Prerpints.org logo
Preprint
Review

COVID-19 Vaccines: Where Do We Stand at the End of 2023?

Altmetrics

Downloads

223

Views

84

Comments

0

A peer-reviewed article of this preprint also exists.

This version is not peer-reviewed

Preprints on COVID-19 and SARS-CoV-2

Submitted:

04 January 2024

Posted:

05 January 2024

You are already at the latest version

Alerts
Abstract
Vaccine development against SARS-CoV-2 has been highly successful in slowing down the COVID-19 pandemic. A wide spectrum of approaches including vaccines based on whole viruses, protein subunits and peptides, viral vectors, and nucleic acids have been developed in parallel. For all types of COVID-19 vaccines, good safety and efficacy have been obtained in both preclinical animal studies and in clinical trials in humans. Moreover, emergency use authorization has been granted for all types of COVID-19 vaccines. Although high safety has been demonstrated, rare cases of severe adverse events have been detected after global mass vaccinations. Emerging SARS-CoV-2 variants possessing enhanced infectivity have affected vaccine protection efficacy requiring re-design and re-engineering of novel COVID-19 vaccine candidates. Furthermore, insight into preparedness against emerging SARS-CoV-2 variants and other future viral infections is given.
Keywords: 
Subject: Biology and Life Sciences  -   Virology

1. Introduction

During the last three years, the global population has been exposed to the serious COVID-19 pandemic followed by tragic loss of lives, lockdowns, and social and economic consequences [1]. Although the pandemic was due to the rapid development and mass vaccinations with efficient COVID-19 vaccines [2] downgraded to an endemic status in the spring of 2023 [3], the emergence of more infectious SARS-CoV-2 variants [4] has further presented new challenges to provide a complete eradication of the disease.
The extensive and rapid spread of SARS-CoV-2 triggered the development of COVID-19 vaccines in a broad front including inactivated and attenuated whole viruses, protein subunit and peptide, viral vector, DNA, and RNA vaccines [2]. The unprecedented collaboration of academic institutions, pharmaceutical and biotechnology companies, and governmental authorities managed to demonstrate the safety and efficacy of different types of COVID-19 in animal models and clinical trials allowing the granting of emergency use authorization (EUA) in a number of countries around the world. In this review, the different types of COVID-19 vaccines are described based on their composition, efficacy, and potential relationship to post-vaccination adverse events. Moreover, the effect of SARS-CoV-2 variants of concern (VoC) related to vaccine efficacy and the re-engineering to address immune escape by VoC are presented. Moreover, strategies for future approaches to address emerging variants and other future viral infections.

2. COVID-19 Vaccines

The urgent need for efficient vaccines against SARS-CoV-2 has resulted in parallel development including classic whole virus vaccines and more novel approaches based on nucleic acids. As these approaches are significantly different, it is appropriate to describe them separately below. The COVID-19 vaccine development is further summarized in Table 1.

2.1. Inactivated and Attenuated Whole Virus Vaccines

The classic whole virus vaccine development comprises the application of inactivated or live attenuated whole virus [5]. One aspect of applying whole viruses for vaccine development is the possibility of inducing pan-immune responses, which are not restricted to targeting only the commonly used spike (S) protein, but also the matrix, envelope, and nucleoprotein of SARS-CoV-2. Another essential feature is that whole virus vaccines can be stored at 2-8°C, also facilitating distribution and administration in developing countries [6]. In the case of inactivated whole virus vaccines the SARS-CoV-2 cultured in cells was inactivated by formaldehyde or glutaraldehyde treatment or UV or gamma radiation [7]. The downside of using whole viruses relates to the production of contagious virus particles and the potential degradation of viral antigens and epitopes caused by the inactivation process [7,8]. Several inactivated whole-virus COVID-19 vaccines have been developed [7] (Table 1).
The COVI-VAC vaccine is based on a single-dose intranasal administration of a live-attenuated SARS-CoV-2 carrying the S protein with 283 silent mutations, which induced strong immune responses and long-lasting cellular immunity [9]. Moreover, good tolerability and safety, and a seroconversion rate of 83% were achieved in a phase I/II trial [10]. The two-dose CoronaVac (Sinovac) aluminum (Alum) hydroxide adjuvanted whole-virus vaccine, inactivated by β- propiolactone (BPL) treatment, showed good seroconversion and immune memory causing only minor or moderate adverse events in phase I and II trials [11,12]. In phase III, CoronaVac provided 50.7% and 100% efficacy against symptomatic COVID-19 and hospitalization, respectively [13]. In June 2021, CoronaVac was granted EUA in 54 countries [14]. Another BPL-inactivated whole-virus vaccine, VLA2001, which is adjuvanted with alum and CpG 1018.31 adjuvants elicited robust antibody responses in preclinical studies [15] and showed good safety and dose-dependent humoral and cellular responses in a phase I/II study [16]. The VLA2001 was superior to the adenovirus-based ChAdOx1-S vaccine in phase III [17]. EUA was granted for VLA 2001 in Bahrain in March 2022 [18].
The Vero cell-based ERUCOV-VAC vaccine provided 100% protection in K18-hACE2 mice challenged with SARS-CoV-2 [19]. Moreover, acceptable immunogenicity and safety were established in phase I/II in healthy volunteers vaccinated with ERUCOV-VAC [20]. In phase III, interim results demonstrated a 41.03% reduced risk of COVID-19 compared to the CoronaVac vaccine [21]. The alum-adjuvanted COVIran Barekat vaccine showed efficient protection against SARS-CoV-2 in rhesus macaques [22]. In a cohort study, the COVIran Barekat vaccine demonstrated an 85% reduction in mortality and a significant reduction in hospital admissions [23]. The Indian Covaxin (BBV152) inactivated whole virus vaccine elicited strong immunogenicity and protected rhesus macaques against challenges against SARS-CoV-2 [24]. Moreover, a 93.4% vaccine efficacy in a phase II trial [25] and good safety and efficacy against symptomatic COVID-19 was reported in phase III [26] for BBV152. Another whole virus vaccine, the alum hydroxide-adjuvanted and formalin-inactivated QazCovid-in, protected hamsters against SARS-CoV-2 challenges [27] and showed 100% and 92-94% seroconversion in phase I and phase II studies, respectively [28]. In phase III, an 82% vaccine efficacy was achieved after two doses of QazCovid-in [29].
The inactivated BBIBP-CorV (Sinopharm) whole virus vaccine, based on a SARS-CoV-2 isolate from a COVID-19 patient in China [30], induced strong neutralizing antibody responses in several animal models and protected rhesus macaques from SARS-CoV-2 challenges [30]. In phase I, BBIP-CorV showed good safety and tolerability and induced robust humoral responses and high titers of neutralizing antibodies [31]. A vaccine efficacy of 78.1% was reported in phase III [32]. The BBiP-CorV vaccine was granted EUA in China in July 2020 [33] and by the WHO in May 2021 [34].

2.2. Protein Subunit and Peptide Vaccines

In the case of protein subunit and peptide vaccines, three main approaches have been explored comprising recombinant the SARS-CoV-2 S protein, its receptor binding domain (RBD), and nanoparticle formulations for vaccine development [35] as described below and summarized in Table 1.
Several vaccine development approaches have involved purified the recombinant prefusion-stabilized and transmembrane-deleted SARS-CoV-2 S expressed in insect cells from baculovirus vectors [36]. For example, protection against SARS-CoV-2 was demonstrated in non-human primates after immunization with the AS03-adjuvanted preS dTM vaccine [36]. In phase I, although good safety was obtained lower-than-expected immunogenicity suggested that additional antigen formulation and dose optimization was required [37]. Two doses of the preS dTM-AS03 vaccine showed acceptable safety and elicited strong immune responses in phase II [38]. The AS03- or CpG/alum-adjuvanted SCB-2019 vaccine comprising the trimeric S protein (STrimer) provided protection against SARS-CoV-2 in immunized non-human primates [39]. Strong humoral and cellular responses and high titers of neutralizing antibodies were obtained in a phase I study [40]. In phase II/III, SCB-2019 elicited immunogenicity and cross-reactivity against SARS-CoV-2 [41].
In the COVAX-19 vaccine, the extracellular domain (ECD) of SARS-CoV-2 S is adjuvanted with Alum-CpG55.2 or Advax-CpG55.2, which induced robust humoral and cellular immune responses in mice and demonstrated protection against SARS-CoV-2 challenges in hamsters [42]. In phase II, COVAX-19 showed good safety and strong humoral and cellular immunogenicity [43]. Additionally, significantly reduced COVID-19 rates and severity of disease were reported for COVAX-19 in phase III [44]. The Alum-hydroxide-adjuvanted Nanocovax vaccine expressing SARS-CoV-2 S generated neutralizing antibodies in mice, hamsters, and macaques [45]. Good safety, tolerability, and robust immune responses were demonstrated in phase I/II [46]. Moreover, a 90% vaccine efficacy against the SARS-CoV-2 Wuhan strain was established in phase III [47].
In another approach, intranasal administration of two doses of the Razi Cov Pars SARS-CoV-2 S protein subunit vaccine adjuvanted with RAS-01 elicited robust humoral and cellular responses and protected hamsters from SARS-CoV-2 challenges [48]. Moreover, durable humoral and cellular immunogenicity was obtained in phase II [49]. The CpG 1018 and Alum hydroxide-adjuvanted prefusion stabilized S Trimer MVC-COV1901 vaccine reduced lung pathology and protected hamsters against SARS-CoV-2 challenges [50]. Strong neutralizing antibody responses were obtained in phase I [51] and a good safety profile and promising immunogenicity were seen in phase II [52]. These findings were confirmed in a phase III trial in Paraguay [53]. The EpiVarCorona (EVCV) vaccine is based on synthesized peptide antigens and immunogens from the SARS-CoV-2 S protein, which elicited immune responses in various animal models and prevented pneumonia in hamsters and non-human primates [54]. Moreover, good safety and prevention of COVID-19 was observed in phase I/II [55] and an 82.5% vaccine efficacy was reported in phase III [56]. In the case of the bivalent SCTV01C vaccine, the trimeric extracellular domain of SARS-CoV-2 S adjuvanted with squalene-based oil-in-water immunization of mice provided protection against SARS-CoV-2 challenges [57]. The SCTV01C vaccine showed promising immune responses in phase I [58], which was confirmed in phase III [59]. EUA was granted for SCTV01C in China [60].
Among recombinant RBD vaccines, the ZF2001 which is based on tandem RDB repeats of alum hydroxide-adjuvanted SARS-CoV-2 S, protected mice, and non-human primates from SARS-CoV-2 challenges [61]. In phase I/II neutralizing antibodies were detected in 83% of vaccinees after two doses and in 97% after three injections [62]. In phase III, immunization with ZF2001 provided protection against symptomatic and severe-to-critical COVID-19 [63]. ZF2001 was granted EUA in China and Uzbekistan in March 2021 [64]. Another RBD SARS-CoV-2 S-based subunit vaccine CIGB-66 (Abdala) expressed from Pichia pastoris yeast cells was adjuvanted with alum hydroxide [65]. CIGB-66 induced robust immune responses in mice and primates [65]. Good safety, tolerability, and robust immune responses were obtained in phase I [66]. A 92.3% vaccine efficacy was demonstrated in phase III [67]. EUA was granted for CIGB-66 in Cuba in July 2021 [68]. In another approach, the BECOV2 vaccine based on the expression of the RBD in yeast cells adjuvanted with alum and CpG deoxynucleotide elicited high levels of neutralizing antibodies and T-cell immunity in mice [69]. Hugh neutralizing antibody titers were also obtained for BECOV2 (Corbevax) in phase I/II [70]. Moreover, in comparison to the Covishield vaccine, Corbevax showed superior immunogenicity and 50% fewer adverse events in phase III [71]. Corbevax has received EUA in India and Botswana [72].
In another approach, the SARS-CoV-2 RBD was chemically coupled to the tetanus toxoid and adjuvanted with alum hydroxide at the Finlay Institute in Cuba as the FINLAY-FR-2 vaccine candidate [73]. Immunization of BALB/c mice induced strong immune responses [73]. In phase I/II two doses of FINLAY-FR-2 elicited comparable humoral immune responses to natural SARS-CoV-2 infections [74]. Elevated levels of immune responses were obtained in children receiving a booster immunization [74]. In phase III, 76.8% protection against severe COVID-19 and 77.7% against hospitalization was achieved after two doses of FINLAY-FR-2 [75]. Furthermore, a booster vaccination increased the percentage to 96.6 for severe disease and hospitalization [75].
The UB-612 subunit protein-peptide vaccine was engineered to contain the RBD fused to a single-chain human IgG1 Fc, five synthetic peptides covering helper and cytotoxic T lymphocyte (Th/CTL epitopes from S2, membrane (M), and nucleocapsid (N) of SARS-CoV-2, and one universal Th peptide plus an alum phosphate adjuvant [76]. Robust immune responses were obtained in several rodent species and protection against SARS-CoV-2 challenges was achieved in mice and non-human primates [76]. UB-612 elicited long-lasting neutralizing antibody responses and broad T-cell immunity in phase I/II [77].
The ReCoV vaccine, comprising the trimeric two-component N-terminal domain (NTD) and RBD subunits and a novel adjuvant (BFA03) for binding to the ACE2 receptor, elicited robust immune responses and protected mice and macaques against SARS-CoV-2 challenges [78]. In phase II in the Philippines, a comparison to mRNA vaccines demonstrated favorable safety and superior immunogenicity of the ReCoV vaccine [79]. Moreover, EUA has been granted for ReCoV in Mongolia in March 2023 [80].
Among nanoparticle-based protein subunit vaccines the NVX-CoV2373 containing the full-length SARS-CoV-2 S and the Matrix-M1 adjuvant, showed protection against SARS-CoV-2 in rats and baboons [81]. In comparison to sera from convalescent COVID-19 patients, NVX-CoV2373 induced superior immune responses and CD4+ T-cell responses biased towards Th1 in phase I/II [82]. The NVX-CoV2373 demonstrated 100% efficacy against severe COVID-19 and 76.3% efficacy against symptomatic disease in phase III [83]. Conditional marketing authorization was granted in the EU in December 2021 and in Great Britain in February 2022 [84].
The GBP510 vaccine is based on self-assembled nanoparticles adjuvanted with AS03 [85]. In phase I/II, GBP510 showed good tolerability and high immunogenicity [86]. In phase III, superior neutralizing antibody titers and seroconversion rates were obtained for GBP510 compared to the adenovirus-based ChAdOy1-S vaccine [87].

