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    "titulo" => "The impact of spike mutated variants of SARS-CoV2 &#91;<span class="elsevierStyleItalic">Alpha&#44; Beta&#44; Gamma&#44; Delta&#44;</span> and <span class="elsevierStyleItalic">Lambda</span>&#93; on the efficacy of subunit recombinant vaccines"
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          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">The representative scheme of functional domains in S protein of SARS-CoV-2&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Introduction</span><p id="para0001" class="elsevierStylePara elsevierViewall">The routine living status in the world stopped by severe acute respiratory syndrome coronavirus 2 &#40;SARS-CoV-2&#41; pandemic&#46; It is causing significant health&#44; social and economic global burden&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> The SARS-CoV-2 is a positive-sense&#44; single-stranded RNA virus that is rapidly evolving and continually accrues genomic mutations as it continues to be transmitted&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> Since the first described human infection with SARS-CoV-2 in Wuhan in December of 2019&#44;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a> many subunit protein vaccines have been presented for use in humans&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> Still&#44; viral genomic mutations leading to new variants is a real challenge in tackling this pandemic worldwide&#46;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a> A primary focus of this review is to assess the impact of spike mutated variants of SARS-CoV2 &#40;B&#46;1&#46;1&#46;7&#44; B&#46;1&#46;351&#44; and B&#46;1&#46;1&#46;28&#46;1&#41; on the efficacy of subunit recombinant vaccines designed to elicit an immune response against the spike protein of SARS-CoV2&#46;</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Methods</span><p id="para0002" class="elsevierStylePara elsevierViewall">Independent searches in PubMed&#44; Web of Science&#44; and Global Index Medicus were conducted by two researchers in June 2021&#46; The search strategy consisted of a word combination covering the following areas &#40;Covid-19 OR SARS-CoV-2&#41; AND Vaccine AND B&#46;1&#46;1&#46;7 Variant OR B&#46;1&#46;351 variant OR B&#46;1&#46;1&#46;28&#46;1 Variant OR B&#46;1&#46;617&#46;2 OR C&#46;37 variant&#46; The search had no geographic or language restrictions and included all studies reporting on efficacy of SARS-CoV-2 vaccines against variants Alpha&#44; Beta&#44; Gamma&#44; Delta&#44; and Lambda&#46; Herein we narratively describe the main findings of the included studies&#46;</p><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">The SARS-CoV-2 genomic features</span><p id="para0003" class="elsevierStylePara elsevierViewall">The SARS-CoV-2 is a spherical-shaped virion with a positive-strand RNA virus&#44; with a genome length of approximately 29&#44;700 nucleotides&#46;<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> The 5&#714; end includes more than two-thirds of the genome and comprises a long ORF1ab poly protein&#44; which encodes 16 non-structural proteins&#46;<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a> The 3&#714; end encodes four major structural proteins&#44; namely the spike &#40;S&#41; protein&#44; nucleocapsid &#40;N&#41; protein&#44; membrane &#40;M&#41; protein&#44; and envelope &#40;E&#41; protein&#46;<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> Additionally&#44; the virus contains six accessory proteins encoded by ORF3a&#44; ORF6&#44; ORF7a&#44; ORF7b&#44; ORF8&#44; and ORF9b genes&#46;<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> ORF3a is a trans membrane protein that forms ion channels in the host membrane and ORF7a encodes a type I trans membrane protein&#40;10&#41;&#46; ORF8 is a protein with an N-terminal signal sequence for transport to the endoplasmic reticulum and ORF9b suppresses IFN-I response&#40;9&#41;&#46;</p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0006">Structure&#44; function&#44; and antigenicity of the SARS-CoV-2 spike glycoprotein</span><p id="para0004" class="elsevierStylePara elsevierViewall">The S protein&#44; a glycoprotein&#44; is a homotrimer that plays a crucial role in the first step of the infection&#46;<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a> The monomer of S protein contains 1273 amino acids and a molecular weight of about 140 kDa&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> The primary function of S protein is to bind to the Angiotensin-Converting Enzyme 2 &#40;ACE2&#41; receptor entering the host cell after binding&#46;<a class="elsevierStyleCrossRefs" href="#bib0014"><span class="elsevierStyleSup">14&#8211;16</span></a> ACE2 is a type I integral membrane protein that functions as a carboxy peptidase&#44; cleaving angiotensin II to angiotensin regulating blood pressure&#46;<a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a> The virus binds to ACE2 on the host cell &#40;lungs&#44; heart&#44; etc&#46;&#41; for virus entry and subsequent pathogenesis&#44; resulting in severe respiratory infection&#46;<a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">15&#8211;17</span></a> Therefore&#44; the S protein-ACE2 interaction is an easy target for vaccines&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a> First&#44; it is exposed at the surface and can be recognized directly by the host immune system&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a> Second&#44; it mediates the interaction with the host cell binding to the ACE2 receptor&#44; which is essential for subsequent virus entry into target cells causing subsequent pathogenicity&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a> Finally&#44; the homolog proteins had been already used for vaccine development against SARS-CoV and MERS-CoV and proved effective&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">20</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a></p><p id="para0005" class="elsevierStylePara elsevierViewall">The S protein comprises two functional subunits that include an N-terminal S1 subunit &#40;Val16&#8211;Gln690&#41;&#46; It consists of S1A&#44; S1B&#44; S1C&#44; and S1D domains&#46; The latter is responsible for binding to the host cell receptor&#46; A C-terminal membrane-proximal S2 subunit contains the essential elements and is responsible for fusion of the viral and cellular membranes&#46;<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0014"><span class="elsevierStyleSup">14&#8211;16</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0021"><span class="elsevierStyleSup">21&#8211;24</span></a> This subunit has four parts including an internal membrane fusion peptide &#40;FP&#41;&#44; two 7-peptide repeats&#44; a membrane-proximal external region&#44; and a trans membrane domain &#40;TM&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a> The S1A domain&#44; alluded to