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. 2011 Jan;89(1):75-82.
doi: 10.1016/j.antiviral.2010.11.007. Epub 2010 Nov 18.

Single-dose intranasal administration with mDEF201 (adenovirus vectored mouse interferon-alpha) confers protection from mortality in a lethal SARS-CoV BALB/c mouse model

Yohichi Kumaki  1 , Jane Ennis, Ramtin Rahbar, Jeffrey D Turner, Miles K Wandersee, Aaron J Smith, Kevin W Bailey, Zachary G Vest, Jason R Madsen, Joseph K-K Li, Dale L Barnard
Affiliations

Single-dose intranasal administration with mDEF201 (adenovirus vectored mouse interferon-alpha) confers protection from mortality in a lethal SARS-CoV BALB/c mouse model

Yohichi Kumaki et al. Antiviral Res. 2011 Jan.

Abstract

Interferons (IFNs) are a first line of defense against viral infection. Herein we describe the use of an adenovirus vectored mouse IFN alpha gene (mDEF201) as a prophylactic and treatment countermeasure in a SARS-CoV-infected BALB/c mouse model. Complete survival protection was observed in mice given a single dose of mDEF201 administered intranasally 1, 3, 5, 7, or 14 days prior to lethal SARS-CoV challenge (p<0.001), and body weights of these treated mice were unaffected by the challenge. In addition, low doses of mDEF201 protected lungs in a dose dependent manner as measured by a reduction in gross pathology. Intranasal treatment with mDEF201 ranging from 10(6) to 10(8)PFU significantly protected mice against a lethal SARS-CoV infection in a dose dependent manner up to 12h post infection (p<0.001). The data suggest that mDEF201 is a new class of antiviral agent further development as treatment for SARS-CoV infections.