2.3. Viral Vector Vaccines

Much attention has been given to viral vector-based COVID-19 vaccines where the aim has been to efficiently deliver and express SARS-CoV-2 proteins or their epitopes as antigens [88,89]. The S protein has been the most frequently used target for the expression from a large spectrum of viral vectors such as adenoviruses (Ad), vaccinia viruses (VV), Newcastle disease virus (NDV), measles viruses (MV), rhabdoviruses (RABV), alphaviruses, lentiviruses (LV), and influenza viruses. Various viral vector-based vaccine candidates are described below and summarized in Table 1.
Adenoviruses (Ad) have been most frequently used and provided the best progress, so far. For example, the ChAdOx1 nCoV-19 vaccine, based on a Chimpanzee Ad vector expressing the full-length S protein, has demonstrated robust immune responses in several species and protection against SARS-CoV-2 in rhesus macaques [90]. In phase I/II humoral and cellular immune responses were obtained [91]. Depending on dosing, a vaccine efficacy of 62-90% was achieved in phase III [92]. The ChAdOx1 nCoV-19 was granted EUA in the UK in December 2020 [93]. The third-generation human Ad5 serotype has been utilized for the expression of the S protein providing protection against SARS-CoV-2 in immunized mice, ferrets, and macaques [94,95]. Both binding and neutralizing antibody responses were detected in volunteers in phase I [96]. However, the immune responses were dependent on pre-existing Ad5 antibodies and the age of the vaccinee as demonstrated in phase II [97]. Good safety and efficacy were achieved in phase III [98]. EUA was granted to Ad5-nCoV in February 2021 in China [99]. Application of the Ad26 serotype for the expression of the prefusion-stabilized S protein (Ad26.COV2.S) [100] required only a single immunization to elicit robust immune responses and provide protection against SARS-CoV-2 in non-human primates [101]. In phase I/II, Ad26-COV2.S was safe and induced strong immune responses [102]. In phase III, a 52.9% vaccine efficacy was achieved after a single injection [103]. EUA was granted in the US in February 2021 [104]. In another approach with the aim of limiting pre-existing Ad immunity, the SARS-CoV-2 S was expressed from Ad26 and Ad5 vectors. The Sputnik V vaccine strategy comprises prime immunization with rAd26-S followed by booster immunization with Ad5-S [105], which has been indicated to elicit strong immune responses in animal models although no results have been published. Good safety, robust humoral and T-cell-mediated immune responses, and vaccine efficacy were reported in phase I/II [106,107]. Moreover, a 91.6% vaccine efficacy was obtained in phase III [108]. Quite controversially, the Sputnik V vaccine was granted EUA in Russia in July 2020 despite only interim vaccine evaluation being reported in 76 volunteers and no phase III data were available [109]. Recently, the GRAd gorilla adenovirus has been applied for the expression of the prefusion-stabilized SARS-CoV-2 S protein, which elicited robust immune responses in mice and macaques [110]. In phase I, good safety and 97.7 and 100% seroconversion rates were obtained in young volunteers (18-55 years old) and older adults (65-85 years old), respectively [111].
Among vaccinia viruses, poxviruses such as the Modified Vaccinia Ankara (MVA) strain have been utilized for the expression of the SARS-CoV-2 S and N proteins [112]. Immunization of mice with MVA-COV2-S elicited antigen-specific humoral and cellular immune responses [113]. Additionally, immunization of C57NL/6 mice was well tolerated and induced S-specific humoral and cellular immune responses [114]. In clinical settings, the recruitment for phase I evaluation for MVA-COV2-S has been described [115]. Currently, a phase II trial for MVA-COV2-S (MVA-SARS-2-S) is in progress [116].
The oncolytic Newcastle disease virus (NDV) has also been engineered for the expression of the SARS-CoV-2 S protein, which induced strong binding and neutralizing antibodies and protected immunized mice and hamsters against SARS-CoV-2 [117]. In phase I, the inactivated SARS-CoV-2 S expressing NDV-HXP-S adjuvanted with CpG 1018 showed acceptable safety and potent immune responses [118].
Lentiviruses (LVs) belonging to the retrovirus family have been utilized for the expression of the full-length SARS-CoV-2 S protein and after systemic administration to ACE2-humanized mice elicited robust immune responses but only partial protection against challenges with SARS-CoV-2 [119]. In contrast, intranasal LV-SARS-CoV-2 S administration was superior providing a significant decrease in viral load in the lung and reduced local inflammation [119]. Lung injury was also prevented in hamsters immunized with LV-SARS-CoV-2 S. In another approach, LV vectors have been engineered for the expression of conserved domains of the SARS-CoV-2 structural proteins and the protease using the SMENP minigenes [120]. Dendritic cells (DCs) are transduced with LV-SMENP and subcutaneously administered to antigen-presenting cells (APCs) for induced immune responses. A phase I/II trial with LV-SMENP-DC is in progress [121].
Engineering of a chimeric influenza virus vector where the neuraminidase (NA) gene was replaced with a membrane-anchored form of the SARS-CoV-2 S RBD elicited robust neutralizing antibody responses in intranasally immunized mice [122]. In phase I and II, the dNS1-RBD vaccine comprising a cold-adapted influenza virus strain without its non-structural protein 1 (NS1) with an insertion of the SARS-CoV-2 S RBD induced only weak T-cell responses and modest humoral and mucosal immune responses [123].
Measles viruses (MV) belong to self-amplifying RNA (saRNA) viruses, which have been applied for the expression of the full-length SARS-CoV-2 S protein [124]. Immunization of mice with MV-SARS-COV-2 S induced Th1-biased antibody and T-cell responses [124]. In phase I, the MV-SARS-COV-2 S (TMV-083) vaccine showed good tolerability [125]. However, the immune responses were inferior to those seen in convalescent COVID-19 patients, which led to premature discontinuation of the study [125].
Vesicular stomatitis virus (VSV), a member of the rhabdovirus family, has also been used for SARS-CoV-2 S protein expression resulting in the protection of BALB/c mice against SARS-CoV-2 [126]. The VSV-SARS-CoV-2 S (V590) vaccine showed good safety and tolerability in phase I [127]. Disappointingly, the inferior immune responses compared to those detected in convalescent COVID-19 patients resulted in the termination of the trial. In an alternative approach, the VSV G protein was replaced by the SARS-CoV-2 S protein in a chimeric vector (VSV-ΔG) showing potent neutralizing antibody responses in golden Syrian hamsters [128]. In phase II, robust neutralizing antibody responses against SARS-CoV-2 were obtained after immunization with the VSV-ΔG vaccine [129]. Moreover, a single-round rhabdovirus vaccine has been engineered, where a chimeric minispike comprising the RBD domain linked to a rabies virus (RABV) transmembrane stem-anchor sequence was engineered [130], VSV replicons generated cell surface expression of antigen and incorporation into the envelope of secreted non-infectious particles. A
single administration of VSV replicon complemented with VSV G (VSV-ΔG-minispike-eGFP) protected transgenic K18-hACE2 mice from COVID-19-like disease [130].

2.4. DNA Vaccines

The DNA-based vaccine approach is attractive due to its easy manufacturing, convenient storage temperature, and handling [131]. However, transfection of plasmid DNA is inferior to viral infection and in contrast to mRNA-based vaccines, translocation of DNA to the cell nucleus is necessary for in vivo RNA transcription [132]. Although DNA-based vaccine candidates have been subjected to more than 500 clinical trials, only a single DNA vaccine against the H5N1 influenza virus in chicken has been approved by the USDA [131] prior to granting EUA for DNA-based COVID-19 vaccines. DNA-based vaccines are described below and summarized in Table 1. Typically, DNA-based vaccines contain the full-length SARS-CoV-2 S protein, a soluble version of it, or the RBD, and a prefusion-stabilized ectodomain [133].
The synthetic INO-4800 DNA vaccine expressing the SARS-CoV-2 S elicited strong immune responses and neutralized SARS-CoV-2 in mice and guinea pigs [134]. In phase I, INO-4800 demonstrated good safety and tolerability and induced cellular and humoral immune responses [135]. Furthermore, good safety and tolerability were achieved for 1 and 2 mg doses of INO-4800 in phase II [136]. As the higher dose generated superior immunogenicity, it was selected for phase III.
In another approach, the ZyCoV-D vaccine expressing the SARS-CoV-2 S RBD induced neutralizing antibodies and Th1-biased immune responses in mice, guinea pigs, and rabbits [137]. Good safety without any serious adverse events and robust immune responses were reported in phase I/II [138]. A 66.6% vaccine efficacy was obtained in phase III [139]. EUA was granted for ZyCoV-D in India in 2021 [140].
Engineering of a synthetic soluble SARS-CoV-2 S in a plasmid generated the GX-19 vaccine [141]. Immunization of mice elicited S-specific antibody responses and protected macaques against challenges with SARS-CoV-2 [141]. Both the GX-19 vaccine and the RBD foldon, N and S protein-containing GX-19N vaccine demonstrated good safety and tolerability profiles in phase I [142]. The GX-19 vaccine showed a superior neutralizing antibody response in comparison to the GX-19N vaccine [142].
In a different approach, saRNA DNA vectors based on the Semliki Forest virus (SFV) have been utilized for the expression of the full-length SARS-CoV-2 S protein (DREP-S) and an ectodomain of the prefusion-stabilized S protein (DREP-S-ecto) [143]. Immunization of mice with DREP-S and DREP-S-ecto induced binding and neutralizing antibodies with a superior potency detected for the former vaccine candidate. No information on clinical trials is available.

2.5. RNA Vaccines

The most innovative approach to COVID-19 vaccines comprises mRNA-based approaches, where the synthetic mRNA introduced into the cytoplasm of host cells produces large quantities of antigen [144]. However, the single-stranded structure of mRNA makes it sensitive to degradation by cellular RNases, which has been addressed by the introduction of chemical modifications and anti-reverse cap analogs [144]. The efficacy of mRNA delivery and protection against degradation have also been addressed by various nanoparticle (NP) formulations. Vaccine development based on mRNA has been carried out for more than 20 years, but with the COVID-19 pandemic, the real breakthrough of the technology took place [144]. Selected mRNA-based COVID-19 vaccines are described below and summarized in Table 1.
Encapsulation of the prefusion-stabilized full-length SARS-CoV-2 S RNA into NPs resulted in the BNT162b2 vaccine [145]. Immunization of mice with BNT162b2 elicited dose-dependent antibody responses [145]. Moreover, protection against SARS-CoV-2 challenges were obtained in immunized macaques [145]. BNT162b2 showed good safety and generated robust immune responses in phase I/II [146]. In phase III, a 95% vaccine efficacy was achieved [147]. The BNT162b2 vaccine was granted EUA in the EU and Switzerland in December 2020 [148] and regulatory approval by the US FDA in August 2021 [149].
The mRNA-1273 vaccine is also based on the prefusion-stabilized full-length SARS-CoV-2 S RNA encapsulated in lipid nanoparticles (LNPs), which provided protection against SARS-coV-2 in immunized mice [150] and primates [151]. In phase I, mRNA-1273 induced S-specific immune responses in all vaccinated volunteers [152]. In phase III, a 94.1% vaccine efficacy was obtained [153]. The mRNA-1273 vaccine was granted EUA in the US in December 2020 [154]. Similarly, the CVnCOV vaccine comprising LNP-encapsulated full-length SARS-CoV-2 S mRNA elicited strong humoral responses in hamsters and protected against SARS-CoV-2 challenges [155]. The immune responses were comparable to those seen in convalescent COVID-19 patients in phase I [156]. However, the vaccine efficacy was only 48.2% in phase III [157].
In contrast to the mRNA vaccines described above, the ARCoV vaccine is based on the SARS-CoV-2 S RBD encapsulated in LNPs [158]. Immunization of mice and primates induced neutralizing antibodies and Th1-biased responses [158]. Immunized mice were protected after two doses of the ARCoV vaccine [158]. An advantageous feature of the ARCoV vaccine is its thermostability [159]. The ARCoV vaccine could be stored for at least one week at room temperature and for 6 months at 2-8°C without any degradation in immunogenicity [159]. In phase I, immunization with ARCoV induced robust humoral and cellular responses [160].
The application of saRNA has due to the RNA amplification step generated superior quantities of mRNA and/or the possibility to use much lower doses of RNA for immunization [161]. Venezuelan equine encephalitis (VEE) replicons carrying full-length SARS-CoV-2 S RNA elicited robust S-specific antibody responses in mice and neutralized pseudovirus and wildtype SARS-CoV-2 [161]. In phase I the LNP-nCoVsaRNA vaccine was safe, well tolerated, and elicited specific immune responses but failed to reach 100% seroconversion rates [162]. However, in phase II, superior seroconversion rates were achieved by either a prolonged dosing interval or the administration of a 1.0 μg prime dose followed by a 10 μg booster dose [163]. Another similar nanostructural lipid carrier (NLC) -encapsulated VEE-based saRNA vaccine including the SARS-CoV-2 S RNA induced robust Th1-biased T-cell responses in immunized mice [164]. The lyophilized thermostable saRNA/NLC vaccine could be stored at refrigerated temperatures for at least 10 months. Additionally, the LUNAR-COV19 vaccine based on VEE saRNA carrying the full-length SARS-CoV-2 S RNA induced robust antibody responses, high neutralizing antibody responses, and provided full protection of immunized humanized ACE2 transgenic mice [165].

3. SARS-CoV-2 Variants and Vaccine Efficacy

Although the different COVID-19 vaccines have played a significant role in reducing the COVID-19 pandemic to an endemic status in April 2023 [3,166] the emergence of SARS-CoV-2 variants has complicated the situation and can substantially reduce the efficacy of existing vaccines [167]. Emerging variants have been classified as VoC, variants of interest (VoI), and variants variants under monitoring (VuM) [168].
To address the reduction of vaccine efficacy due to the waning of vaccine potency booster vaccinations with either homologous or heterologous vaccines have been conducted [169]. Additionally, intensive re-engineering of existing vaccines to especially address the mutated SARS-CoV-2 S protein is in continuous process [170].
However, the first step has involved the testing of existing vaccines for the protection against novel variants. Obviously, it has been of major interest to verify vaccine efficacy against the most prominent variants such as alpha, beta, delta, gamma, omicron, and recent subvariants of omicron [171]. However, it is impossible in this review to describe the efficacy of all existing vaccines against each VoC. Therefore, some examples are presented below and summarized in Table 2.
For example, the efficacy of the whole virus vaccine VLA2001 against the delta and omicron variants was improved after both homologous and ChAdOx1 nCoV-19 heterologous booster immunizations [172]. In another study, it was demonstrated that individuals originally vaccinated with mRNA or Ad-based vaccines, who received a booster immunization with the preS dTM-AS03 protein unit vaccine carrying the beta variant S protein elicited robust neutralizing antibody responses against several SARS-CoV-2 VoC [173]. The booster formulation induced cross-reacting neutralizing antibodies against the beta (B.1.351) and omicron (BA.1, BA.2, and BA.4/5) [173]. It has also been shown that the SCB-2019 protein subunit vaccine induced immunogenicity and cross-reactivity against the alpha, beta, gamma, delta, and mu variants in phase II/III [174]. In addition, vaccination with the COVAX-19 vaccine based on the S protein ECD resulted in significantly reduced COVID-19 rates and severity of disease caused by the delta variant [45]. Moreover, the Nanocovax vaccine showed good safety and a 51.5% vaccine efficacy against the delta variant [48]. The NVX-CoV2373 protein subunit vaccine showed the highest pseudovirus-neutralizing antibody (PsVNA) responses for the SARS-CoV-2 D614G variant and the lowest PsVNA responses for the omicron BQ.1.1 and XBB.1 variants after heterologous booster vaccination of individuals previously vaccinated with Ad26.COV2.S, mRNA-1273, or BNT162b2 vaccines [175]. In the case of the SCTV01C based on the SARS-CoV-2 S ECD elicited promising immunogenicity against alpha and beta variants and cross-neutralizing antibodies against delta and omicron variants in phase I [59]. Furthermore, booster vaccinations with SCTV01C of individuals previously vaccinated with the whole virus vaccine BBIBP-CoV resulted in superior neutralizing antibody titers against delta and omicron variants in phase III [176]. In the case of the S protein epitope-based UB-612 vaccine induced long-lasting neutralizing antibody responses and a broad T-cell immunity against delta and omicron variants in phase I/II [177]. Moreover, booster vaccinations with UB-612 enhanced the neutralizing antibody levels by 131-, 61-, and 49-fold against the ancestral SARS-CoV-2 strain, the omicron BA.1 and BA.2 variants, respectively [178].
Related to viral vector-based vaccines, ChAdOx1 has been evaluated in a two-dose regimen against the beta variant in pseudovirus and live-virus neutralization assays [179]. The study showed that the vaccination was unable to provide protection against mild-to-moderate COVID-19 caused by the beta variant. In another study, the association between transmission of the alpha and delta variants and vaccination with either the ChAdOx1 nCoV-19 vaccine or the BNT162b2 mRNA vaccine [180]. The effect of vaccination on reduced transmission was inferior for the delta variant compared to the alpha variant. Moreover, the mRNA-based vaccine provided a greater decrease in transmission than the Ad-based ChAdOx1 nCoV-19. The ChAdOx1 nCoV-19 vaccine showed in another study neutralizing activity against alpha, beta, delta, gamma, and omicron variants [181]. In the case of the single-dose Ad26.COV2.S vaccine, neutralizing antibody responses were reduced against the beta and gamma variants compared to the original SARS-CoV-2 strain [182]. In another study, it was demonstrated that the vaccine efficacy against the delta variant was stable for at least 6 months [183]. The Ad-based Sputnik V vaccine showed a moderate decrease in the neutralization activity of a VSV-based pseudovirus for the alphavirus variant, whereas the reduced activity for the beta variant was 6.1-fold [184]. In the case of the gamma [185] and delta [186] variants, 2.8- and 2.5-fold reduced neutralization activity was detected, respectively.
In the case of NDV-based vaccines, the next-generation trivalent NDV-HXP-S vaccines expressing the prefusion-stabilized S protein of the original SARS-CoV-2 strain, the gamma, and delta variants significantly enhanced the protection against disease and provided cross-neutralizing antibodies against distant variants such as omicron [187]. In another approach, the inactivated influenza A virus (Flu) was conjugated with the recombinant SARS-CoV-2 S RBD, which generated SARS-CoV-2 virus-like particles (VLPs) [188]. The Flu-RBD VLPs induced strong neutralization activity against both wildtype SARS-CoV-2 and the delta variant.
In an approach to address the potential vaccine escape of VoC, the replication-competent VSV-ΔG-S (BriLife®) has been utilized for the expression of S mutations corresponding to those present in VoC [130]. It was demonstrated that the VSV-ΔG-S vaccine elicited comparable neutralizing antibody levels against alpha, gamma, and delta variants and a 3-fold reduction against beta and omicron compared to the original SARS-CoV-2 strain.
In the case of DNA vaccines, the INO-4800 vaccine showed comparable levels of neutralizing antibodies for the gamma variant and the original SARS-CoV-2 strain and 2.1-fold and 6.9-fold reduced levels of neutralizing antibodies for the alpha and beta strains, respectively [189]. To better address the vaccine efficacy against emerging variants, the pan-SARS-CoV-2 DNA vaccine INO-4802 was designed [190]. INO-4802 elicited potent neutralizing antibodies and T-cell responses against the original SARS-CoV-2 strain, the alpha, beta, and gamma variants. Moreover, a prime-boost regimen with INO-4802 enhanced and broadened the immune response in rhesus macaques [191].
Related to mRNA-based vaccines, the BNT162b2 vaccine showed efficacy in preventing symptomatic COVID-19 and severe disease against the alpha, beta, gamma, and delta variants [192]. In other studies, 67% and 90% efficacy against the delta variant were reported for vaccinations with BNT162b2 in Spain [193] and the UK [194], respectively. In the case of the omicron variant, 25% vaccine efficacy was discovered in the US [195], 30% in Israel [196], and in Qatar [197] 51% efficacy against the omicron BA.1 and BA.2 variants were reported. In the case of the mRNA-1273 vaccine, a 1.2-fold statistically non-significant reduction in neutralizing antibody titers was obtained against the alpha variant in comparison to the D614G strain [198]. In contrast, a 2.1 to 8.4-fold reduction in titers was seen for beta, gamma and delta variants [198]. In another study, the mRNA.1273 induced neutralizing antibodies against omicron in both adolescents and children although at lower levels compared to the D614G strain [199]. A comparative phase II/III study of booster vaccinations was conducted with the original mRNA-1273 and the bivalent novel mRNA-1273.214 vaccine comprising the original mRNA-1273 and the omicron BA.1 S RNA [200]. The bivalent vaccine elicited neutralizing antibody titers against the omicron BA.1 of 2372.4 compared to 1473.5 for the original mRNA-1273 vaccine. Moreover, mRNA-1273.214 induced neutralizing antibody titers of 727.4 and 492.1 against omicron BA.4 and Ba.5 variants, respectively. The bivalent vaccine also induced higher binding activity against the alpha, beta, gamma, and delta variants than the mRNA-1273 vaccine [200]. The mRNA XBB.1.5 vaccine booster elicited 27-fold and 27.6-fold enhanced neutralizing antibody levels against the omicron XBB.1.5 and EG5.1 variants [201].In the case of the CVnCoV mRNA vaccine, a third dose elicited neutralizing antibody responses against both the SARS-CoV-2 wildtype and the delta variant [202]. The antibody levels were higher than those obtained after two vaccinations.
In the context of saRNA-based COVID-19 vaccines, the LNP-nCoVsaRNA vaccine elicited strong immune responses and protected immunized hamsters against the D614G strain and the alpha variant [203]. In another saRNA-based vaccine, the ZIP1642 saRNA encoding both the SARS-CoV-2 S RBD and N RNA elicit high neutralizing antibody titers against the beta and delta variants [204]. Moreover, the thermostable saRNA/NLC SARS-CoV-2 vaccine elicited robust neutralizing antibody responses and Th1-biased T-cell responses against the alpha, beta, and delta variants [205].
Comparative studies on current COVID-19 vaccines have been carried out. For example, T-cell responses against the alpha, beta, gamma, kappa, delta, lambda, and omicron variants after vaccinations with Ad26.COV2.S, NVX-CoV2373, mRNA-1273, and BNT162b2 [174]. The study demonstrated that the cross-reactivity against early variants (alpha and beta) was preserved for the different vaccines. In the case of omicron, memory T-cell responses were also preserved. However, the memory B cells and neutralizing antibodies were reduced to 42%. In a systematic review and meta-analysis, eleven COVID-19 vaccines were evaluated for vaccine efficacy against the alpha, beta, gamma, delta, and omicron variants [206]. Full vaccinations against all variants were effective, ranging between 88.0 and 55.9%. The booster vaccinations were superior for the delta and omicron variants. The mRNA-based COVID-19 vaccines generated better vaccine efficacy against the alpha, beta, gamma, and delta variants compared to the Ad- and protein-based vaccines. Not enough evidence was available for the evaluation of the omicron variant at the time of publication [206].