as the N-terminal domain &#40;NTD&#41;&#44; recognizes carbohydrates&#44; such as sialic acid&#44; required for virus attachment to host cell surface&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a> The S1B domain &#40;Arg319&#8211;Phe541&#41;&#44; referred to as the receptor-binding domain &#40;RBD&#41; of the SARS-CoV-2 spike protein&#44; interacts with the human ACE2 receptor&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a> The S1 subunit can be defined further in two domains termed the N-terminal domain &#40;NTD&#41; and the C-terminal domain &#40;CTD&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a> The RBD is located in the CTD&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a> The structural parts within the S2 subunit include three long &#945;-helices&#44; multiple &#945;-helical segments&#44; extended twisted &#946;-sheets&#44; membrane-spanning &#945;-helix&#44; and an intracellular cysteine-rich segment&#46;<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">25</span></a> The PRRA sequence motif located between the S1 and S2 subunits in SARS-CoV-2 presents a furin-cleavage site&#46; In the S2 subunit&#44; there is a second proteolytic cleavage site S20&#44; upstream of the fusion peptide&#46; Both these cleavage sites participate in viral entry into host cells <a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia><p id="para0006" class="elsevierStylePara elsevierViewall">The S protein is a potential fragment to be used as antigens in vaccine designing including various forms of the full-length S protein&#44; RBD domain&#44; S1 subunit&#44; NTD&#44; and FP&#46;<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a> The RBD of S protein interacts with the ACE2 receptor on host cells directly&#46; The RBD immunization-induced specific antibodies may block this recognition and effectively prevent the viral invasion&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a> Most SARS-CoV-2 subunit vaccines currently under development use RBD as the antigen&#46;<a class="elsevierStyleCrossRefs" href="#bib0019"><span class="elsevierStyleSup">19&#8211;21</span></a> Moreover&#44; the RBD domain was also used to develop SARS-CoV and MERS-CoV vaccines&#46;<a class="elsevierStyleCrossRefs" href="#bib0019"><span class="elsevierStyleSup">19&#8211;21</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a></p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0007">Subunit vaccines against SARS-CoV-2</span><p id="para0007" class="elsevierStylePara elsevierViewall">Subunit vaccines use one or more antigens suitable for eliciting a robust immune response&#46;<a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a> In theory&#44; the subunit vaccine is very easy and safe&#44; but in practice&#44; it requires a suitable adjuvant to stimulate the host immune response&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0027"><span class="elsevierStyleSup">27</span></a> Several previous attempts were partially successful with SARS-CoV&#46;<a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0028"><span class="elsevierStyleSup">28</span></a> Immunization of animals with the S1 RBD domain fused with the IgG1 FC portion &#40;RBD-FC&#41; induced highly potent antibodies&#44; which could bind with the RBD domain of the S1 domain&#44; completely neutralized SARS-CoV&#44; and inhibited SARS-CoV entry into Vero E6 cells&#46;<a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0029"><span class="elsevierStyleSup">29</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">30</span></a></p><p id="para0008" class="elsevierStylePara elsevierViewall">So far&#44; several companies and academics have started plans on the SARS-CoV-2 subunit vaccine &#40;<a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>&#41;&#46; Almost all of them use the S protein as an antigenic target&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0028"><span class="elsevierStyleSup">28</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a> For example&#44; Novavax&#44; Inc&#46; announced to have produced multiple nanoparticle vaccine candidates based on S protein&#46;<a class="elsevierStyleCrossRef" href="#bib0032"><span class="elsevierStyleSup">32</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0033"><span class="elsevierStyleSup">33</span></a> Besides&#44; the Pasteur Institute of Iran and Finley institute of Cuba also prepared subunit vaccines against SARS-CoV-2&#46;<a class="elsevierStyleCrossRef" href="#bib0034"><span class="elsevierStyleSup">34</span></a> To facilitate the development of a SARS-CoV-2 vaccine&#44; the preferred adjuvant varied widely&#44; including the classic aluminum adjuvant that enhances the immune response by facilitating phagocytosis and slowing the diffusion of antigens from the injection site&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0027"><span class="elsevierStyleSup">27</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">35&#8211;37</span></a> It can efficiently stimulate the Th2 immune response upon injection&#46; The F59&#44; MF59 have already been used in flu vaccines in Europe and the United States&#46;<a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0037"><span class="elsevierStyleSup">37&#8211;42</span></a> The mechanism of MF59 is to recruit immune cells to induce antigen-specific immune responses&#46; The adjuvant system &#40;AS&#41; comprises a series of adjuvants improved by GlaxoSmithKline &#40;GSK&#41;&#44; including AS01&#44; AS02&#44; AS03&#44; and AS04&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">30</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">35</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0041"><span class="elsevierStyleSup">41&#8211;43</span></a> Among them&#44; AS01 is a liposome adjuvant&#46;<a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0044"><span class="elsevierStyleSup">44</span></a></p><elsevierMultimedia ident="tbl0001"></elsevierMultimedia></span></span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0008">Variant analysis of SARS-CoV-2 in spike protein mutations</span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Alpha &#40;B&#46;1&#46;1&#46;7 or VOC 202012&#47;01 or 20B&#47;501Y&#46;V1&#41; variant</span><p id="para0009" class="elsevierStylePara elsevierViewall">The B&#46;1&#46;1&#46;7 &#40;Alpha&#41; variant was presented on December 14&#44; 2020 by the United Kingdom &#40;UK&#41; authorities&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">45</span></a> The robust characterization of this variant which greater transmission&#44; accompanying an increase in incidence&#44; hospitalizations&#44; and pressure on the health system&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">45&#8211;47</span></a> Epidemiological reports and modeling suggest that it spreads 56&#37; faster than other lineages&#46; Studies estimated a 35&#37; &#40;12&#8211;64&#37;&#41; increased risk of death associated with the Alpha variant&#46; However&#44; there