Identification and Characterization of CD4+ T Cell Epitopes after Shingrix Vaccination

Understanding the T cell profile associated with the protection observed in elderly vaccinees following Shingrix vaccination is relevant to the general definition of correlates of vaccine efficacy. Our study enables these future studies by clarifying the patterns of immunodominance associated with Shingrix vaccination, as opposed to natural infection or Zostavax vaccination. Identification of epitopes recognized by Shingrix-induced CD4 T cells and their associated HLA restrictions enables the generation of tetrameric staining reagents and, more broadly, the capability to characterize the specificity, magnitude, and phenotype of VZV-specific T cells. ABSTRACT Infections with varicella-zoster virus (VZV) are associated with a range of clinical manifestations. Primary infection with VZV causes chicken pox. The virus remains latent in neurons, and it can reactivate later in life, causing herpes zoster (HZ). Two different vaccines have been developed to prevent HZ; one is based on a live attenuated VZV strain (Zostavax), and the other is based on adjuvanted gE recombinant protein (Shingrix). While Zostavax efficacy wanes with age, Shingrix protection retains its efficacy in elderly subjects (individuals 80 years of age and older). In this context, it is of much interest to understand if there is a role for T cell immunity in the differential clinical outcome and if there is a correlate of protection between T cell immunity and Shingrix efficacy. In this study, we characterized the Shingrix-specific ex vivo CD4 T cell responses in the context of natural exposure and HZ vaccination using pools of predicted epitopes. We show that T cell reactivity following natural infection and Zostavax vaccination dominantly targets nonstructural (NS) proteins, while Shingrix vaccination redirects dominant reactivity to target gE. We mapped the gE-specific responses following Shingrix vaccination to 89 different gE epitopes, 34 of which accounted for 80% of the response. Using antigen presentation assays and single HLA molecule-transfected lines, we experimentally determined HLA restrictions for 94 different donor/peptide combinations. Finally, we used our results as a training set to assess strategies to predict restrictions based on measured or predicted HLA binding and the corresponding HLA types of the responding subjects. IMPORTANCE Understanding the T cell profile associated with the protection observed in elderly vaccinees following Shingrix vaccination is relevant to the general definition of correlates of vaccine efficacy. Our study enables these future studies by clarifying the patterns of immunodominance associated with Shingrix vaccination, as opposed to natural infection or Zostavax vaccination. Identification of epitopes recognized by Shingrix-induced CD4 T cells and their associated HLA restrictions enables the generation of tetrameric staining reagents and, more broadly, the capability to characterize the specificity, magnitude, and phenotype of VZV-specific T cells.

[1]  J. Kolls,et al.  Faculty Opinions recommendation of Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. , 2020, Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature.

[2]  J. Greenbaum,et al.  Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals , 2020, Cell.

[3]  B. Weinberger,et al.  Vaccines to Prevent Infectious Diseases in the Older Population: Immunological Challenges and Future Perspectives , 2020, Frontiers in Immunology.

[4]  B. Pulendran,et al.  Persistence of Varicella-Zoster Virus-Specific Plasma Cells in Adult Human Bone Marrow following Childhood Vaccination , 2020, Journal of Virology.

[5]  C. Hervé,et al.  The Adjuvanted Recombinant Zoster Vaccine in Adults Aged ≥65 Years Previously Vaccinated With a Live-Attenuated Herpes Zoster Vaccine , 2020, The Journal of infectious diseases.

[6]  Morten Nielsen,et al.  T Cell Epitope Predictions. , 2020, Annual review of immunology.

[7]  A. Sette,et al.  Major Histocompatibility Complex Binding, Eluted Ligands, and Immunogenicity: Benchmark Testing and Predictions , 2020, Frontiers in Immunology.

[8]  S. Lai.  Effectiveness of the herpes zoster vaccine Zostavax. , 2019, Vaccine.

[9]  A. Sette,et al.  Human T Cell Response to Dengue Virus Infection , 2019, Front. Immunol..

[10]  M. Levin,et al.  Understanding the immunology of Shingrix, a recombinant glycoprotein E adjuvanted herpes zoster vaccine. , 2019, Current opinion in immunology.

[11]  B. Pulendran,et al.  Understanding the immunology of the Zostavax shingles vaccine. , 2019, Current opinion in immunology.

[12]  K. Blom,et al.  Effectiveness of the herpes zoster vaccine Zostavax® in Stockholm County, Sweden. , 2019, Vaccine.

[13]  S. Mallal,et al.  Characterization of Magnitude and Antigen Specificity of HLA-DP, DQ, and DRB3/4/5 Restricted DENV-Specific CD4+ T Cell Responses , 2019, Front. Immunol..

[14]  Morten Nielsen,et al.  IEDB-AR: immune epitope database—analysis resource in 2019 , 2019, Nucleic Acids Res..