4. Conclusions and Future Aspects

Various COVID-19 vaccines based on whole viruses, protein subunits, viral vectors, and nucleic acids have demonstrated efficacy in protecting against SARS-CoV-2 infections and reducing the severity of COVID-19. Vaccine efficacy in the range of 90-95% has been achieved in clinical evaluations for different types [83,92,147,153]. Moreover, EUA has been granted for COVID-19 vaccines in a large number of countries around the world [14,18,33,34,60,64,72,80,84,93,99,104,140,148,154], which led to unprecedented global mass vaccinations. As of the end of November 2023, a total of 13.6 billion vaccine doses have been administered globally, and more than 5.2 billion individuals have received a primary series of vaccines [207]. The vaccination strategy significantly contributed to the downgrading of the pandemic to an endemic status [2]. However, the mass vaccinations presented major issues related to the logistics of distribution, storage, and administration on a global scale, especially in developing countries. Not surprisingly, the administration of billions of doses revealed adverse events never accounted for before including severe cases of adverse events such as vaccine-induced thrombocytic thrombosis (VITT) [207]. Despite numerous efforts of unfounded statements, disinformation, and conspiracy theories indicating major danger and serious consequences of vaccinations, scientific evidence clearly demonstrated that the advantages of COVID-19 vaccines strongly outweigh the risks of SARS-CoV-2 and severe disease.
Another issue of COVID-19 vaccines relates to the waning of vaccine potency with time, which has been addressed by booster vaccinations with both homologous and heterologous vaccines [169]. Moreover, the emergence of SARS-CoV-2 variants, classified as VoC, VoI, and VuM, has hampered the potency of existing vaccines [4]. This has triggered the engineering of bivalent [200] and novel variant-specific vaccines [170]. Several studies as described above and summarized in Table 2 have confirmed that the vaccine efficacy is reduced for most of the variants, especially for the most recent omicron variants. However, booster vaccinations can enhance immune responses and thereby provide better protection against COVID-19 and also reduce the severity of the disease. Evidently, both bivalent and variant-specific vaccines have proven superior to the original vaccines.
In general, vaccine development seems to be a race between emerging variants and the re-engineering of novel vaccines specifically targeting those modifications in the SARS-CoV-2 S protein enabling immune escape. However, alternative approaches of targeting other SARS-CoV-2 proteins than the S protein such as the pan-immune responses for whole virus vaccines [5]¨and the INO-4802 pan-SARS-CoV-2 vaccine [190] have been engineered. Another improvement relates to the development of thermostable vaccines such as the saRNA/NLC vaccine [165] and saRNA/NLC SARS-CoV-2 vaccine [205], which facilitate transport and storage but should also improve vaccine stability upon administration.
In summary, the experience from the COVID-19 pandemic and the awareness of the necessity to sustain vaccine efficacy against emerging SARS-CoV-2 variants put the world in a better place to meet the challenge of facing potential new outbreaks to prevent new pandemics [208].

Author Contributions

This review has been solely planned and authored by K.L.

Funding

No funding has been received for the manuscript.

Institutional Review Board Statement

No statement from the Institutional Review Board is required for the review.

Informed Consent Statement

No primary study including humans is included in the manuscript although several studies conducted by external researchers have been described and properly cited.

Data Availability Statement

No research data are generated in this review.