were no scientific reports of more severe diseases in children and young people&#46;<a class="elsevierStyleCrossRef" href="#bib0046"><span class="elsevierStyleSup">46</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0048"><span class="elsevierStyleSup">48</span></a></p><p id="para0010" class="elsevierStylePara elsevierViewall">In comparison with ancestral viruses containing the D614G mutation&#44; the Alpha variant has accumulated 23 mutations&#46; Of these mutations&#44; 14 are non-synonymous&#58; &#91;T1001I&#44; A1708D&#44; and I2230T&#93; in the open reading frame ORF1ab&#59; &#91;N501Y&#44; A570D&#44; P681H&#44; T716I&#44; S982A&#44; and D1118H&#93; in the S protein&#59; &#91;Q27stop&#44; R52I&#44; and Y73C&#93; in ORF8&#59; and &#91;D3L and S235F&#93; in the nucleocapsid &#40;N&#41; protein&#93;&#59; six are synonymous&#58; &#91;C913T&#44; C5986T&#44; C14676T&#44; C15279T&#44; and T16176C&#93; in ORF1ab&#59; and &#91;T26801C&#93; in M &#40;membrane&#41; gene&#59; and three are deletions&#58; &#91;SGF 3675-3677del&#93; in ORF1ab&#59; and &#91;H69-V70del and Y144del&#93; in S protein <a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">45</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0048"><span class="elsevierStyleSup">48&#8211;57</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0002">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0002"></elsevierMultimedia><p id="para0011" class="elsevierStylePara elsevierViewall">Forty-seven percent of reported changes in the Alpha variant occur in the gene encoding for the S protein&#44; including the RBD&#46; These mutations can play a role in &#40;i&#41; changing the interaction with the human angiotensin-converting enzyme-2 &#40;hACE2&#41; receptor&#44; increasing the infection rate&#59; &#40;ii&#41; compromising efficacy of both neutralizing antibodies and specific T cells elicited either during natural infection or through vaccination&#59; or &#40;iii&#41; altering sensitivity to neutralization by monoclonal antibodies or sera from convalescent patients&#44; compromising the efficacy of treatments <a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">45</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0048"><span class="elsevierStyleSup">48&#8211;57</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0002"></elsevierMultimedia><p id="para0012" class="elsevierStylePara elsevierViewall">The three mutations of the Alpha variant with the most significant potential to influence the biological characteristics of the virus are H69-V70del&#44; N501Y&#44; and P681H&#46; How does Alpha distribution impact the efficacy of vaccines and treatments that are being administered globally&#63; To date&#44; the ALPHA variant appears to have low or no significant impact on vaccine effectiveness&#46;<a class="elsevierStyleCrossRef" href="#bib0032"><span class="elsevierStyleSup">32</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">45</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0048"><span class="elsevierStyleSup">48&#8211;59</span></a></p></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">Beta &#40;B&#46;1&#46;351 or 20H&#47;501Y&#46;V2&#41; variant</span><p id="para0013" class="elsevierStylePara elsevierViewall">The B&#46;1&#46;351 <a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">60</span></a> variant&#44; also known as 20H&#47;501Y&#46;V2&#44; was first reported on December 18&#44; 2020 by the Republic of South Africa&#46;<a class="elsevierStyleCrossRef" href="#bib0061"><span class="elsevierStyleSup">61</span></a> The significant feature of this variant is the higher transmission rate&#46;<a class="elsevierStyleCrossRef" href="#bib0049"><span class="elsevierStyleSup">49</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0062"><span class="elsevierStyleSup">62</span></a> The Beta variant has 12 non-synonymous mutations and one deletion compared to the Wuhan reference strain&#46; Approximately 77&#37; of these mutations are located in the S protein &#91;L18F&#44; D80A&#44; D215G&#44; LAL 242&#8211;244 del&#44; R246I&#44; K417N&#44; E484K&#44; N501Y&#44; D614G&#44; and A701V&#93; while the remaining ones are located in ORF1a &#91;K1655N&#93;&#44; envelope &#40;E&#41; &#91;P71L&#93;&#44; and N &#91;T205I&#93; viral proteins&#46;<a class="elsevierStyleCrossRef" href="#bib0047"><span class="elsevierStyleSup">47</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0049"><span class="elsevierStyleSup">49</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0056"><span class="elsevierStyleSup">56</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0058"><span class="elsevierStyleSup">58</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0063"><span class="elsevierStyleSup">63-65</span></a> Most mutations are within two of the most immuno dominant regions&#44; such as NTD and RBD domains&#46; This issue suggests that Beta variant mutations could escape neutralizing antibodies and compromise vaccine efficacy <a class="elsevierStyleCrossRef" href="#bib0047"><span class="elsevierStyleSup">47</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0049"><span class="elsevierStyleSup">49</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0056"><span class="elsevierStyleSup">56</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0058"><span class="elsevierStyleSup">58</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0063"><span class="elsevierStyleSup">63&#8211;65</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0002">Table 2</a>&#41;&#46;</p><p id="para0014" class="elsevierStylePara elsevierViewall">Various studies determined that a combination of RBD and NTD mutations in the Beta spike protein considerably influences neutralization activity in vaccinated patients&#46; Vaccine efficacy are more compromised against the Beta variant than against the varinat B&#46;1&#46;1&#46;7 <a class="elsevierStyleCrossRef" href="#bib0049"><span class="elsevierStyleSup">49</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0053"><span class="elsevierStyleSup">53</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0061"><span class="elsevierStyleSup">61&#8211;63</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">65&#8211;68</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>&#41;&#46;</p></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">Gamma &#40;P&#46;1 or B&#46;1&#46;1&#46;28&#46;1&#41; variant</span><p id="para0015" class="elsevierStylePara elsevierViewall">The B&#46;1&#46;1&#46;28&#46;1&#46; &#40;Gamma or P&#46;1&#41; variant was first detected by Japan&#39;s National Institute of Infectious Diseases on January 6&#44; 2021 and was isolated from four travelers who arrived in Tokyo coming from Amazonas&#44; Brazil&#44; on January 2&#44; 2021 at airport control&#46;<a class="elsevierStyleCrossRef" href="#bib0047"><span class="elsevierStyleSup">47</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0061"><span class="elsevierStyleSup">61</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0064"><span