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1.
Molecules ; 27(7)2022 Apr 06.
Article in English | MEDLINE | ID: covidwho-1776294

ABSTRACT

The continued emergence of human coronaviruses (hCoVs) in the last few decades has posed an alarming situation and requires advanced cross-protective strategies against these pandemic viruses. Among these, Middle East Respiratory Syndrome coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), and Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) have been highly associated with lethality in humans. Despite the challenges posed by these viruses, it is imperative to develop effective antiviral therapeutics and vaccines for these human-infecting viruses. The proteomic similarity between the receptor-binding domains (RBDs) among the three viral species offers a potential target for advanced cross-protective vaccine designs. In this study, putative immunogenic epitopes including Cytotoxic T Lymphocytes (CTLs), Helper T Lymphocytes (HTLs), and Beta-cells (B-cells) were predicted for each RBD-containing region of the three highly pathogenic hCoVs. This was followed by the structural organization of peptide- and mRNA-based prophylactic vaccine designs. The validated 3D structures of these epitope-based vaccine designs were subjected to molecular docking with human TLR4. Furthermore, the CTL and HTL epitopes were processed for binding with respective human Lymphocytes Antigens (HLAs). In silico cloning designs were obtained for the prophylactic vaccine designs and may be useful in further experimental designs. Additionally, the epitope-based vaccine designs were evaluated for immunogenic activity through immune simulation. Further studies may clarify the safety and efficacy of these prophylactic vaccine designs through experimental testing against these human-pathogenic coronaviruses.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/prevention & control , Epitopes, B-Lymphocyte , Epitopes, T-Lymphocyte , Humans , Molecular Docking Simulation , Proteomics , RNA, Messenger , Vaccines, Subunit/chemistry , Vaccinology
2.
J Med Chem ; 65(4): 3563-3574, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1671476

ABSTRACT

Safe and effective vaccines are the best method to defeat worldwide SARS-CoV-2 and its circulating variants. The SARS-CoV-2 S protein and its subunits are the most attractive targets for the development of protein-based vaccines. In this study, we evaluated three lipophilic adjuvants, monophosphoryl lipid A (MPLA), Toll-like receptor (TLR) 1/2 ligand Pam3CSK4, and α-galactosylceramide (α-GalCer), in liposomal and nonliposomal vaccines. The immunological results showed that the MPLA-adjuvanted liposomal vaccine induced the strongest humoral and cellular immunity. Therefore, we further performed a systematic comparison of S-trimer, S-ECD, S1, and RBD as antigens in MPLA-adjuvanted liposomes and found that, although these four vaccines all induced robust specific antibody responses, only S-trimer, S1, and RBD liposomes, but not S-ECD, elicited potent neutralizing antibody responses. Moreover, RBD, S-trimer, and S1 liposomes effectively neutralized variants (B.1.1.7/alpha, B.1.351/beta, P.1/gamma, B.1.617.2/delta, and B.1.1.529/omicron). These results provide important information for the subunit vaccine design against SARS-CoV-2 and its variants.


Subject(s)
Antibodies, Viral/immunology , Lipid A/analogs & derivatives , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Subunit/immunology , Adjuvants, Immunologic , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/chemistry , Female , Lipid A/chemistry , Lipid A/immunology , Liposomes/immunology , Mice , Mice, Inbred BALB C , Molecular Structure , Vaccination , Vaccines, Subunit/chemistry
3.
Brief Bioinform ; 23(1)2022 01 17.
Article in English | MEDLINE | ID: covidwho-1598089

ABSTRACT

The current global pandemic due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has taken a substantial number of lives across the world. Although few vaccines have been rolled-out, a number of vaccine candidates are still under clinical trials at various pharmaceutical companies and laboratories around the world. Considering the intrinsic nature of viruses in mutating and evolving over time, persistent efforts are needed to develop better vaccine candidates. In this study, various immuno-informatics tools and bioinformatics databases were deployed to derive consensus B-cell and T-cell epitope sequences of SARS-CoV-2 spike glycoprotein. This approach has identified four potential epitopes which have the capability to initiate both antibody and cell-mediated immune responses, are non-allergenic and do not trigger autoimmunity. These peptide sequences were also evaluated to show 99.82% of global population coverage based on the genotypic frequencies of HLA binding alleles for both MHC class-I and class-II and are unique for SARS-CoV-2 isolated from human as a host species. Epitope number 2 alone had a global population coverage of 98.2%. Therefore, we further validated binding and interaction of its constituent T-cell epitopes with their corresponding HLA proteins using molecular docking and molecular dynamics simulation experiments, followed by binding free energy calculations with molecular mechanics Poisson-Boltzmann surface area, essential dynamics analysis and free energy landscape analysis. The immuno-informatics pipeline described and the candidate epitopes discovered herein could have significant impact upon efforts to develop globally effective SARS-CoV-2 vaccines.


