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Immunoinformatic Analysis of T- and B-Cell Epitopes for SARS-Cov-2 Vaccine Design

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Immunoinformatic Analysis of T- and B-Cell Epitopes for SARS-Cov-2 Vaccine Design Article Immunoinformatic Analysis of T- and B-Cell Epitopes for SARS-CoV-2 Vaccine Design Dongliang Wang 1, Jinhui Mai 1, Wenfeng Zhou 1, Wanting Yu 1,2, Yang Zhan 1, Naidong Wang 1, Neal D. Epstein 3,* and Yi Yang 1,* 1 Hunan Provincial Key Laboratory of Protein Engineering in Animal Vaccines, Laboratory of Functional Proteomics (LFP), Research Center of Reverse Vaccinology (RCRV), College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China; [email protected] (D.W.); [email protected] (J.M.); [email protected] (W.Z.); [email protected] (W.Y.); [email protected] (Y.Z.); [email protected] (N.W.) 2 State Key Laboratory of Membrane Biology, Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China 3 Cell and Developmental Biology Center, NHLBI, NIH, Bethesda, MD 20892, USA * Correspondence: [email protected] (N.D.E.); [email protected] (Y.Y.) Received: 28 May 2020; Accepted: 30 June 2020; Published: 3 July 2020 Abstract: Currently, there is limited knowledge about the immunological profiles of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). We used computer-based immunoinformatic analysis and the newly resolved 3-dimensional (3D) structures of the SARS-CoV-2 S trimeric protein, together with analyses of the immunogenic profiles of SARS-CoV, to anticipate potential B-cell and T-cell epitopes of the SARS-CoV-2 S protein for vaccine design, particularly for peptide-driven vaccine design and serological diagnosis. Nine conserved linear B-cell epitopes and multiple discontinuous B-cell epitopes composed of 69 residues on the surface of the SARS-CoV-2 trimeric S protein were predicted to be highly antigenic. We found that the SARS-CoV-2 S protein has a different antigenic profile than that of the SARS-CoV S protein due to the variations in their primary and 3D structures. Importantly, SARS-CoV-2 may exploit an immune evasion mechanism through two point mutations in the critical and conserved linear neutralization epitope (overlap with fusion peptide) around a sparsely glycosylated area. These mutations lead to a significant decrease in the antigenicity of this epitope in the SARS-CoV-2 S protein. In addition, 62 T-cell epitopes in the SARS-CoV-2 S protein were predicted in our study. The structure-based immunoinformatic analysis for the SARS-CoV-2 S protein in this study may improve vaccine design, diagnosis, and immunotherapy against the pandemic of COVID-19. Keywords: SARS-CoV-2; S protein; B-cell and T-cell epitopes; vaccine 1. Introduction The outbreak of the coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) [1]. By 16 June 2020, SARS-CoV-2 has been reported in 216 nations and has resulted in 7,941,791 confirmed cases (https: //www.who.int/emergencies/diseases/novel-coronavirus-2019). Coronavirus (CoV) belongs to the family of Coronaviridae, and it is an enveloped, positive-sense single-stranded RNA virus. Both SARS-CoV-2 and SARS-CoV fit into the subgenus of Sarbecovirus within the genus of Betacoronavirus (Beta-CoV), based on phylogenetic tree analysis [1–3]. The viral genome, approximately 30 kb in size, encodes four structural proteins including the spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins. The S protein is composed of an ectodomain, Vaccines 2020, 8, 355; doi:10.3390/vaccines8030355 www.mdpi.com/journal/vaccines Vaccines 2020, 8, x 2 of 18 ectodomain, a transmembrane domain (TM), and a short cytoplasmic tail region (CP) (Figure 1). The S protein forms homotrimers on the viral membrane surface. The ectodomain of S protein is composed of two subunits (S1 and S2) which are responsible for host cell receptor engagement and membrane fusion, respectively. The S1 subunit contains an NH2-terminal domain (NTD) and the carboxyl-terminal domain (CTD), which is also called the receptor-binding domain (RBD). Coronaviruses may use both domains to interact with a variety of host cell receptors for cell entry. For instance, both SARS-CoV and SARS-CoV-2 use the RBD to specifically bind angiotensin-converting enzyme 2 (ACE2) on host cells for virus entry [4–6]. Molecular modeling has suggested that the SARS- CoV-2 receptor-binding domain (RBD) has a stronger binding affinity to ACE2 [7]. Middle East Respiratory Syndrome Coronavirus (MERS-CoV) uses its RBD to bind to host cell receptor dipeptidyl peptidase 4 (DPP4) [8]. Some other members, such as porcine epidemic diarrhea virus (PEDV), employ the NTD to interact with a sugar moiety on the host cell membrane for binding and entry [9]. SARS- CoV receptor (ACE2) binding to RBD of the S1 subunit induces subsequent conformational changes of the S2 subunit, which leads to the fusion of the cell and the virus membranes [10,11]. The S2 subunit contains two heptad repeat domains (HR1 and HR2) that play a critical role in SARS-CoV membrane