class="elsevierStyleSup">64</span></a> The rapid increase in the number of hospital admissions was a significant problem with this variant&#46; This variant contains 17 non-synonymous mutations&#58; &#91;L18F&#44; T20N&#44; P26S&#44; D138Y&#44; R190S&#44; K417T&#44; E484K&#44; N501Y&#44; D614G&#44; H655Y&#44; T1027I&#44; and V1176F&#93; in S protein&#44; &#91;S1188L&#44; K1795Q&#44; and E5665D&#93; in ORF1ab&#44; &#91;E92K&#93; in ORF8&#44; and &#91;P80K&#93; in N protein&#59; 1 deletion&#58; &#91;SGF 3675-3677del&#93; in ORF1ab&#59; and four synonymous mutations&#46; Gamma is the SARS-CoV-2 variant that accumulates the highest number of mutations in the S protein &#40;12 mutations&#41; <a class="elsevierStyleCrossRef" href="#bib0046"><span class="elsevierStyleSup">46</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0054"><span class="elsevierStyleSup">54</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0056"><span class="elsevierStyleSup">56</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0057"><span class="elsevierStyleSup">57</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0061"><span class="elsevierStyleSup">61</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0064"><span class="elsevierStyleSup">64</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0069"><span class="elsevierStyleSup">69</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">70</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0002">Table 2</a>&#41;&#46;</p><p id="para0016" class="elsevierStylePara elsevierViewall">The mutation N501Y is present in the three variants&#44; while L18F&#44; K417T&#44; E484K&#44; and D614G mutations are present in the Beta variants&#46; This group of S mutations has important implications for the evasion of antibody-mediated immunity&#46; The efficacy of serum neutralization against the virus holding the E484K mutation was decreased in both vaccination and convalescent sera <a class="elsevierStyleCrossRef" href="#bib0046"><span class="elsevierStyleSup">46</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0054"><span class="elsevierStyleSup">54</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0056"><span class="elsevierStyleSup">56</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0057"><span class="elsevierStyleSup">57</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0061"><span class="elsevierStyleSup">61</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0064"><span class="elsevierStyleSup">64</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0069"><span class="elsevierStyleSup">69</span></a><a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">70</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a>&#41;&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">Delta &#40;B&#46;1&#46;617&#46;2&#41; variant</span><p id="para0017" class="elsevierStylePara elsevierViewall">The SARS-CoV-2 B&#46;1&#46;617&#46;2 &#40;Delta&#41; variant was first reported in the state of Maharashtra in October 2020 with subsequent dissemination throughout India&#46; The virus sequences extracted in India had two critical amino acid substitutions &#40;L452R and E484Q&#41; in the RDB of the S glycoprotein&#46; This &#8220;double mutant&#8221; has three sub-lineages &#40;B&#46;1&#46;617&#46;1&#44; B&#46;1&#46;617&#46;2&#44; and B&#46;1&#46;617&#46;3&#41; characterized by the spike mutation L452R&#44; whilst E484Q is present in B&#46;1&#46;617&#46;1 and B&#46;1&#46;617&#46;3 but not in B&#46;1&#46;617&#46;2&#46; The B&#46;1&#46;617&#46;2 is now the major variant in the UK&#46; The lineages have mutations in the gene encoding the SARS-CoV-2 S protein&#46; The Delta genome has 17 mutation of which four are of particular concern&#46; In the D614G&#44; substitution at position 614&#44; an aspartic acid-to-glycine substitution&#44; is shared with other highly transmissible variants like Alpha&#44; Beta&#44; and Gamma&#46; T478K is an exchange at position 478&#46; The L452R is a substitution at position 452&#44; confers a stronger affinity of the S protein for the ACE2 receptor and decreased recognition capability of the immune system&#46; The P681R is a substitution at position 681&#44; may boost cell-level infectivity of the variant&#46;<a class="elsevierStyleCrossRefs" href="#bib0071"><span class="elsevierStyleSup">71-74</span></a></p></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Lambda &#40;C&#46;37&#41; variant</span><p id="para0018" class="elsevierStylePara elsevierViewall">The Lambda &#40;C&#46;37&#41; variant was first reported in Peru in December of 2020&#46; The Sequencing of the variant genome revealed a deletion &#40;&#916;3675- 3677&#41; in open reading frame 1a &#40;ORF1a&#41; of wild type&#46; The Lambda variant also has of a new deletion &#40;&#916;246-252&#41; and multiple non-synonymous mutations &#40;G75V&#44; T76I&#44; L452Q&#44; F490S&#44; D614G&#44; and T859N&#41; in S protein&#46; The mutations L452Q and F490S are present in the spike RBD&#46; The F490S mutation is associated with decreased susceptibility to antibody neutralization&#46; This variant has 19 mutations that made it more transmissible or with increased resistance to antibodies induced by vaccination or by prior exposure to the virus&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">75&#8211;77</span></a></p></span><span id="sec0012" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0014">Other variants</span><p id="para0019" class="elsevierStylePara elsevierViewall">The Eta &#40;B&#46;1&#46;525&#41; variant was first identified in Nigeria in December of 2020&#46; Its spike mutations include E484K&#44; D614G&#44; Q677H which impact antibody neutralization and transmission&#46; The Epsilon &#40;B&#46;1&#46;427&#47;B&#46;1&#46;429&#41; variant was first identified in the USA in September of 2020 showing L452R&#44; D614G as spike mutations&#44; but their impact on antibody neutralization and transmission is unclear&#46; The Theta &#40;P&#46;3&#41; variant was first identified in the Philippines in January of 2021&#44; with E484K&#44; N501Y&#44; D614G&#44; P681H as spike mutations which impact antibody neutralization and transmission&#46; The Kappa &#40;B&#46;1&#46;617&#46;1&#41; variant was first identified in India in December of 2020&#44; with L452R&#44; E484Q&#44; D614G&#44; P681R as spike mutations which also impact antibody neutralization and transmission&#46; The Iota &#40;B&#46;1&#46;526&#41; variant was first identified in the USA in December of 2020&#44; with E484K&#44; D614G&#44; A701V as spike mutations which impact antibody neutralization&#46; The Zeta &#40;P&#46;2&#41; variant was first identified in Brazil in January of 2021&#44; with E484K&#44; D614G as spike mutations which impact antibody neutralization&#46; All of the above variants have not been shown to cause more severe disease&#46;</p></span><span id="sec0013" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0015">The mutated spike variants