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1.
Infect Disord Drug Targets ; 21(4): 541-552, 2021.
Article in English | MEDLINE | ID: covidwho-1496791

ABSTRACT

BACKGROUND: Since December 2019, a novel coronavirus, SARS-CoV-2, has caused global public health issues after being reported for the first time in Wuhan province of China. So far, there have been approximately 14.8 million confirmed cases and 0.614 million deaths due to the SARS-CoV-2 infection globally, and still, numbers are increasing. Although the virus has caused a global public health concern, no effective treatment has been developed. OBJECTIVE: One of the strategies to combat the COVID-19 disease caused by SARS-CoV-2 is the development of vaccines that can make humans immune to these infections. Considering this approach, in this study, an attempt has been made to design epitope-based vaccine for combatting COVID-19 disease by analyzing the complete proteome of the virus by using immuno-informatics tools. METHODS: The protein sequence of the SARS-CoV-2 was retrieved and the individual proteins were checked for their allergic potential. Then, from non-allergen proteins, antigenic epitopes were identified that could bind with MHCII molecules. The epitopes were modeled and docked to predict the interaction with MHCII molecules. The stability of the epitope-MHCII complex was further analyzed by performing a molecular dynamics simulation study. The selected vaccine candidates were also analyzed for their global population coverage and conservancy among SARS-related coronavirus species. RESULTS: The study has predicted 5 peptide molecules that can act as potential candidates for epitope- based vaccine development. Among the 5 selected epitopes, the peptide LRARSVSPK can be the most potent epitope because of its high geometric shape complementarity score, low ACE and very high response towards it by the world population (81.81% global population coverage). Further, molecular dynamic simulation analysis indicated the formation of a stable epitope-MHCII complex. The epitope LRARSVSPK was also found to be highly conserved among the SARS-CoV- -2 isolated from different countries. CONCLUSION: The study has predicted T-cell epitopes that can elicit a robust immune response in the global human population and act as potential vaccine candidates. However, the ability of these epitopes to act as vaccine candidate needs to be validated in wet lab studies.


Subject(s)
COVID-19 , Vaccines , Epitopes, B-Lymphocyte , Epitopes, T-Lymphocyte , Humans , Molecular Docking Simulation , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
2.
J Infect Dis ; 224(6): 956-966, 2021 09 17.
Article in English | MEDLINE | ID: covidwho-1429243

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) continues to be a major public health challenge globally. The identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived T-cell epitopes is of critical importance for peptide vaccines or diagnostic tools of COVID-19. METHODS: In this study, several SARS-CoV-2-derived human leukocyte antigen (HLA)-I binding peptides were predicted by NetMHCpan-4.1 and selected by Popcover to achieve pancoverage of the Chinese population. The top 5 ranked peptides derived from each protein of SARS-CoV-2 were then evaluated using peripheral blood mononuclear cells from unexposed individuals (negative for SARS-CoV-2 immunoglobulin G). RESULTS: Seven epitopes derived from 4 SARS-CoV-2 proteins were identified. It is interesting to note that most (5 of 7) of the SARS-CoV-2-derived peptides with predicted affinities for HLA-I molecules were identified as HLA-II-restricted epitopes and induced CD4+ T cell-dependent responses. These results complete missing pieces of pre-existing SARS-CoV-2-specific T cells and suggest that pre-existing T cells targeting all SARS-CoV-2-encoded proteins can be discovered in unexposed populations. CONCLUSIONS: In summary, in the current study, we present an alternative and effective strategy for the identification of T-cell epitopes of SARS-CoV-2 in healthy subjects, which may indicate an important role in the development of peptide vaccines for COVID-19.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , Epitopes, T-Lymphocyte/immunology , Vaccines, Subunit/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Line , Humans , Leukocytes, Mononuclear/immunology , SARS-CoV-2
3.
Cell Rep Med ; 2(6): 100312, 2021 06 15.
Article in English | MEDLINE | ID: covidwho-1275763

ABSTRACT

Knowledge of the epitopes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targeted by T cells in recovered (convalescent) individuals is important for understanding T cell immunity against coronavirus disease 2019 (COVID-19). This information can aid development and assessment of COVID-19 vaccines and inform novel diagnostic technologies. Here, we provide a unified description and meta-analysis of SARS-CoV-2 T cell epitopes compiled from 18 studies of cohorts of individuals recovered from COVID-19 (852 individuals in total). Our analysis demonstrates the broad diversity of T cell epitopes that have been recorded for SARS-CoV-2. A large majority are seemingly unaffected by current variants of concern. We identify a set of 20 immunoprevalent epitopes that induced T cell responses in multiple cohorts and in a large fraction of tested individuals. The landscape of SARS-CoV-2 T cell epitopes we describe can help guide immunological studies, including those related to vaccines and diagnostics. A web-based platform has been developed to help complement these efforts.