Subject(s)
COVID-19 Vaccines , Epitopes, B-Lymphocyte , Epitopes, T-Lymphocyte , Molecular Docking Simulation , SARS-CoV-2 , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , Epitopes, B-Lymphocyte/chemistry , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/immunology , Humans , SARS-CoV-2/chemistry , SARS-CoV-2/immunology , Vaccines, Subunit/chemistry , Vaccines, Subunit/immunology
4.
Cells ; 10(11)2021 11 04.
Article in English | MEDLINE | ID: covidwho-1502369

ABSTRACT

During the current era of the COVID-19 pandemic, the dissemination of Mucorales has been reported globally, with elevated rates of infection in India, and because of the high rate of mortality and morbidity, designing an effective vaccine against mucormycosis is a major health priority, especially for immunocompromised patients. In the current study, we studied shared Mucorales proteins, which have been reported as virulence factors, and after analysis of several virulent proteins for their antigenicity and subcellular localization, we selected spore coat (CotH) and serine protease (SP) proteins as the targets of epitope mapping. The current study proposes a vaccine constructed based on top-ranking cytotoxic T lymphocyte (CTL), helper T lymphocyte (HTL), and B cell lymphocyte (BCL) epitopes from filtered proteins. In addition to the selected epitopes, ß-defensins adjuvant and PADRE peptide were included in the constructed vaccine to improve the stimulated immune response. Computational tools were used to estimate the physicochemical and immunological features of the proposed vaccine and validate its binding with TLR-2, where the output data of these assessments potentiate the probability of the constructed vaccine to stimulate a specific immune response against mucormycosis. Here, we demonstrate the approach of potential vaccine construction and assessment through computational tools, and to the best of our knowledge, this is the first study of a proposed vaccine against mucormycosis based on the immunoinformatics approach.


Subject(s)
Fungal Vaccines/chemistry , Fungal Vaccines/immunology , Mucormycosis/prevention & control , Rhizopus/immunology , Adjuvants, Immunologic , Antigens, Fungal/immunology , Computational Biology , Cross Reactions , Epitope Mapping , Epitopes, B-Lymphocyte/chemistry , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/immunology , Humans , Models, Molecular , Mucorales/immunology , Protein Conformation , Toll-Like Receptor 2/chemistry , Vaccines, Subunit/chemistry , Vaccines, Subunit/immunology
5.
Adv Mater ; 33(51): e2104362, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1469404

ABSTRACT

The development of effective vaccines that can be rapidly manufactured and distributed worldwide is necessary to mitigate the devastating health and economic impacts of pandemics like COVID-19. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, which mediates host cell entry of the virus, is an appealing antigen for subunit vaccines because it is efficient to manufacture, highly stable, and a target for neutralizing antibodies. Unfortunately, RBD is poorly immunogenic. While most subunit vaccines are commonly formulated with adjuvants to enhance their immunogenicity, clinically-relevant adjuvants Alum, AddaVax, and CpG/Alum are found unable to elicit neutralizing responses following a prime-boost immunization. Here, it has been shown that sustained delivery of an RBD subunit vaccine comprising CpG/Alum adjuvant in an injectable polymer-nanoparticle (PNP) hydrogel elicited potent anti-RBD and anti-spike antibody titers, providing broader protection against SARS-CoV-2 variants of concern compared to bolus administration of the same vaccine and vaccines comprising other clinically-relevant adjuvant systems. Notably, a SARS-CoV-2 spike-pseudotyped lentivirus neutralization assay revealed that hydrogel-based vaccines elicited potent neutralizing responses when bolus vaccines did not. Together, these results suggest that slow delivery of RBD subunit vaccines with PNP hydrogels can significantly enhance the immunogenicity of RBD and induce neutralizing humoral immunity.


