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. 2018 Aug:156:64-71.
doi: 10.1016/j.antiviral.2018.06.006. Epub 2018 Jun 7.

Prophylactic and therapeutic efficacy of mAb treatment against MERS-CoV in common marmosets

Emmie de Wit  1 , Friederike Feldmann  2 , Atsushi Okumura  3 , Eva Horne  4 , Elaine Haddock  4 , Greg Saturday  2 , Dana Scott  2 , Karl J Erlandson  5 , Neil Stahl  6 , Leah Lipsich  6 , Christos A Kyratsous  6 , Heinz Feldmann  4
Affiliations

Prophylactic and therapeutic efficacy of mAb treatment against MERS-CoV in common marmosets

Emmie de Wit et al. Antiviral Res. 2018 Aug.

Abstract

The high case-fatality rate of confirmed MERS-CoV infections underlines the urgent need for an effective treatment to reduce the disease severity and mortality. REGN3051 and REGN3048 are two fully human neutralizing monoclonal antibodies (mAb) against MERS-CoV that reduced virus replication in mice expressing human DPP4 upon prophylactic and therapeutic treatment. Here, we evaluated the prophylactic and therapeutic efficacy of REGN3048 and REGN3051 in the common marmoset model of MERS-CoV infection. Intravenous administration of mAb resulted in high levels of MERS-CoV-neutralizing activity in circulating blood. When animals were treated with mAbs one day before challenge, respiratory disease was less severe and, in animals treated with both REGN3048 and REGN3051, viral loads in the lungs were reduced. However, therapeutic treatment on day one after challenge was less efficacious as it did not prevent the development of severe respiratory disease and all treated animals developed bronchointerstitial pneumonia of similar severity as the control animals. Thus, mAb administration may be more effective in a prophylactic treatment regimen rather than treatment of MERS.

Keywords: Animal model; Common marmoset; MERS-CoV; Monoclonal antibody treatment; Neutralizing antibody.