of SARS-CoV-2 and vaccines efficacy reports</span><p id="para0020" class="elsevierStylePara elsevierViewall">The main concern for healthcare systems related to the variants of SARS-CoV-2 are the potential compromise of antibody neutralization and subunit vaccines efficacy&#46; Various reports demonstrate the interaction between SARS-CoV-2 and vaccine efficacy&#46;<a class="elsevierStyleCrossRefs" href="#bib0046"><span class="elsevierStyleSup">46&#8211;48</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0057"><span class="elsevierStyleSup">57</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0064"><span class="elsevierStyleSup">64</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">70</span></a> In the present work&#44; the main objective was to assess the impact of the variants that mutated in the target site of the vaccine &#40;S protein&#41; on subunit vaccines efficacy&#46;</p><p id="para0021" class="elsevierStylePara elsevierViewall">Yiska et al&#46; demonstrated that functional SARS-CoV-2 S protein variants with mutations in RBD confer resistance to monoclonal antibodies or convalescent plasma and can be readily selected&#46; Therefore&#44; the virus S variants can resist commonly elicited neutralizing antibodies&#46;<a class="elsevierStyleCrossRef" href="#bib0078"><span class="elsevierStyleSup">78</span></a> Pengfei et al&#46; showed that the B&#46;1&#46;351 variant is refractory to neutralization by most monoclonal antibodies against the N-terminal domain and multiple individual monoclonal antibodies against the receptor-binding motif of the RBD&#46; Moreover&#44; B&#46;1&#46;351 is markedly more resistant to neutralization by convalescent plasma and sera from individuals who have been vaccinated&#46;<a class="elsevierStyleCrossRef" href="#bib0049"><span class="elsevierStyleSup">49</span></a></p><p id="para0022" class="elsevierStylePara elsevierViewall">Delphine et al&#46; demonstrated that B1&#46;351&#44; but not B&#46;1&#46;1&#46;7&#44; may increase the risk of infection in immunized individuals&#46;<a class="elsevierStyleCrossRef" href="#bib0053"><span class="elsevierStyleSup">53</span></a> A description by Rees et al&#46; shown that the neutralizing activity of some antibodies was dramatically reduced by Spike mutations &#40;B&#46;1&#46;1&#46;7&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0064"><span class="elsevierStyleSup">64</span></a> In Rita et al&#46; reported the impact on antibody neutralization of a panel of authentic SARS-CoV-2 variants&#44; including a B&#46;1&#46;1&#46;7 isolate&#44; chimeric strains with South African&#44; Brazilian spike genes&#44; and isogenic recombinant viral variants&#46; They showed reduced inhibitory activity against viruses containing an E484K spike mutation as antibodies binding to spike RBD demonstrate diminished neutralization potency <span class="elsevierStyleItalic">in vitro</span> against some emerging variants&#46;<a class="elsevierStyleCrossRef" href="#bib0079"><span class="elsevierStyleSup">79</span></a></p><p id="para0023" class="elsevierStylePara elsevierViewall">Xiu et al&#46; revealed that UK and Brazil variants have no significantly decreased effect on vaccine impact and neutralization by sera from vaccinated individuals after two BNT162b2 &#40;Pfizer&#41; doses&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">80</span></a> Collier et al&#46; did not observe a significant decrease in the ability of sera from vaccinated persons &#40;Pfizer&#41; to inhibit parental or mutant pseudo viruses&#44; including only three &#40;H69&#47;V70del&#44; N501Y&#44; and A570D&#41; S mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0081"><span class="elsevierStyleSup">81</span></a> Wu et al&#46; found no considerable impact in the neutralizing potency of sera from people who received the Moderna vaccine against the B&#46;1&#46;1&#46;7 variant&#46;<a class="elsevierStyleCrossRef" href="#bib0082"><span class="elsevierStyleSup">82</span></a> Nevertheless&#44; Wang et al&#46; reported that B&#46;1&#46;351 variant was particularly more resistant to neutralization in people immunized with Pfizer or Moderna vaccines&#46;<a class="elsevierStyleCrossRef" href="#bib0049"><span class="elsevierStyleSup">49</span></a> On the other side&#44; he reported considerable decrease in the neutralization of B&#46;1&#46;351 variants by sera from volunteers who were vaccinated with Moderna&#46;<a class="elsevierStyleCrossRef" href="#bib0049"><span class="elsevierStyleSup">49</span></a> Wilfredo et al&#46; analyzed neutralization potency in individuals who received one or two doses of either BNT162b2 or mRNA-1273 vaccines&#44; suggesting that a relatively small number of mutations&#44; like B&#46;1&#46;351 can mediate potent escape from vaccine responses&#46; Their results highlight the potential for variants to escape neutralizing humoral immunity and emphasize the need to develop broadly protective interventions against the evolving pandemic&#46;<a class="elsevierStyleCrossRef" href="#bib0083"><span class="elsevierStyleSup">83</span></a></p><p id="para0024" class="elsevierStylePara elsevierViewall">In this review&#44; we highlight the compromise of subunit vaccine efficacy against the variants&#46; In the study by Arturo Chang et al&#46; the vaccine based on recombinant dimeric receptor-binding domain &#40;d-RBD&#44; 50 g&#41; on alum &#40;FINLAY-FR-1A&#41; in clinical development in Cuba&#44; and they hypothesized that a single dose of that vaccine might be an effective booster for individuals with pre-existing immunity to SARS-CoV-2&#46;<a class="elsevierStyleCrossRef" href="#bib0034"><span class="elsevierStyleSup">34</span></a> The report by Shilong et al&#46; focused on the ZF2001 vaccine &#40;protein-based COVID-19&#41;&#46; They indicated that the RBD-based protein subunit vaccine could be safe and immunogenic&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">30</span></a> Shinde et al&#46; reported on a comprehensive analysis of the NVX-CoV2373 vaccine in 4387 participants&#46; They revealed that efficacy against B&#46;1&#46;351 was 51&#46;0&#37;&#46; The NVX-CoV2373 vaccine was efficacious in preventing Covid-19&#44; which was predominantly mild to moderate and due to the B&#46;1&#46;351 variant&#46;<a class="elsevierStyleCrossRef" href="#bib0066"><span class="elsevierStyleSup">66</span></a></p><p id="para0025" class="elsevierStylePara elsevierViewall">SARS-CoV-2 vaccine NVX-CoV2373&#44; produced by Novavax is based on S protein derived from the SARS-CoV-2 Wuhan reference strain&#44; has shown 85&#46;6&#37; efficacy against the B&#46;1&#46;1&#46;7 variant &#40;95&#46;6&#37; against the original strain&#41; in phase 3 clinical trial&#46;<a class="elsevierStyleCrossRef" href="#bib0032"><span class="elsevierStyleSup">32</span></a> However&#44; in a study in South Africa Callaway et al&#46; reported a 49&#46;4&#37; efficacy against B&#46;1&#46;351 variant in the overall population&#46;<a