Subject(s)
COVID-19/immunology , Epitopes, T-Lymphocyte/metabolism , Amino Acid Sequence , COVID-19/pathology , COVID-19/virology , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/immunology , HLA Antigens/genetics , Humans , Immunity , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , T-Lymphocytes/cytology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
4.
J Virol ; 95(17): e0066721, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1274527

ABSTRACT

Cellular immune responses play a key role in the control of viral infection. The nucleocapsid (N) protein of infectious bronchitis virus (IBV) is a major immunogenic protein that can induce protective immunity. To screen for potential T-cell epitopes on IBV N protein, 40 overlapping peptides covering the entirety of the N protein were designed and synthesized. Four T-cell epitope peptides were identified by gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot), intracellular cytokine staining, and carboxyfluorescein succinimidyl ester (CFSE) lymphocyte proliferation assays; among them, three peptides (N211-230, N271-290, and N381-400) were cytotoxic T lymphocyte (CTL) epitopes, and one peptide (N261-280) was a dual-specific T-cell epitope, which can be recognized by both CD8+ and CD4+ T cells. Multi-epitope gene transcription cassettes comprising four neutralizing epitope domains and four T-cell epitope peptides were synthesized and inserted into the genome of Newcastle disease virus strain La Sota between the P and M genes. Recombinant IBV multi-epitope vaccine candidate rLa Sota/SBNT was generated via reverse genetics, and its immune protection efficacy was evaluated in specific-pathogen-free chickens. Our results show that rLa Sota/SBNT induced IBV-specific neutralizing antibody and T-cell responses and provided significant protection against homologous and heterologous IBV challenge. Thus, the T-cell epitope peptides identified in this study could be good candidates for IBV vaccine development, and recombinant Newcastle disease virus-expressing IBV multi-epitope genes represent a safe and effective vaccine candidate for controlling infectious bronchitis. IMPORTANCE T-cell-mediated immune responses are critical for the elimination of IBV-infected cells. To screen conserved T-cell epitopes in the IBV N protein, 40 overlapping peptides covering the entirety of the N protein were designed and synthesized. By combining IFN-γ ELISpot, intracellular cytokine staining, and CFSE lymphocyte proliferation assays, we identified three CTL epitopes and one dual-specific T-cell epitope. The value of T-cell epitope peptides identified in the N protein was further verified by the design of an IBV multi-epitope vaccine. Results show that IBV multi-epitope vaccine candidate rLa Sota/SBNT provided cross protection against challenges with a QX-like or a TW-like IBV strain. So, T-cell-mediated immune responses play an important role in the control of viral infection, and conserved T-cell epitopes serve as promising candidates for use in multi-epitope vaccine construction. Our results provide a new perspective for the development of a safer and more effective IBV vaccine.


Subject(s)
Coronavirus Infections/prevention & control , Epitopes, T-Lymphocyte/immunology , Immunity, Cellular/immunology , Infectious bronchitis virus/immunology , Nucleocapsid Proteins/immunology , Poultry Diseases/prevention & control , Viral Vaccines/administration & dosage , Animals , Chickens , Coronavirus Infections/immunology , Coronavirus Infections/virology , Immunity, Cellular/drug effects , Poultry Diseases/immunology , Specific Pathogen-Free Organisms , T-Lymphocytes, Cytotoxic/immunology , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/immunology , Viral Vaccines/immunology
5.
Immunol Cell Biol ; 99(9): 990-1000, 2021 10.
Article in English | MEDLINE | ID: covidwho-1258941