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Figures

Fig. 1
Fig. 1
MERS-CoV neutralization titers in the serum of common marmosets treated with monoclonal antibodies. Five groups of six marmosets were inoculated with MERS-CoV and treated with mAb as indicated in Table 1. On 0, 2 and 6 dpi, serum was collected and tested for the presence of neutralizing antibodies. Treatment groups: Group I: 25 mg/kg REGN684 administered prophylactically or therapeutically in three animals each; Group II: 25 mg/kg REGN3051 prophylactically; Group III: 12.5 mg/kg REGN3048 and 12.5 mg/kg REGN3051 prophylactically; Group IV: 10 mg/kg REGN 3051 therapeutically; Group V: 25 mg/kg REGN3051 therapeutically.
Fig. 2
Fig. 2
Clinical findings in common marmosets inoculated with MERS-CoV and treated with neutralizing mAbs. Five groups of six marmosets were inoculated with MERS-CoV and treated with mAb as indicated in Table 1. After inoculation, the animals were observed twice daily for clinical signs of disease and scored using a clinical scoring system prepared for common marmosets (Falzarano et al., 2014) (A). On 0, 2, 4 and 6 dpi, clinical exams were performed during which bodyweight (B) and respiration rate (C) were determined and radiographs were taken. Radiographs were used to score individual lung lobes for severity of pulmonary infiltrates by a clinical veterinarian according to a standard scoring system (0: normal; 1: mild interstitial pulmonary infiltrates; 2: moderate pulmonary infiltrates perhaps with partial cardiac border effacement and small areas of pulmonary consolidation; 3: serious interstitial infiltrates, alveolar patterns and air bronchograms); the cumulative x-ray score is the sum of the scores of the four individual lung lobes per animal (D). Symbols indicate statistically significant difference in a 2-way ANOVA with Dunnett's multiple comparisons between 2: group I and II; 3: group I and III; 4: group I and group IV; 5: group I and V. Treatment groups: Group I: 25 mg/kg REGN684; Group II: 25 mg/kg REGN3051 prophylactically; Group III: 12.5 mg/kg REGN3048 and 12.5 mg/kg REGN3051 prophylactically; Group IV: 10 mg/kg REGN3051 therapeutically; Group V: 25 mg/kg REGN3051 therapeutically; when no symbols are present, differences were not statistically significant.
Fig. 3
Fig. 3
Viral loads in the lungs of common marmosets inoculated with MERS-CoV and treated with neutralizing mAbs. Five groups of six marmosets were inoculated with MERS-CoV and treated with mAb as indicated in Table 1. On 6 dpi all animals were euthanized and tissue samples were collected from all 4 lung lobes, RNA was extracted and viral load determined as TCID50 equivalents per gram tissue. Individual animals and lung lobes are indicated (A) and averages and standard deviations per group (B). One-way ANOVA with Dunnett's multiple comparisons test was performed to determine statistical significant differences between Group I and the other 4 groups. *** indicates P < 0.0001. Treatment groups: Group I: 25 mg/kg REGN684; Group II: 25 mg/kg REGN3051 prophylactically; Group III: 12.5 mg/kg REGN3048 and 12.5 mg/kg REGN3051 prophylactically; Group IV: 10 mg/kg REGN3051 therapeutically; Group V: 25 mg/kg REGN3051 therapeutically.
Fig. 4
Fig. 4
Viral loads in tissues of common marmosets inoculated with MERS-CoV and treated with neutralizing mAbs. Five groups of six marmosets were inoculated with MERS-CoV and treated with mAb as indicated in Table 1. On 6 dpi all animals were euthanized and tissue samples were collected from all respiratory (A) and extra-respiratory (B) tissues, RNA was extracted and viral loads were determined as TCID50 equivalents per gram tissue. Two-way ANOVA with Tukey's multiple comparisons test was performed to determine statistical significant differences between Group I and the other 4 groups. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Treatment groups: Group I: 25 mg/kg REGN684; Group II: 25 mg/kg REGN3051 prophylactically; Group III: 12.5 mg/kg REGN3048 and 12.5 mg/kg REGN3051 prophylactically; Group IV: 10 mg/kg REGN3051 therapeutically; Group V: 25 mg/kg REGN3051 therapeutically.
Fig. 5
Fig. 5
Histopathological changes in the lungs of common marmosets inoculated with MERS-CoV and treated with neutralizing mAbs. Five groups of six marmosets were inoculated with MERS-CoV and treated with mAb as indicated in Table 1. On 6 dpi all animals were euthanized and lung samples were collected and stained with hematoxylin and eosin (A, B, D, E, G, H, J, K, M, N) or a polyclonal α-MERS-CoV antibody (C, F, I, L, O). One representative image was chosen for group I (A, B, C), group II (D, E, F), group III (G, H, I), group IV (J, K, L) and group V (M, N, O). Treatment groups: Group I: 25 mg/kg REGN684; Group II: 25 mg/kg REGN3051 prophylactically; Group III: 12.5 mg/kg REGN3048 and 12.5 mg/kg REGN3051 prophylactically; Group IV: 10 mg/kg REGN3051 therapeutically; Group V: 25 mg/kg REGN3051 therapeutically. Panels were chosen to reflect the overall histopathology in the lung most accurately and were therefore not all collected from the same lung lobe; however, the 20x HE and IHC panels are from consecutive tissue sections. Magnification is indicated at the top of the figure.
Fig. 6
Fig. 6
Quantification of MERS-CoV-positive cells in the lungs of common marmosets inoculated with MERS-CoV and treated with neutralizing mAbs. Five groups of six marmosets were inoculated with MERS-CoV and treated with mAb as indicated in Table 1. On 6 dpi all animals were euthanized and lung samples were collected and stained with a polyclonal α-MERS-CoV antibody; slides of all four lung lobes of all animals were digitized and antigen-positive pixels were quantified using the ImageScope positive pixel algorithm. The percentage antigen-positive pixels was calculated as the number of pixels stained for MERS-CoV antigen divided by the total number of stained pixels (i.e. non-stained areas such as air spaces were excluded from the analysis). Two-way ANOVA with Dunnett's multiple comparisons test was performed to determine statistical significant differences between Group I and the other 4 groups. * indicates P < 0.05. Treatment groups: Group I: 25 mg/kg REGN684; Group II: 25 mg/kg REGN3051 prophylactically; Group III: 12.5 mg/kg REGN3048 and 12.5 mg/kg REGN3051 prophylactically; Group IV: 10 mg/kg REGN3051 therapeutically; Group V: 25 mg/kg REGN3051 therapeutically.
Fig. S1
Fig. S1
Viral loads in tissues of a common marmoset euthanized with severe respiratory disease on 5 dpi. One animal in group IV had to be euthanized with severe respiratory signs on 5 dpi. Tissue samples were collected from this animal, RNA extracted and viral loads were determined as TCID50 equivalents per gram tissue.
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