Subject(s)
Antibodies, Neutralizing/immunology , Hydrogels/chemistry , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Subunit/immunology , Adjuvants, Immunologic/chemistry , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/prevention & control , COVID-19/virology , CpG Islands/genetics , Female , Humans , Immunity, Humoral , Mice , Mice, Inbred C57BL , Nanoparticles/chemistry , Polymers/chemistry , Protein Domains/immunology , SARS-CoV-2/chemistry , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/isolation & purification , Vaccines, Subunit/chemistry , Vaccines, Subunit/metabolism
6.
Molecules ; 26(2)2021 Jan 15.
Article in English | MEDLINE | ID: covidwho-1389464

ABSTRACT

Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of life. They have aroused considerable interest due to their unique features and great promise in innovative bio-therapies. This work focusing on the current state-of-the-art short peptide-based therapeutical developments is the first global review written by researchers from all continents, as a celebration of 100 years of peptide therapeutics since the commencement of insulin therapy in the 1920s. Peptide "drugs" initially played only the role of hormone analogs to balance disorders. Nowadays, they achieve numerous biomedical tasks, can cross membranes, or reach intracellular targets. The role of peptides in bio-processes can hardly be mimicked by other chemical substances. The article is divided into independent sections, which are related to either the progress in short peptide-based theranostics or the problems posing challenge to bio-medicine. In particular, the SWOT analysis of short peptides, their relevance in therapies of diverse diseases, improvements in (bio)synthesis platforms, advanced nano-supramolecular technologies, aptamers, altered peptide ligands and in silico methodologies to overcome peptide limitations, modern smart bio-functional materials, vaccines, and drug/gene-targeted delivery systems are discussed.


Subject(s)
Anti-Infective Agents/pharmacology , Antiviral Agents/pharmacology , Peptides/chemistry , Peptides/pharmacology , Peptides/therapeutic use , Amino Acids/chemistry , Anti-Infective Agents/chemistry , Antiviral Agents/chemistry , COVID-19/drug therapy , Computer Simulation , Cosmeceuticals/chemistry , Cosmeceuticals/therapeutic use , Dietary Supplements , Gene Transfer Techniques , Humans , Lactoferrin/chemistry , Lipid Bilayers , Nanostructures/administration & dosage , Nanostructures/chemistry , Peptides/administration & dosage , Stem Cells , Vaccines, Subunit/chemistry , Vaccines, Subunit/pharmacology
7.
Brief Bioinform ; 22(2): 1309-1323, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1352112

ABSTRACT

The recurrent and recent global outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has turned into a global concern which has infected more than 42 million people all over the globe, and this number is increasing in hours. Unfortunately, no vaccine or specific treatment is available, which makes it more deadly. A vaccine-informatics approach has shown significant breakthrough in peptide-based epitope mapping and opens the new horizon in vaccine development. In this study, we have identified a total of 15 antigenic peptides [including thymus cells (T-cells) and bone marrow or bursa-derived cells] in the surface glycoprotein (SG) of SARS-CoV-2 which is nontoxic and nonallergenic in nature, nonallergenic, highly antigenic and non-mutated in other SARS-CoV-2 virus strains. The population coverage analysis has found that cluster of differentiation 4 (CD4+) T-cell peptides showed higher cumulative population coverage over cluster of differentiation 8 (CD8+) peptides in the 16 different geographical regions of the world. We identified 12 peptides ((LTDEMIAQY, WTAGAAAYY, WMESEFRVY, IRASANLAA, FGAISSVLN, VKQLSSNFG, FAMQMAYRF, FGAGAALQI, YGFQPTNGVGYQ, LPDPSKPSKR, QTQTNSPRRARS and VITPGTNTSN) that are $80\hbox{--} 90\%$ identical with experimentally determined epitopes of SARS-CoV, and this will likely be beneficial for a quick progression of the vaccine design. Moreover, docking analysis suggested that the identified peptides are tightly bound in the groove of human leukocyte antigen molecules which can induce the T-cell response. Overall, this study allows us to determine potent peptide antigen targets in the SG on intuitive grounds, which opens up a new horizon in the coronavirus disease (COVID-19) research. However, this study needs experimental validation by in vitro and in vivo.


Subject(s)
COVID-19/prevention & control , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/immunology , SARS-CoV-2/immunology , Vaccines, Subunit/immunology , Amino Acid Sequence , COVID-19/immunology , Computational Biology , Epitopes, B-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/chemistry , HLA Antigens/chemistry , Humans , Molecular Docking Simulation , Vaccines, Subunit/chemistry
8.
Sci Rep ; 11(1): 3238, 2021 02 05.
Article in English | MEDLINE | ID: covidwho-1065946