ABSTRACT

In-depth understanding of human T-cell-mediated immunity in coronavirus disease 2019 (COVID-19) is needed if we are to optimize vaccine strategies and immunotherapies. Identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T-cell epitopes and generation of peptide-human leukocyte antigen (peptide-HLA) tetramers facilitate direct ex vivo analyses of SARS-CoV-2-specific T cells and their T-cell receptor (TCR) repertoires. We utilized a combination of peptide prediction and in vitro peptide stimulation to validate novel SARS-CoV-2 epitopes restricted by HLA-A*24:02, one of the most prominent HLA class I alleles, especially in Indigenous and Asian populations. Of the peptides screened, three spike-derived peptides generated CD8+ IFNγ+ responses above background, S1208-1216 (QYIKWPWYI), S448-456 (NYNYLYRLF) and S193-201 (VFKNIDGYF), with S1208 generating immunodominant CD8+ IFNγ+ responses. Using peptide-HLA-I tetramers, we performed direct ex vivo tetramer enrichment for HLA-A*24:02-restricted CD8+ T cells in COVID-19 patients and prepandemic controls. The precursor frequencies for HLA-A*24:02-restricted epitopes were within the range previously observed for other SARS-CoV-2 epitopes for both COVID-19 patients and prepandemic individuals. Naïve A24/SARS-CoV-2-specific CD8+ T cells increased nearly 7.5-fold above the average precursor frequency during COVID-19, gaining effector and memory phenotypes. Ex vivo single-cell analyses of TCRαß repertoires found that the A24/S448 + CD8+ T-cell TCRαß repertoire was driven by a common TCRß chain motif, whereas the A24/S1208 + CD8+ TCRαß repertoire was diverse across COVID-19 patients. Our study provides an in depth characterization and important insights into SARS-CoV-2-specific CD8+ T-cell responses associated with a prominent HLA-A*24:02 allomorph. This contributes to our knowledge on adaptive immune responses during primary COVID-19 and could be exploited in vaccine or immunotherapeutic approaches.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19 , HLA-A24 Antigen , Receptors, Antigen, T-Cell/immunology , COVID-19/immunology , Humans , SARS-CoV-2
6.
NPJ Vaccines ; 6(1): 71, 2021 May 13.
Article in English | MEDLINE | ID: covidwho-1228257

ABSTRACT

Natural and vaccine-induced SARS-CoV-2 immunity in humans has been described but correlates of protection are not yet defined. T cells support the SARS-CoV-2 antibody response, clear virus-infected cells, and may be required to block transmission. In this study, we identified peptide epitopes associated with SARS-CoV-2 T-cell immunity. Using immunoinformatic methods, T-cell epitopes from spike, membrane, and envelope were selected for maximal HLA-binding potential, coverage of HLA diversity, coverage of circulating virus, and minimal potential cross-reactivity with self. Direct restimulation of PBMCs collected from SARS-CoV-2 convalescents confirmed 66% of predicted epitopes, whereas only 9% were confirmed in naive individuals. However, following a brief period of epitope-specific T-cell expansion, both cohorts demonstrated robust T-cell responses to 97% of epitopes. HLA-DR3 transgenic mouse immunization with peptides co-formulated with poly-ICLC generated a potent Th1-skewed, epitope-specific memory response, alleviating safety concerns of enhanced respiratory disease associated with Th2 induction. Taken together, these epitopes may be used to improve our understanding of natural and vaccine-induced immunity, and to facilitate the development of T-cell-targeted vaccines that harness pre-existing SARS-CoV-2 immunity.

7.
J Immunol ; 206(11): 2527-2535, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1227097

ABSTRACT

The T cell response is an important detection index in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine development. The present study was undertaken to determine the T cell epitopes in the spike (S) protein of SARS-CoV-2 that dominate the T cell responses in SARS-CoV-2-infected patients. PBMCs from rhesus macaques vaccinated with a DNA vaccine encoding the full-length S protein were isolated, and an ELISPOT assay was used to identify the recognized T cell epitopes among a total of 158 18-mer and 10-aa-overlapping peptides spanning the full-length S protein. Six multipeptide-based epitopes located in the S1 region, with four of the six located in the receptor-binding domain, were defined as the most frequently recognized epitopes in macaques. The conservation of the epitopes across species was also verified, and peptide mixtures for T cell response detection were established. Six newly defined T cell epitopes were found in the current study, which may provide a novel potential target for T cell response detection and the diagnosis and vaccine design of SARS-CoV-2 based on multipeptide subunit-based epitopes.


