{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T01:47:30Z","timestamp":1789523250485,"version":"build-2803163510"},"reference-count":40,"publisher":"American Society of Tropical Medicine and Hygiene","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,10,5]]},"abstract":"<jats:p>A tetravalent live attenuated vaccine composed of chimeras of yellow fever 17D and the four dengue viruses (chimeric yellow fever dengue [CYD]) manufactured by Sanofi Pasteur has completed phase III clinical testing in over 35,000 children 2\u201316 years of age. The vaccine was recently licensed in four countries. During the first 2 years of observation, CYD vaccine efficacy ranged between 30% and 79% in 10 different countries with an overall efficacy of 56.8%. During year 3, there was an overall efficacy against hospitalization of 16.7%, but a relative risk of hospitalization of 1.6 among children younger than 9 years and 4.95 in children 5 years of age and younger. Vaccination of seronegative children resulted in universal broad dengue neutralizing antibody responses, but poor protection against breakthrough dengue cases. Unless proven otherwise, such breakthrough cases in vaccinated subjects should be regarded as vaccine antibody-enhanced (ADE). The provenance of these cases can be studied serologically using original antigenic sin immune responses in convalescent sera. In conventional dengue vaccine efficacy clinical trials, persons vaccinated as seronegatives may be hospitalized with breakthrough ADE infections, whereas in the placebo group, dengue infection of monotypic immunes results in hospitalization. Vaccine efficacy trial design must identify dengue disease etiology by separately measuring efficacy in seronegatives and seropositives. The reason(s) why CYD vaccine failed to raise protective dengue virus immunity are unknown. To achieve a safe and protective dengue vaccine, careful studies of monotypic CYD vaccines in humans should precede field trials of tetravalent formulations.<\/jats:p>","DOI":"10.4269\/ajtmh.16-0222","type":"journal-article","created":{"date-parts":[[2016,6,29]],"date-time":"2016-06-29T17:10:39Z","timestamp":1467220239000},"page":"741-745","source":"Crossref","is-referenced-by-count":44,"title":["Licensed Dengue Vaccine: Public Health Conundrum and Scientific Challenge"],"prefix":"10.4269","volume":"95","author":[{"given":"Scott B.","family":"Halstead","sequence":"first","affiliation":[{"name":"1Department of Preventive Medicine and Biometrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2795","reference":[{"key":"ref1","series-title":"Dengvaxia\u00ae First Dengue Vaccine Approved in Brazil","author":"Sanofi Pasteur","year":"2016"},{"key":"ref2","series-title":"Sanofi Pasteur's Dengue Vaccine Approved in the Philippines","author":"Sanofi Pasteur","year":"2016"},{"key":"ref3","series-title":"Dengvaxia\u00ae, World's First Dengue Vaccine, Approved in Mexico","author":"Sanofi Pasteur","year":"2016"},{"key":"ref4","series-title":"El Salvador Becomes the 4th Country to Approve Dengue Vaccine","author":"Outbreak News Today","year":"2016"},{"key":"ref5","series-title":"J Virol","first-page":"4761","article-title":"Safety and efficacy of chimeric yellow fever-dengue virus tetravalent vaccine formulations in nonhuman primates","volume":"78","author":"Guirakhoo","year":"2004"},{"key":"ref6","series-title":"N Engl J Med","first-page":"1195","article-title":"Efficacy and long-term safety of a dengue vaccine in regions of endemic disease","volume":"373","author":"Hadinegoro","year":"2015"},{"key":"ref7","series-title":"Lancet","first-page":"1358","article-title":"Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial","volume":"384","author":"Capeding","year":"2014"},{"key":"ref8","series-title":"N Engl J Med","first-page":"113","article-title":"Efficacy of a tetravalent dengue vaccine in children in Latin America","volume":"372","author":"Villar","year":"2014"},{"key":"ref9","series-title":"Vaccine","first-page":"1643","article-title":"Protective and immunological behavior of chimeric yellow fever dengue vaccine","volume":"34","author":"Halstead","year":"2016"},{"key":"ref10","series-title":"Nat Rev Microbiol","first-page":"45","article-title":"Dengue vaccine: hypotheses to understand CYD-TDV-induced protection","volume":"14","author":"Guy","year":"2016"},{"key":"ref11","series-title":"Hum Vaccin","first-page":"60","article-title":"Live attenuated chimeric yellow fever dengue type 2 (ChimeriVax-DEN2) vaccine: Phase I clinical trial for safety and immunogenicity: effect of yellow fever pre-immunity in induction of cross neutralizing antibody responses to all 4 dengue serotypes","volume":"2","author":"Guirakhoo","year":"2006"},{"key":"ref12","series-title":"Hum Vaccin","first-page":"696","article-title":"Development of Sanofi Pasteur tetravalent dengue vaccine","volume":"6","author":"Guy","year":"2010"},{"key":"ref13","series-title":"Vaccine","first-page":"5047","article-title":"Safety and immunogenicity of three tetravalent dengue vaccine formulations in healthy adults in the USA","volume":"31","author":"Dayan","year":"2013"},{"key":"ref14","series-title":"J Infect Dis","first-page":"527","article-title":"In vivo enhancement of dengue infection with passively transferred antibody","volume":"140","author":"Halstead","year":"1979"},{"key":"ref15","series-title":"J Virol","first-page":"5477","article-title":"Recombinant chimeric yellow fever-dengue type 2 virus is immunogenic and protective in nonhuman primates","volume":"74","author":"Guirakhoo","year":"2000"},{"key":"ref16","series-title":"Am J Trop Med Hyg","first-page":"30","article-title":"Research on dengue during