Prophylactic and therapeutic intranasal administration with an immunomodulator, Hiltonol® (Poly IC:LC), in a lethal SARS-CoV-infected BALB/c mouse model

Yohichi Kumaki, Andres M Salazar, Miles K Wandersee, Dale L Barnard, Yohichi Kumaki, Andres M Salazar, Miles K Wandersee, Dale L Barnard

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.

Keywords: BALB/c mouse; Hiltonol(®); MERS-CoV; SARS-CoV.

Published by Elsevier B.V.

Figures

Fig. 1
Fig. 1
A. Effects of Hiltonol® on survival of BALB/c mice with a lethal SARS-CoV infection. ***p < 0.001 versus PSS. The SARS-CoV-infected BALB/c mice were treated with PSS (●: −24 h, +24 h, +48 h); Hiltonol® at 5 mg/kg/day (■: −24 h, +24 h, +48 h), (▲: −24 h, +8 h, +48 h), (▼: −16 h, +8 h, +24 h), (◆: +12 h), (○: −24 h); Hiltonol® at 1.0 mg/kg/day (□: −24 h, +24 h, +48 h), (△: −24 h, +8 h, +24 h), (▽: −16 h, +8 h, +32 h), (◇: −24 h). B. Effects of various long-term dosing regimens of Hiltonol® on survival of BALB/c mice with a lethal SARS-CoV infection. ****p < 0.0001 versus PSS. The SARS-CoV-infected BALB/c mice were treated with PSS (●: day −21), (○: day −14), (◇: day −7); Hiltonol® (■: 2.5 mg/kg/day −21), (□: 2.5 mg/kg/day −14), (▼: 2.5 mg/kg/day −7); (▲: 0.75 mg/kg/day −21), (▽: 0.75 mg/kg/day −14), (△: 0.75 mg/kg/day −7). A second dose was given 24 h later. (♦) Ampligen® 10 mg/kg/day (bid x 2 beg, 4 h).
Fig. 2
Fig. 2
Effects of various long-term dosing regimens of Hiltonol® on neutralizing antibody titers of BALB/c mice at day 7 (A) and 14 (B) post virus challenge with a lethal dose of SARS-CoV. **p < 0.01 versus PSS (day −14), ***p < 0.001 versus Hiltonol® 2.5 mg/kg (day −14) or Hiltonol® 0.75 mg/kg (day −7). The SARS-CoV-infected BALB/c mice were treated with PSS (●: day −21), (○: day −14), (◇: day −7); Hiltonol® (■: 2.5 mg/kg/day −21), (□: 2.5 mg/kg/day −14), (▼: 2.5 mg/kg/day −7); (▲: 0.75 mg/kg/day −21), (▽: 0.75 mg/kg/day −14), (△: 0.75 mg/kg/day −7), (♦) Ampligen® 10 mg/kg/day (bid x 2 beg, 4 h).
Fig. 3
Fig. 3
Histological slides show representative lung pathology. (a). SARS-CoV-infected, Hiltonol®-treated lung with small numbers of neutrophils within groups of alveoli and moderate rims of lymphocytes surrounding scattered vessels. (b). SARS-CoV-infected, Hiltonol®-treated lung with moderate rims of lymphocytes surrounding scattered vessels. (c). SARS-CoV-infected, Hiltonol®-treated lung with clusters of alveolar macrophages and neutrophils filled small groups of alveoli. (d). Un-infected, Hiltonol®-treated lung with moderate rims of lymphocytes surround scattered vessels. (e). SARS-CoV-infected, Ampligen®-treated lung with approximately 80% airspaces contain erythrocytes. (f). SARS-CoV-infected, PSS-treated lung with small number of alveolar macrophages and fewer neutrophils within alveoli.

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Source: PubMed

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