Subject(s)
Epitopes, T-Lymphocyte/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Macaca mulatta
8.
Can J Infect Dis Med Microbiol ; 2021: 6627141, 2021.
Article in English | MEDLINE | ID: covidwho-1201679

ABSTRACT

SARS-CoV-2 (Severe acute respiratory syndrome coronavirus-2) is a newly emerged beta coronavirus and etiolating agent of COVID-19. Considering the unprecedented increasing number of COVID-19 cases, the World Health Organization declared a public health emergency internationally on 11th March 2020. However, existing drugs are insufficient in dealing with this contagious virus infection; therefore, a vaccine is exigent to curb this pandemic disease. In the present study, B- and T-cell immune epitopes were identified for RdRp (RNA-dependent RNA polymerase) protein using immunoinformatic techniques, which is proved to be a rapid and efficient method to explore the candidate peptide vaccine. Subsequently, antigenicity and interactions with HLA (human leukocyte antigen) alleles were estimated. Further, physicochemical properties, allergenicity, toxicity, and stability of RdRp protein were evaluated to demonstrate the specificity of the epitope candidates. Interestingly, we identified a total of 36 B-cell and 16 T-cell epitopes using epitopes predictive tools. Among the predicted epitopes, 26 B-cell and 9 T-cell epitopes showed non-allergenic, non-toxic, and highly antigenic properties. Altogether, our study revealed that RdRp of SARS-CoV-2 (an epitope-based peptide fragment) can be a potentially good candidate for the development of a vaccine against SARS-CoV-2.

9.
Front Immunol ; 12: 636118, 2021.
Article in English | MEDLINE | ID: covidwho-1190312

ABSTRACT

Following respiratory viral infections or local immunizations, lung resident-memory T cells (TRM) of the CD8 lineage provide protection against the same pathogen or related pathogens with cross-reactive T cell epitopes. Yet, it is now clear that, if homeostatic controls are lost following viral pneumonia, CD8 TRM cells can mediate pulmonary pathology. We recently showed that the aging process can result in loss of homeostatic controls on CD8 TRM cells in the respiratory tract. This may be germane to treatment modalities in both influenza and coronavirus disease 2019 (COVID-19) patients, particularly, the portion that present with symptoms linked to long-lasting lung dysfunction. Here, we review the developmental cues and functionalities of CD8 TRM cells in viral pneumonia models with a particular focus on their capacity to mediate heterogeneous responses of immunity and pathology depending on immune status.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/virology , Immunologic Memory , Lung/immunology , Lung/virology , SARS-CoV-2/immunology , Age Factors , Animals , Biomarkers , CD8-Positive T-Lymphocytes/metabolism , COVID-19/metabolism , COVID-19/pathology , Disease Resistance/immunology , Homeostasis , Host-Pathogen Interactions/immunology , Humans , Immunophenotyping , Lung/metabolism , Lung/pathology , Lymphocyte Count , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/pathology
10.
J Virol ; 95(6)2021 02 24.
Article in English | MEDLINE | ID: covidwho-1150200

ABSTRACT

Developing optimal T-cell response assays to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is critical for measuring the duration of immunity to this disease and assessing the efficacy of vaccine candidates. These assays need to target conserved regions of SARS-CoV-2 global variants and avoid cross-reactivity to seasonal human coronaviruses. To contribute to this effort, we employed an in silico immunoinformatics analysis pipeline to identify immunogenic peptides resulting from conserved and highly networked regions with topological importance from the SARS-CoV-2 nucleocapsid and spike proteins. A total of 57 highly networked T-cell epitopes that are conserved across geographic viral variants were identified from these viral proteins, with a binding potential to diverse HLA alleles and 80 to 100% global population coverage. Importantly, 18 of these T-cell epitope derived peptides had limited homology to seasonal human coronaviruses making them promising candidates for SARS-CoV-2-specific T-cell immunity assays. Moreover, two of the NC-derived peptides elicited effector/polyfunctional responses of CD8+ T cells derived from SARS-CoV-2 convalescent patients.IMPORTANCE The development of specific and validated immunologic tools is critical for understanding the level and duration of the cellular response induced by SARS-CoV-2 infection and/or vaccines against this novel coronavirus disease. To contribute to this effort, we employed an immunoinformatics analysis pipeline to define 57 SARS-CoV-2 immunogenic peptides within topologically important regions of the nucleocapsid (NC) and spike (S) proteins that will be effective for detecting cellular immune responses in 80 to 100% of the global population. Our immunoinformatics analysis revealed that 18 of these peptides had limited homology to circulating seasonal human coronaviruses and therefore are promising candidates for distinguishing SARS-CoV-2-specific immune responses from pre-existing coronavirus immunity. Importantly, CD8+ T cells derived from SARS-CoV-2 survivors exhibited polyfunctional effector responses to two novel NC-derived peptides identified as HLA-binders. These studies provide a proof of concept that our immunoinformatics analysis pipeline identifies novel immunogens which can elicit polyfunctional SARS-CoV-2-specific T-cell responses.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Coronavirus Nucleocapsid Proteins/immunology , Epitopes, T-Lymphocyte/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Amino Acid Sequence , Antigen Presentation , COVID-19/blood , COVID-19/immunology , Computational Biology , Coronavirus/classification , Coronavirus/immunology , Coronavirus Nucleocapsid Proteins/chemistry , Coronavirus Nucleocapsid Proteins/genetics , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/genetics , HLA Antigens/immunology , Humans , Immunity, Cellular , Mutation , Phosphoproteins/chemistry , Phosphoproteins/genetics , Phosphoproteins/immunology , Protein Binding , SARS-CoV-2/genetics , Species Specificity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics
11.
Sci Rep ; 11(1): 5402, 2021 03 08.
Article in English | MEDLINE | ID: covidwho-1123146