Acknowledgments

Not applicable.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Hu, B.; Guo, H.; Zhou, P.; Shi, Z.-L. Characteristics of SARS-CoV-2 and COVID-19. Nat. Rev. Microbiol. 2021, 19, 141–154. [Google Scholar] [CrossRef] [PubMed]
  2. Li, M.; Wang, H.; Tian, L.; Pang, Z.; Yang, Q.; Huang, T.; Fan, J.; Song, L.; Tong, Y.; Fan, H. COVID-19 vaccine development: milestones, lessons, and prospects. Signal Transduct Target Ther. 2022, 7, 146. [Google Scholar] [CrossRef] [PubMed]
  3. Biancolella, M.; Colona, V.L.; Mehrian-Shai, R.; Watt, J.L.; Luzzatto, L.; Novelli, G.; Reichardt, J.K.V. COVID-19 2022 update: transition of the pandemic to the endemic phase. Hum. Genomics 2022, 16, 19. [Google Scholar] [CrossRef]
  4. Zhang, Y.; Zhang, H.; Zhang, W. SARS-CoV-2 variants, immune escape, and countermeasures. Front. Med. 2022, 16, 196–207. [Google Scholar] [CrossRef]
  5. Khoshnood, S.; Arshadi, M.; Akrami, S.; Koupaei, M.; Ghahramanpour, H.; Shariati, A.; Sadeghifard, N.; Heidary, M. An overview on inactivated and live-attenuated SARS-CoV-2 vaccines. J Clin Lab Anal 2022, 36, e24418. [Google Scholar] [CrossRef]
  6. Al Kaabi, N.; Oulhaj, A.; Al Hosani, F.I.; Al Mazrouei, S.; Najim, O.; Hussein, S.E.; Abdalla, J.S.; Fasihuddin, M.S.; Hassan, A.A.; Elghazali, G.; et al. The incidence of COVID-19 infection following emergency use authorization of BBIBP-CORV inactivated vaccine in frontline workers in the United Arab Emirates. Sci Rep 2022, 12, 490. [Google Scholar] [CrossRef] [PubMed]
  7. Delrue, I.; Verzele, D.; Madder, A.; Nauwynck, H.J. Inactivated virus vaccines from chemistry to prophylaxis: merits, risks and challenges. Expert Rev. Vaccines 2012, 11, 695–719. [Google Scholar] [CrossRef]
  8. Awadasseid, A.; Wu, Y.; Tanaka, Y.; Zhang, W. Current advances in the development of SARS-CoV-2 vaccines. Int. J. Biol. Sci. 2021, 17, 8–19. [Google Scholar] [CrossRef]
  9. Sheridan, C. Innovators target vaccines for variants and shortages in global South. Nat. Biotechnol. 2021, 39, 393–396. [Google Scholar] [CrossRef]
  10. Gordeychuk, I.V.; Kozlovskaya, L.I.; Siniugina, A.A.; Yagovkina, N.V.; Kuzubov, V.I.; Zakharov, K.A.; Volok, V.P.; Dodina, M.S.; Gmyl, L.V.; Korotina, N.A.; et al. Safety and Immunogenicity of Inactivated Whole Virion COVID-19 Vaccine CoviVac in Clinical Trials in 18-60 and 60+ Age Cohorts. Viruses 2023, 15. [Google Scholar] [CrossRef]
  11. Wu, Z.; Hu, Y.; Xu, M.; Chen, Z.; Yang, W.; Jiang, Z.; Li, M.; Jin, H.; Cui, G.; Chen, P.; et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis 2021, 21, 803–812. [Google Scholar] [CrossRef]
  12. Zhang, Y.; Zeng, G.; Pan, H.; Li, C.; Hu, Y.; Chu, K.; Han, W.; Chen, Z.; Tang, R.; Yin, W.; et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis 2021, 21, 181–192. [Google Scholar] [CrossRef]
  13. Palacios, R.; Patiño, E.G.; de Oliveira Piorelli, R.; Conde, M.; Batista, A.P.; Zeng, G.; Xin, Q.; Kallas, E.G.; Flores, J.; Ockenhouse, C.F.; Gast, C. Double-Blind, Randomized, Placebo-Controlled Phase III Clinical Trial to Evaluate the Efficacy and Safety of treating Healthcare Professionals with the Adsorbed COVID-19 (Inactivated) Vaccine Manufactured by Sinovac - PROFISCOV: A structured summary of a study protocol for a randomised controlled trial. Trials 2020, 21, 853. [Google Scholar] [CrossRef]
  14. www.who.int The WHO validates Sinovac COVID-19 vaccine for emergency use and issues interim policy recommendations, June 1, 2021, accessed November 14, 2023.
  15. Kuo, T.Y.; Lin, M.Y.; Coffman, R.L.; Campbell, J.D.; Traquina, P.; Lin, Y.J.; Liu, L.T.; Cheng, J.; Wu, Y.C.; Wu, C.C.; et al. Development of CpG-adjuvanted stable prefusion SARS-CoV-2 spike antigen as a subunit vaccine against COVID-19. Sci Rep 2020, 10, 20085. [Google Scholar] [CrossRef]
  16. Lazarus, R.; Taucher, C.; Brown, C.; Čorbic Ramljak, I.; Danon, L.; Dubischar, K.; Duncan, C.J.A.; Eder-Lingelbach, S.; Faust, S.N.; Green, C.; et al. Safety and immunogenicity of the inactivated whole-virus adjuvanted COVID-19 vaccine VLA2001: A randomized, dose escalation, double-blind phase 1/2 clinical trial in healthy adults. J Infect 2022, 85, 306–317. [Google Scholar] [CrossRef] [PubMed]
  17. Lazarus, R.; Querton, B.; Corbic Ramljak, I.; Dewasthaly, S.; Jaramillo, J.C.; Dubischar, K.; Krammer, M.; Weisova, P.; Hochreiter, R.; Eder-Lingelbach, S.; et al. Immunogenicity and safety of an inactivated whole-virus COVID-19 vaccine (VLA2001) compared with the adenoviral vector vaccine ChAdOx1-S in adults in the UK (COV-COMPARE): interim analysis of a randomised, controlled, phase 3, immunobridging trial. Lancet Infect Dis 2022, 22, 1716–1727. [Google Scholar] [CrossRef] [PubMed]
  18. www.valneva.com. Valneva Receives Emergency Use Authorization from Bahrain for its Inactivated COVID-19 Vaccine VLA2001 (press release), accessed November 14, 2023.
  19. Pavel, S.T.I.; Yetiskin, H.; Uygut, M.A.; Aslan, A.F.; Aydın, G.; İnan, Ö.; Kaplan, B.; Ozdarendeli, A. Development of an Inactivated Vaccine against SARS CoV-2. Vaccines 2021, 9. [Google Scholar] [CrossRef] [PubMed]
  20. Ozdarendeli, A.; Sezer, Z.; Pavel, S.T.I.; Inal, A.; Yetiskin, H.; Kaplan, B.; Uygut, M.A.; Bayram, A.; Mazicioglu, M.; Unuvar, G.K.; et al. Safety and immunogenicity of an inactivated whole virion SARS-CoV-2 vaccine, TURKOVAC, in healthy adults: Interim results from randomised, double-blind, placebo-controlled phase 1 and 2 trials. Vaccine 2023, 41, 380–390. [Google Scholar] [CrossRef] [PubMed]
  21. Tanriover, M.D.; Aydin, O.A.; Guner, R.; Yildiz, O.; Celik, I.; Doganay, H.L.; Kose, S.; Akhan, S.; Akalin, E.H.; Sezer, Z.; et al. Efficacy. Immunogenicity, and Safety of the Two-Dose Schedules of TURKOVAC versus CoronaVac in Healthy Subjects: A Randomized, Observer-Blinded, Non-Inferiority Phase III Trial. Vaccines 2022, 10, 1865. [Google Scholar] [CrossRef] [PubMed]
  22. Abdoli, A.; Aalizadeh, R.; Aminianfar, H.; Kianmehr, Z.; Teimoori, A.; Azimi, E.; Emamipour, N.; Eghtedardoost, M.; Siavashi, V.; Jamshidi, H.; et al. Safety and potency of BIV-1 CovIran inactivated vaccine candidate for SARS-CoV-2: A preclinical study. Rev. Med. Virol. 2022, 32, e2305. [Google Scholar] [CrossRef]
  23. Mirahmadizadeh, A.; Heiran, A.; Bagheri Lankarani, K.; Serati, M.; Habibi, M.; Eilami, O.; Heiran, F.; Moghadami, M. Effectiveness of Coronavirus Disease 2019 Vaccines in Preventing Infection, Hospital Admission, and Death: A Historical Cohort Study Using Iranian Registration Data During Vaccination Program. Open Forum Infect. Dis. 2022, 9, ofact77. [Google Scholar] [CrossRef]
  24. Yadav, P.D.; Ella, R.; Kumar, S.; Patil, D.R.; Mohandas, S.; Shete, A.M.; Vadrevu, K.M.; Bhati, G.; Sapkal, G.; Kaushal, H.; et al. Immunogenicity and protective efficacy of inactivated SARS-CoV-2 vaccine candidate, BBV152 in rhesus macaques. Nat Commun 2021, 12, 1386. [Google Scholar] [CrossRef] [PubMed]
  25. Ella, R.; Vadrevu, K.M.; Jogdand, H.; Prasad, S.; Reddy, S.; Sarangi, V.; Ganneru, B.; Sapkal, G.; Yadav, P.; Abraham, P.; et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial. Lancet Infect Dis 2021, 21, 637–646. [Google Scholar] [CrossRef]
  26. Ella, R.; Reddy, S.; Blackwelder, W.; Potdar, V.; Yadav, P.; Sarangi, V.; Aileni, V.K.; Kanungo, S.; Rai, S.; Reddy, P.; et al. Efficacy, safety, and lot-to-lot immunogenicity of an inactivated SARS-CoV-2 vaccine (BBV152): interim results of a randomised, double-blind, controlled, phase 3 trial. Lancet 2021, 398, 2173–2184. [Google Scholar] [CrossRef]
  27. Zhugunissov, K.; Zakarya, K.; Khairullin, B.; Orynbayev, M.; Abduraimov, Y.; Kassenov, M.; Sultankulova, K.; Kerimbayev, A.; Nurabayev, S.; Myrzakhmetova, B.; et al. Development of the Inactivated QazCovid-in Vaccine: Protective Efficacy of the Vaccine in Syrian Hamsters. Front Microbiol 2021, 12, 720437. [Google Scholar] [CrossRef] [PubMed]
  28. Zakarya, K.; Kutumbetov, L.; Orynbayev, M.; Abduraimov, Y.; Sultankulova, K.; Kassenov, M.; Sarsenbayeva, G.; Kulmagambetov, I.; Davlyatshin, T.; Sergeeva, M.; et al. Safety and immunogenicity of a QazCovid-in® inactivated whole-virion vaccine against COVID-19 in healthy adults: A single-centre, randomised, single-blind, placebo-controlled phase 1 and an open-label phase 2 clinical trials with a 6 months follow-up in Kazakhstan. EClinicalMedicine 2021, 39, 101078. [Google Scholar] [CrossRef]
  29. Khairullin, B.; Zakarya, K.; Orynbayev, M.; Abduraimov, Y.; Kassenov, M.; Sarsenbayeva, G.; Sultankulova, K.; Chervyakova, O.; Myrzakhmetova, B.; Nakhanov, A.; et al. Efficacy and safety of an inactivated whole-virion vaccine against COVID-19, QazCovid-in®, in healthy adults: A multicentre, randomised, single-blind, placebo-controlled phase 3 clinical trial with a 6-month follow-up. EClinicalMedicine 2022, 50, 101526. [Google Scholar] [CrossRef]
  30. Wang, H.; Zhang, Y.; Huang, B.; Deng, W.; Quan, Y.; Wang, W.; Xu, W.; Zhao, Y.; Li, N.; Zhang, J.; et al. Development of an Inactivated Vaccine Candidate, BBIBP-CorV, with Potent Protection against SARS-CoV-2. Cell 2020, 182, 713–721.e719. [Google Scholar] [CrossRef]
  31. Xia, S.; Zhang, Y.; Wang, Y.; Wang, H.; Yang, Y.; Gao, G.F.; Tan, W.; Wu, G.; Xu, M.; Lou, Z.; et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial. Lancet Infect Dis 2021, 21, 39–51. [Google Scholar] [CrossRef]
  32. Al Kaabi, N.; Zhang, Y.; Xia, S.; Yang, Y.; Al Qahtani, M.M.; Abdulrazzaq, N.; Al Nusair, M.; Hassany, M.; Jawad, J.S.; Abdalla, J.; et al. Effect of 2 Inactivated SARS-CoV-2 Vaccines on Symptomatic COVID-19 Infection in Adults: A Randomized Clinical Trial. Jama 2021, 326, 35–45. [Google Scholar] [CrossRef]
  33. https://www.reuters. "Sinovac's coronavirus vaccine candidate approved for emergency use in China - source". Reuters. 29 August 2020. Accessed November 15, 2023. 2023; 15.
  34. Taylor A (7 May 2021). "WHO grants emergency use authorization for Chinese-made Sinopharm coronavirus vaccine". The Washington Post. Accessed November 15, 2023.
  35. Heidary, M.; Kaviar, V.H.; Shirani, M.; Ghanavati, R.; Motahar, M.; Sholeh, M.; Ghahramanpour, H.; Khoshnood, S. A Comprehensive Review of the Protein Subunit Vaccines Against COVID-19. Front Microbiol 2022, 13, 927306. [Google Scholar] [CrossRef] [PubMed]
  36. Francica, J.R.; Flynn, B.J.; Foulds, K.E.; Noe, A.T.; Werner, A.P.; Moore, I.N.; Gagne, M.; Johnston, T.S.; Tucker, C.; Davis, R.L.; et al. Protective antibodies elicited by SARS-CoV-2 spike protein vaccination are boosted in the lung after challenge in nonhuman primates. Sci Transl Med 2021, 13. [Google Scholar] [CrossRef]
  37. Goepfert, P.A.; Fu, B.; Chabanon, A.L.; Bonaparte, M.I.; Davis, M.G.; Essink, B.J.; Frank, I.; Haney, O.; Janosczyk, H.; Keefer, M.C.; et al. Safety and immunogenicity of SARS-CoV-2 recombinant protein vaccine formulations in healthy adults: interim results of a randomised, placebo-controlled, phase 1-2, dose-ranging study. Lancet Infect Dis 2021, 21, 1257–1270. [Google Scholar] [CrossRef] [PubMed]
  38. Sridhar, S.; Joaquin, A.; Bonaparte, M.I.; Bueso, A.; Chabanon, A.L.; Chen, A.; Chicz, R.M.; Diemert, D.; Essink, B.J.; Fu, B.; et al. Safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein vaccine (CoV2 preS dTM) in healthy adults: interim findings from a phase 2, randomised, dose-finding, multicentre study. Lancet Infect Dis 2022, 22, 636–648. [Google Scholar] [CrossRef]
  39. Liang, J.G.; Su, D.; Song, T.Z.; Zeng, Y.; Huang, W.; Wu, J.; Xu, R.; Luo, P.; Yang, X.; Zhang, X.; et al. S-Trimer, a COVID-19 subunit vaccine candidate, induces protective immunity in nonhuman primates. Nat Commun 2021, 12, 1346. [Google Scholar] [CrossRef] [PubMed]
  40. Richmond, P.; Hatchuel, L.; Dong, M.; Ma, B.; Hu, B.; Smolenov, I.; Li, P.; Liang, P.; Han, H.H.; Liang, J.; Clemens, R. Safety and immunogenicity of S-Trimer (SCB-2019), a protein subunit vaccine candidate for COVID-19 in healthy adults: a phase 1, randomised, double-blind, placebo-controlled trial. Lancet 2021, 397, 682–694. [Google Scholar] [CrossRef]
  41. Buntinx, E.; Brochado, L.; Borja-Tabora, C.; Yu, C.Y.; Alberto, E.R.; Montellano, M.E.B.; Carlos, J.C.; Toloza, L.B.; Hites, M.; Siber, G.; et al. Immunogenicity of an adjuvanted SARS-CoV-2 trimeric S-protein subunit vaccine (SCB-2019) in SARS-CoV-2-naïve and exposed individuals in a phase 2/3, double-blind, randomized study. Vaccine 2023, 41, 1875–1884. [Google Scholar] [CrossRef]
  42. Akhter, A.; Schulz, L.; Inger, H.E.; McGregor, J.M. Current Indications for Management Options in Pseudotumor Cerebri. Neurol Clin 2022, 40, 391–404. [Google Scholar] [CrossRef]
  43. Tabarsi, P.; Anjidani, N.; Shahpari, R.; Mardani, M.; Sabzvari, A.; Yazdani, B.; Roshanzamir, K.; Bayatani, B.; Taheri, A.; Petrovsky, N.; et al. Safety and immunogenicity of SpikoGen®, an Advax-CpG55.2-adjuvanted SARS-CoV-2 spike protein vaccine: a phase 2 randomized placebo-controlled trial in both seropositive and seronegative populations. Clin Microbiol Infect 2022, 28, 1263–1271. [Google Scholar] [CrossRef]
  44. Tabarsi, P.; Anjidani, N.; Shahpari, R.; Mardani, M.; Sabzvari, A.; Yazdani, B.; Kafi, H.; Fallah, N.; Ebrahimi, A.; Taheri, A.; et al. Evaluating the efficacy and safety of SpikoGen®, an Advax-CpG55.2-adjuvanted severe acute respiratory syndrome coronavirus 2 spike protein vaccine: a phase 3 randomized placebo-controlled trial. Clin Microbiol Infect 2023, 29, 215–220. [Google Scholar] [CrossRef]
  45. Tran, T.N.M.; May, B.P.; Ung, T.T.; Nguyen, M.K.; Nguyen, T.T.T.; Dinh, V.L.; Doan, C.C.; Tran, T.V.; Khong, H.; Nguyen, T.T.T.; et al. Preclinical Immune Response and Safety Evaluation of the Protein Subunit Vaccine Nanocovax for COVID-19. Front Immunol 2021, 12, 766112. [Google Scholar] [CrossRef]
  46. Nguyen, T.P.; Do, Q.; Phan, L.T.; Dinh, D.V.; Khong, H.; Hoang, L.V.; Nguyen, T.V.; Pham, H.N.; Chu, M.V.; Nguyen, T.T.; et al. Safety and immunogenicity of Nanocovax, a SARS-CoV-2 recombinant spike protein vaccine: Interim results of a double-blind, randomised controlled phase 1 and 2 trial. Lancet Reg Health West Pac 2022, 24, 100474. [Google Scholar] [CrossRef]
  47. Nguyen, T.P.; Do, Q.; Phan, L.T.; Anh, D.D.; Khong, H.; Nguyen, T.V.; Hoang, L.V.; Dinh, D.V.; Pham, H.N.; Chu, M.V.; et al. The efficacy, safety and immunogenicity of Nanocovax: results of a randomized, double-blind, placebo-controlled Phase 3 trial. medRxiv 2022. [Google Scholar] [CrossRef]
  48. Banihashemi, S.R.; Es-Haghi, A.; Fallah Mehrabadi, M.H.; Nofeli, M.; Mokarram, A.R.; Ranjbar, A.; Salman, M.; Hajimoradi, M.; Razaz, S.H.; Taghdiri, M.; et al. Safety and Efficacy of Combined Intramuscular/Intranasal RAZI-COV PARS Vaccine Candidate Against SARS-CoV-2: A Preclinical Study in Several Animal Models. Front Immunol 2022, 13, 836745. [Google Scholar] [CrossRef]
  49. Mohazzab, A.; Fallah Mehrabadi, M.H.; Es-Haghi, A.; Kalantari, S.; Mokhberalsafa, L.; Setarehdan, S.A.; Sadeghi, F.; Rezaei Mokarram, A.; Haji Moradi, M.; Razaz, S.H.; et al. Phase II, Safety and Immunogenicity of RAZI Cov Pars (RCP) SARS Cov-2 Vaccine in Adults Aged 18-70 Years; A Randomized, Double-Blind Clinical Trial. J Pharm Sci 2023. [Google Scholar] [CrossRef] [PubMed]
  50. Lien, C.E.; Lin, Y.J.; Chen, C.; Lian, W.C.; Kuo, T.Y.; Campbell, J.D.; Traquina, P.; Lin, M.Y.; Liu, L.T.; Chuang, Y.S.; et al. CpG-adjuvanted stable prefusion SARS-CoV-2 spike protein protected hamsters from SARS-CoV-2 challenge. Sci Rep 2021, 11, 8761. [Google Scholar] [CrossRef]