ABSTRACT

The rampant spread of COVID-19, an infectious disease caused by SARS-CoV-2, all over the world has led to over millions of deaths, and devastated the social, financial and political entities around the world. Without an existing effective medical therapy, vaccines are urgently needed to avoid the spread of this disease. In this study, we propose an in silico deep learning approach for prediction and design of a multi-epitope vaccine (DeepVacPred). By combining the in silico immunoinformatics and deep neural network strategies, the DeepVacPred computational framework directly predicts 26 potential vaccine subunits from the available SARS-CoV-2 spike protein sequence. We further use in silico methods to investigate the linear B-cell epitopes, Cytotoxic T Lymphocytes (CTL) epitopes, Helper T Lymphocytes (HTL) epitopes in the 26 subunit candidates and identify the best 11 of them to construct a multi-epitope vaccine for SARS-CoV-2 virus. The human population coverage, antigenicity, allergenicity, toxicity, physicochemical properties and secondary structure of the designed vaccine are evaluated via state-of-the-art bioinformatic approaches, showing good quality of the designed vaccine. The 3D structure of the designed vaccine is predicted, refined and validated by in silico tools. Finally, we optimize and insert the codon sequence into a plasmid to ensure the cloning and expression efficiency. In conclusion, this proposed artificial intelligence (AI) based vaccine discovery framework accelerates the vaccine design process and constructs a 694aa multi-epitope vaccine containing 16 B-cell epitopes, 82 CTL epitopes and 89 HTL epitopes, which is promising to fight the SARS-CoV-2 viral infection and can be further evaluated in clinical studies. Moreover, we trace the RNA mutations of the SARS-CoV-2 and ensure that the designed vaccine can tackle the recent RNA mutations of the virus.


Subject(s)
COVID-19 Vaccines , Deep Learning , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Allergens , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , COVID-19 Vaccines/toxicity , Codon Usage , Computational Biology , Drug Design , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/immunology , Humans , Immunogenicity, Vaccine , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Mutation , Protein Conformation , RNA, Viral , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Solubility , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Helper-Inducer/immunology , Vaccines, Subunit/chemistry , Vaccines, Subunit/immunology
10.
Hum Vaccin Immunother ; 16(12): 2944-2953, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-969292

ABSTRACT

There is an urgent need for a safe, efficacious, and cost-effective vaccine for the coronavirus disease 2019 (COVID-19) pandemic caused by novel coronavirus strain, severe acute respiratory syndrome-2 (SARS-CoV-2). The protective immunity of certain types of vaccines can be enhanced by the addition of adjuvants. Many diverse classes of compounds have been identified as adjuvants, including mineral salts, microbial products, emulsions, saponins, cytokines, polymers, microparticles, and liposomes. Several saponins have been shown to stimulate both the Th1-type immune response and the production of cytotoxic T lymphocytes against endogenous antigens, making them very useful for subunit vaccines, especially those for intracellular pathogens. In this review, we discuss the structural characteristics, mechanisms of action, structure-activity relationship of saponins, biological activities, and use of saponins in various viral vaccines and their applicability to a SARS-CoV-2 vaccine.


Subject(s)
Adjuvants, Immunologic/administration & dosage , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Saponins/administration & dosage , Adjuvants, Immunologic/chemistry , Animals , COVID-19/immunology , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , Humans , Saponins/chemistry , Saponins/immunology , Structure-Activity Relationship , Vaccines, Subunit/administration & dosage , Vaccines, Subunit/chemistry , Vaccines, Subunit/immunology
11.
Comput Biol Med ; 128: 104124, 2021 01.
Article in English | MEDLINE | ID: covidwho-938855

ABSTRACT

The aim of the present study is to discuss the design of peptide vaccines and peptidomimetics against SARS-COV-2, to develop and apply a method of protein structure analysis that is particularly appropriate to applying and discussing such design, and also to use that method to summarize some important features of the SARS-COV-2 spike protein sequence. A tool for assessing sidechain exposure in the SARS-CoV-2 spike glycoprotein is described. It extends to assessing accessibility of sidechains by considering several different three-dimensional structure determinations of SARS-CoV-2 and SARS-CoV-1 spike protein. The method is designed to be insensitive to a distance limit for counting neighboring atoms and the results are in good agreement with the physical chemical properties and exposure trends of the 20 naturally occurring sidechains. The spike protein sequence is analyzed with comment regarding exposable character. It includes studies of complexes with antibody elements and ACE2. These indicate changes in exposure at sites remote to those at which the antibody binds. They are of interest concerning design of synthetic peptide vaccines, and for peptidomimetics as a basis of drug discovery. The method was also developed in order to provide linear (one-dimensional) information that can be used along with other bioinformatics data of this kind in data mining and machine learning, potentially as genomic data regarding protein polymorphisms to be combined with more traditional clinical data.