ABSTRACT

Most multiple sclerosis (MS) patients given currently available disease-modifying drugs (DMDs) experience progressive disability. Accordingly, there is a need for new treatments that can limit the generation of new waves T cell autoreactivity that drive disease progression. Notably, immune cells express GABAA-receptors (GABAA-Rs) whose activation has anti-inflammatory effects such that GABA administration can ameliorate disease in models of type 1 diabetes, rheumatoid arthritis, and COVID-19. Here, we show that oral GABA, which cannot cross the blood-brain barrier (BBB), does not affect the course of murine experimental autoimmune encephalomyelitis (EAE). In contrast, oral administration of the BBB-permeable GABAA-R-specific agonist homotaurine ameliorates monophasic EAE, as well as advanced-stage relapsing-remitting EAE (RR-EAE). Homotaurine treatment beginning after the first peak of paralysis reduced the spreading of Th17 and Th1 responses from the priming immunogen to a new myelin T cell epitope within the CNS. Antigen-presenting cells (APC) isolated from homotaurine-treated mice displayed an attenuated ability to promote autoantigen-specific T cell proliferation. The ability of homotaurine treatment to limit epitope spreading within the CNS, along with its safety record, makes it an excellent candidate to help treat MS and other inflammatory disorders of the CNS.


Subject(s)
Central Nervous System/pathology , Multiple Sclerosis/immunology , T-Lymphocytes/immunology , Taurine/analogs & derivatives , Animals , Antigen Presentation/drug effects , Antigen-Presenting Cells/drug effects , Antigen-Presenting Cells/immunology , Cell Proliferation/drug effects , Central Nervous System/drug effects , Central Nervous System/immunology , Disease Models, Animal , Disease Progression , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Mice, Inbred C57BL , Multiple Sclerosis/pathology , Myelin Proteolipid Protein/immunology , Peptide Fragments/immunology , Recurrence , Spleen/pathology , T-Lymphocytes/drug effects , Taurine/pharmacology , gamma-Aminobutyric Acid/pharmacology
12.
J Biomol Struct Dyn ; : 1-26, 2021 Feb 15.
Article in English | MEDLINE | ID: covidwho-1081511

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the most cryptic pandemic outbreak of the 21st century, has gripped more than 1.8 million people to death and infected almost eighty six million. As it is a new variant of SARS, there is no approved drug or vaccine available against this virus. This study aims to predict some promising cytotoxic T lymphocyte epitopes in the SARS-CoV-2 proteome utilizing immunoinformatic approaches. Firstly, we identified 21 epitopes from 7 different proteins of SARS-CoV-2 inducing immune response and checked for allergenicity and conservancy. Based on these factors, we selected the top three epitopes, namely KAYNVTQAF, ATSRTLSYY, and LTALRLCAY showing functional interactions with the maximum number of MHC alleles and no allergenicity. Secondly, the 3D model of selected epitopes and HLA-A*29:02 were built and Molecular Docking simulation was performed. Most interestingly, the best two epitopes predicted by docking are part of two different structural proteins of SARS-CoV-2, namely Membrane Glycoprotein (ATSRTLSYY) and Nucleocapsid Phosphoprotein (KAYNVTQAF), which are generally target of choice for vaccine designing. Upon Molecular Docking, interactions between selected epitopes and HLA-A*29:02 were further validated by 50 ns Molecular Dynamics (MD) simulation. Analysis of RMSD, Rg, SASA, number of hydrogen bonds, RMSF, MM-PBSA, PCA, and DCCM from MD suggested that ATSRTLSYY is the most stable and promising epitope than KAYNVTQAF epitope. Moreover, we also identified B-cell epitopes for each of the antigenic proteins of SARS CoV-2. Findings of our work will be a good resource for wet lab experiments and will lessen the timeline for vaccine construction.Communicated by Ramaswamy H. Sarma.

