title: The human CD8+ T cell responses induced by a live attenuated tetravalent dengue vaccine are directed against highly conserved epitopes.
abstract: The incidence of infection with any of the four dengue virus serotypes (DENV1 to -4) has increased dramatically in the last few decades, and the lack of a treatment or vaccine has contributed to significant morbidity and mortality worldwide. A recent comprehensive analysis of the human T cell response against wild-type DENV suggested an human lymphocyte antigen (HLA)-linked protective role for CD8(+) T cells. We have collected one-unit blood donations from study participants receiving the monovalent or tetravalent live attenuated DENV vaccine (DLAV), developed by the U.S. National Institutes of Health. Peripheral blood mononuclear cells from these donors were screened in gamma interferon enzyme-linked immunosorbent spot assays with pools of predicted, HLA-matched, class I binding peptides covering the entire DENV proteome. Here, we characterize for the first time CD8(+) T cell responses after live attenuated dengue vaccination and show that CD8(+) T cell responses in vaccinees were readily detectable and comparable to natural dengue infection. Interestingly, whereas broad responses to structural and nonstructural (NS) proteins were observed after monovalent vaccination, T cell responses following tetravalent vaccination were, dramatically, focused toward the highly conserved NS proteins. Epitopes were highly conserved in a vast variety of field isolates and able to elicit multifunctional T cell responses. Detailed knowledge of the T cell response will contribute to the identification of robust correlates of protection in natural immunity and following vaccination against DENV.
  
  
  OBJECTIVE
  The development of effective vaccination strategies against dengue virus (DENV) infection and clinically significant disease is a task of high global public health value and significance, while also being a challenge of significant complexity. A recent efficacy trial of the most advanced dengue vaccine candidate, demonstrated only partial protection against all four DENV serotypes, despite three subsequent immunizations and detection of measurable neutralizing antibodies to each serotype in most subjects. These results challenge the hypothesis that seroconversion is the only reliable correlate of protection. Here, we show that CD8(+) T cell responses in vaccinees were readily detectable and comparable to natural dengue virus infection. Detailed knowledge of the T cell response may further contribute to the identification of robust correlates of protection in natural immunity and vaccination against DENV.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA daniela@liai.org.
authors.forename: Daniela
authors.initials: D
authors.lastname: Weiskopf
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Angelo
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Bangs
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Sinu
authors.initials: S
authors.lastname: Paul
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA Genetech Research Institute, Colombo, Sri Lanka.
authors.forename: Aruna D
authors.initials: AD
authors.lastname: de Silva
authors.affiliation: University of Vermont College of Medicine and Vaccine Testing Center, Burlington, Vermont, USA.
authors.forename: Janet C
authors.initials: JC
authors.lastname: Lindow
authors.affiliation: University of Vermont College of Medicine and Vaccine Testing Center, Burlington, Vermont, USA.
authors.forename: Sean A
authors.initials: SA
authors.lastname: Diehl
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Whitehead
authors.affiliation: Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Durbin
authors.affiliation: University of Vermont College of Medicine and Vaccine Testing Center, Burlington, Vermont, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Kirkpatrick
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
mesh_terms: D000293:Adolescent; D000328:Adult; D000956:Antigens, Viral / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D053059:Dengue Vaccines / Q000008:administration & dosage / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology*; D058501:Enzyme-Linked Immunospot Assay; D000939:Epitopes / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009316:National Institutes of Health (U.S.); D014481:United States; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology; D055815:Young Adult
chemical_list: D000956:Antigens, Viral; D053059:Dengue Vaccines; D000939:Epitopes; D014613:Vaccines, Attenuated; D007371:Interferon-gamma