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Figures

Fig. 1
Fig. 1
Effects of mDEF201 on survival of female BALB/c mice infected with a lethal dose of mouse-adapted SARS-CoV. A total of 106 or 105 PFU of mDEF201 or vehicle placebo were administered intranasally 24 h prior to challenge with mouse-adapted virus. Experimental groups, n = 10; placebo group, n = 15. Data were statistically analyzed by Logrank test followed by Gehan–Breslow–Wilcoxon pairwise comparison tests. Relative significance was adjusted to a Bonferroni-corrected significance threshold for the number of treatment comparisons done. (●) PSS (−24 h), (■) PSS (−24 h, +8 h), (▴) mDEF201 (106 PFU, −24 h), (▾) mDEF201 mDEF201 (105 PFU, −24 h), (♦) Poly ICLC (1 mg/kg, −24 h, +8 h). *** p < 0.001 each compound vs. PSS.
Fig. 2
Fig. 2
(A) Effects of mDEF201 on survival of female BALB/c mice infected with a lethal dose of mouse-adapted SARS-CoV. A total of 106 PFU of mDEF201 or vehicle placebo were administered intranasally 14, 7, 5 and 3 day prior to challenge with mouse-adapted virus. Experimental groups, n = 10; placebo group, n = 15. Data were statistically by Logrank test followed by Gehan–Breslow–Wilcoxon pairwise comparison tests. Relative significance was adjusted to a Bonferroni-corrected significance threshold for the number of treatment comparisons done. *** p < 0.001 each compound vs. respective PSS. (●) PSS (−14 days), (■) PSS (−7 day), (▴) PSS (−5 days), (▾) PSS (−3 days), (○) mDEF201 (−14 days), (□) mDEF201 (−7 days), (▵) mDEF201 (−5 days), (▿) mDEF201 (−3 days), (♢) Poly ICLC (1 mg/kg, −24 h, +8 h). * p < 0.001 each compound vs. respective PSS. (B) Effects of mDEF201 on individual mouse weight of female BALB/c mice infected with a lethal dose of mouse-adapted SARS-CoV. Data were statistically analyzed by two-way analysis of variance. Post-tests were done using Bonferroni's pairwise comparison tests. (●) PSS (−14 days), (■) PSS (−7 days), (▴) PSS (−5 days), (▾) PSS (−3 days), (○) mDEF201 (−14 days), (□) mDEF201 (−7 days), (▵) mDEF201 (−5 days), (▿) mDEF201 (−3 days), (♢) Poly ICLC (1 mg/kg, −24 h, +8 h). *** p < 0.001 each compound vs. respective PSS.
Fig. 3
Fig. 3
(A) Dose–response of mDEF201 on survival of female BALB/c mice infected with a lethal dose of mouse-adapted SARS-CoV. SARS-CoV-infected BALB/c mice were administered with mDEF201 (105, 104, 103 and 102 PFU) or vehicle placebo intranasally 24 h prior to challenge with mouse-adapted virus. Experimental groups, n = 10; placebo group, n = 15. Data were statistically by Logrank test followed by Gehan–Breslow–Wilcoxon pairwise comparison tests. Relative significance was adjusted to a Bonferroni-corrected significance threshold for the number of treatment comparisons done. (●) PSS, (□) mDEF201 (105 PFU), (▵) mDEF201 (104 PFU), (▿) mDEF201 (103 PFU), (♢) mDEF201 (102 PFU), ○ Poly ICLC (1 mg/kg). *** p < 0.001 each compound vs. PSS. (B) Effects of mDEF201 on individual mouse weights of female BALB/c mice infected with a lethal dose of mouse-adapted SARS-CoV. Data were statistically analyzed by two-way analysis of variance. Post-tests were done using Bonferroni's pairwise comparison tests. (●) PSS, (□) mDEF201 (105 PFU), (▵) mDEF201 (104 PFU), ▿ mDEF201 (103 PFU), ♢ mDEF201 (102 PFU), (○) Poly ICLC (1 mg/kg). *** p < 0.001 Poly ICLC vs. PSS.
Fig. 4
Fig. 4
Effects of mDEF201 on lung scores of female BALB/c mice infected with a lethal dose of mouse-adapted SARS-CoV at day 3. Each mouse lung lobe was removed, weighed, placed in a plastic dish, and then assigned a score ranging from 0 (normal appearing lung) to 4 (maximal plum coloration in 100% of lung). Scatter plots are reported as individual values and mean ± SD are indicated by horizontal bars. The significance of the lung score differences between treatment groups was determined using a Kruskal–Wallis test, followed by Dunn's post-tests for evaluating significant pairwise comparisons. Significant lung weight differences compared to the placebo-treated mice were evaluated by analysis of variance, after which individual treatment values were compared to the PSS control using Newman–Keuls pair-wise comparison tests. (●) PSS, (■) mDEF201 (105 PFU, (▴) mDEF201 (104 PFU), (▾) mDEF201 (103 PFU), (□) mDEF201 (−106 PFU, +12 h), (▵) mDEF201 (−106 PFU, +24 h), (▿) mDEF201 (−105 PFU, +6 h), (○) mDEF201 (−105 PFU, +12 h), (*) mDEF201 (−105 PFU, +24 h), (♢) Poly ICLC (1 mg/kg, −24 h, +8). ** p < 0.01, *** p < 0.001 each compound vs. PSS.
Fig. 5
Fig. 5
Therapeutic effects of mDEF201 on survival of female BALB/c mice infected with a lethal dose of mouse-adapted SARS-CoV. A total of 106 or 105 PFU of mDEF201 or vehicle placebo were administered intranasally 6, 12 or 24 h after challenge with mouse-adapted virus. Experimental groups, n = 10; placebo group, n = 15. Data were statistically by Logrank test followed by Gehan–Breslow–Wilcoxon pairwise comparison tests. Relative significance was adjusted to a Bonferroni-corrected significance threshold for the number of treatment comparisons done. (●) PSS (+6 h), (■) PSS (+12 h), (▴) PSS (+24 h), (○) mDEF201 (106 PFU, +6 h), (♢) Poly ICLC (1 mg/kg, −24 h, +8 h). *** p < 0.001 each compound vs. respective PSS.
Fig. 6
Fig. 6
Therapeutic effects of high dose mDEF201 on survival of female BALB/c mice infected with a lethal dose of mouse-adapted SARS-CoV. Data were statistically by Logrank test followed by Gehan–Breslow–Wilcoxon pairwise comparison tests. Relative significance was adjusted to a Bonferroni-corrected significance threshold for the number of treatment comparisons done. (●) PSS (+6 h), (■) PSS (+12 h), (▴) PSS (+24 h), (○) mDEF201 (−107 PFU, +6 h), (□) mDEF201 (107 PFU, +12 h), (▵) mDEF201 (107 PFU, +24 h), (▿) mDEF201 (−108 PFU, +6 h), (○) mDEF201 (108 PFU, +12 h), (*) mDEF201 (108 PFU, +24 h), (♢) Poly ICLC (1 mg/kg, −24 h, +8 h). *** p < 0.0001, each compound vs. mDEF201 empty vector.
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