title: Antibody Epitopes Identified in Critical Regions of Dengue Virus Nonstructural 1 Protein in Mouse Vaccination and Natural Human Infections.
abstract: Dengue is a global public health problem and is caused by four dengue virus (DENV) serotypes (DENV1-4). A major challenge in dengue vaccine development is that cross-reactive anti-DENV Abs can be protective or potentially increase disease via Ab-dependent enhancement. DENV nonstructural protein 1 (NS1) has long been considered a vaccine candidate as it avoids Ab-dependent enhancement. In this study, we evaluated survival to challenge in a lethal DENV vascular leak model in mice immunized with NS1 combined with aluminum and magnesium hydroxide, monophosphoryl lipid A + AddaVax, or Sigma adjuvant system+CpG DNA, compared with mice infected with a sublethal dose of DENV2 and mice immunized with OVA (negative control). We characterized Ab responses to DENV1, 2, and 3 NS1 using an Ag microarray tiled with 20-mer peptides overlapping by 15 aa and identified five regions of DENV NS1 with significant levels of Ab reactivity in the NS1 + monophosphoryl lipid A + AddaVax group. Additionally, we profiled the Ab responses to NS1 of humans naturally infected with DENV2 or DENV3 in serum samples from Nicaragua collected at acute, convalescent, and 12-mo timepoints. One region in the wing domain of NS1 was immunodominant in both mouse vaccination and human infection studies, and two regions were identified only in NS1-immunized mice; thus, vaccination can generate Abs to regions that are not targeted in natural infection and could provide additional protection against lethal DENV infection. Overall, we identified a small number of immunodominant regions, which were in functionally important locations on the DENV NS1 protein and are potential correlates of protection.
authors.affiliation: Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.|Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; and.
authors.forename: Tomer
authors.identifier: 0000-0002-0561-1578
authors.initials: T
authors.lastname: Hertz
authors.affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720.
authors.forename: P Robert
authors.initials: PR
authors.lastname: Beatty
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; and.
authors.forename: Zachary
authors.initials: Z
authors.lastname: MacMillen
authors.affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720.
authors.forename: Sarah S
authors.identifier: 0000-0002-8643-0778
authors.initials: SS
authors.lastname: Killingbeck
authors.affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720.
authors.forename: Chunling
authors.initials: C
authors.lastname: Wang
authors.affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720 eharris@berkeley.edu.
authors.forename: Eva
authors.initials: E
authors.lastname: Harris
mesh_terms: D000276:Adjuvants, Immunologic; D000293:Adolescent; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000956:Antigens, Viral / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003429:Cross Reactions; D003715:Dengue / Q000453:epidemiology / Q000276:immunology* / Q000821:virology; D053059:Dengue Vaccines / Q000276:immunology*; D003716:Dengue Virus / Q000737:chemistry / Q000276:immunology*; D004195:Disease Models, Animal; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D016056:Immunodominant Epitopes / Q000235:genetics; D007223:Infant; D008297:Male; D051379:Mice; D009527:Nicaragua / Q000453:epidemiology; D011446:Prospective Studies; D012703:Serotyping; D014611:Vaccination; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D000956:Antigens, Viral; D053059:Dengue Vaccines; D000939:Epitopes; D016056:Immunodominant Epitopes; C079340:NS1 protein, Dengue virus type 2; C546113:NS1 protein, Dengue virus type 3; C082515:NS1 protein, dengue-1 virus; D017361:Viral Nonstructural Proteins