class="elsevierStyleCrossRef" href="#bib0033"><span class="elsevierStyleSup">33</span></a> These interim data evidence a significant decrease in vaccine efficacy influenced by variants such as B&#46;1&#46;351&#46;</p><p id="para0026" class="elsevierStylePara elsevierViewall">In the report of Xiaoying et al&#46; B&#46;1&#46;1&#46;7 remained sensitive to neutralization&#44; albeit at moderately reduced levels&#44; by serum samples from convalescent individuals and recipients of an mRNA vaccine &#40;Moderna&#41; and a protein nanoparticle vaccine &#40;NVXCoV2373&#44; Novavax&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">45</span></a></p><p id="para0027" class="elsevierStylePara elsevierViewall">Mlcochova et al&#46; showed evasion of the Delta variant from neutralizing antibodies present in convalescent patients&#44; as well as in vaccinated individuals with two different vaccines in the UK &#40;adenovirus vector &#40;ChAdOx-1&#41;&#44; and the other mRNA 19 &#40;BNT162b2&#41;&#41;&#46; They demonstrated a reduced susceptibility of Delta to vaccine-elicited neutralization&#46; In their data&#44; the variant showed approximately 8 to 20-fold reduced sensitivity to vaccine-elicited antibodies&#46; Serum neutralizing titers against the variant were significantly lower in vaccinated persons with ChadOx-1 as compared to BNT162b2&#46; These data revealed that the Delta variant can evade from neutralizing antibodies in previously infected individuals&#44; although severe disease in fully vaccinated was rare&#46;<a class="elsevierStyleCrossRef" href="#bib0084"><span class="elsevierStyleSup">84</span></a></p><p id="para0028" class="elsevierStylePara elsevierViewall">In another report by Davis et al&#46; reductions in the neutralization of B&#46;1&#46;617&#46;1 and B&#46;1&#46;617&#46;2 were 4&#46;31- and 5&#46;11-fold&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0071"><span class="elsevierStyleSup">71</span></a> In another report&#44; Lustig and et al&#46; demonstrated significant fold change reduction in neutralizing titers&#58; Gamma &#40;P&#46;1&#41; 2&#46;3&#44; Beta &#40;B&#46;1&#46;351&#41; 10&#46;4&#44; Delta 2&#46;1&#44; and 2&#46;6&#46; The fold reduction of the Alpha &#40;B&#46;1&#46;1&#46;7&#41; variant was not significant&#46;<a class="elsevierStyleCrossRef" href="#bib0073"><span class="elsevierStyleSup">73</span></a></p><p id="para0029" class="elsevierStylePara elsevierViewall">No published report demonstrated subunit vaccine efficacy on Delta variant&#44; and all other reports were based on Pfizer and Oxford vaccines and their antibody neutralization&#46; No published report demonstrated subunit vaccine efficacy against Delta variant&#46;</p><p id="para0030" class="elsevierStylePara elsevierViewall">Acevedo et al&#46; observed greater infectivity mediated by the Lambda spike protein compared to D614G &#40;lineage B&#41; or Alpha and Gamma variants&#46; In addition&#44; neutralization was reduced by 3&#46;05-fold for the Lambda variant&#44; 2&#46;33-fold for the Gamma variant and 2&#46;03-fold for the Alpha variant&#46;<a class="elsevierStyleCrossRef" href="#bib0077"><span class="elsevierStyleSup">77</span></a> Tada et al&#46; showed an average 2&#46;3-3&#46;3-fold reduction of antibody titers against Lambda variant&#46;<a class="elsevierStyleCrossRef" href="#bib0076"><span class="elsevierStyleSup">76</span></a></p></span></span><span id="sec0014" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0016">Conclusion</span><p id="para0031" class="elsevierStylePara elsevierViewall">Subunit vaccines with strong immunogenic capacity can efficiently elicit host immune response&#46; However&#44; the major healthcare concern is a reduction of subunit vaccines efficacy in translated by lower antibody neutralization potency against SARS-CoV-2 Alpha&#44; Beta&#44; Gamma&#44; Delta&#44; and Lambda variants&#46; To date&#44; low or no significant impact on vaccine efficacy against Alpha variants has been reported&#46; Concern about and Delta&#44; Beta&#44; Gamma&#44; and Lambda mutations on vaccine efficacy and treatments is greater than for the Alpha variant&#46; Further comprehensive analyses all over the world validated by clinical trials are clearly warranted&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0017">Author contributions</span><p id="para0032" class="elsevierStylePara elsevierViewall">The article was conceived and critically reviewed by Mehrdad Mohammadi and performed the literature search and drafted the work&#46; Dr&#46; Mohammadi Shayestepour approved the work and agreed to be accountable for the work&#46; Dr&#46; Hamed Mirzaei designed all of the figures&#46;</p></span><span id="sec0016" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0018">Funding</span><p id="para0033" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Methods"
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              "titulo" => "The SARS-CoV-2 genomic features"
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              "titulo" => "Structure&#44; function&#44; and antigenicity of the SARS-CoV-2 spike glycoprotein"
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              "titulo" => "Subunit vaccines against SARS-CoV-2"
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          "titulo" => "Variant analysis of SARS-CoV-2 in spike protein mutations"
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            0 => array:2 [
              "identificador" => "sec0007"
              "titulo" => "Alpha &#40;B&#46;1&#46;1&#46;7 or VOC 202012&#47;01 or 20B&#47;501Y&#46;V1&#41; variant"
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              "titulo" => "Beta &#40;B&#46;1&#46;351 or 20H&#47;501Y&#46;V2&#41; variant"
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              "identificador" => "sec0009"
              "titulo" => "Gamma &#40;P&#46;1 or B&#46;1&#46;1&#46;28&#46;1&#41; variant"
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              "identificador" => "sec0010"
              "titulo" => "Delta &#40;B&#46;1&#46;617&#46;2&#41; variant"
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              "titulo" => "Lambda &#40;C&#46;37&#41; variant"
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              "titulo" => "Other variants"
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              "titulo" => "The mutated spike variants of SARS-CoV-2 and vaccines efficacy reports"