  51. Hsieh, S.M.; Chang, S.C.; Cheng, H.Y.; Shih, S.R.; Lien, C.E. Durability and Immunogenicity of Neutralizing Antibodies Response Against Omicron Variants After Three Doses of Subunit SARS-CoV-2 Vaccine MVC-COV1901: An Extension to an Open-Label, Dose-Escalation Phase 1 Study. Infect Dis Ther 2022, 11, 1493–1504. [Google Scholar] [CrossRef]
  52. Hsieh, S.M.; Liu, M.C.; Chen, Y.H.; Lee, W.S.; Hwang, S.J.; Cheng, S.H.; Ko, W.C.; Hwang, K.P.; Wang, N.C.; Lee, Y.L.; et al. Safety and immunogenicity of CpG 1018 and aluminium hydroxide-adjuvanted SARS-CoV-2 S-2P protein vaccine MVC-COV1901: interim results of a large-scale, double-blind, randomised, placebo-controlled phase 2 trial in Taiwan. Lancet Respir Med 2021, 9, 1396–1406. [Google Scholar] [CrossRef] [PubMed]
  53. Torales, J.; Cuenca-Torres, O.; Barrios, L.; Armoa-Garcia, L.; Estigarribia, G.; Sanabria, G.; Lin, M.Y.; Antonio Estrada, J.; Estephan, L.; Cheng, H.Y.; et al. An evaluation of the safety and immunogenicity of MVC-COV1901: Results of an interim analysis of a phase III, parallel group, randomized, double-blind, active-controlled immunobridging study in Paraguay. Vaccine 2023, 41, 109–118. [Google Scholar] [CrossRef] [PubMed]
  54. Arzumanyan, V.G.; Bystritskaya, E.P.; Kolyganova, T.I.; Iksanova, A.M.; Samoilikov, P.V.; Konanykhina, S.Y.; Vartanova, A.A.; Svitich, O.A. Antimicrobial Activity of the Serum before and after Vaccination with EpiVacCorona. Bull. Exp. Biol. Med. 2022, 173, 354–360. [Google Scholar] [CrossRef] [PubMed]
  55. Ryzhikov, A.B.; Ryzhikov, E.А.; Bogryantseva, M.P.; Danilenko, E.D.; Imatdinov, I.R.; Nechaeva, E.A.; Pyankov, O.V.; Pyankova, O.G.; Susloparov, I.M.; Taranov, O.S. Immunogenicity and protectivity of the peptide vaccine against SARS-CoV-2. Ann. Russian Acad. Med. Sci. 2021, 76, 5–19. [Google Scholar] [CrossRef]
  56. Ryzhikov, A.B.; Ryzhikov, E.A.; Bogryantseva, M.P.; Usova, S.V.; Nechaeva, E.A.; Danilenko, E.D.; Pyankov, S.A.; Gudymo, A.S.; Moiseeva, A.A.; Onkhonova, G.S.; et al. Assessment of Safety and Prophylactic Efficacy of the EpiVacCorona Peptide Vaccine for COVID-19 Prevention (Phase III). Vaccines (Basel) 2023, 11. [Google Scholar] [CrossRef]
  57. Wang, R.; Sun, C.; Ma, J.; Yu, C.; Kong, D.; Chen, M.; Liu, X.; Zhao, D.; Gao, S.; Kou, S.; et al. A Bivalent COVID-19 Vaccine Based on Alpha and Beta Variants Elicits Potent and Broad Immune Responses in Mice against SARS-CoV-2 Variants. Vaccines (Basel) 2022, 10. [Google Scholar] [CrossRef]
  58. Wang, G.; Zhao, K.; Han, J.; Hu, Z.; Zhang, T.; Wang, Y.; Shi, R.; Li, Y.; Song, Q.; Du, H.; et al. Safety and immunogenicity of a bivalent SARS-CoV-2 recombinant protein vaccine, SCTV01C in unvaccinated adults: a randomized, double-blinded, placebo-controlled, phase I clinical trial. J. Infect. 2022, 86, 154–225. [Google Scholar] [CrossRef]
  59. Hannawi, S.; Yan, L.; Saifeldin, L.; Abuquta, A.; Alamadi, A.; Mahmoud, S.A.; Hassan, A.; Zhang, M.; Gao, C.; Chen, Y.; et al. Safety and immunogenicity of multivalent SARS-CoV-2 protein vaccines: a randomized phase 3 trial. EClinicalMedicine 2023, 64, 102195. [Google Scholar] [CrossRef]
  60. Yu, D. China grants emergency use of new vaccines as it eases COVID-19 policy, BioWorld 2022, www.bioworld.com/articles/692398-china-grants-emergency-use-of-new-vaccines-as-it-eases-covid-19-policy?v=preview Accessed on December 21, 2023.
  61. An, Y.; Li, S.; Jin, X.; Han, J.B.; Xu, K.; Xu, S.; Han, Y.; Liu, C.; Zheng, T.; Liu, M.; et al. A tandem-repeat dimeric RBD protein-based covid-19 vaccine zf2001 protects mice and nonhuman primates. Emerg Microbes Infect 2022, 11, 1058–1071. [Google Scholar] [CrossRef]
  62. Yang, S.; Li, Y.; Dai, L.; Wang, J.; He, P.; Li, C.; Fang, X.; Wang, C.; Zhao, X.; Huang, E.; et al. Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19 in adults: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials. Lancet Infect Dis 2021, 21, 1107–1119. [Google Scholar] [CrossRef]
  63. Dai, L.; Gao, L.; Tao, L.; Hadinegoro, S.R.; Erkin, M.; Ying, Z.; He, P.; Girsang, R.T.; Vergara, H.; Akram, J.; et al. Efficacy and Safety of the RBD-Dimer-Based Covid-19 Vaccine ZF2001 in Adults. N Engl J Med 2022, 386, 2097–2111. [Google Scholar] [CrossRef]
  64. Duan, M.; Duan, H.; An, Y.; Zheng, T.; Wan, S.; Wang, H.; Zhao, X.; Dai, L.; Xu, K.; Gao, G.F. A booster of Delta-Omicron RBD-dimer protein subunit vaccine augments sera neutralization of Omicron sub-variants BA.1/BA.2/BA.2.12.1/BA.4/BA.5. Emerg Microbes Infect 2023, 12, e2179357. [Google Scholar] [CrossRef]
  65. Limonta-Fernández, M.; Chinea-Santiago, G.; Martín-Dunn, A.M.; Gonzalez-Roche, D.; Bequet-Romero, M.; Marquez-Perera, G.; González-Moya, I.; Canaan-Haden-Ayala, C.; Cabrales-Rico, A.; Espinosa-Rodríguez, L.A.; et al. An engineered SARS-CoV-2 receptor-binding domain produced in Pichia pastoris as a candidate vaccine antigen. N Biotechnol 2022, 72, 11–21. [Google Scholar] [CrossRef]
  66. Hernández-Bernal, F.; Ricardo-Cobas, M.C.; Martín-Bauta, Y.; Navarro-Rodríguez, Z.; Piñera-Martínez, M.; Quintana-Guerra, J.; Urrutia-Pérez, K.; Urrutia-Pérez, K.; Chávez-Chong, C.O.; Azor-Hernández, J.L.; et al. Safety, tolerability, and immunogenicity of a SARS-CoV-2 recombinant spike RBD protein vaccine: A randomised, double-blind, placebo-controlled, phase 1-2 clinical trial (ABDALA Study). EClinicalMedicine 2022, 46, 101383. [Google Scholar] [CrossRef]
  67. Hernández-Bernal, F.; Ricardo-Cobas, M.C.; Martín-Bauta, Y.; Rodríguez-Martínez, E.; Urrutia-Pérez, K.; Urrutia-Pérez, K.; Quintana-Guerra, J.; Navarro-Rodríguez, Z.; Piñera-Martínez, M.; Rodríguez-Reinoso, J.L.; et al. A phase 3, randomised, double-blind, placebo-controlled clinical trial evaluation of the efficacy and safety of a SARS-CoV-2 recombinant spike RBD protein vaccine in adults (ABDALA-3 study). Lancet Reg Health Am 2023, 21, 100497. [Google Scholar] [CrossRef]
  68. Reuters. Cuban drug regulator gives emergency approval to Abdala COVID-19 vaccine. Available online: Cuban drug regulator gives emergency approval to Abdala COVID-19 vaccine. www.reuters.com/world/americas/cuban-drug-regulator-gives-emergency-approval-abdala-covid-19-vaccine-2021-07-09/, Accessed on November 24, 2023.
  69. Pollet, J.; Chen, W.H.; Versteeg, L.; Keegan, B.; Zhan, B.; Wei, J.; Liu, Z.; Lee, J.; Kundu, R.; Adhikari, R.; et al. SARS-CoV-2 RBD219-N1C1: A yeast-expressed SARS-CoV-2 recombinant receptor-binding domain candidate vaccine stimulates virus neutralizing antibodies and T-cell immunity in mice. Hum Vaccin Immunother 2021, 17, 2356–2366. [Google Scholar] [CrossRef]
  70. Thuluva, S.; Paradkar, V.; Gunneri, S.R.; Yerroju, V.; Mogulla, R.; Turaga, K.; Kyasani, M.; Manoharan, S.K.; Medigeshi, G.; Singh, J.; et al. Evaluation of safety and immunogenicity of receptor-binding domain-based COVID-19 vaccine (Corbevax) to select the optimum formulation in open-label, multicentre, and randomised phase-1/2 and phase-2 clinical trials. EBioMedicine 2022, 83, 104217. [Google Scholar] [CrossRef]
  71. Thuluva, S.; Paradkar, V.; Gunneri, S.; Yerroju, V.; Mogulla, R.; Suneetha, P.V.; Turaga, K.; Kyasani, M.; Manoharan, S.K.; Adabala, S.; et al. Immunogenicity and safety of Biological E's CORBEVAX™ vaccine compared to COVISHIELD™ (ChAdOx1 nCoV-19) vaccine studied in a phase-3, single blind, multicentre, randomized clinical trial. Hum Vaccin Immunother 2023, 19, 2203632. [Google Scholar] [CrossRef]
  72. Pulla, P. India’s speedy vaccine approvals come under fire. Science 2022, 376, 442–443. [Google Scholar] [CrossRef]
  73. Valdes-Balbin, Y.; Santana-Mederos, D.; Quintero, L.; Fernández, S.; Rodriguez, L.; Sanchez Ramirez, B.; Perez-Nicado, R.; Acosta, C.; Méndez, Y.; Ricardo, M.G.; et al. SARS-CoV-2 RBD-Tetanus Toxoid Conjugate Vaccine Induces a Strong Neutralizing Immunity in Preclinical Studies. ACS Chem Biol 2021, 16, 1223–1233. [Google Scholar] [CrossRef]
  74. Puga-Gómez, R.; Ricardo-Delgado, Y.; Rojas-Iriarte, C.; Céspedes-Henriquez, L.; Piedra-Bello, M.; Vega-Mendoza, D.; Pérez, N.P.; Paredes-Moreno, B.; Rodríguez-González, M.; Valenzuela-Silva, C.; et al. Open-label phase I/II clinical trial of SARS-CoV-2 receptor binding domain-tetanus toxoid conjugate vaccine (FINLAY-FR-2) in combination with receptor binding domain-protein vaccine (FINLAY-FR-1A) in children. Int J Infect Dis 2023, 126, 164–173. [Google Scholar] [CrossRef]
  75. Mostafavi, E.; Eybpoosh, S.; Karamouzian, M.; Khalili, M.; Haji-Maghsoudi, S.; Salehi-Vaziri, M.; Khamesipour, A.; Jalali, T.; Nakhaeizadeh, M.; Sharifi, H.; et al. Efficacy and Safety of a Protein-Based SARS-CoV-2 Vaccine: A Randomized Clinical Trial. JAMA Netw Open 2023, 6, e2310302. [Google Scholar] [CrossRef]
  76. Wang, S.; Wang, C.Y.; Kuo, H.K.; Peng, W.J.; Huang, J.H.; Kuo, B.S.; Lin, F.; Liu, Y.J.; Liu, Z.; Wu, H.T.; et al. A novel RBD-protein/peptide vaccine elicits broadly neutralizing antibodies and protects mice and macaques against SARS-CoV-2. Emerg Microbes Infect 2022, 11, 2724–2734. [Google Scholar] [CrossRef]
  77. Wang, C.Y.; Hwang, K.P.; Kuo, H.K.; Peng, W.J.; Shen, Y.H.; Kuo, B.S.; Huang, J.H.; Liu, H.; Ho, Y.H.; Lin, F.; et al. A multitope SARS-CoV-2 vaccine provides long-lasting B cell and T cell immunity against Delta and Omicron variants. J Clin Invest 2022, 132. [Google Scholar] [CrossRef]
  78. Jiaping, Y.; Wenrong, Y.; Yingsong, H.; Shuang, W.; Jiao, L.; Hongjun, Z.; Kunxue, H.; Jianping, C.; Longding, L.; Ke, L.; et al. A trimeric NTD and RBD SARS-CoV-2 subunit vaccine induced protective immunity in CAG-hACE2 transgenic mice and rhesus macaques. bioRxiv 2011, 2021.2011.2003.467182. [Google Scholar] [CrossRef]
  79. Technology, J.R. The Philippines Has Approved ReCOV For Phase II/III Cinical Research. Available online: https://www.recbio.cn/en/media/press-release/the-philippines-has-approved-recov-for-phase-iiiii-cinical-research/ (accessed on 6 December 2023).
  80. Technology, J.R. Two-Component Recombinant COVID-19 Vaccine ReCOV Granted With Emergency Use Authorization In Mongolia. Available online: https://www.recbio.cn/en/media/press-release/20230320/ (accessed on 21 December 2023).
  81. Tian, J.H.; Patel, N.; Haupt, R.; Zhou, H.; Weston, S.; Hammond, H.; Logue, J.; Portnoff, A.D.; Norton, J.; Guebre-Xabier, M.; et al. SARS-CoV-2 spike glycoprotein vaccine candidate NVX-CoV2373 immunogenicity in baboons and protection in mice. Nat Commun 2021, 12, 372. [Google Scholar] [CrossRef]
  82. Keech, C.; Albert, G.; Cho, I.; Robertson, A.; Reed, P.; Neal, S.; Plested, J.S.; Zhu, M.; Cloney-Clark, S.; Zhou, H.; et al. Phase 1-2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine. N Engl J Med 2020, 383, 2320–2332. [Google Scholar] [CrossRef]
  83. Heath, P.T.; Galiza, E.P.; Baxter, D.N.; Boffito, M.; Browne, D.; Burns, F.; Chadwick, D.R.; Clark, R.; Cosgrove, C.A.; Galloway, J.; et al. Safety and Efficacy of the NVX-CoV2373 Coronavirus Disease 2019 Vaccine at Completion of the Placebo-Controlled Phase of a Randomized Controlled Trial. Clin Infect Dis 2023, 76, 398–407. [Google Scholar] [CrossRef] [PubMed]
  84. Parums, D.V. Editorial: First Approval of the Protein-Based Adjuvanted Nuvaxovid (NVX-CoV2373) Novavax Vaccine for SARS-CoV-2 Could Increase Vaccine Uptake and Provide Immune Protection from Viral Variants. Med Sci Monit 2022, 28, e936523. [Google Scholar] [CrossRef]
  85. Jacob-Dolan, C.; Yu, J.; McMahan, K.; Giffin, V.; Chandrashekar, A.; Martinot, A.J.; Anioke, T.; Powers, O.C.; Hall, K.; Hope, D.; et al. Immunogenicity and protective efficacy of GBP510/AS03 vaccine against SARS-CoV-2 delta challenge in rhesus macaques. NPJ Vaccines 2023, 8, 23. [Google Scholar] [CrossRef]
  86. Song, J.Y.; Choi, W.S.; Heo, J.Y.; Lee, J.S.; Jung, D.S.; Kim, S.W.; Park, K.H.; Eom, J.S.; Jeong, S.J.; Lee, J.; et al. Safety and immunogenicity of a SARS-CoV-2 recombinant protein nanoparticle vaccine (GBP510) adjuvanted with AS03: A randomised, placebo-controlled, observer-blinded phase 1/2 trial. EClinicalMedicine 2022, 51, 101569. [Google Scholar] [CrossRef]
  87. Song, J.Y.; Choi, W.S.; Heo, J.Y.; Kim, E.J.; Lee, J.S.; Jung, D.S.; Kim, S.W.; Park, K.H.; Eom, J.S.; Jeong, S.J.; et al. Immunogenicity and safety of SARS-CoV-2 recombinant protein nanoparticle vaccine GBP510 adjuvanted with AS03: interim results of a randomised, active-controlled, observer-blinded, phase 3 trial. EClinicalMedicine 2023, 64, 102140. [Google Scholar] [CrossRef]
  88. Vanaparthy, R.; Mohan, G.; Vasireddy, D.; Atluri, P. Review of COVID-19 viral vector-based vaccines and COVID-19 variants. Infez Med 2021, 29, 328–338. [Google Scholar] [CrossRef] [PubMed]
  89. Lundstrom, K. Viral Vectors for COVID-19 Vaccine Development. Viruses 2021, 13. [Google Scholar] [CrossRef] [PubMed]
  90. van Doremalen, N.; Lambe, T.; Spencer, A.; Belij-Rammerstorfer, S.; Purushotham, J.N.; Port, J.R.; Avanzato, V.A.; Bushmaker, T.; Flaxman, A.; Ulaszewska, M.; et al. ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature 2020, 586, 578–582. [Google Scholar] [CrossRef] [PubMed]
  91. Folegatti, P.M.; Ewer, K.J.; Aley, P.K.; Angus, B.; Becker, S.; Belij-Rammerstorfer, S.; Bellamy, D.; Bibi, S.; Bittaye, M.; Clutterbuck, E.A.; et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 2020, 396, 467–478. [Google Scholar] [CrossRef] [PubMed]
  92. Voysey, M.; Clemens, S.A.C.; Madhi, S.A.; Weckx, L.Y.; Folegatti, P.M.; Aley, P.K.; Angus, B.; Baillie, V.L.; Barnabas, S.L.; Bhorat, Q.E.; et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021, 397, 99–111. [Google Scholar] [CrossRef] [PubMed]
  93. UK, G.O.V. Regulatory approval of COVID-19 vaccine AstraZeneca. GOV. UK 2021.
  94. Wu, S.; Zhong, G.; Zhang, J.; Shuai, L.; Zhang, Z.; Wen, Z.; Wang, B.; Zhao, Z.; Song, X.; Chen, Y.; et al. A single dose of an adenovirus-vectored vaccine provides protection against SARS-CoV-2 challenge. Nat Commun 2020, 11, 4081. [Google Scholar] [CrossRef]
  95. Feng, L.; Wang, Q.; Shan, C.; Yang, C.; Feng, Y.; Wu, J.; Liu, X.; Zhou, Y.; Jiang, R.; Hu, P.; et al. An adenovirus-vectored COVID-19 vaccine confers protection from SARS-COV-2 challenge in rhesus macaques. Nat Commun 2020, 11, 4207. [Google Scholar] [CrossRef]
  96. Zhu, F.C.; Li, Y.H.; Guan, X.H.; Hou, L.H.; Wang, W.J.; Li, J.X.; Wu, S.P.; Wang, B.S.; Wang, Z.; Wang, L.; et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet 2020, 395, 1845–1854. [Google Scholar] [CrossRef]
  97. Zhu, F.C.; Guan, X.H.; Li, Y.H.; Huang, J.Y.; Jiang, T.; Hou, L.H.; Li, J.X.; Yang, B.F.; Wang, L.; Wang, W.J.; et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2020, 396, 479–488. [Google Scholar] [CrossRef]
  98. Halperin, S.A.; Ye, L.; MacKinnon-Cameron, D.; Smith, B.; Cahn, P.E.; Ruiz-Palacios, G.M.; Ikram, A.; Lanas, F.; Lourdes Guerrero, M.; Muñoz Navarro, S.R.; et al. Final efficacy analysis, interim safety analysis, and immunogenicity of a single dose of recombinant novel coronavirus vaccine (adenovirus type 5 vector) in adults 18 years and older: an international, multicentre, randomised, double-blinded, placebo-controlled phase 3 trial. Lancet 2022, 399, 237–248. [Google Scholar] [CrossRef]
  99. Staff, R. China approves two more domestic COVID-19 vaccines for public use. 2021.
  100. Bos, R.; Rutten, L.; van der Lubbe, J.E.M.; Bakkers, M.J.G.; Hardenberg, G.; Wegmann, F.; Zuijdgeest, D.; de Wilde, A.H.; Koornneef, A.; Verwilligen, A.; et al. Ad26 vector-based COVID-19 vaccine encoding a prefusion-stabilized SARS-CoV-2 Spike immunogen induces potent humoral and cellular immune responses. NPJ Vaccines 2020, 5, 91. [Google Scholar] [CrossRef] [PubMed]