Subject(s)
COVID-19 Vaccines/chemistry , Models, Molecular , Peptidomimetics/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Computer Simulation , Humans , Vaccines, Subunit/chemistry
12.
Front Immunol ; 11: 592370, 2020.
Article in English | MEDLINE | ID: covidwho-937449

ABSTRACT

Prior to 2020, the threat of a novel viral pandemic was omnipresent but largely ignored. Just 12 months prior to the Coronavirus disease 2019 (COVID-19) pandemic our team received funding from the Coalition for Epidemic Preparedness Innovations (CEPI) to establish and validate a rapid response pipeline for subunit vaccine development based on our proprietary Molecular Clamp platform. Throughout the course of 2019 we conducted two mock tests of our system for rapid antigen production against two potential, emerging viral pathogens, Achimota paramyxovirus and Wenzhou mammarenavirus. For each virus we expressed a small panel of recombinant variants of the membrane fusion protein and screened for expression level, product homogeneity, and the presence of the expected trimeric pre-fusion conformation. Lessons learned from this exercise paved the way for our response to COVID-19, for which our candidate antigen is currently in phase I clinical trial.


Subject(s)
Drug Design , Vaccines, Subunit , Animals , Arenaviridae , COVID-19 Vaccines , Civil Defense , Clinical Trials as Topic , Humans , Molecular Structure , Paramyxovirinae/immunology , Time Factors , Vaccines, Subunit/chemistry , Viral Vaccines
13.
J Phys Chem Lett ; 11(22): 9920-9930, 2020 Nov 19.
Article in English | MEDLINE | ID: covidwho-919398

ABSTRACT

The emergence of severe acute respiratory syndrome from novel Coronavirus (SARS-CoV-2) has put an immense pressure worldwide where vaccination is believed to be an efficient way for developing hard immunity. Herein, we employ immunoinformatic tools to identify B-cell, T-cell epitopes associated with the spike protein of SARS-CoV-2, which is important for genome release. The results showed that the highly immunogenic epitopes located at the stalk part are mostly conserved compared to the receptor binding domain (RDB). Further, two vaccine candidates were computationally modeled from the linear B-cell, T-cell epitopes. Molecular docking reveals the crucial interactions of the vaccines with immune-receptors, and their stability is assessed by MD simulation studies. The chimeric vaccines showed remarkable binding affinity toward the immune cell receptors computed by the MM/PBSA method. van der Waals and electrostatic interactions are found to be the dominant factors for the stability of the complexes. The molecular-level interaction obtained from this study may provide deeper insight into the process of vaccine development against the pandemic of COVID-19.


Subject(s)
COVID-19 Vaccines/immunology , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Subunit/immunology , Amino Acid Sequence , COVID-19/prevention & control , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/metabolism , Epitopes, B-Lymphocyte/chemistry , Epitopes, B-Lymphocyte/metabolism , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/metabolism , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Protein Domains , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Vaccines, Subunit/chemistry , Vaccines, Subunit/metabolism
14.
Protein Pept Lett ; 28(5): 573-588, 2021.
Article in English | MEDLINE | ID: covidwho-918981

ABSTRACT

AIMS: The aim of this study was to create a new version of the PentaFOLD algorithm and to test its performance experimentally in several proteins and peptides. BACKGROUND: Synthetic vaccines can cause production of neutralizing antibodies only in case if short peptides form the same secondary structure as fragments of full-length proteins. The Penta- FOLD 3.0 algorithm was designed to check stability of alpha helices, beta strands, and random coils using several propensity scales obtained during analysis of 1730 3D structures of proteins. OBJECTIVE: The algorithm has been tested in the three peptides known to keep the secondary structure of the corresponding fragments of full-length proteins: the NY25 peptide from the Influenza H1N1 hemagglutinin, the SF23 peptide from the diphtheria toxin, the NQ21 peptide from the HIV1 gp120; as well as in the CC36 peptide from the human major prion protein. METHODS: Affine chromatography for antibodies against peptides accompanied by circular dichroism and fluorescence spectroscopy were used to check the predictions of the algorithm. RESULTS: Immunological experiments showed that all abovementioned peptides are more or less immunogenic in rabbits. The fact that antibodies against the NY25, the SF23, and the NQ21 form stable complexes with corresponding full-length proteins has been confirmed by affine chromatography. The surface of SARS CoV-2 spike receptor-binding domain interacting with hACE2 has been shown to be unstable according to the results of the PentaFOLD 3.0. CONCLUSION: The PentaFOLD 3.0 algorithm (http://chemres.bsmu.by/PentaFOLD30.htm) can be used with the aim to design vaccine peptides with stable secondary structure elements.