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        "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><p id="spara005" class="elsevierStyleSimplePara elsevierViewall">Since the first described human infection with SARS-CoV-2 in December of 2019 many subunit protein vaccines have been proposed for use in humans&#46; Subunit vaccines use one or more antigens suitable for eliciting a robust immune response&#46; However&#44; the major concern is the efficacy of subunit vaccines and elicited antibodies to neutralize the variants of SARS-CoV-2 like B&#46;1&#46;1&#46;7 &#40;Alpha&#41;&#44; B&#46;1&#46;351 &#40;Beta&#41; and P1 &#40;Gamma&#41;&#44; B&#46;1&#46;617 &#40;Delta&#41; and C&#46;37 &#40;Lambda&#41;&#46; The Spike protein &#40;S&#41; is a potential fragment for use as an antigen in vaccine development&#46; This protein plays a crucial role in the first step of the infection process&#44; as it binds to Angiotensin-Converting Enzyme 2 &#40;ACE2&#41; receptor and enters the host cell after binding&#46; Immunization-induced specific antibodies against the receptor binding domain &#40;RBD&#41; may block and effectively prevent virus invasion&#46; The focus of this review is the impact of spike mutated variants of SARS-CoV2 &#40;Alpha&#44; Beta&#44; Gamma&#44; Delta&#44; and Lambda&#41; on the efficacy of subunit recombinant vaccines&#46; To date&#44; a low or no significant impact on vaccine efficacy against Alpha and Delta variants has been reported&#46; Such an impact on vaccine efficacy for Beta&#44; Delta&#44; Gamma&#44; and Lambda variants may be even greater compared to the Alpha variant&#46; Nonetheless&#44; more comprehensive analyses are needed to assess the real impact on vaccine efficacy brought about by SARS-CoV-2 variants&#46;</p></span>"
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                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Type of subunit vaccine&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Company&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Current clinical phase trial number&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">SARS-CoV-2 rS&#47;Matrix M1-Adjuvant &#40;Full length recombinant SARS-CoV-2 glycoprotein nano particle vaccine adjuvant with Matrix M&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">Novavax&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04611802EUCTR2020-004123-16-GB NCT04583995&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">Recombinant SARS-CoV-2 vaccine &#40;CHO Cell&#41;This is not a pattern of &#39;ctgov&#39; external object linking&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0011"></a><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="top">Anhui Zhifei LongcomBiopharmaceutical&#160;&#43;&#160;Institute of Microbiology&#44; Chinese Academy of Sciences&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04646590&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Kentucky Bioprocessing Inc&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0016"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04473690&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">VAT00002&#58; SARS-CoV-2 S protein with adjuvant&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">Sanofi Pasteur&#160;&#43;&#160;GSK&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">PACTR202011523101903&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><a name="en0022"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">SCB-2019&#160;&#43;&#160;AS03 or CpG 1018 adjuvant plus Alum adjuvant &#40;Native like Trimeric subunit Spike Protein vaccine&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0023"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Clover Biopharmaceuticals Inc&#46;&#47;GSK&#47;Dynavax&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0024"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04672395&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0025"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0026"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">COVAX-19&#174; Recombinant spike protein&#160;&#43;&#160;adjuvant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0027"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Vaxine Pty Ltd&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0028"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04453852&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0029"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0030"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">MVC-COV1901 &#40;S-2P protein&#160;&#43;&#160;CpG 1018&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0031"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Medigen Vaccine Biologics&#160;&#43;&#160;Dynavax&#160;&#43;&#160;National Institute of Allergy and Infectious Diseases &#40;NIAID&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0032"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04695652&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0033"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0034"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">FINLAY-FR1 anti-SARS-CoV-2 Vaccine &#40;RBD&#160;&#43;&#160;adjuvant&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0035"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Instituto Finlay de Vacunas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0036"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">RPCEC00000332&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0037"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0038"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">FINLAY-FR-2 anti-SARS-CoV-2 Vaccine &#40;RBD chemically conjugated to tetanus toxoid plus adjuvant&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0039"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Instituto Finlay de Vacunas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0040"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">RPCEC00000354&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0041"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0042"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">EpiVacCorona &#40;EpiVacCorona vaccine based on peptide antigens for the prevention of COVID-19&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0043"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Federal Budgetary Research Institution State Research Center of Virology and Biotechnology &#8220;Vector&#8221;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0044"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04780035&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0045"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0046"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">RBD &#40;baculovirus production expressed in Sf9 cells&#41; Recombinant SARS-CoV-2 vaccine &#40;Sf9 Cell&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0047"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">West China Hospital&#160;&#43;&#160;Sichuan University&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0048"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04718467&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0049"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0050"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">IMP CoVac-1 &#40;SARS-CoV-2 HLA-DR peptides&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0051"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">University Hospital