  101. Mercado, N.B.; Zahn, R.; Wegmann, F.; Loos, C.; Chandrashekar, A.; Yu, J.; Liu, J.; Peter, L.; McMahan, K.; Tostanoski, L.H.; et al. Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques. Nature 2020, 586, 583–588. [Google Scholar] [CrossRef]
  102. Sadoff, J.; Le Gars, M.; Shukarev, G.; Heerwegh, D.; Truyers, C.; de Groot, A.M.; Stoop, J.; Tete, S.; Van Damme, W.; Leroux-Roels, I.; et al. Interim Results of a Phase 1-2a Trial of Ad26.COV2.S Covid-19 Vaccine. N Engl J Med 2021, 384, 1824–1835. [Google Scholar] [CrossRef]
  103. Sadoff, J.; Gray, G.; Vandebosch, A.; Cárdenas, V.; Shukarev, G.; Grinsztejn, B.; Goepfert, P.A.; Truyers, C.; Van Dromme, I.; Spiessens, B.; et al. Final Analysis of Efficacy and Safety of Single-Dose Ad26.COV2.S. N Engl J Med 2022, 386, 847–860. [Google Scholar] [CrossRef]
  104. Shay, D.K.; Gee, J.; Su, J.R.; Myers, T.R.; Marquez, P.; Liu, R.; Zhang, B.; Licata, C.; Clark, T.A.; Shimabukuro, T.T. Safety Monitoring of the Janssen (Johnson & Johnson) COVID-19 Vaccine - United States, March-April 2021. MMWR Morb Mortal Wkly Rep 2021, 70, 680–684. [Google Scholar] [CrossRef]
  105. Balakrishnan, V.S. The arrival of Sputnik V. Lancet Infect Dis 2020, 20, 1128. [Google Scholar] [CrossRef]
  106. Logunov, D.Y.; Dolzhikova, I.V.; Zubkova, O.V.; Tukhvatulin, A.I.; Shcheblyakov, D.V.; Dzharullaeva, A.S.; Grousova, D.M.; Erokhova, A.S.; Kovyrshina, A.V.; Botikov, A.G.; et al. , Safety and immunogenicity of an RAd26 and RAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet 2020, 396, 887–897. [Google Scholar] [CrossRef]
  107. Tukhvatulin, A.I.; Dolzhikova, I.V.; Dzharullaeva, A.S.; Grousova, D.M.; Kovyrshina, A.V.; Zubkova, O.V.; Zorkov, I.D.; Iliukhina, A.A.; Shelkov, A.Y.; Erokhova, A.S.; et al. Safety and immunogenicity of rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine against SARS-CoV-2 in healthy adolescents: an open-label, non-randomized, multicenter, phase 1/2, dose-escalation study. Front Immunol 2023, 14, 1228461. [Google Scholar] [CrossRef]
  108. Logunov, D.Y.; Dolzhikova, I.V.; Shcheblyakov, D.V.; Tukhvatulin, A.I.; Zubkova, O.V.; Dzharullaeva, A.S.; Kovyrshina, A.V.; Lubenets, N.L.; Grousova, D.M.; Erokhova, A.S.; et al. , Safety and efficacy of an RAd26 and RAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet 2021, 397, 671–681. [Google Scholar] [CrossRef]
  109. Callaway, E. Russia's fast-track coronavirus vaccine draws outrage over safety. Nature 2020, 584, 334–335. [Google Scholar] [CrossRef]
  110. Capone, S.; Raggioli, A.; Gentile, M.; Battella, S.; Lahm, A.; Sommella, A.; Contino, A.M.; Urbanowicz, R.A.; Scala, R.; Barra, F.; et al. Immunogenicity of a new gorilla adenovirus vaccine candidate for COVID-19. Mol Ther 2021, 29, 2412–2423. [Google Scholar] [CrossRef]
  111. Lanini, S.; Capone, S.; Antinori, A.; Milleri, S.; Nicastri, E.; Camerini, R.; Agrati, C.; Castilletti, C.; Mori, F.; Sacchi, A.; et al. GRAd-COV2, a gorilla adenovirus-based candidate vaccine against COVID-19, is safe and immunogenic in younger and older adults. Sci Transl Med 2022, 14, eabj1996. [Google Scholar] [CrossRef]
  112. Chiuppesi, F.; Salazar, M.D.; Contreras, H.; Nguyen, V.H.; Martinez, J.; Park, Y.; Nguyen, J.; Kha, M.; Iniguez, A.; Zhou, Q.; et al. Development of a multi-antigenic SARS-CoV-2 vaccine candidate using a synthetic poxvirus platform. Nat Commun 2020, 11, 6121. [Google Scholar] [CrossRef]
  113. García-Arriaza, J.; Garaigorta, U.; Pérez, P.; Lázaro-Frías, A.; Zamora, C.; Gastaminza, P.; Del Fresno, C.; Casasnovas, J.M.; Sorzano CÓ, S.; Sancho, D.; Esteban, M. COVID-19 vaccine candidates based on modified vaccinia virus Ankara expressing the SARS-CoV-2 spike induce robust T- and B-cell immune responses and full efficacy in mice. J Virol 2021, 95. [Google Scholar] [CrossRef] [PubMed]
  114. Lázaro-Frías, A.; Pérez, P.; Zamora, C.; Sánchez-Cordón, P.J.; Guzmán, M.; Luczkowiak, J.; Delgado, R.; Casasnovas, J.M.; Esteban, M.; García-Arriaza, J. Full efficacy and long-term immunogenicity induced by the SARS-CoV-2 vaccine candidate MVA-CoV2-S in mice. npj Vaccines 2022, 7. [Google Scholar] [CrossRef]
  115. Shamsrizi, P.; Kramer, F.J.; Addo, M.M.; Fathi, A. Characterization of Individuals Interested in Participating in a Phase I SARS-CoV-2 Trial Vaccine Trial. Vaccines 2021, 9, 1208. [Google Scholar] [CrossRef]
  116. COVID-19 Trial of the Candidate Vaccine MVA-SARS-2-S in Adults. www.clinicaltrials.gov/NCT05950776.
  117. Sun, W.; McCroskery, S.; Liu, W.C.; Leist, S.R.; Liu, Y.; Albrecht, R.A.; Slamanig, S.; Oliva, J.; Amanat, F.; Schäfer, A.; et al. A Newcastle Disease Virus (NDV) Expressing a Membrane-Anchored Spike as a Cost-Effective Inactivated SARS-CoV-2 Vaccine. Vaccines (Basel) 2020, 8. [Google Scholar] [CrossRef]
  118. Pitisuttithum, P.; Luvira, V.; Lawpoolsri, S.; Muangnoicharoen, S.; Kamolratanakul, S.; Sivakorn, C.; Narakorn, P.; Surichan, S.; Prangpratanporn, S.; Puksuriwong, S.; et al. Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomised, placebo-controlled, phase 1 trial. EClinicalMedicine 2022, 45, 101323. [Google Scholar] [CrossRef]
  119. Ku, M.W.; Bourgine, M.; Authié, P.; Lopez, J.; Nemirov, K.; Moncoq, F.; Noirat, A.; Vesin, B.; Nevo, F.; Blanc, C.; et al. Intranasal vaccination with a lentiviral vector protects against SARS-CoV-2 in preclinical animal models. Cell Host Microbe 2021, 29, 236–249.e236. [Google Scholar] [CrossRef]
  120. Arif, K.; Malhotra, S.; Mohammad, S.; Fatima, S.; Farooqui, S.; Saleem, M. Review of current vaccine development platform to prevent coronavirus disease. Natl. J. Maxillofac. Surg. 2022, 13, 337–346. [Google Scholar] [CrossRef]
  121. Immunity and Safety of Covid-19 Synthetic Minigene Vaccine. www.clinicaltrials.gov/NCT04276896.
  122. Loes, A.N.; Gentles, L.E.; Greaney, A.J.; Crawford, K.H.D.; Bloom, J.D. Attenuated Influenza Virions Expressing the SARS-CoV-2 Receptor-Binding Domain Induce Neutralizing Antibodies in Mice. Viruses 2020, 12. [Google Scholar] [CrossRef]
  123. Zhu, F.; Zhuang, C.; Chu, K.; Zhang, L.; Zhao, H.; Huang, S.; Su, Y.; Lin, H.; Yang, C.; Jiang, H. Safety and immunogenicity of a live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine in adults: randomised, double-blind, placebo-controlled, phase 1 and 2 trials. Lancet Respir. Med. 2022, 10, 749–760. [Google Scholar] [CrossRef] [PubMed]
  124. Hörner, C.; Schürmann, C.; Auste, A.; Ebenig, A.; Muraleedharan, S.; Dinnon, K.H., 3rd; Scholz, T.; Herrmann, M.; Schnierle, B.S.; Baric, R.S.; Mühlebach, M.D. A highly immunogenic and effective measles virus-based Th1-biased COVID-19 vaccine. Proc Natl Acad Sci U S A 2020, 117, 32657–32666. [Google Scholar] [CrossRef]
  125. Launay, O.; Artaud, C.; Lachâtre, M.; Ait-Ahmed, M.; Klein, J.; Luong Nguyen, L.B.; Durier, C.; Jansen, B.; Tomberger, Y.; Jolly, N.; et al. Safety and immunogenicity of a measles-vectored SARS-CoV-2 vaccine candidate, V591 / TMV-083, in healthy adults: results of a randomized, placebo-controlled Phase I study. EBioMedicine 2022, 75, 103810. [Google Scholar] [CrossRef] [PubMed]
  126. Case, J.B.; Rothlauf, P.W.; Chen, R.E.; Kafai, N.M.; Fox, J.M.; Smith, B.K.; Shrihari, S.; McCune, B.T.; Harvey, I.B.; Keeler, S.P.; et al. Replication-Competent Vesicular Stomatitis Virus Vaccine Vector Protects against SARS-CoV-2-Mediated Pathogenesis in Mice. Cell Host Microbe 2020, 28, 465–474.e464. [Google Scholar] [CrossRef] [PubMed]
  127. Robbins, J.A.; Tait, D.; Huang, Q.; Dubey, S.; Crumley, T.; Cote, J.; Luk, J.; Sachs, J.R.; Rutkowski, K.; Park, H.; et al. Safety and immunogenicity of intramuscular, single-dose V590 (rVSV-SARS-CoV-2 Vaccine) in healthy adults: Results from a phase 1 randomised, double-blind, placebo-controlled, dose-ranging trial. EBioMedicine 2022, 82, 104138. [Google Scholar] [CrossRef] [PubMed]
  128. Yahalom-Ronen, Y.; Tamir, H.; Melamed, S.; Politi, B.; Shifman, O.; Achdout, H.; Vitner, E.B.; Israeli, O.; Milrot, E.; Stein, D.; et al. A single dose of recombinant VSV-∆G-spike vaccine provides protection against SARS-CoV-2 challenge. Nat Commun 2020, 11, 6402. [Google Scholar] [CrossRef]
  129. Yahalom-Ronen, Y.; Erez, N.; Fisher, M.; Tamir, H.; Politi, B.; Achdout, H.; Melamed, S.; Glinert, I.; Weiss, S.; Cohen-Gihon, I.; et al. Neutralization of SARS-CoV-2 Variants by rVSV-∆G-Spike-Elicited Human Sera. Vaccines 2022, 10, 291. [Google Scholar] [CrossRef]
  130. Hennrich, A.A.; Sawatsky, B.; Santos-Mandujano, R.; Banda, D.H.; Oberhuber, M.; Schopf, A.; Pfaffinger, V.; Wittwer, K.; Riedel, C.; Pfaller, C.K.; et al. Safe and effective two-in-one replicon-and-VLP minispike vaccine for COVID-19: Protection of mice after a single immunization. PLoS Pathog. 2021, 17, e1009064. [Google Scholar] [CrossRef]
  131. Jazayeri, S.D.; Poh, C.L. Recent advances in delivery of veterinary DNA vaccines against avian pathogens. Vet. Res. 2019, 50, 78. [Google Scholar] [CrossRef]
  132. Liu, H.; Yang, Z.; Xun, Z.; Gao, Z.; Sun, Y.; Yu, J.; Yang, T.; Zhao, X.; Cai, C.; Ding, P. Nuclear delivery of plasmid DNA determines the efficiency of gene expression. Cell Biol Int 2019, 43, 789–798. [Google Scholar] [CrossRef]
  133. Yu, J.; Tostanoski, L.H.; Peter, L.; Mercado, N.B.; McMahan, K.; Mahrokhian, S.H.; Nkolola, J.P.; Liu, J.; Li, Z.; Chandrashekar, A.; et al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science 2020, 369, 806–811. [Google Scholar] [CrossRef] [PubMed]
  134. Smith, T.R.F.; Patel, A.; Ramos, S.; Elwood, D.; Zhu, X.; Yan, J.; Gary, E.N.; Walker, S.N.; Schultheis, K.; Purwar, M.; et al. Immunogenicity of a DNA vaccine candidate for COVID-19. Nat Commun 2020, 11, 2601. [Google Scholar] [CrossRef] [PubMed]
  135. Kraynyak, K.A.; Blackwood, E.; Agnes, J.; Tebas, P.; Giffear, M.; Amante, D.; Reuschel, E.L.; Purwar, M.; Christensen-Quick, A.; Liu, N.; et al. SARS-CoV-2 DNA Vaccine INO-4800 Induces Durable Immune Responses Capable of Being Boosted in a Phase 1 Open-Label Trial. J Infect Dis 2022, 225, 1923–1932. [Google Scholar] [CrossRef]
  136. Mammen, M.P.; Tebas, P.; Agnes, J.; Giffear, M.; Kraynyak, K.A.; Blackwood, E.; Amante, D.; Reuschel, E.L.; Purwar, M.; Christensen-Quick, A.; et al. Safety and immunogenicity of INO-4800 DNA vaccine against SARS-CoV-2: a preliminary report of a randomized, blinded, placebo-controlled, Phase 2 clinical trial in adults at high risk of viral exposure. medRxiv 2021. [Google Scholar] [CrossRef]
  137. Dey, A.; Chozhavel Rajanathan, T.M.; Chandra, H.; Pericherla, H.P.R.; Kumar, S.; Choonia, H.S.; Bajpai, M.; Singh, A.K.; Sinha, A.; Saini, G.; et al. Immunogenic potential of DNA vaccine candidate, ZyCoV-D against SARS-CoV-2 in animal models. Vaccine 2021, 39, 4108–4116. [Google Scholar] [CrossRef]
  138. Momin, T.; Kansagra, K.; Patel, H.; Sharma, S.; Sharma, B.; Patel, J.; Mittal, R.; Sanmukhani, J.; Maithal, K.; Dey, A.; et al. Safety and Immunogenicity of a DNA SARS-CoV-2 vaccine (ZyCoV-D): Results of an open-label, non-randomized phase I part of phase I/II clinical study by intradermal route in healthy subjects in India. EClinicalMedicine 2021, 38, 101020. [Google Scholar] [CrossRef] [PubMed]
  139. Khobragade, A.; Bhate, S.; Ramaiah, V.; Deshpande, S.; Giri, K.; Phophle, H.; Supe, P.; Godara, I.; Revanna, R.; Nagarkar, R.; et al. Efficacy, safety, and immunogenicity of the DNA SARS-CoV-2 vaccine (ZyCoV-D): the interim efficacy results of a phase 3, randomised, double-blind, placebo-controlled study in India. Lancet 2022, 399, 1313–1321. [Google Scholar] [CrossRef]
  140. Mallapaty, S. India's DNA COVID vaccine is a world first - more are coming. Nature 2021, 597, 161–162. [Google Scholar] [CrossRef]
  141. Seo, Y.B.; Suh, Y.S.; Ryu, J.I.; Jang, H.; Oh, H.; Koo, B.S.; Seo, S.H.; Hong, J.J.; Song, M.; Kim, S.J.; et al. Soluble Spike DNA Vaccine Provides Long-Term Protective Immunity against SARS-CoV-2 in Mice and Nonhuman Primates. Vaccines (Basel) 2021, 9. [Google Scholar] [CrossRef]
  142. Ahn, J.Y.; Lee, J.; Suh, Y.S.; Song, Y.G.; Choi, Y.J.; Lee, K.H.; Seo, S.H.; Song, M.; Oh, J.W.; Kim, M.; et al. Safety and immunogenicity of two recombinant DNA COVID-19 vaccines containing the coding regions of the spike or spike and nucleocapsid proteins: an interim analysis of two open-label, non-randomised, phase 1 trials in healthy adults. Lancet Microbe 2022, 3, e173–e183. [Google Scholar] [CrossRef]
  143. Szurgot, I.; Hanke, L.; Sheward, D.J.; Vidakovics, L.P.; Murrell, B.; McInerney, G.M.; Liljeström, P. DNA-launched RNA replicon vaccines induce potent anti-SARS-CoV-2 immune responses in mice. Sci Rep 2021, 11, 3125. [Google Scholar] [CrossRef]
  144. Lundstrom, K. The Current Status of COVID-19 Vaccines. Front Genome Ed 2020, 2, 579297. [Google Scholar] [CrossRef]
  145. Vogel, A.B.; Kanevsky, I.; Che, Y.; Swanson, K.A.; Muik, A.; Vormehr, M.; Kranz, L.M.; Walzer, K.C.; Hein, S.; Güler, A.; et al. BNT162b vaccines protect rhesus macaques from SARS-CoV-2. Nature 2021, 592, 283–289. [Google Scholar] [CrossRef]
  146. Sahin, U.; Muik, A.; Derhovanessian, E.; Vogler, I.; Kranz, L.M.; Vormehr, M.; Baum, A.; Pascal, K.; Quandt, J.; Maurus, D.; et al. COVID-19 vaccine BNT162b1 elicits human antibody and T(H)1 T cell responses. Nature 2020, 586, 594–599. [Google Scholar] [CrossRef] [PubMed]
  147. Polack, F.P.; Thomas, S.J.; Vogler, I.; Derhovanessian, E.; Kranz, L.M.; Vormehr, M.; Quandt, J.; Bidmon, N.; Ulges, A.; Baum, A.; et al. BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans. Nature 2021, 595, 572–577. [Google Scholar] [CrossRef]
  148. Lamb, Y.N. BNT162b2 mRNA COVID-19 Vaccine: First Approval. Drugs 2021, 81, 495–501. [Google Scholar] [CrossRef]
  149. FDA Approves First COVID-19 Vaccine. Available online: https://www.fda.gov/news-events/press-announcements/fda-approves-first-covid-19-vaccine (accessed on 6 December 2023).
  150. Corbett, K.S.; Edwards, D.K.; Leist, S.R.; Abiona, O.M.; Boyoglu-Barnum, S.; Gillespie, R.A.; Himansu, S.; Schäfer, A.; Ziwawo, C.T.; DiPiazza, A.T.; et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 2020, 586, 567–571. [Google Scholar] [CrossRef] [PubMed]
  151. Corbett, K.S.; Flynn, B.; Foulds, K.E.; Francica, J.R.; Boyoglu-Barnum, S.; Werner, A.P.; Flach, B.; O'Connell, S.; Bock, K.W.; Minai, M.; et al. Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates. N Engl J Med 2020, 383, 1544–1555. [Google Scholar] [CrossRef]
  152. Jackson, L.A.; Anderson, E.J.; Rouphael, N.G.; Roberts, P.C.; Makhene, M.; Coler, R.N.; McCullough, M.P.; Chappell, J.D.; Denison, M.R.; Stevens, L.J.; et al. An mRNA Vaccine against SARS-CoV-2 - Preliminary Report. N Engl J Med 2020, 383, 1920–1931. [Google Scholar] [CrossRef]
  153. Baden, L.R.; El Sahly, H.M.; Essink, B.; Kotloff, K.; Frey, S.; Novak, R.; Diemert, D.; Spector, S.A.; Rouphael, N.; Creech, C.B.; et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 2021, 384, 403–416. [Google Scholar] [CrossRef]
  154. Commissioner, O. of the FDA Takes Additional Action in Fight Against COVID-19 By Issuing Emergency Use Authorization for Second COVID-19 Vaccine. Available online: https://www.fda.gov/news-events/press-announcements/fda-takesadditional-action-fight-against-covid-19-issuing-emergency-use-authorizatio n-second-covid (accessed on 6 December 2023).
  155. Rauch, S.; Roth, N.; Schwendt, K.; Fotin-Mleczek, M.; Mueller, S.O.; Petsch, B. mRNA-based SARS-CoV-2 vaccine candidate CVnCoV induces high levels of virus-neutralising antibodies and mediates protection in rodents. NPJ Vaccines 2021, 6, 57. [Google Scholar] [CrossRef] [PubMed]
