{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T17:12:24Z","timestamp":1784740344570,"version":"3.55.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T00:00:00Z","timestamp":1629417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013275","name":"Instituto Serrapilheira","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013275","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The four serotypes of Dengue virus (DENV1-4) are arboviruses (<jats:underline>ar<\/jats:underline>thropod-<jats:underline>bo<\/jats:underline>rne <jats:underline>viruses<\/jats:underline>) that belong to the <jats:italic>Flavivirus<\/jats:italic> genus, <jats:italic>Flaviviridae<\/jats:italic> family. They are the causative agents of an infectious disease called dengue, an important global public health problem with significant social-economic impact. Thus, the development of safe and effective dengue vaccines is a priority according to the World Health Organization. Only one anti-dengue vaccine has already been licensed in endemic countries and two formulations are under phase III clinical trials. In this study, we aimed to compare the main anti-dengue virus vaccines, DENGVAXIA<jats:sup>\u00ae<\/jats:sup>, LAV-TDV, and TAK-003, regarding their antigens and potential to protect. We studied the conservation of both, B and T cell epitopes involved in immunological control of DENV infection along with vaccine viruses and viral isolates. In addition, we assessed the population coverage of epitope sets contained in each vaccine formulation with regard to different human populations. As main results, we found that all three vaccines contain the main B cell epitopes involved in viral neutralization. Similarly, LAV-TDV and TAK-003 contain most of T cell epitopes involved in immunological protection, a finding not observed in DENGVAXIA<jats:sup>\u00ae<\/jats:sup>, which explains main limitations of the only licensed dengue vaccine. In summary, the levels of presence and absence of epitopes that are target for protective immune response in the three main anti-dengue virus vaccines are shown in this study. Our results suggest that investing in vaccines that contain the majority of epitopes involved in protective immunity (cellular and humoral arms) is an important issue to be considered.<\/jats:p>","DOI":"10.3389\/fimmu.2021.715136","type":"journal-article","created":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T08:27:38Z","timestamp":1629448058000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Comparison of Neutralizing Dengue Virus B Cell Epitopes and Protective T Cell Epitopes With Those in Three Main Dengue Virus Vaccines"],"prefix":"10.3389","volume":"12","author":[{"given":"Josilene Ramos","family":"Pinheiro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Camilo dos Reis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rayane da Silva Oliveira","family":"Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Lu\u00edza Silva","family":"Rocha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lincoln","family":"Suesdek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasco","family":"Azevedo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep","family":"Tiwari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz Gon\u00e7alves Silva","family":"Rocha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Birbrair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erick Carvalho","family":"M\u00e9ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilson Barros","family":"Luiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime Henrique","family":"Amorim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nrdp.2016.55","article-title":"Dengue Infection","volume":"2","author":"Guzman","year":"2016","journal-title":"Nat Rev Dis Prim"},{"key":"B2","article-title":"Dengue and Severe Dengue","volume-title":"WHO.","year":""},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cimid.2004.03.013","article-title":"The Changing Epidemiology of Yellow Fever and Dengue, 1900 to 2003: Full Circle","volume":"27","author":"Gubler","year":"2004","journal-title":"Comp Immunol Microbiol Infect Dis"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)60572-9","article-title":"Dengue","volume":"385","author":"Guzman","year":"2015","journal-title":"Lancet"},{"key":"B5","unstructured":"Casos De Dengue Nas Am\u00e9ricas Chegam a 1,6 Milh\u00e3o, O Que Destaca a Necessidade do Controle De Mosquitos Durante a Pandemia - OPAS\/OMS"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2007.05.042","article-title":"Characterization of an Antigenic Site That Contains a Dominant, Type-Specific Neutralization Determinant on the Envelope Protein Domain III (ED3) of Dengue 2 Virus","volume":"366","author":"Gromowski","year":"2007","journal-title":"Virology"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02099-10","article-title":"The Helical Domains of the Stem Region of Dengue Virus Envelope Protein