13.
Nat Immunol ; 22(1): 74-85, 2021 01.
Article in English | MEDLINE | ID: covidwho-1065902

ABSTRACT

T cell immunity is central for the control of viral infections. To characterize T cell immunity, but also for the development of vaccines, identification of exact viral T cell epitopes is fundamental. Here we identify and characterize multiple dominant and subdominant SARS-CoV-2 HLA class I and HLA-DR peptides as potential T cell epitopes in COVID-19 convalescent and unexposed individuals. SARS-CoV-2-specific peptides enabled detection of post-infectious T cell immunity, even in seronegative convalescent individuals. Cross-reactive SARS-CoV-2 peptides revealed pre-existing T cell responses in 81% of unexposed individuals and validated similarity with common cold coronaviruses, providing a functional basis for heterologous immunity in SARS-CoV-2 infection. Diversity of SARS-CoV-2 T cell responses was associated with mild symptoms of COVID-19, providing evidence that immunity requires recognition of multiple epitopes. Together, the proposed SARS-CoV-2 T cell epitopes enable identification of heterologous and post-infectious T cell immunity and facilitate development of diagnostic, preventive and therapeutic measures for COVID-19.


Subject(s)
COVID-19/immunology , Epitopes, T-Lymphocyte/immunology , Peptides/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Viral Vaccines/immunology , COVID-19/prevention & control , COVID-19/virology , Cross Reactions/immunology , HLA-DR Antigens/immunology , HLA-DR Antigens/metabolism , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class I/metabolism , Humans , Immunologic Memory/immunology , SARS-CoV-2/physiology , T-Lymphocytes/metabolism , Viral Vaccines/administration & dosage
14.
Adv Drug Deliv Rev ; 171: 29-47, 2021 04.
Article in English | MEDLINE | ID: covidwho-1064698

ABSTRACT

Growing evidence suggests that T cells may play a critical role in combating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hence, COVID-19 vaccines that can elicit a robust T cell response may be particularly important. The design, development and experimental evaluation of such vaccines is aided by an understanding of the landscape of T cell epitopes of SARS-CoV-2, which is largely unknown. Due to the challenges of identifying epitopes experimentally, many studies have proposed the use of in silico methods. Here, we present a review of the in silico methods that have been used for the prediction of SARS-CoV-2 T cell epitopes. These methods employ a diverse set of technical approaches, often rooted in machine learning. A performance comparison is provided based on the ability to identify a specific set of immunogenic epitopes that have been determined experimentally to be targeted by T cells in convalescent COVID-19 patients, shedding light on the relative performance merits of the different approaches adopted by the in silico studies. The review also puts forward perspectives for future research directions.


Subject(s)
COVID-19 Vaccines/metabolism , COVID-19/metabolism , Computer Simulation , Epitopes, T-Lymphocyte/metabolism , SARS-CoV-2/metabolism , Animals , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Computer Simulation/trends , Epitopes, T-Lymphocyte/immunology , Humans , SARS-CoV-2/immunology
15.
Clin Transl Immunology ; 9(12): e1227, 2020.
Article in English | MEDLINE | ID: covidwho-1037499

ABSTRACT

OBJECTIVES: Bacillus Calmette-Guérin (BCG) vaccination has been implicated in protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and as a non-specific immunisation method against the virus. We therefore decided to investigate T-cell and B-cell epitopes within the BCG-Pasteur strain proteome for similarity to immunogenic peptides of SARS-CoV-2. METHODS: We used NetMHC 4.0 and BepiPred 2.0 epitope prediction methods for the analysis of the BCG-Pasteur proteome to identify similar peptides to established and novel SARS-CoV-2 T-cell and B-cell epitopes. RESULTS: We found 112 BCG MHC-I-restricted T-cell epitopes similar to MHC-I-restricted T-cell SARS-CoV-2 epitopes and 690 BCG B-cell epitopes similar to SARS-CoV-2 B-cell epitopes. The SARS-CoV-2 T-cell epitopes represented 16 SARS-CoV-2 proteins, and the SARS-CoV-2 B-cell epitopes represented 5 SARS-CoV-2 proteins, including the receptor binding domain of the spike glycoprotein. CONCLUSION: Altogether, our results provide a mechanistic basis for the potential cross-reactive adaptive immunity that may exist between the two microorganisms.