[15]  M. Bassetti,et al.  Serological and T Cell Responses After Varicella Zoster Virus Vaccination in HIV-Positive Patients Undergoing Renal Dialysis. , 2019, Viral immunology.

[16]  A. Ko,et al.  Efficient induction of cell-mediated immunity to varicella-zoster virus glycoprotein E co-lyophilized with a cationic liposome-based adjuvant in mice. , 2019, Vaccine.

[17]  M. Levin,et al.  Immune responses to zoster vaccines , 2019, Human vaccines & immunotherapeutics.

[18]  D. Stevenson,et al.  High Constitutive Interleukin 10 Level Interferes With the Immune Response to Varicella-Zoster Virus in Elderly Recipients of Live Attenuated Zoster Vaccine , 2018, The Journal of infectious diseases.

[19]  The UniProt Consortium,et al.  UniProt: a worldwide hub of protein knowledge , 2018, Nucleic Acids Res..

[20]  Alessandro Sette,et al.  The Immune Epitope Database (IEDB): 2018 update , 2018, Nucleic Acids Res..

[21]  G. Verjans,et al.  Immunobiology of Varicella-Zoster Virus Infection. , 2018, The Journal of infectious diseases.

[22]  Miranda E. Kroehl,et al.  Th1 memory differentiates recombinant from live herpes zoster vaccines , 2018, The Journal of clinical investigation.

[23]  J. Greenbaum,et al.  Improved methods for predicting peptide binding affinity to MHC class II molecules , 2018, Immunology.

[24]  Alessandro Sette,et al.  ImmunomeBrowser: a tool to aggregate and visualize complex and heterogeneous epitopes in reference proteins , 2018, Bioinform..

[25]  D. Depledge,et al.  Molecular Aspects of Varicella-Zoster Virus Latency , 2018, Viruses.

[26]  B. Pulendran,et al.  Breadth and Functionality of Varicella-Zoster Virus Glycoprotein-Specific Antibodies Identified after Zostavax Vaccination in Humans , 2018, Journal of Virology.

[27]  R. Hardy,et al.  Conflict in the Intracellular Lives of Endosymbionts and Viruses: A Mechanistic Look at Wolbachia-Mediated Pathogen-blocking , 2018, Viruses.

[28]  H. Ikematsu,et al.  Immune Responses to a Recombinant Glycoprotein E Herpes Zoster Vaccine in Adults Aged 50 Years or Older , 2018, The Journal of infectious diseases.

[29]  E. Belongia,et al.  Recommendations of the Advisory Committee on Immunization Practices for Use of Herpes Zoster Vaccines , 2018, MMWR. Morbidity and mortality weekly report.

[30]  M. V. van Zelm,et al.  Age-Dependent Pre-Vaccination Immunity Affects the Immunogenicity of Varicella Zoster Vaccination in Middle-aged Adults , 2018, Front. Immunol..

[31]  S. Mallal,et al.  Correction: Definition of Human Epitopes Recognized in Tetanus Toxoid and Development of an Assay Strategy to Detect Ex Vivo Tetanus CD4+ T Cell Responses , 2017, PloS one.

[32]  S. Mallal,et al.  Global Assessment of Dengue Virus-Specific CD4+ T Cell Responses in Dengue-Endemic Areas , 2017, Front. Immunol..

[33]  R. A. van den Berg,et al.  Cellular and molecular synergy in AS01-adjuvanted vaccines results in an early IFNγ response promoting vaccine immunogenicity , 2017 .

[34]  Bjoern Peters,et al.  Experimental validation of the RATE tool for inferring HLA restrictions of T cell epitopes , 2017, BMC Immunology.

[35]  Shuzhao Li,et al.  Metabolic Phenotypes of Response to Vaccination in Humans , 2017, Cell.

[36]  S. Mallal,et al.  Patterns of Cellular Immunity Associated with Experimental Infection with rDEN2Δ30 (Tonga/74) Support Its Suitability as a Human Dengue Virus Challenge Strain , 2017, Journal of Virology.

[37]  S. Mallal,et al.  Definition of Human Epitopes Recognized in Tetanus Toxoid and Development of an Assay Strategy to Detect Ex Vivo Tetanus CD4+ T Cell Responses , 2017, PloS one.

[38]  Alessandro Sette,et al.  A Cytokine-Independent Approach To Identify Antigen-Specific Human Germinal Center T Follicular Helper Cells and Rare Antigen-Specific CD4+ T Cells in Blood , 2016, The Journal of Immunology.

[39]  Bjoern Peters,et al.  A Quantitative Analysis of Complexity of Human Pathogen-Specific CD4 T Cell Responses in Healthy M. tuberculosis Infected South Africans , 2016, PLoS pathogens.

[40]  J. Richardus,et al.  Long-term immunogenicity and safety of an investigational herpes zoster subunit vaccine in older adults. , 2016, Vaccine.