are Involved in Both Virus Assembly and Entry","volume":"85","author":"Lin","year":"2011","journal-title":"J Virol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"5","DOI":"10.5123\/S0104-16731999000400002","article-title":"Epidemiologia E Medidas De Preven\u00e7\u00e3o do Dengue Epidemiology and Preventive Measures of Dengue","volume":"8","author":"Teixeira M da","year":"1999","journal-title":"Inf Epidemiol\u00f3gico do Sus"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01252","article-title":"Anti-Dengue Vaccines: From Development to Clinical Trials","volume":"11","author":"Pinheiro-Michelsen","year":"2020","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2010.08.007","article-title":"The Human Immune Response to Dengue Virus is Dominated by Highly Cross-Reactive Antibodies Endowed With Neutralizing and Enhancing Activity","volume":"8","author":"Beltramello","year":"2010","journal-title":"Cell Host Microbe"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aar4297","article-title":"Flavivirus Serocomplex Cross-Reactive Immunity is Protective by Activating Heterologous Memory CD4 T Cells","volume":"4","author":"Saron","year":"2018","journal-title":"Sci Adv"},{"key":"B12","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1089\/vim.2008.0063","article-title":"The Cellular Immune Response Plays an Important Role in Protecting Against Dengue Virus in the Mouse Encephalitis Model","volume":"22","author":"Gil","year":"2009","journal-title":"Viral Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02129-14","article-title":"The Human CD8+ T Cell Responses Induced by a Live Attenuated Tetravalent Dengue Vaccine are Directed Against Highly Conserved Epitopes","volume":"89","author":"Weiskopf","year":"2015","journal-title":"J Virol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2016.10.006","article-title":"Protective Role of Cross-Reactive CD8 T Cells Against Dengue Virus Infection","volume":"13","author":"Elong Ngono","year":"2016","journal-title":"EBioMedicine"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph10116049","article-title":"Flaviviruses in Europe: Complex Circulation Patterns and Their Consequences for the Diagnosis and Control of West Nile Disease","volume":"10","author":"Beck","year":"2013","journal-title":"Int J Environ Res Public Health"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1690","article-title":"Prospects for a Dengue Virus Vaccine","volume":"5","author":"Whitehead","year":"2017","journal-title":"Nat Rev Microbiol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nri3014","article-title":"Immunity to Dengue Virus: A Tale of Original Antigenic Sin and Tropical Cytokine Storms","volume":"11","author":"Rothman","year":"2011","journal-title":"Nat Rev Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201745302","article-title":"The Bright and the Dark Side of Human Antibody Responses to Flaviviruses: Lessons for Vaccine Design","volume":"19","author":"Rey","year":"2018","journal-title":"EMBO Rep"},{"key":"B19","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1186\/s12929-017-0395-z","article-title":"In Silico Design of a Zika Virus non-Structural Protein 5 Aiming Vaccine Protection Against Zika and Dengue in Different Human Populations","volume":"24","author":"dos Santos Franco","year":"2017","journal-title":"J BioMed Sci"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02260","article-title":"Seeking Flavivirus Cross-Protective Immunity","volume":"10","author":"Dos Santos Franco","year":"2019","journal-title":"Front Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2007.11.082","article-title":"Dengue Virus Type 3 Vaccine Candidates Generated by Introduction of Deletions in the 3\u2032 Untranslated Region (3\u2032-UTR) or by Exchange of the DENV-3 3\u2032-UTR With That of DENV-4","volume":"26","author":"Blaney","year":"2008","journal-title":"Vaccine"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.2011.10-0592","article-title":"Efficacy of a Tetravalent Chimeric Dengue Vaccine (Denvax) in Cynomolgus Macaques","volume":"84","author":"Osorio","year":"2011","journal-title":"Am J Trop Med Hyg"},{"key":"B23","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1007\/bf01311115","article-title":"Variation of the Nucleotide and Encoded Amino Acid Sequences of the Envelope Gene From Eight Dengue-2 Viruses","volume":"105","author":"Blok","year":"1989","journal-title":"Arch Virol"},{"key":"B24","first-page":"545","volume-title":"Imunologia - Abbas 7a Ed.Pdf","author":"Abbas","year":"2011"},{"key":"B25","doi-asserted-by":"publisher","first-page":"74","DOI":"10.4269\/ajtmh.2005.72.74","article-title":"Replication of Chimeric Yellow Fever Virus \u2013 Dengue Serotype 1-4 Virus Vaccine Strains in Dendritic and Hepatic Cells","volume":"72","author":"Brandler","year":"2005","journal-title":"Am J Trop Med Hyg"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2011.03.057","article-title":"Live-Attenuated, Tetravalent Dengue