16.
Comput Struct Biotechnol J ; 19: 518-529, 2021.
Article in English | MEDLINE | ID: covidwho-1002467

ABSTRACT

The development of effective and safe vaccines is the ultimate way to efficiently stop the ongoing COVID-19 pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Built on the fact that SARS-CoV-2 utilizes the association of its Spike (S) protein with the human angiotensin-converting enzyme 2 (ACE2) receptor to invade host cells, we computationally redesigned the S protein sequence to improve its immunogenicity and antigenicity. Toward this purpose, we extended an evolutionary protein design algorithm, EvoDesign, to create thousands of stable S protein variants that perturb the core protein sequence but keep the surface conformation and B cell epitopes. The T cell epitope content and similarity scores of the perturbed sequences were calculated and evaluated. Out of 22,914 designs with favorable stability energy, 301 candidates contained at least two pre-existing immunity-related epitopes and had promising immunogenic potential. The benchmark tests showed that, although the epitope restraints were not included in the scoring function of EvoDesign, the top S protein design successfully recovered 31 out of the 32 major histocompatibility complex (MHC)-II T cell promiscuous epitopes in the native S protein, where two epitopes were present in all seven human coronaviruses. Moreover, the newly designed S protein introduced nine new MHC-II T cell promiscuous epitopes that do not exist in the wildtype SARS-CoV-2. These results demonstrated a new and effective avenue to enhance a target protein's immunogenicity using rational protein design, which could be applied for new vaccine design against COVID-19 and other pathogens.

17.
Sci Rep ; 10(1): 22375, 2020 12 23.
Article in English | MEDLINE | ID: covidwho-997939

ABSTRACT

The global population is at present suffering from a pandemic of Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The goal of this study was to use artificial intelligence (AI) to predict blueprints for designing universal vaccines against SARS-CoV-2, that contain a sufficiently broad repertoire of T-cell epitopes capable of providing coverage and protection across the global population. To help achieve these aims, we profiled the entire SARS-CoV-2 proteome across the most frequent 100 HLA-A, HLA-B and HLA-DR alleles in the human population, using host-infected cell surface antigen presentation and immunogenicity predictors from the NEC Immune Profiler suite of tools, and generated comprehensive epitope maps. We then used these epitope maps as input for a Monte Carlo simulation designed to identify statistically significant "epitope hotspot" regions in the virus that are most likely to be immunogenic across a broad spectrum of HLA types. We then removed epitope hotspots that shared significant homology with proteins in the human proteome to reduce the chance of inducing off-target autoimmune responses. We also analyzed the antigen presentation and immunogenic landscape of all the nonsynonymous mutations across 3,400 different sequences of the virus, to identify a trend whereby SARS-COV-2 mutations are predicted to have reduced potential to be presented by host-infected cells, and consequently detected by the host immune system. A sequence conservation analysis then removed epitope hotspots that occurred in less-conserved regions of the viral proteome. Finally, we used a database of the HLA haplotypes of approximately 22,000 individuals to develop a "digital twin" type simulation to model how effective different combinations of hotspots would work in a diverse human population; the approach identified an optimal constellation of epitope hotspots that could provide maximum coverage in the global population. By combining the antigen presentation to the infected-host cell surface and immunogenicity predictions of the NEC Immune Profiler with a robust Monte Carlo and digital twin simulation, we have profiled the entire SARS-CoV-2 proteome and identified a subset of epitope hotspots that could be harnessed in a vaccine formulation to provide a broad coverage across the global population.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Machine Learning , Pandemics/prevention & control , Proteome , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/immunology , Algorithms , Alleles , Amino Acid Sequence , COVID-19/virology , Drug Evaluation, Preclinical/methods , Epitopes, T-Lymphocyte/immunology , HLA Antigens/genetics , Haplotypes , Humans , Immunogenicity, Vaccine , Mutation , Proteomics/methods , SARS-CoV-2/genetics , Software
18.
Biology (Basel) ; 9(9)2020 Sep 18.
Article in English | MEDLINE | ID: covidwho-789329

