known as CELLECTRA® which used a short electric pulse to open small pores in the cell reversibly to easier the entry of plasmid to stimulate immune responses. The preclinical studies demonstrated the vaccine candidate can stimulate functional blocking antibody responses to S protein of SARS-CoV-2 in animal models. It was demonstrated there was an effective immune response influenced by the presence of humoral and T cell responses (48). In United States clinical studies (NCT04336410) for Phase I and II, the investigators found this vaccine displayed excellent safety, immunogenic and tolerable by producing humoral and cellular immunity. This can be supported with evidence of the presence of antigen-specific CD4+ and CD8+ T-cells showing the characteristics of differentiation into central and effector memory cells indicated persistence cellular immunity formed. Moreover, the cellular immunity was achieved while reducing the stimulation of IL-4 demonstrated this vaccine has an immune phenotype which fewer possibilities for the production of greater disease to happen (49). Inovio Pharmaceutical has announced the vaccine candidate induced the neutralising antibodies and T cell responses against a few variants in the United Kingdom, South Africa, and Brazil in April 2021. The antibodies capable of neutralising activity were measured against B.1.1.7 (UK), B.1.351 (South Africa), and P.1.(Brazil). The findings displayed induction of T cell responses by vaccine candidates was fully consistent against those variants and better neutralising activity in the Brazilian variant compared to another vaccine candidate even it is decreased in the activity of neutralising antibodies (50).

NVX-CoV2373:

The developer for this vaccine is Novavax Incorporation in Maryland, United States. This vaccine candidate is using recombinant, suitably folded, in the pre-fusion condition created from insect cells as well as a combination of nanoparticle technology and proprietary saponin adjuvant along with full-length spike glycoprotein of SARS-CoV-2 virus. This may offer the vaccine formulation to produce injectable antigen compounds and a highly immunogenic mechanism to the vaccinees. In preclinical studies, the vaccine displayed high immunogenicity in the animal model. In single vaccination, it exhibited high levels of spike protein-specific antibodies against an anti-spike protein that obstructed the human angiotensin-converting enzyme 2 (hACE2) receptor binding along with SARS-CoV-2 wild type virus-neutralising antibodies. Moreover, in the second dose, it showed improvement which 8-times higher microneutralization which solely for human protection (51). In clinical trial Phase I, the study was intended to assess the safety and immunogenicity of the vaccine (NCT04368988), different dose levels of SARS-CoV-2 rS nanoparticle vaccine with or without the adjuvant of Matrix-M in Australia. The overall in Phase I displayed the vaccine had convincing safety profile, generally well-tolerated and the Matrix-M, generated robust polyfunctional CD4 T cell responses (52). In January 2021, Novavax has released a statement that indicated that the vaccine efficacy in clinical trial Phase III is 89.3% which met the primary endpoint and well-tolerated vaccine(53). Furthermore, the vaccine is the first one to exhibit high clinical efficacy in COVID-19 as well as substantial against rapidly emerging variants in the UK and South Africa. The vaccine efficacy is 95.6% effective against the initial variant of SARS-CoV-2 whereas, 85.6% against B.1.1.7 variant in the UK(54).

CONCLUSION:

In summary, the development of COVID-19 vaccine candidates not only proves with a promising future but also with shortcoming challenges. Even the vaccine development is a long and tedious journey, auspicious progress has been made in a short period. As of now, there is a limited source on the efficacy studies but some of the vaccine candidates have been used as emergency use authorization around the world in search of its efficacy, safety, and immunogenicity of the vaccine profile. Now, an ideal vaccine profile should elicit high titres of neutralising antibodies, it should give minimize antibody-dependent enhancement (ADE), preserve long term of immunological memory, and offer cross-protection between coronaviruses. The vaccine efficacy studies of the SARS-CoV-2 vaccine will take usually one to two years so, from this point forward, future studies should cover more about the clinical trial studies to prove to society that this vaccine is aiding in a pandemic situation. From the summarized clinical trial, it showed a few limitations where there are not enough participants and a short period of evaluation time in the participants so the observation results are limited. In addition, there are a few types of variants on SARS-CoV-2 strains detected and some of the developers had tested on the developed vaccine candidates to investigate vaccines’ efficacious towards the mutated virus. Hence, the strength and weaknesses of these vaccine candidates should be investigated further to have a better understanding related to their safety, efficacy, immunogenicity as well as protection rate.

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Received on 28.10.2021 Modified on 30.03.2022

Research J. Pharm. and Tech 2022; 15(12):5868-5874.

DOI: 10.52711/0974-360X.2022.00990