Vaccine in Children, Adolescents and Adults in a Dengue Endemic Country: Randomized Controlled Phase I Trial in the Philippines","volume":"29","author":"Capeding","year":"2011","journal-title":"Vaccine"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2015.1076598","article-title":"Immunogenicity and Safety of a Tetravalent Dengue Vaccine in Healthy Adults in India: A Randomized, Observer-Blind, Placebo-Controlled Phase II Trial","volume":"2","author":"Dubey","year":"2016","journal-title":"Hum Vaccines Immunother"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.4161\/21645515.2014.972131","article-title":"Assessment of Bivalent and Tetravalent Dengue Vaccine Formulations in Flavivirus-Naive Adults in Mexico","volume":"10","author":"Dayan","year":"2014","journal-title":"Hum Vaccines Immunother"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2012.01.001","article-title":"Article Mechanism of Dengue Virus by a Monoclonal Antibody","volume":"20","author":"Cockburn","year":"2012","journal-title":"Struct Des"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2009.07.035","article-title":"Interaction of the Dengue Virus Fusion Peptide With Membranes Assessed by NMR: The Essential Role of the Envelope Protein Trp101 for Membrane Fusion","volume":"392","author":"Melo","year":"2009","journal-title":"J Mol Biol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00432-07","article-title":"Type- and Subcomplex-Specific Neutralizing Antibodies Against Domain III of Dengue Virus Type 2 Envelope Protein Recognize Adjacent Epitopes","volume":"81","author":"Sukupolvi-Petty","year":"2007","journal-title":"J Virol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.51.3.682-686.1984","article-title":"Biology of Cloned Cytotoxic T Lymphocytes Specific for Lymphocytic Choriomeningitis Virus : Clearance of Virus In Vivo","volume":"51","author":"Byrne","year":"1984","journal-title":"J Virol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-7915(96)80042-2","article-title":"DNA Vaccines Jerald C Sadoffs and Margaret a Liu *\u00a7","volume":"8","author":"Ulmer","year":"1996","journal-title":"Curr Opin Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.8.6559-6564.1998","article-title":"Critical Role for CD4 xxx03E8; T Cells in Controlling Retrovirus Replication and Spread in Persistently Infected Mice","volume":"72","author":"Hasenkrug","year":"1998","journal-title":"J Virol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1084\/jem.191.9.1499","article-title":"Analysis of Successful Immune Responses in Persons Infected With Hepatitis C Virus","volume":"191","author":"Lechner","year":"2000","journal-title":"J Exp Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.68.12.8056-8063.1994","article-title":"CD4 + T Cells are Required to Sustain CD8 + Cytotoxic T-Cell Responses During Chronic Viral Infection","volume":"68","author":"Matloubian","year":"1994","journal-title":"J\u00a0Virol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1084\/jem.194.10.1395","article-title":"Determinants of Viral Clearance and Persistence During Acute Hepatitis C Virus Infection","volume":"194","author":"Thimme","year":"2001","journal-title":"J\u00a0Exp Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1305227110","article-title":"Comprehensive Analysis of Dengue Virus-Speci Fi C Responses Supports an HLA-Linked Protective Role for CD8 + T Cells","volume":"110","author":"Weiskopf","year":"2013","journal-title":"Proc Nat Acad Sci"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1056\/NEJMoa1506223","article-title":"Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease","volume":"373","author":"Hadinegoro","year":"2015","journal-title":"N Engl J Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61428-7","article-title":"Protective Efficacy of the Recombinant, Live-Attenuated, CYD Tetravalent Dengue Vaccine in Thai Schoolchildren: A Randomised, Controlled Phase 2b Trial","volume":"380","author":"Sabchareon","year":"2012","journal-title":"Lancet"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1903869","article-title":"Efficacy of a Tetravalent Dengue Vaccine in Healthy Children and Adolescents","volume":"381","author":"Biswal","year":"2019","journal-title":"N Engl J Med"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1056\/NEJMoa1800820","article-title":"Effect of Dengue Serostatus on Dengue Vaccine Safety and Efficacy","volume":"379","author":"Savarino","year":"2018","journal-title":"N\u00a0Engl J Med"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.715136\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T08:27:48Z","timestamp":1629448068000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.715136\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,20]]},"references-count":42,"alternative-id":["10.3389\/fimmu.2021.715136"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.715136","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,20]]},"article-number":"715136"}}