ABSTRACT

The outbreak of 2019-novel coronavirus (SARS-CoV-2) that causes severe respiratory infection (COVID-19) has spread in China, and the World Health Organization has declared it a pandemic. However, no approved drug or vaccines are available, and treatment is mainly supportive and through a few repurposed drugs. The urgency of the situation requires the development of SARS-CoV-2-based vaccines. Immunoinformatic and molecular modelling are time-efficient methods that are generally used to accelerate the discovery and design of the candidate peptides for vaccine development. In recent years, the use of multiepitope vaccines has proved to be a promising immunization strategy against viruses and pathogens, thus inducing more comprehensive protective immunity. The current study demonstrated a comprehensive in silico strategy to design stable multiepitope vaccine construct (MVC) from B-cell and T-cell epitopes of essential SARS-CoV-2 proteins with the help of adjuvants and linkers. The integrated molecular dynamics simulations analysis revealed the stability of MVC and its interaction with human Toll-like receptors (TLRs), which trigger an innate and adaptive immune response. Later, the in silico cloning in a known pET28a vector system also estimated the possibility of MVC expression in Escherichia coli. Despite that this study lacks validation of this vaccine construct in terms of its efficacy, the current integrated strategy encompasses the initial multiple epitope vaccine design concepts. After validation, this MVC can be present as a better prophylactic solution against COVID-19.

19.
Sci Rep ; 10(1): 14179, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-741695

ABSTRACT

A novel coronavirus (SARS-CoV-2) emerged from China in late 2019 and rapidly spread across the globe, infecting millions of people and generating societal disruption on a level not seen since the 1918 influenza pandemic. A safe and effective vaccine is desperately needed to prevent the continued spread of SARS-CoV-2; yet, rational vaccine design efforts are currently hampered by the lack of knowledge regarding viral epitopes targeted during an immune response, and the need for more in-depth knowledge on betacoronavirus immunology. To that end, we developed a computational workflow using a series of open-source algorithms and webtools to analyze the proteome of SARS-CoV-2 and identify putative T cell and B cell epitopes. Utilizing a set of stringent selection criteria to filter peptide epitopes, we identified 41 T cell epitopes (5 HLA class I, 36 HLA class II) and 6 B cell epitopes that could serve as promising targets for peptide-based vaccine development against this emerging global pathogen. To our knowledge, this is the first study to comprehensively analyze all 10 (structural, non-structural and accessory) proteins from SARS-CoV-2 using predictive algorithms to identify potential targets for vaccine development.


Subject(s)
Betacoronavirus/immunology , Computational Biology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/immunology , Host-Pathogen Interactions/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Viral Proteins/immunology , Amino Acid Sequence , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Betacoronavirus/classification , Betacoronavirus/genetics , Betacoronavirus/metabolism , COVID-19 , Computational Biology/methods , Coronavirus Infections/metabolism , Epitopes, B-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/chemistry , Genome, Viral , Genomics/methods , Humans , Models, Molecular , Pandemics , Peptides/chemistry , Peptides/immunology , Phylogeny , Pneumonia, Viral/metabolism , SARS-CoV-2 , Structure-Activity Relationship , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Vaccines, Subunit/immunology , Viral Proteins/chemistry , Viral Vaccines/immunology
20.
Science ; 370(6512): 89-94, 2020 10 02.
Article in English | MEDLINE | ID: covidwho-695026

ABSTRACT

Many unknowns exist about human immune responses to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. SARS-CoV-2-reactive CD4+ T cells have been reported in unexposed individuals, suggesting preexisting cross-reactive T cell memory in 20 to 50% of people. However, the source of those T cells has been speculative. Using human blood samples derived before the SARS-CoV-2 virus was discovered in 2019, we mapped 142 T cell epitopes across the SARS-CoV-2 genome to facilitate precise interrogation of the SARS-CoV-2-specific CD4+ T cell repertoire. We demonstrate a range of preexisting memory CD4+ T cells that are cross-reactive with comparable affinity to SARS-CoV-2 and the common cold coronaviruses human coronavirus (HCoV)-OC43, HCoV-229E, HCoV-NL63, and HCoV-HKU1. Thus, variegated T cell memory to coronaviruses that cause the common cold may underlie at least some of the extensive heterogeneity observed in coronavirus disease 2019 (COVID-19) disease.


Subject(s)
Betacoronavirus/immunology , CD4-Positive T-Lymphocytes/immunology , Coronavirus Infections/immunology , Epitopes, T-Lymphocyte/immunology , Immunologic Memory , Pneumonia, Viral/immunology , Betacoronavirus/genetics , Blood Donors , COVID-19 , Cross Reactions , Epitope Mapping , Epitopes, T-Lymphocyte/genetics , Genome, Viral , Humans , Open Reading Frames , Pandemics , SARS-CoV-2 , Sequence Homology
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