title: Prophylactic and therapeutic intranasal administration with an immunomodulator, Hiltonol®(Poly IC:LC), in a lethal SARS-CoV-infected BALB/c mouse model.
abstract: Hiltonol®, (Poly IC:LC), a potent immunomodulator, is a synthetic, double-stranded polyriboinosinic-polyribocytidylic acid (poly IC) stabilized with Poly-L-lysine and carboxymethyl cellulose (LC). Hiltonol®was tested for efficacy in a lethal SARS-CoV-infected BALB/c mouse model. Hiltonol®at 5, 1, 0.5 or 0.25 mg/kg/day by intranasal (i.n.) route resulted in significant survival benefit when administered at selected times 24 h prior to challenge with a lethal dose of mouse-adapted severe acute respiratory syndrome coronavirus (SARS-CoV). The infected BALB/c mice receiving the Hiltonol®treatments were also significantly effective in protecting mice against weight loss due to infection (p < 0.001). Groups of 20 mice were dosed with Hiltonol®at 2.5 or 0.75 mg/kg by intranasal instillation 7, 14, and 21 days before virus exposure and a second dose was given 24 h later, prophylactic Hiltonol®treatments (2.5 mg/kg/day) were completely protective in preventing death, and in causing significant reduction in lung hemorrhage scores, lung weights and lung virus titers. Hiltonol®was also effective as a therapeutic when give up to 8 h post virus exposure; 100% of the-infected mice were protected against death when Hiltonol®was administered at 5 mg/kg/day 8 h after infection. Our data suggest that Hiltonol®treatment of SARS-CoV infection in mice leads to substantial prophylactic and therapeutic effects and could be used for treatment of other virus disease such as those caused by MERS-CoV a related coronavirus. These properties might be therapeutically advantageous if Hiltonol®is considered for possible clinical use.
authors.affiliation: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Science, 5600 Old Main Hill, Logan, Utah State University, Logan, UT 84322, USA. Electronic address: yohichi.kumaki@usu.edu.
authors.forename: Yohichi
authors.initials: Y
authors.lastname: Kumaki
authors.affiliation: Oncovir, Inc., Washington, DC, USA.
authors.forename: Andres M
authors.initials: AM
authors.lastname: Salazar
authors.affiliation: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Science, 5600 Old Main Hill, Logan, Utah State University, Logan, UT 84322, USA.
authors.forename: Miles K
authors.initials: MK
authors.lastname: Wandersee
authors.affiliation: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Science, 5600 Old Main Hill, Logan, Utah State University, Logan, UT 84322, USA.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Barnard
mesh_terms: D000276:Adjuvants, Immunologic; D000281:Administration, Intranasal; D000818:Animals; D002266:Carboxymethylcellulose Sodium / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D056747:Immunomodulation; D007369:Interferon Inducers / Q000008:administration & dosage / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D011070:Poly I-C / Q000008:administration & dosage / Q000627:therapeutic use*; D011107:Polylysine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control* / Q000821:virology; D016019:Survival Analysis
chemical_list: D000276:Adjuvants, Immunologic; D007369:Interferon Inducers; D011107:Polylysine; C019531:poly ICLC; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C
keywords: BALB/c mouse; Hiltonol(®); MERS-CoV; SARS-CoV