fusion with target cells. SARS-CoV infection triggers a series of humoral and cellular immune responses, including the production of high titers of specific neutralizing antibodies and specific cytotoxic T lymphocyte responses to SARS-CoV [12,13]. The S protein is the major structural antigenic component through Vaccines 2020, 8, 355 2 of 15 which effective protective immunity is raised against virus infection. A vaccine based on the S protein could elicit antibodies to neutralize virus infection by blocking virus fusion and entry. The SARS- aCoV-2 transmembrane S protein shares domain a high (TM), degree and of a similarity short cytoplasmic to the SARS-CoV tail region S protein (CP) (Figure [14,15],1). and The it Salso protein binds formsin similar homotrimers fashion to on the the human viral membrane ACE2 receptor surface. and The thus ectodomain is likely ofto S employ protein isa composedsimilar cell of entry two subunitsmechanism (S1 [4,16]. and S2) As which such, the are S responsible protein is an for effective host cell antigenic receptor component engagement for and SARS-CoV-2 membrane vaccine fusion, respectively.design and development. The S1 subunit However, contains ancurrently, NH2-terminal there is domain little or (NTD) limite andd information the carboxyl-terminal about the domainimmunogenic (CTD), profiles whichis of also SARS-CoV-2 called the and receptor-binding the immune responses domain (RBD). against Coronaviruses SARS-CoV-2. may Despite use boththis, domainscomputer-based to interact immunoinformatics with a variety of host [17], cell together receptors with for cellthe entry.recent For progress instance, on both the SARS-CoV3-dimensional and SARS-CoV-2(3D) SARS-CoV-2 use the S RBDprotein to specifically [14,15,18–21], bind offers angiotensin-converting a powerful strategy enzyme providing 2 (ACE2) rational on host and cells rapid for virusguidelines entry [for4– 6the]. Molecular design and modeling development has suggested of effective that thevaccines SARS-CoV-2 against receptor-bindingthis emerging infectious domain (RBD)disease. has a stronger binding affinity to ACE2 [7]. Middle East Respiratory Syndrome Coronavirus (MERS-CoV)In this study, uses itsthe RBD close to genetic bind to relationship host cell receptor of SARS-CoV-2 dipeptidyl with peptidase other 4members (DPP4) [of8]. the Some genus other of members,Beta-CoV, suchespecially as porcine with epidemicSARS-CoV diarrhea, prompted virus us (PEDV), to explore employ the po thetential NTD immunogenic to interact with profiles a sugar of moietySARS-CoV-2 on the for host vaccine cell membrane design and for bindingdevelopmen and entryt. We[ 9used]. SARS-CoV computer-based receptor immunoinformatic (ACE2) binding to RBDanalysis, of the together S1 subunit with induces analyses subsequent of the immunogeni conformationalc profiles changes of SARS-CoV, of the S2 to subunit, anticipate which potential leads toB- thecell fusionand T-cell of the epitopes cell and of the the S virus protein membranes of SARS-CoV [10,11-2 ].for The vaccine S2 subunit design, contains particularly two peptide-driven heptad repeat domainsvaccine design, (HR1 and immunotherapy, HR2) that play and a critical serological role in diagnosis. SARS-CoV membrane fusion with target cells. FigureFigure 1.1. Schematic of Severe Acute Respiratory SyndromeSyndrome CoronavirusCoronavirus (SARS-CoV) (SARS-CoV) and and SARS-CoV-2 SARS-CoV- S2 protein.S protein. (A ,(AB), SchematicB) Schematic of SARS-CoV of SARS-CoV and SARS-CoV-2and SARS-CoV-2 genome genome encoding encoding spike protein.spike protein. SP: signal SP: peptide;signal peptide; NTD: N-terminal NTD: N-terminal domain; domain; RBD: receptor-binding RBD: receptor-binding domain; RBM:domain; receptor-binding RBM: receptor-binding motif; FP: fusionmotif; peptide;FP: fusion HR1 peptide; and HR2: HR1 heptad and HR2: repeat heptad regions repeat 1 and regions 2; TM: 1 transmembrane; and 2; TM: transmembrane; CP: cytoplasmic CP: tail region. cytoplasmic tail region. SARS-CoV infection triggers a series of humoral and cellular immune responses, including the production of high titers of specific neutralizing antibodies and specific cytotoxic T lymphocyte responses to SARS-CoV [12,13]. The S protein is the major structural antigenic component through which effective protective immunity is raised against virus infection. A vaccine based on the S protein could elicit antibodies to neutralize virus infection by blocking virus fusion and entry. The SARS-CoV-2 S protein shares a high degree of similarity to the SARS-CoV S protein [14,15], and it also binds in similar fashion to the human ACE2 receptor and thus is likely to employ a similar cell entry mechanism [4,16]. As such, the S protein is an effective antigenic component for SARS-CoV-2 vaccine design and development. However, currently, there is little or limited information about the immunogenic profiles of SARS-CoV-2 and the immune responses against SARS-CoV-2.
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