title: Targeting the non-structural protein 1 from dengue virus to a dendritic cell population confers protective immunity to lethal virus challenge.
abstract: Dengue is the most prevalent arboviral infection, affecting millions of people every year. Attempts to control such infection are being made, and the development of a vaccine is a World Health Organization priority. Among the proteins being tested as vaccine candidates in preclinical settings is the non-structural protein 1 (NS1). In the present study, we tested the immune responses generated by targeting the NS1 protein to two different dendritic cell populations. Dendritic cells (DCs) are important antigen presenting cells, and targeting proteins to maturing DCs has proved to be an efficient means of immunization. Antigen targeting is accomplished by the use of a monoclonal antibody (mAb) directed against a DC cell surface receptor fused to the protein of interest. We used two mAbs (αDEC205 and αDCIR2) to target two distinct DC populations, expressing either DEC205 or DCIR2 endocytic receptors, respectively, in mice. The fusion mAbs were successfully produced, bound to their respective receptors, and were used to immunize BALB/c mice in the presence of polyriboinosinic: polyribocytidylic acid (poly (I:C)), as a DC maturation stimulus. We observed induction of strong anti-NS1 antibody responses and similar antigen binding affinity irrespectively of the DC population targeted. Nevertheless, the IgG1/IgG2a ratios were different between mouse groups immunized with αDEC-NS1 and αDCIR2-NS1 mAbs. When we tested the induction of cellular immune responses, the number of IFN-γ producing cells was higher in αDEC-NS1 immunized animals. In addition, mice immunized with the αDEC-NS1 mAb were significantly protected from a lethal intracranial challenge with the DENV2 NGC strain when compared to mice immunized with αDCIR2-NS1 mAb. Protection was partially mediated by CD4(+) and CD8(+) T cells as depletion of these populations reduced both survival and morbidity signs. We conclude that targeting the NS1 protein to the DEC205(+) DC population with poly (I:C) opens perspectives for dengue vaccine development.
authors.affiliation: Laboratory of Antigen Targeting to Dendritic Cells, Department of Parasitology, University of São Paulo, São Paulo, Brazil.
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Henriques
authors.forename: Eline V
authors.initials: EV
authors.lastname: Rampazo
authors.forename: Antonio J S
authors.initials: AJ
authors.lastname: Gonçalves
authors.forename: Elaine C M
authors.initials: EC
authors.lastname: Vicentin
authors.forename: Jaime H
authors.initials: JH
authors.lastname: Amorim
authors.forename: Raquel H
authors.initials: RH
authors.lastname: Panatieri
authors.forename: Kelly N S
authors.initials: KN
authors.lastname: Amorim
authors.forename: Marcio M
authors.initials: MM
authors.lastname: Yamamoto
authors.forename: Luís C S
authors.initials: LC
authors.lastname: Ferreira
authors.forename: Ada M B
authors.initials: AM
authors.lastname: Alves
authors.forename: Silvia B
authors.initials: SB
authors.lastname: Boscardin
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000914:Antibodies, Viral / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D003715:Dengue / Q000517:prevention & control*; D053059:Dengue Vaccines / Q000008:administration & dosage / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011070:Poly I-C / Q000008:administration & dosage; D021381:Protein Transport; D016019:Survival Analysis; D017361:Viral Nonstructural Proteins / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D053059:Dengue Vaccines; D007074:Immunoglobulin G; C100315:NS1 protein, Flavivirus; D017361:Viral Nonstructural Proteins; D007371:Interferon-gamma; D011070:Poly I-C