  156. Kremsner, P.G.; Mann, P.; Kroidl, A.; Leroux-Roels, I.; Schindler, C.; Gabor, J.J.; Schunk, M.; Leroux-Roels, G.; Bosch, J.J.; Fendel, R.; et al. Safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate against SARS-CoV-2 : A phase 1 randomized clinical trial. Wien Klin Wochenschr 2021, 133, 931–941. [Google Scholar] [CrossRef] [PubMed]
  157. Cromer, D.; Reynaldi, A.; Steain, M.; Triccas, J.A.; Davenport, M.P.; Khoury, D.S. Relating In Vitro Neutralization Level and Protection in the CVnCoV (CUREVAC) Trial. Clin Infect Dis 2022, 75, e878–e879. [Google Scholar] [CrossRef] [PubMed]
  158. Zhang, N.N.; Li, X.F.; Deng, Y.Q.; Zhao, H.; Huang, Y.J.; Yang, G.; Huang, W.J.; Gao, P.; Zhou, C.; Zhang, R.R.; et al. A Thermostable mRNA Vaccine against COVID-19. Cell 2020, 182, 1271–1283.e1216. [Google Scholar] [CrossRef]
  159. Zhao, H.; Wang, T.C.; Li, X.F.; Zhang, N.N.; Li, L.; Zhou, C.; Deng, Y.Q.; Cao, T.S.; Yang, G.; Li, R.T.; et al. Long-term stability and protection efficacy of the RBD-targeting COVID-19 mRNA vaccine in nonhuman primates. Signal Transduct Target Ther 2021, 6, 438. [Google Scholar] [CrossRef]
  160. Chen, G.L.; Li, X.F.; Dai, X.H.; Li, N.; Cheng, M.L.; Huang, Z.; Shen, J.; Ge, Y.H.; Shen, Z.W.; Deng, Y.Q.; et al. Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Microbe 2022, 3, e193–e202. [Google Scholar] [CrossRef] [PubMed]
  161. McKay, P.F.; Hu, K.; Blakney, A.K.; Samnuan, K.; Brown, J.C.; Penn, R.; Zhou, J.; Bouton, C.R.; Rogers, P.; Polra, K.; et al. Self-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine candidate induces high neutralizing antibody titers in mice. Nat Commun 2020, 11, 3523. [Google Scholar] [CrossRef]
  162. Pollock, K.M.; Cheeseman, H.M.; Szubert, A.J.; Libri, V.; Boffito, M.; Owen, D.; Bern, H.; O'Hara, J.; McFarlane, L.R.; Lemm, N.M.; et al. EClinicalMedicine 2022, 44, 101262. [CrossRef]
  163. Szubert, A.J.; Pollock, K.M.; Cheeseman, H.M.; Alagaratnam, J.; Bern, H.; Bird, O.; Boffito, M.; Byrne, R.; Cole, T.; Cosgrove, C.A.; et al. COVAC1 phase 2a expanded safety and immunogenicity study of a self-amplifying RNA vaccine against SARS-CoV-2. EClinicalMedicine 2023, 56, 101823. [Google Scholar] [CrossRef]
  164. Voigt, E.A.; Gerhardt, A.; Hanson, D.; Jennewein, M.F.; Battisti, P.; Reed, S.; Singh, J.; Mohamath, R.; Bakken, J.; Beaver, S.; et al. Author Correction: A self-amplifying RNA vaccine against COVID-19 with long-term room-temperature stability. NPJ Vaccines 2022, 7, 150. [Google Scholar] [CrossRef]
  165. de Alwis, R.; Gan, E.S.; Chen, S.; Leong, Y.S.; Tan, H.C.; Zhang, S.L.; Yau, C.; Low, J.G.H.; Kalimuddin, S.; Matsuda, D.; et al. A single dose of self-transcribing and replicating RNA-based SARS-CoV-2 vaccine produces protective adaptive immunity in mice. Mol Ther 2021, 29, 1970–1983. [Google Scholar] [CrossRef] [PubMed]
  166. “WHO downgrades COVID-19 pandemic, says it’s no longer a global emergency”. www.cbc.ca/news/health/who-pandemic-not-emergency-1.6833321. (Accessed on December 7, 2023).
  167. Lundstrom, K. Role of Nucleic Acid Vaccines for the Management of Emerging Variants of SARS-CoV-2. In SARS-CoV-2 Variants and Global Vulnerability (Eds. Chavda, V.; Uversky, V.N.) 2023, Apple Academic Press, Palm Bay, FL, USA, in press.
  168. Choi, J.Y.; Smith, D.M. SARS-CoV-2 variants of concern. Yonsei Med. J. 2021, 62, 961–968. [Google Scholar] [CrossRef] [PubMed]
  169. Chenchula, S.; Karunakaran, P.; Sharma, S.; Chavan, M. (2022). Current evidence on efficacy of COVID-19 booster vaccination against the Omicron variant: A systematic review. J. Med. Virol. 2022, 94, 2969–2976. [Google Scholar] [CrossRef] [PubMed]
  170. Redwan, E.M.; Elrashdy, F.; Aljabali, A.A.A.; Baetas-da-Cruz, W.; Barh, D.; Brufsky, A.; Hassan, Sk.S.; Lundstrom, K.; Serrano-Aroca, Á.; Takayama, K.; et al. Would New SARS-CoV-2 Variants Change the War against COVID-19? Epidemiologia 2022, 3, 229–237. [Google Scholar] [CrossRef] [PubMed]
  171. Taucher, C.; Lazarus, R.; Dellago, H.; Maurer, G.; Weisova, P.; Corbic-Ramljak, I.; Dubischar, K.; Lilja, A.; Eder-Lingelbach, S.; Hochreiter, R.; et al. Safety and immunogenicity against ancestral, Delta and Omicron virus variants following a booster dose of an inactivated whole-virus COVID-19 vaccine VLA2001: A randomized, controlled, phase 3COV-COMPARE trial. J. Infect. 2023, 87, 242–254. [Google Scholar] [CrossRef]
  172. De Bruyn, G.; Wang, J.; Purvis, A.; Sanchez Ruiz, M.; Adhikarla, H.; Alvi, S.; Bonaparte, M.I.; Brune, D.; Bueso, A.; Canter, R.M.; et al. Safety and immunogenicity of a variant-adapted SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant as a booster in adults primed with authorized vaccines: a phase 3, parallel-group study. EClinicalMedicine 2023, 62, 102109. [Google Scholar] [CrossRef]
  173. Buntinx, E.; Brochado, L.; Borja-Tabora, C.; Yu, C.Y.; Alberto, E.R.; Montellano, M.E.B.; Carlos, J.C.; Toloza, L.B.; Hites, M.; Siber, G.; et al. Immunogenicity of an adjuvanted SARS-CoV-2 trimeric S-protein subunit vaccine (SCB-2019) in SARS-CoV-2-naive and exposed individuals in a phase 2/3, double-blind, randomized study. Vaccine 2023, 41, 1875–1884. [Google Scholar] [CrossRef]
  174. Zeng, B.; Gao, L.; Zhou, Q.; Yu, K.; Sun, F. Effectiveness of COVID-19 vaccines against SARS-CoV-2 variants of concern: a systematic review and meta-analysis. BMC Med. 2022, 20, 200. [Google Scholar] [CrossRef]
  175. Lyke, K.E.; Atmar, R.L.; Dominguez Islas, C.; Posavad, C.M.; Deming, M.E.; Branche, A.R.; Johnston, C.; El Sahly, H.M.; Edupuganti, S.; Mulligan, M.J. ; Immunogenicity of NVX-CoV2373 heterologous boost against SARS-CoV-2 variants. NPJ Vaccines 2023, 8, 98. [Google Scholar] [CrossRef]
  176. Kumar, S.; Saikia, D.; Bankar, M.; Saurabh, M.K.; Singh, H.; Varikasuvu, S.R.; Maharshi, V. Efficacy of COVID-19 vaccines: a systematic review and network meta-analysis of phase 3 randomized controlled trials. Pharmacol Rep 2022, 74, 1228–1237. [Google Scholar] [CrossRef]
  177. Guirakhoo, F.; Wang, S.; Wang, C.Y.; Kuo, H.K.; Peng, W.J.; Liu, H.; Wang, L.; Johnson, M.; Hunt, A.; Hu, M.M.; et al. High Neutralizing Antibody Levels Against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron BA.1 and BA.2 After UB-612 Vaccine Booster. J. Infect. Dis. 2022, 226, 1401–1406. [Google Scholar] [CrossRef] [PubMed]
  178. Madhi, S.A.; Baillie, V.; Cutland, C.L.; Voysey, M.; Koen, A.L.; Fairlie, L.; Padayachee, S.D.; Dheda, K.; Barnabas, S.L.; Bhorat, Q.E. Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant. N. Engl. J. Med. 2021, 384(1885-1898. [CrossRef]
  179. Eyre, D.W.; Taylor, D.; Purver, M.; Chapman, D.; Fowler, T.; Pouwels, K.B.; Walker, A.S.; Peto, T.E.A. Effect of Covid-19 Vaccination on Transmission of Alpha and Delta Variants. N. Engl. J. Med. 2022, 386, 744–756. [Google Scholar] [CrossRef] [PubMed]
  180. Seow, J.; Graham, C.; Hallett, S.R.; Lechmere, T.; Maguire, T.J.A.; Huettner, I.; Cox, D.; Khan, H.; Pickering, S.; Roberts, R.; et al. ChAdOx1 nCoV-19 vaccine elicits monoclonal antibodies with cross-neutralizing activity against SARS-CoV-2 viral variants. Cell Rep. 2022, 39, 110757. [Google Scholar] [CrossRef] [PubMed]
  181. Alter, G.; Yu, J.; Liu, J.; Chandrashekar, A.; Borducchi, E.N.; Tostanoski, L.H.; McMahan, K.; Jacob-Dolan, C.; Martinez, D.R.; Chang, A.; et al. Immunogenicity of Ad26.COV2.S vaccine against SARS-CoV-2 variants in humans. Nature 2021, 596, 268–272. [Google Scholar] [CrossRef] [PubMed]
  182. Polinski, J.M.; Weckstein, A.R.; Batech, M.; Kabelac, C.; Kamath, T.; Harvey, R.; Jain, S.; Rassen, J.A.; Khan, N.; Schneeweiss, S. Durability of the Single-Dose Ad26.COV2.S Vaccine in the Prevention of COVID-19 Infections and Hospitalizations in the US Before and During the Delta Variant Surge. JAMA Netw. Open. 2022, 5, e222959. [Google Scholar] [CrossRef] [PubMed]
  183. Ikegame, S.; Siddiquey, M.N.A.; Hung, C.-T.; Haas, G.; Brambilla, L.; Oguntuyo, K.Y.; Kowdle, S.; Vilardo, A.E.; Edelstein, A.; Perandones, C.; et al. Qualitatively distinct modes of Sputnik V vaccine-neutralization escape by SARS-CoV-2 Spike variants. medRxiv 1101. [Google Scholar] [CrossRef]
  184. Gonzalez Lopez Ledesma, M.; Sanchez, L.; Ojeda, D.S.; Oviedo Rouco, S.; Rossi, A.H.; Varesse, A.; Mazzitelli, I.; Pascuale, C.A.; Miglietta, E.A.; Rodriguez, P.E.; et al. Longitudinal Study after Sputnik V Vaccination Shows Durable SARS-CoV-2 Neutralizing Antibodies and Reduced Viral Variant Escape to Neutralization over Time. mBio 2022, 13. [Google Scholar] [CrossRef] [PubMed]
  185. Gushchin, V.A.; Dolzhikova, I.V.; Shchetinin, A.M.; Odintsova, A.S.; Siniavin, A.E.; Nikiforova, M.A.; Pochtovyi, A.A.; Shidlovskaya, E.V.; Kuznetsova, N.A.; Burgasova, O.A.; et al. Neutralizing Activity of Sera from Sputnik V-Vaccinated People against Variants of Concern (VOC: B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.617.3) and Moscow Endemic SARS-CoV-2 Variants. Vaccines 2021, 9, 779. [Google Scholar] [CrossRef]
  186. Gonzalez-Dominguez, I.; Martinez, J.L.; Slamanig, S.; Lemus, N.; Liu, Y.; Lai, T.Y.; Carrero, J.M.; Singh, G.; Singh, G.; Schotsaert, M.; et al. Trivalent NDV-HXP-S Vaccine Protects against Phylogenetically Distant SARS-CoV-2 Variants of Concern in Mice. Microbiol. Spectr. 2022, 10, e0153822. [Google Scholar] [CrossRef]
  187. Wang, Z.; Li, Z.; Shi, W.; Zhu, D.; Hu, S.; Dinh, P.-U.C.; Cheng, K. A SARS-CoV-2 and influenza double hit vaccine based on RBD-conjugated inactivated influenza A virus. 2023, Sci. Adv. 2023, 9, eabo4100. [Google Scholar] [CrossRef]
  188. Andrade, V.M.; Christensen-Quick, A.; Agnes, J.; Tur, J.; Reed, C.; Kalia, R.; Marrero, I.; Elwood, D.; Schultheis, K.; Purwar, M.; et al. INO-4800 DNA vaccine induces neutralizing antibodies and T cell activity against global SARS-CoV-2 variants. npj Vaccines 2021, 6, 121. [Google Scholar] [CrossRef]
  189. Reed, C.C.; Schultheis, K.; Andrade, V.M.; Kalla, R.; Tur, J.; Schouest, B.; Elwood, D.; Walters, J.N.; Maricic, I.; Doan, A.; et al. Design, immunogenicity and efficacy of a Pan-SARS-CoV-2 synthetic DNA vaccine. bioRxiv 2021, 2021.05.11.443592. [Google Scholar] [CrossRef]
  190. Walters, J.N.; Schouest, B.; Patel, A.; Reuschel, E.; Schultheis, K.; Parzych, E.; Maricic, I.; Gary, E.N.; Purwar, M.; Andrade, V.M.; et al. Prime-boost vaccination regimens with INO-4800 and INO-4802 augment and broaden immune responses against SARS-CoV-2 in nonhuman primates. Vaccine 2022, 40, 2960–2969. [Google Scholar] [CrossRef] [PubMed]
  191. Fiolet, T.; Kherabi, Y.; MacDonald, C.J.; Ghosn, J.; Peiffer-Smadja, N. Comparing COVID-19 vaccines for their characteristics, efficacy and effectiveness against SARS-CoV-2 and variants of concern: a narrative review. Clin. Microbiol. Infect. 2022, 28, 202–221. [Google Scholar] [CrossRef]
  192. Martınez-Baz, I.; Trobajo-Sanmartín, C.; Miqueleiz, A.; Guevara, M.; Fernández-Huerta, M.; Burgui, C.; Casado, I.; Portillo, M.E.; Navascués, A.; Ezpeleta, C.; et al. Product-Specific COVID-19 Vaccine Effectiveness Against Secondary Infection in Close Contacts, Navarre, Spain, April to August 2021. Euro Surveill. 2021, 26, 2100894. [Google Scholar] [CrossRef]
  193. Sheikh, A.; Robertson, C.; Taylor, B. BNT162b2 and ChAdOx1 nCoV-19 Vaccine Effectiveness Against Death From the Delta Variant. N. Engl. J. Med. 2021, 385, 2195–2197. [Google Scholar] [CrossRef]
  194. Young-Xu, Y.; Zwain, G.M.; Izurieta, H.S.; Korves, C.; Powell, E.I.; Smith, J.; Balajee, A.S.; Holodniy, M.; Beenhouwer, D.O.; Rodriguez-Barradas, M.; et al. Effectiveness of mRNA COVID-19 Vaccines Against Omicron Among Veterans. medRxiv 2022, 15, 2022–01. [Google Scholar] [CrossRef]
  195. Regev-Yochay, G.; Gonen, T.; Gilboa, M.; Mandelboim, M.; Indenbaum, V.; Amit, S.; et al. 4th Dose COVID mRNA Vaccines’ Immunogenicity & Efficacy Against Omicron VOC. medRxiv 2022, 15, 2022–02. [Google Scholar] [CrossRef]
  196. Altarawneh, H.N.; Chemaitelly, H.; Ayoub, H.H.; Tang, P.; Hasan, M.R.; Yassine, H.M.; et al. Effect of Prior Infection, Vaccination, and Hybrid Immunity Against Symptomatic BA.1 and BA.2 Omicron Infections and Severe COVID-19 in Qatar. medRxiv 2022, 22, 2022–03. [Google Scholar] [CrossRef]
  197. Choi, A.; Koch, M.; Wu, K.; Dixon, G.; Oestreicher, J.; Legault, H.; Stewart-Jones, G.B.E.; Colpitts, T.; Pajon, R.; Bennett, H.; et al. Serum Neutralizing Activity of mRNA-1273 against SARS-CoV-2 Variants. J. Virol. 2021, 95, e0131321. [Google Scholar] [CrossRef]
  198. Girard, B.; Tomassini, J.E.; Deng, W.; Maglinao, M.; Zhou, H.; Figueroa, A.; Ghamloush, S.S.; Montefiori, D.C.; Das, R.; Pajon, R. mRNA-1273 Vaccine-elicited Neutralization of SARS-CoV-2 Omicron in Adolescents and Children. medRxiv 2022, 2022.01.24.22269666. [Google Scholar] [CrossRef]
  199. Chalkias, S.; Harper, C.; Vrbicky, K.; Walsh, S.R.; Essink, B.; Brosz, A.; McGhee, N.; Tomassini, J.E.; Chen, X.; Chang, Y.; et al. A Bivalent Omicron-Containing Booster Vaccine against Covid-19. N. Engl. J. Med. 2022, 387, 1279–1291. [Google Scholar] [CrossRef]
  200. Wang, Q.; Guo, Y.; Bowen, A.; Mellis, I.A.; Valdez, R.; Gherasim, C.; Gordon, A.; Liu, L.; Ho, D.D. XBB.1.5 monovalent mRNA vaccine booster elicits robust neutralizing antibodies against emerging SARS.CoV-2 bioRxiv 2023. [CrossRef]
  201. Wolz, O.O.; Kays, S.K.; Junker, H.; Koch, S.D.; Mann, P.; Quintini, G.; von Eisenhart-Rothe, P.; Oostvogels, L. A Third dose of the COVID-19 Vaccine, CVnCoV, Increased the Neutralizing Activity against the SARS-CoV-2 Wild-type and Delta Variant. Vaccines 2022, 10, 508. [Google Scholar] [CrossRef] [PubMed]
  202. Frise, R.; Baillin, L.; Zhou, J.; Kugathasan, R.; Peacock, T.P.; Brown, J.C.; Samnuan, K.; McKay, P.F.; Shattock, R.J.; Barclay, W.S. A self-amplifying RNA vaccine protects against SARS-CoV-2 (D614G) and Alpha variant of concern (B.1.1.7) in a transmission-challenge hamster model. Vaccine 2022, 40, 2848–2855. [Google Scholar] [CrossRef] [PubMed]
  203. McCafferty, S.; Ashiqui Haque, A.K.M.; Vandierendonck, A.; Weidensee, B.; Plovyt, M.; Stuchlikova, M.; Françcois, N.; Valembois, S.; Heyndrickx, L.; Michiels, J.; et al. A dual-antigen self-amplifying RNA SARS-CoV-2 vaccine induces potent humoral and cellular immune responses and protects against SARS-CoV-2 variants through T Cell-mediated immunity. Mol. Ther. 2022, 30, 2968–2983. [Google Scholar] [CrossRef] [PubMed]
  204. Voigt, E.A.; Gerhardt, A.; Hanson, D.; Jennewein, M.F.; Battisti, P.; Reed, S.; Singh, J.; Mohamath, R.; Bakken, J.; Beaver, S.; et al. A self-amplifying RNA vaccine against COVID-19 with long-term room-temperature stability. npj Vaccines 2022, 7, 150. [Google Scholar] [CrossRef] [PubMed]
  205. Tarke, A.; Coelho, C.H.; Zhang, Z.; Dan, J.M.; Yu, E.D.; Methot, N.; Bloom, N.I.; Goodwin, B.; Phillips, E.; Malla,l S. ; et al. SARS-CoV-2 vaccination induces immunological T cell memory able to cross-recognize variants from Alpha to Omicron. Cell 2022, 185, 847–859.e11. [Google Scholar] [CrossRef] [PubMed]
  206. WHO Coronavirus (COVID-19) Dashboard. https://covid19.who.int/?mapFilter=vaccinations.
  207. Lundstrom, K.; Hromić-Jahjefendić, A.; Bilajac, E.; Aljabali, A.A.A.; Baralić, K.; Sabri, N.A.; Shehata, E.M.; Raslan, M.; Ferreira, A.C.B.H.; Orlandi, L.; et al. COVID-19 signalome: Pathways for SARS-CoV-2 infection and impact on COVID-19 associated comorbidity. Cellular Signalling 2023, 101, 110495. [Google Scholar] [CrossRef]
  208. Gates, B. How to prevent the next pandemic. 2022, Penguin Random House, UK.
Table 1. Examples of different COVID-19 vaccines in clinical trials.
Table 1. Examples of different COVID-19 vaccines in clinical trials.
Type of Vaccine Vaccine Design Stage Observations
Whole-virus
COVI-VAC
(Codagenix)
CoronaVac
(Sinovac)
 