Subject(s)
Algorithms , Peptides/chemistry , Proteins/chemistry , Vaccines, Subunit/chemistry , Vaccines, Synthetic/chemistry , Diphtheria Toxin/chemistry , HIV Envelope Protein gp120/chemistry , Hemagglutinin Glycoproteins, Influenza Virus/chemistry , Humans , Influenza A Virus, H1N1 Subtype/chemistry , Models, Molecular , Prions/chemistry , Protein Conformation , Protein Structure, Secondary , Software , Spike Glycoprotein, Coronavirus/chemistry
15.
PLoS One ; 15(10): e0240577, 2020.
Article in English | MEDLINE | ID: covidwho-874195

ABSTRACT

The causative agent of severe acute respiratory syndrome (SARS) reported by the Chinese Center for Disease Control (China CDC) has been identified as a novel Betacoronavirus (SARS-CoV-2). A computational approach was adopted to identify multiepitope vaccine candidates against SARS-CoV-2 based on S, N and M proteins being able to elicit both humoral and cellular immune responses. In this study, the sequence of the virus was obtained from NCBI database and analyzed with in silico tools such as NetMHCpan, IEDB, BepiPred, NetCTL, Tap transport/proteasomal cleavage, Pa3P, GalexyPepDock, I-TASSER, Ellipro and ClusPro. To identify the most immunodominant regions, after analysis of population coverage and epitope conservancy, we proposed three different constructs based on linear B-cell, CTL and HTL epitopes. The 3D structure of constructs was assessed to find discontinuous B-cell epitopes. Among CTL predicted epitopes, S257-265, S603-611 and S360-368, and among HTL predicted epitopes, N167-181, S313-330 and S1110-1126 had better MHC binding rank. We found one putative CTL epitope, S360-368 related to receptor-binding domain (RBD) region for S protein. The predicted epitopes were non-allergen and showed a high quality of proteasomal cleavage and Tap transport efficiency and 100% conservancy within four different clades of SARS-CoV-2. For CTL and HTL epitopes, the highest population coverage of the world's population was calculated for S27-37 with 86.27% and for S196-231, S303-323, S313-330, S1009-1030 and N328-349 with 90.33%, respectively. We identified overall 10 discontinuous B-cell epitopes for three multiepitope constructs. All three constructs showed strong interactions with TLRs 2, 3 and 4 supporting the hypothesis of SARS-CoV-2 susceptibility to TLRs 2, 3 and 4 like other Coronaviridae families. These data demonstrated that the novel designed multiepitope constructs can contribute to develop SARS-CoV-2 peptide vaccine candidates. The in vivo studies are underway using several vaccination strategies.


Subject(s)
Coronavirus Infections/prevention & control , Epitopes/immunology , Nucleocapsid Proteins/immunology , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Subunit/immunology , Viral Matrix Proteins/immunology , COVID-19 , Coronavirus Infections/immunology , Coronavirus Nucleocapsid Proteins , Epitopes/chemistry , HLA Antigens/chemistry , HLA Antigens/immunology , Humans , Molecular Docking Simulation , Nucleocapsid Proteins/chemistry , Phosphoproteins , Pneumonia, Viral/immunology , Spike Glycoprotein, Coronavirus/chemistry , Toll-Like Receptors/chemistry , Toll-Like Receptors/metabolism , Vaccines, Subunit/chemistry , Viral Matrix Proteins/chemistry
16.
Sci Rep ; 10(1): 16219, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-811544

ABSTRACT

COVID-19 pandemic has resulted in 16,114,449 cases with 646,641 deaths from the 217 countries, or territories as on July 27th 2020. Due to multifaceted issues and challenges in the implementation of the safety and preventive measures, inconsistent coordination between societies-governments and most importantly lack of specific vaccine to SARS-CoV-2, the spread of the virus that initially emerged at Wuhan is still uprising after taking a heavy toll on human life. In the present study, we mapped immunogenic epitopes present on the four structural proteins of SARS-CoV-2 and we designed a multi-epitope peptide based vaccine that, demonstrated a high immunogenic response with a vast application on world's human population. On codon optimization and in-silico cloning, we found that candidate vaccine showed high expression in E. coli and immune simulation resulted in inducing a high level of both B-cell and T-cell mediated immunity. The results predicted that exposure of vaccine by administrating three injections significantly subsidized the antigen growth in the system. The proposed candidate vaccine found promising by yielding desired results and hence, should be validated by practical experimentations for its functioning and efficacy to neutralize SARS-CoV-2.