[41]  K. Vora,et al.  Effector and Central Memory Poly-Functional CD4+ and CD8+ T Cells are Boosted upon ZOSTAVAX® Vaccination , 2015, Front. Immunol..

[42]  Bjoern Peters,et al.  Automatic Generation of Validated Specific Epitope Sets , 2015, Journal of immunology research.

[43]  J. Haas,et al.  Zoster Vaccination Increases the Breadth of CD4+ T Cells Responsive to Varicella Zoster Virus. , 2015, The Journal of infectious diseases.

[44]  Bjoern Peters,et al.  Definition of a pool of epitopes that recapitulates the T cell reactivity against major house dust mite allergens , 2015, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[45]  Morten Nielsen,et al.  Accurate pan-specific prediction of peptide-MHC class II binding affinity with improved binding core identification , 2015, Immunogenetics.

[46]  R. Cohrs,et al.  Varicella zoster virus infection , 2015, Nature Reviews Disease Primers.

[47]  Mark M. Davis,et al.  A Population Response Analysis Approach To Assign Class II HLA-Epitope Restrictions , 2015, The Journal of Immunology.

[48]  John Sidney,et al.  Development and validation of a broad scheme for prediction of HLA class II restricted T cell epitopes , 2014, BCB.

[49]  B. Lambrecht,et al.  Enhancement of Adaptive Immunity by the Human Vaccine Adjuvant AS01 Depends on Activated Dendritic Cells , 2014, The Journal of Immunology.

[50]  Bjoern Peters,et al.  A strategy to determine HLA class II restriction broadly covering the DR, DP, and DQ allelic variants most commonly expressed in the general population , 2013, Immunogenetics.

[51]  Clemencia Pinilla,et al.  Measurement of MHC/Peptide Interactions by Gel Filtration or Monoclonal Antibody Capture , 2013, Current protocols in immunology.

[52]  Ravi V. Kolla,et al.  T Cell Responses to Known Allergen Proteins Are Differently Polarized and Account for a Variable Fraction of Total Response to Allergen Extracts , 2012, The Journal of Immunology.

[53]  M. Levin.  Immune senescence and vaccines to prevent herpes zoster in older persons. , 2012, Current opinion in immunology.

[54]  Ravi V. Kolla,et al.  Analysis of T Cell Responses to the Major Allergens from German Cockroach: Epitope Specificity and Relationship to IgE Production , 2012, The Journal of Immunology.

[55]  Bjoern Peters,et al.  A Meta-Analysis of the Existing Knowledge of Immunoreactivity against Hepatitis C Virus (HCV) , 2012, PloS one.

[56]  J. Greenbaum,et al.  Dissecting Mechanisms of Immunodominance to the Common Tuberculosis Antigens ESAT-6, CFP10, Rv2031c (hspX), Rv2654c (TB7.7), and Rv1038c (EsxJ) , 2012, The Journal of Immunology.

[57]  J. Greenbaum,et al.  Identification of novel epitopes from Mycobacterium tuberculosis , 2012 .

[58]  G. Nepom.  MHC Class II Tetramers , 2012, The Journal of Immunology.

[59]  Mark M. Davis,et al.  Interrogating the repertoire: broadening the scope of peptide–MHC multimer analysis , 2011, Nature Reviews Immunology.

[60]  Bjoern Peters,et al.  Functional classification of class II human leukocyte antigen (HLA) molecules reveals seven different supertypes and a surprising degree of repertoire sharing across supertypes , 2011, Immunogenetics.

[61]  R. Cohrs,et al.  Herpes simplex virus-1 and varicella-zoster virus latency in ganglia , 2003, Journal of NeuroVirology.

[62]  Morten Nielsen,et al.  Peptide binding predictions for HLA DR, DP and DQ molecules , 2010, BMC Bioinformatics.

[63]  Bjoern Peters,et al.  Molecular Determinants of T Cell Epitope Recognition to the Common Timothy Grass Allergen , 2010, The Journal of Immunology.

[64]  Ravi V. Kolla,et al.  Definition of epitopes and antigens recognized by vaccinia specific immune responses: their conservation in variola virus sequences, and use as a model system to study complex pathogens. , 2009, Vaccine.

[65]  Morten Nielsen,et al.  NN-align. An artificial neural network-based alignment algorithm for MHC class II peptide binding prediction , 2009, BMC Bioinformatics.

[66]  Bjoern Peters,et al.  Quantitative peptide binding motifs for 19 human and mouse MHC class I molecules derived using positional scanning combinatorial peptide libraries , 2008, Immunome research.

[67]  P. Kennedy,et al.  The neurotropic herpes viruses: herpes simplex and varicella-zoster , 2007, The Lancet Neurology.

[68]  Morten Nielsen,et al.  Prediction of MHC class II binding affinity using SMM-align, a novel stabilization matrix alignment method , 2007, BMC Bioinformatics.

[69]  J. S. Stevenson,et al.  Older Adults , 1980, Suicide Prevention.