World War II","volume":"1","author":"Sabin","year":"1952"},{"key":"ref17","series-title":"Int J Infect Dis","first-page":"118","article-title":"Effect of age on outcome of secondary dengue 2 infections","volume":"6","author":"Guzman","year":"2002"},{"key":"ref18","series-title":"Am J Trop Med Hyg","first-page":"127","article-title":"Epidemiological factors associated with dengue shock syndrome and mortality in hospitalized dengue patients in Ho Chi Minh City, Vietnam","volume":"84","author":"Anders","year":"2011"},{"key":"ref19","series-title":"PAHO J Epidemiol","first-page":"223","article-title":"Enhanced severity of secondary dengue 2 infections occurring at an interval of 20 compared with 4 years after dengue 1 infection","volume":"11","author":"Guzman","year":"2002"},{"key":"ref20","series-title":"J Infect Dis","first-page":"360","article-title":"A shorter time interval between first and second dengue infections is associated with protection from clinical illness in a school-based cohort in Thailand","volume":"209","author":"Anderson","year":"2013"},{"key":"ref21","series-title":"Am J Trop Med Hyg","first-page":"179","article-title":"Dengue hemorrhagic fever in Cuba, 1981: a retrospective seroepidemiologic study","volume":"42","author":"Guzman","year":"1990"},{"key":"ref22","series-title":"Am J Epidemiol","first-page":"793","article-title":"Epidemiologic studies on dengue in Santiago de Cuba, 1997","volume":"152","author":"Guzman","year":"2000"},{"key":"ref23","series-title":"Am J Trop Med Hyg","first-page":"1113","article-title":"Dengue hemorrhagic fever caused by sequential dengue 1\u20133 infections at a long interval: Havana epidemic, 2001\u20132002","volume":"75","author":"Alvarez","year":"2006"},{"key":"ref24","series-title":"Vaccine","first-page":"4501","article-title":"Identifying protective dengue vaccines: guide to mastering an empirical process","volume":"31","author":"Halstead","year":"2013"},{"key":"ref25","series-title":"Nat Commun","first-page":"6341","article-title":"A highly potent human antibody neutralizes dengue virus serotype 3 by binding across three surface proteins","volume":"6","author":"Fibriansah","year":"2015"},{"key":"ref26","series-title":"Front Immunol","first-page":"93","article-title":"T-cell immunity to infection with dengue virus in humans","volume":"5","author":"Weiskopf","year":"2014"},{"key":"ref27","series-title":"J Virol","first-page":"120","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"},{"key":"ref28","series-title":"Sci Transl Med","first-page":"304ra142","article-title":"Dengue virus NS1 is a viral toxin that activates cells via TLR4 and disrupts endothelial cell monolayer integrity","volume":"7","author":"Modhiran","year":"2015"},{"key":"ref29","series-title":"Sci Transl Med","first-page":"304ra141","article-title":"Dengue virus non-structural protein 1 triggers endothelial permeability and vascular leak that can be inhibited by anti-NS1 antibodies","volume":"7","author":"Beatty","year":"2015"},{"key":"ref30","series-title":"J Gen Virol","first-page":"853","article-title":"Protection of mice against dengue 2 virus encephalitis by immunization with the dengue 2 virus non-structural glycoprotein NS1","volume":"68","author":"Schlesinger","year":"1987"},{"key":"ref31","series-title":"Mol Immunol","first-page":"109","article-title":"Preliminary evaluation of DNA vaccine candidates encoding dengue-2 prM\/E and NS1: their immunity and protective efficacy in mice","volume":"54","author":"Lu","year":"2013"},{"key":"ref32","series-title":"J Clin Microbiol","first-page":"557","article-title":"Nonstructural protein 1-specific immunoglobulin M and G antibody capture enzyme-linked immunosorbent assays in diagnosis of flaviviral infections in humans","volume":"53","author":"Chao","year":"2015"},{"key":"ref33","series-title":"J Virol","first-page":"410","article-title":"An in-depth analysis of original antigenic sin in dengue virus infection","volume":"85","author":"Midgley","year":"2011"},{"key":"ref34","series-title":"Vaccine","first-page":"3746","article-title":"Modelling the immunological response to a tetravalent dengue vaccine from multiple phase-2 trials in Latin America and south east Asia","volume":"33","author":"Dorigatti","year":"2015"},{"key":"ref35","series-title":"J Virol","first-page":"11436","article-title":"Dengue 2 PDK-53 virus as a chimeric carrier for tetravalent dengue vaccine","volume":"77","author":"Huang","year":"2003"},{"key":"ref36","series-title":"J Infect Dis","first-page":"702","article-title":"Robust and balanced immune responses to all 4 dengue virus serotypes following administration of a single dose of a live attenuated tetravalent dengue vaccine to healthy, flavivirus-naive adults","volume":"212","author":"Kirkpatrick","year":"2015"},{"key":"ref37","series-title":"Guidelines for the Clinical Evaluation of Dengue Vaccines in Endemic Areas","first-page":"441","author":"World Health Organization","year":"2008"},{"key":"ref38","series-title":"Vaccine","first-page":"4113","article-title":"\u201cGuidelines for the clinical evaluation of dengue vaccines in endemic areas\u201d: summary of a World Health Organization Technical Consultation","volume":"26","author":"Edelman","year":"2008"},{"issue":"(Suppl 2)","key":"ref39","series-title":"J Clin Virol","first-page":"S7","article-title":"Guidelines for clinical trials of dengue vaccine in endemic areas","volume":"46","author":"Hombach","year":"2009"},{"key":"ref40","series-title":"Vaccine","article-title":"Estimation of parameters related to vaccine efficacy and dengue transmission from two large phase III 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