Subject(s)
Epitopes/immunology , Molecular Docking Simulation , Vaccines, Subunit/immunology , Viral Vaccines/immunology , Antigen-Antibody Complex/chemistry , Antigen-Antibody Complex/immunology , Antigens, Viral/immunology , B-Lymphocytes/immunology , COVID-19 Vaccines , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Coronavirus Nucleocapsid Proteins , Epitopes/chemistry , HLA Antigens/chemistry , HLA Antigens/immunology , Humans , Immunogenicity, Vaccine , Nucleocapsid Proteins/chemistry , Nucleocapsid Proteins/immunology , Phosphoproteins , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , Toll-Like Receptors/immunology , Vaccines, Subunit/chemistry , Viral Matrix Proteins/chemistry , Viral Matrix Proteins/immunology , Viral Vaccines/chemistry
17.
Infect Dis Poverty ; 9(1): 132, 2020 Sep 16.
Article in English | MEDLINE | ID: covidwho-768657

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) linked with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause severe illness and life-threatening pneumonia in humans. The current COVID-19 pandemic demands an effective vaccine to acquire protection against the infection. Therefore, the present study was aimed to design a multiepitope-based subunit vaccine (MESV) against COVID-19. METHODS: Structural proteins (Surface glycoprotein, Envelope protein, and Membrane glycoprotein) of SARS-CoV-2 are responsible for its prime functions. Sequences of proteins were downloaded from GenBank and several immunoinformatics coupled with computational approaches were employed to forecast B- and T- cell epitopes from the SARS-CoV-2 highly antigenic structural proteins to design an effective MESV. RESULTS: Predicted epitopes suggested high antigenicity, conserveness, substantial interactions with the human leukocyte antigen (HLA) binding alleles, and collective global population coverage of 88.40%. Taken together, 276 amino acids long MESV was designed by connecting 3 cytotoxic T lymphocytes (CTL), 6 helper T lymphocyte (HTL) and 4 B-cell epitopes with suitable adjuvant and linkers. The MESV construct was non-allergenic, stable, and highly antigenic. Molecular docking showed a stable and high binding affinity of MESV with human pathogenic toll-like receptors-3 (TLR3). Furthermore, in silico immune simulation revealed significant immunogenic response of MESV. Finally, MEV codons were optimized for its in silico cloning into the Escherichia coli K-12 system, to ensure its increased expression. CONCLUSION: The MESV developed in this study is capable of generating immune response against COVID-19. Therefore, if designed MESV further investigated experimentally, it would be an effective vaccine candidate against SARS-CoV-2 to control and prevent COVID-19.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/immunology , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Viral Vaccines/immunology , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/genetics , Coronavirus Infections/immunology , Epitopes, B-Lymphocyte/chemistry , Epitopes, B-Lymphocyte/genetics , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/genetics , Humans , Immunogenicity, Vaccine/immunology , Molecular Docking Simulation , Pneumonia, Viral/immunology , SARS-CoV-2 , Sequence Analysis, Protein , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Toll-Like Receptor 3/chemistry , Toll-Like Receptor 3/genetics , Toll-Like Receptor 3/immunology , Vaccines, Subunit/chemistry , Vaccines, Subunit/genetics , Vaccines, Subunit/immunology , Vaccinology/methods , Viral Matrix Proteins/chemistry , Viral Matrix Proteins/genetics , Viral Matrix Proteins/immunology , Viral Vaccines/chemistry , Viral Vaccines/genetics
18.
Infect Genet Evol ; 85: 104517, 2020 11.
Article in English | MEDLINE | ID: covidwho-737519

ABSTRACT

The present study aimed to predict a novel chimeric vaccine by simultaneously targeting four major structural proteins via the establishment of ancestral relationship among different strains of coronaviruses. Conserved regions from the homologous protein sets of spike glycoprotein, membrane protein, envelope protein and nucleocapsid protein were identified through multiple sequence alignment. The phylogeny analyses of whole genome stated that four proteins reflected the close ancestral relation of SARS-CoV-2 to SARS-COV-1 and bat coronavirus. Numerous immunogenic epitopes (both T cell and B cell) were generated from the common fragments which were further ranked on the basis of antigenicity, transmembrane topology, conservancy level, toxicity and allergenicity pattern and population coverage analysis. Top putative epitopes were combined with appropriate adjuvants and linkers to construct a novel multiepitope subunit vaccine against COVID-19. The designed constructs were characterized based on physicochemical properties, allergenicity, antigenicity and solubility which revealed the superiority of construct V3 in terms safety and efficacy. Essential molecular dynamics and normal mode analysis confirmed minimal deformability of the refined model at molecular level. In addition, disulfide engineering was investigated to accelerate the stability of the protein. Molecular docking study ensured high binding affinity between construct V3 and HLA cells, as well as with different host receptors. Microbial expression and translational efficacy of the constructs were checked using pET28a(+) vector of E. coli strain K12. However, the in vivo and in vitro validation of suggested vaccine molecule might be ensured with wet lab trials using model animals for the implementation of the presented data.


