title: Randomized, placebo-controlled trial of nonpegylated and pegylated forms of recombinant human alpha interferon 2a for suppression of dengue virus viremia in rhesus monkeys.
abstract: Dengue fever and dengue hemorrhagic fever are caused by infection with any one of the four dengue viruses (DVs) and are significant public health burdens throughout the tropics. Higher viremia levels are associated with greater dengue disease severity. A therapeutic intervention to suppress viremia early in DV infection could potentially ameliorate severe disease. Recombinant alpha interferon 2a (rIFN-alpha-2a, Roferon-A) suppressed DV replication in human peripheral blood mononuclear cells in vitro. We therefore examined the effects of rIFN-alpha-2a and pegylated recombinant IFN-alpha-2a (PEG-rIFN-alpha-2a, PEGASYS) on DV serotype 2 (DV-2) viremia in rhesus monkeys. Flavivirus-naïve monkeys were inoculated with DV-2 and randomized to receive a single dose of rIFN-alpha-2a (10 million international units/m2) versus placebo or PEG-rIFN-alpha-2a (6 microg/kg) versus placebo 1 day after the onset of viremia. Serial daily viremia levels were measured, and convalescent-phase DV-2 neutralizing antibody titers were determined. Compared to placebo, a single injection of rIFN-alpha-2a temporarily suppressed DV-2 replication and delayed the time to peak viremia by a median of 3 days. However, measures of total viral burden were not different between the two groups. A single injection of PEG-rIFN-alpha-2a significantly lowered daily viremia levels and improved virus clearance, starting 48 h after administration. There were no significant differences in DV-2 neutralizing antibody titers between the treatment and placebo groups at 30 and 90 days postinfection. Based on their individual effects, future studies should investigate a combination of rIFN-alpha-2a and PEG-rIFN-alpha-2a for suppression of dengue virus viremia and as a potential therapeutic intervention.
authors.affiliation: United States Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: C
authors.initials: C
authors.lastname: Ajariyakhajorn
authors.forename: M P
authors.initials: MP
authors.lastname: Mammen
authors.forename: T P
authors.initials: TP
authors.lastname: Endy
authors.forename: M
authors.initials: M
authors.lastname: Gettayacamin
authors.forename: A
authors.initials: A
authors.lastname: Nisalak
authors.forename: S
authors.initials: S
authors.lastname: Nimmannitya
authors.forename: D H
authors.initials: DH
authors.lastname: Libraty
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000998:Antiviral Agents / Q000627:therapeutic use*; D003715:Dengue / Q000188:drug therapy*; D003716:Dengue Virus / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D004195:Disease Models, Animal; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D008253:Macaca mulatta; D009500:Neutralization Tests; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011994:Recombinant Proteins; D014766:Viremia / Q000188:drug therapy*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000914:Antibodies, Viral; D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a