VLA2001
(Valneva)
 
ERUCOV-VAC
 
CovIran Barekat
(BIV1 CovIran)
Covaxin
(BBV152)
QazCovid-in
 
 
BBIBP-CorV
(Sinopharm)
 
 
Intranasal delivery of mutated attenuated whole virus
Two-dose BPL-inactivated alum-hydroxide whole virus
 
Alum and CpG 1018.31 adjuvanted, BPL-inactivated whole virus
I/II
 
I/II
III
EUA
I/II
III
EUA
Long-lasting immunity [9], 83% seroconversion [10]
Immune memory, seroconversion [11,12]
Good efficacy against COVID-19 [13]
Approval in 54 countries in June 2021 [14]
Humoral and cellular immunity [16]
Superior Ad vector-based vaccine [17]
Approval in Bahrain in March 2022 [18]
Vero cell-based inactivated whole virus
 
BPL-inactivated alum-adjuvanted whole virus
Inactivated whole virus vaccine based on the SARS-CoV-2 NIV-2020-770 strain
Formalin-inactivated, alum hydroxide-adjuvanted whole virus
 
Inactivated whole-virus vaccine based on SARS-CoV-2 HB02 patient isolate
 
 I/II
III
CS
 
I/II
III
I
II
III
I
III
EUA		 Safety and immunogenicity [20]
Superior to CoronaVac [21]
85% reduction in mortality [23]
 
93.4% vaccine efficacy [25]
Efficacy against symptomatic COVID [26]
100% seroconversion [28]
92-94% seroconversion [28]
82% vaccine efficacy [29]
Humoral and nAb responses [31]
78.1% vaccine efficacy [32]
Approval in China [33], by the WHO [34]
Protein & peptide
preS dTM
 
SCB-2019
 
COVAX-19
 
Nanocovax
 
Razi Cov Pars
MVC-COV1901
 
 
EpiVarCorona
(EVCV)
SCTV01C
 
 
ZF2001
 
 
CIGB-66
(Abdala)
 
BECOV2
(Corbevax)
 
FINLAY-FR-2
 
UB-612
 
ReCoV
 
NVX-CoV2373
 
 
GBP510
 
 
Baculovirus expressed purified prefusion-stabilized S protein + AS03 adjuvant
AS03- or CpG/Alum-adjuvanted S Trimer
 
ECD of SARS-CoV-2 adjuvanted with Alum-CpG55.2 or Advax-CpG55.2
Alum hydroxide-adjuvant SARS-CoV-2 S
 
Intranasal RAS-01 adjuvanted S Trimer
CpG 1018 and Alum hydroxide adjuvanted prefusion stabilized S Trimer
 
Chemically synthesized peptide antigens of SARS-CoV-2 S
Trimeric extracellular SARS-CoV-2 S domain adjuvanted with squalene
 
Tandem RBD SARS-CoV-2 S repeat with alum hydroxide adjuvant
 
RBD SARS-CoV-2 expressed in yeast adjuvanted with alum hydroxide
 
RBD SARS-CoV-2 expressed in yeast adjuvanted with alum and CpG
 
RBD SARS-CoV-2 coupled to tetanus toxoid, adjuvanted to alum hydroxide
RBD fused to sc IgG1 Fc, 5 Th/CTL epitopes + alum phosphate adjuvant
Two-component NTD-RBD subunit vaccine + BFA03 adjuvant
NP-encapsulated full-length SARS-CoV-2 S + Matrix-M1 adjuvant
 
Self-assembled NP vaccine adjuvanted with AS03
 I
I
I
II/III
II
III
I/II
III
II
I
II
III
I/II
III
I
III
EUA
I/II
III
EUA
I
III
EUA
I/II
III
EUA
I/II
III
I/II
 
II
EUA
I/II
III
CMA
I/II
III
 Lower-than-expected immunogenicity [37]
Good safety, robust immunogenicity [38]
Humoral and cellular responses, nAbs [40]
Immunogenicity, cross-reactivity [41]
Safety, humoral & cellular responses [43]
Reduction of COVID-19 and its severity [44]
Safety, tolerability, and immunogenicity [46]
90% vaccine efficacy [47]
Humoral and cellular immunogenicity [49]
nAbs, enhanced immunogenicity ]51]
Safety, promising immune responses [52]
Safety, robust immunogenicity [53]
Safety, prevention of COVID-19 [55]
82.5% vaccine efficacy [56]
Robust immune responses [58]
Confirmed strong immunogenicity [59]
Approved in China [60]
nAb in 83-97% of vaccinees [62]
Protection against COVID-19 [63]
Approval in China and Uzbekistan [64]
Safety, robust immune response [66]
92.3% vaccine efficiency [67]
Approval in Cuba [68]
High nAb titers [70]
High nAB titers, low adverse events [71]
Approval in India and Botswana [72]
Elevated immunogenicity [74]
Good protection against COVID-19 [75]
Long-lasting nAb responses, broad T-cell immunity [77].
Superior to mRNA vaccines [79]
Approval in Mongolia in March 2023 [80]
Robust immunogenicity, Th1-biased [82]
100% protection against severe disease [83]
Approval in the EU and GB [84]
Tolerability, immunogenicity [86]
Superior to ChAdOX1-S [87]
Viral vectors
ChAdOx1 nCoV-19
 
 
Ad5-nCoV
 
 
 
Ad26.COV2.S
 
 
rAd26S/rAd5-S
(Sputnik V)
 
GRAd-COV2
 
MVA-COV2-S
NDV-HXP-S
LV-SMENP-DC
 
IFV dNS1-RBD
 
MV-COV-2 S
(TMV083)
VSV-SARS-CoV-2 S
(V590)
VSV-ΔG
(IIBR-100)
 
Ad-based full-length SARS-CoV-2 S I/II Robust humoral & cellular responses [91]
III 62-90% vaccine efficacy [92]

Ad5-based full-length SARS-CoV-2 S
 
 
 
Ad26-based prefusion-stabilized SARS-CoV-2 S using a single immunization
 
Prime vaccination with Ad26 SARS-CoV-2 S followed by Ad26 SARS.CoV-2 S booster
 
GRAd-based prefusion-stabilized SARS-CoV-2 S
VV MVA strain expressing SARS-CoV-2 S
NDV expressing SARS-CoV-2 S
Transduced LV expressing SARS-CoV-2 structural proteins and protease
Cold-attenuated influenza virus strain with NS1 deletion and RBD insertion
MV-based expression of full-length SARS-
CoV-2 S
VSV-based expression of SARS-CoV-2 S
 
Chimeric VSV where VSV-G replaced by SARS-CoV-2 S
 
 EUA
I
II
III
EUA
I/II
III
EUA
I/II
III
EUA
I
 
II
I
I/II
 
I/II
 
I
 
I
 
II
 
 
 Approval in the UK in December 2020 [93]
Binding and nAb antibody responses [95}
Dose- and age-dependent [97]
Good safety and efficacy [98]
Approval in China in February 2021 [99]
Robust immune responses [102]
52.9% vaccine efficacy [103]
Approval in the US in February 2021 [104]
Humoral & cellular responses [106,107]
91.6% vaccine efficacy [108]
Approval in Russia in July 2020 [109]
97.7-100% seroconversion rates [111]
 
Trial in progress [116]
Safe, potent immunogenicity [118]
Trial in progress [121]
 
Weak T-cell responses, modest humoral and mucosal immune responses [123]
Tolerability, inferior immune response compared to COVID-19 patients [125]
Good safety, and tolerability but weak immunogenicity, termination of trial [127]
Robust nAb responses [129]
 
Nucleic acid – DNA
INO-4800
 
ZyCoV-D
 
 
GX-19
GX-19N
 
 
Nucleic acid – RNA
BNT162b
(Pfizer/BioNTech)
 
 
mRNA-1273
(Moderna)
 
CVnCOV
(Curavec)
 
ARCoV
 
LNP-nCoVsaRNA
DNA-based full-length SARS-CoV-2 S
 
DNA-based SARS-CoV-2 S RBD
 
 
Synthetic SARS-CoV-2 S RBD
S RBD Foldon, N and S proteins
 
 
 
Prefusion-stabilized full-length SARS-CoV-2 S RNA in NPs
 
I
II
I/II
III
EUA
I
 
 
 
 
I/II
III
EUA
RA
Cellular & humoral immune responses [135]
Good safety and tolerability [136]
Robust immune responses [138]
66.6% vaccine efficacy [139]
Approval in India in 2021 [140]
Good safety and tolerability, superior immunity of GX-19 compared to GX-19N [142]
 
 
 
Good safety and immunogenicity [146]
95% vaccine efficacy [147]
Approval in the EU and CH in 2020 [148]
Approval by the FDA in August 2021 [149]
Prefusion-stabilized full-length SARS-CoV-2 S RNA in LNPs
 
Full-length SARS-CoV-2 S RNA in LNPs
 
 
Thermostable LNP-encapsulated SARS-CoV-2 S RBD RNA
LNP-encapsulated VEE-based replicon expression full-length SARS-CoV-2 S
 I
III
EUA
I
III
 
I
 
I
II
 S-specific immune responses [152]
94.1% vaccine efficacy [153]
Approval in the US in December 2020 [154]
S-specific immune responses [156]
48.1% vaccine efficacy [157]
 
Humoral and cellular responses [160]
 
Safe, <100% seroconversion [162]
Prime-booster: > seroconversion [163]
BPL, β-propiolactone; CH, Switzerland; CMA, conditional marketing authorization; CS, cohort study; ECD, extracellular domain; EU, European Union; EUA, emergency use authorization; GB, Great Britain; GRAd, gorilla adenovirus; LNP, lipid nanoparticle; LV, lentivirus; MVA, Modified Vaccina Ankara strain; nAbs, neutralizing antibodies; NDV, Newcastle disease virus; NP, nanoparticle; NTD, N-terminal domain; RA, regulatory approval; RBD, receptor binding domain; VEE, Venezuelan equine encephalitis virus; VV, vaccinia virus.
Table 2. Examples of COVID-19 vaccine efficacy against SARS-CoV-2 variants.
Table 2. Examples of COVID-19 vaccine efficacy against SARS-CoV-2 variants.
Type of Vaccine Variant(s) Findings
Whole-virus
VLA2001
(Valneva)
Delta, omicron
 
Improved vaccine efficacy after both homologous and ChAdOx1 nCoV-19 boosters [172]


Protein & peptide
preS dTM
 
SCB-2019
 
COVAX-19
 
Nanocovax
 
NVX-CoV2373
 
SCTV01C
 
 
 
UB-612
 
 
 
 
 
beta, omicron (BA.1, BA.2, BA.4/5)
 
alpha, beta, delta, gamma, mu
 
delta
 
delta
 
D614G, omicron (BQ.1.1, XBB.1)
 
alpha, beta, delta, omicron
 
 
 
delta, omicron
 
 
 
 
Cross-reacting nAbs against VoC [173]
 
Immunogenicity, cross-reactivity against VoC [174]
 
Significantly reduced COVID-19 rates and severity of disease [45]
51.5% VE against delta [48]
 
High PsVNA for D614G, low for BQ.1.1 and XBB.1 after heterologous booster with NVX-CoV2373 [175]
Promising immunogenicity against alpha and beta, cross-reacting nAbs against delta and omicron [176]
Booster elicited superior nAb titers against delta and omicron [176]
Long-lasting nAbs, T-cell immunity against delta and omicron [177]
61-fold enhanced nAbs against omicron BA.1 and 49-fold against omicron BA.2 [178].


Viral vectors
ChAdOx1 nCoV-19
 
 
 
Ad26.COV2.S
 
rAd26-S/raAd5-S
(Sputnik V)
NDV-HXP-S
 
Flu-RBD VLPs
VSV-ΔG-S
(BriLife®)
 

beta
alpha, delta
 
No protection against mild-to-moderate COVID-19 [179]
Lower transmission reduction of delta than alpha, better efficacy of BNT162b2 than ChAdOx1 nCoV-19 [180]
alpha, beta, delta, gamma, omicron
beta, gamma
 Neutralizing activity against VoC [181)
PsVNA 5-fold (beta) and 3.3-fold (gamma) reduced [182]
Delta
alpha, beta, gamma, delta
 
beta, delta, omicron
 
delta
alpha, beta, gamma, delta, omicron
 
 
 Stable VE for at least 6 months [183]
Moderate (alpha) & 6.1- (beta) [184], 2.8- (gamma) [185], 2.5-fold (delta) [186] reduction in nAb activity
Protection against beta, delta, cross-nAbs against omicron [187]
Induced nAbs [188]
Comparable levels of nAbs for alpha, gamma, delta, 3-fold reduction for beta and omicron [130]

Nucleic acid – DNA
INO-4800
 
INO-4802
 
Nucleic acid – RNA
BNT162b
(Pfizer/BioNTech)
 
 
mRNA-1273
(Moderna)
 
mRNA-1273.214
 
mRNA XBB.1.5
CVnCOV
(Curavec)
LNP-nCoVsaRNA
ZIP1642
saRNA/NLC SARS-CoV-2
 
alpha, beta, gamma
 
alpha, beta, gamma
 
 
alpha, beta, gamma, delta
delta
omicron
 
alpha, beta, gamma, delta
 
omicron
omicron BA.1, BA.4, BA.5
alpha, beta, gamma, delta
omicron XBB.1.5, EG.1.5
delta
 
alpha
 
2.1- (alpha), 6.9 (beta) reduced nAbs, same as for the original strain (gamma) [189]
nAb responses [190], prime-boost strategy [191]
 
 
Prevention of symptomatic and severe COVID-19 [192]
67% (Spain) [193] and 90% (the UK) [194] VE
25% (US) [195], 30% (Israel) [196], 51% (Qatar) [197] VE
 
1.2-fold (alpha), 2.1-8.4-fold (beta, gamma, delta) nAb titer reduction [198]
Reduced nAbs in children compared to D614G [199]
Superior nAb response compared to mRNA-1273 [200]
Superior binding compared to mRNA-1273 [200]
27-27.6-fold increase in nAb levels [201]
Similar nAb levels as for wildtype SARS-CoV-2 [202]
 
Protection against alpha variant in hamsters [203]
beta, delta
alpha, beta, delta
 
 Substantial nAb responses [204]
Robust nAb and Th1-biased T-cell responses [205]
 
Flu, inactivated Influenza A virus; nAbs, neutralizing antibodies; LNP, lipid nanoparticles; NDV, Newcastle disease virus; NLC. nanolipid particles; PsVNA, pseudovirus-neutralizing antibody; RBD, receptor binding domain; saRNA, self-amplifying RNA; VE, vaccine efficacy; VLP, virus-like particle; VoC, variant of concern.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
Prerpints.org logo

Preprints.org is a free preprint server supported by MDPI in Basel, Switzerland.

facebook logotwitter logolinkedin logo
MDPI Initiatives
Important Links
Subscribe

Disclaimer

Terms of Use

Privacy Policy

© 2024 MDPI (Basel, Switzerland) unless otherwise stated