Subject(s)
Epitopes, B-Lymphocyte/genetics , Epitopes, T-Lymphocyte/genetics , SARS-CoV-2/classification , Vaccines, Subunit/genetics , Viral Structural Proteins/genetics , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/immunology , Escherichia coli/genetics , Escherichia coli/growth & development , Evolution, Molecular , Genome, Viral , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Phylogeny , Protein Conformation , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Vaccines, Subunit/chemistry , Vaccines, Subunit/metabolism , Viral Structural Proteins/chemistry , Viral Structural Proteins/immunology , Viral Vaccines/chemistry , Viral Vaccines/genetics , Viral Vaccines/metabolism
19.
Cell Syst ; 11(2): 131-144.e6, 2020 08 26.
Article in English | MEDLINE | ID: covidwho-676381

ABSTRACT

We present a combinatorial machine learning method to evaluate and optimize peptide vaccine formulations for SARS-CoV-2. Our approach optimizes the presentation likelihood of a diverse set of vaccine peptides conditioned on a target human-population HLA haplotype distribution and expected epitope drift. Our proposed SARS-CoV-2 MHC class I vaccine formulations provide 93.21% predicted population coverage with at least five vaccine peptide-HLA average hits per person (≥ 1 peptide: 99.91%) with all vaccine peptides perfectly conserved across 4,690 geographically sampled SARS-CoV-2 genomes. Our proposed MHC class II vaccine formulations provide 97.21% predicted coverage with at least five vaccine peptide-HLA average hits per person with all peptides having an observed mutation probability of ≤ 0.001. We provide an open-source implementation of our design methods (OptiVax), vaccine evaluation tool (EvalVax), as well as the data used in our design efforts here: https://github.com/gifford-lab/optivax.


Subject(s)
Betacoronavirus/immunology , Haplotypes , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class I/genetics , Sequence Analysis, DNA/methods , Vaccines, Subunit/immunology , Viral Vaccines/immunology , Betacoronavirus/genetics , COVID-19 Vaccines , Coronavirus Infections/genetics , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Epitopes/chemistry , Epitopes/genetics , Epitopes/immunology , Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/chemistry , Histocompatibility Antigens Class II/immunology , Humans , Machine Learning , SARS-CoV-2 , Sequence Analysis, DNA/standards , Vaccines, Subunit/chemistry , Vaccines, Subunit/genetics , Viral Vaccines/chemistry , Viral Vaccines/genetics
20.
Vaccine ; 38(32): 5071-5075, 2020 07 06.
Article in English | MEDLINE | ID: covidwho-592568

ABSTRACT

SARS-CoV-2 is the cause of the worldwide outbreak of COVID-19 that has been characterized as a pandemic by the WHO. Since the first report of COVID-19 on December 31, 2019, 179,111 cases were confirmed in 160 countries/regions with 7426 deaths as of March 17, 2020. However, there have been no vaccines approved in the world to date. In this study, we analyzed the biological characteristics of the SARS-CoV-2 Spike protein, Pro330-Leu650 (SARS-CoV-2-SPL), using biostatistical methods. SARS-CoV-2-SPL possesses a receptor-binding region (RBD) and important B (Ser438-Gln506, Thr553-Glu583, Gly404-Aps427, Thr345-Ala352, and Lys529-Lys535) and T (9 CD4 and 11 CD8 T cell antigenic determinants) cell epitopes. High homology in this region between SARS-CoV-2 and SARS-CoV amounted to 87.7%, after taking the biological similarity of the amino acids into account and eliminating the receptor-binding motif (RBM). The overall topology indicated that the complete structure of SARS-CoV-2-SPL was with RBM as the head, and RBD as the trunk and the tail region. SARS-CoV-2-SPL was found to have the potential to elicit effective B and T cell responses. Our findings may provide meaningful guidance for SARS-CoV-2 vaccine design.


Subject(s)
Betacoronavirus/chemistry , Drug Design , Models, Immunological , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Viral Vaccines/chemistry , Viral Vaccines/immunology , Amino Acid Sequence , Antigens, Viral/chemistry , Antigens, Viral/immunology , Betacoronavirus/immunology , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Coronavirus Infections/virology , Epitopes, B-Lymphocyte/chemistry , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/immunology , Humans , Models, Molecular , Pandemics/prevention & control , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/prevention & control , Pneumonia, Viral/virology , SARS-CoV-2 , Sequence Alignment , Vaccines, Subunit/chemistry , Vaccines, Subunit/immunology
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