Tuebingen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0052"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04546841&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0053"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0054"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">UB-612 &#40;Multitope peptide based S1-RBD-protein based vaccine&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0055"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">COVAXX&#160;&#43;&#160;United Biomedical Inc&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0056"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04683224&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0057"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0058"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">AdimrSC-2f &#40;Recombinant RBD &#43;&#47;&#8722; Aluminium&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0059"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Adimmune Corporation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0060"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04522089&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0061"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0062"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">CIGB-669 &#40;RBD&#160;&#43;&#160;AgnHB&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0063"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Center for Genetic Engineering and Biotechnology &#40;CIGB&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0064"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">RPCEC00000345&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0065"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0066"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">CIGB-66 &#40;RBD&#160;&#43;&#160;aluminium hydroxide&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0067"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Center for Genetic Engineering and Biotechnology &#40;CIGB&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0068"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">RPCEC00000359&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0069"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0070"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Recombinant Sars-CoV-2 Spike protein&#44; Aluminum adjuvanted&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0071"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Nanogen PharmaceuticalBiotechnology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0072"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04683484&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0073"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0074"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Recombinant protein vaccine S-268019 &#40;using Baculovirus expression vector system&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0075"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Shionogi&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0076"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">jRCT2051200092&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0077"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0078"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">SARS-CoV-2-RBD-Fc fusion protein&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0079"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">University Medical Center Groningen&#160;&#43;&#160;Akston Biosciences Inc&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0080"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04681092&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0081"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0082"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">COVAC-1 and COVAC-2 sub-unit vaccine &#40;spike protein&#41;&#160;&#43;&#160;SWE adjuvant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0083"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">University of Saskatchewan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0084"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04702178&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0085"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0086"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">GBP510&#44; a recombinant surface protein vaccine with adjuvant AS03 &#40;aluminium hydroxide&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0087"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">SK Biosciences Co&#46; Ltd&#46; And CEPI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0088"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04750343&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0089"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0090"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Razi Cov Pars&#44; recombinant spike protein&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0091"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Razi Vaccine and SerumResearch Institute&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0092"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">IRCT20201214049709N1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0093"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0094"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">MF59 adjuvanted SARS-CoV-2 Sclamp vaccine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0095"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">The University of Queensland&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0096"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04495933&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0097"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0098"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">SK SARS-CoV-2 recombinant surface antigen protein subunit &#40;NBP2001&#41;&#160;&#43;&#160;adjuvanted with alum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0099"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">SK Bioscience Co&#46;&#44; Ltd&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0100"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04760743&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0101"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0102"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">SpFN &#40;spike ferritin nanoparticle&#41; uses spike proteins with a liposomal formulation QS21 &#40;ALFQ&#41; adjuvant&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0103"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Walter Reed Army Institute of Research &#40;WRAIR&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0104"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">NCT04784767&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0105"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0106"></a><td class="td" title="\n
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