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

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.

Prophylactic efficacy of a human monoclonal antibody against MERS-CoV in the common marmoset

“…Taken together, the prophylactic treatment with LCA60 resulted in a moderate clinical benefit, including reduced respiratory involvement and fewer pathological changes in the lungs of LCA60-treated marmosets. These results are in line with a study in common marmosets where treatment with monoclonal antibodies REGN3048 and REGN3051 resulted in less severe respiratory disease (de Wit et al, 2018), and a study in rhesus macaques where prophylactic treatment with the MERS-CoV neutralizing mAb 3B11eN resulted in a reduced pathologic lung volume using computed tomography (Johnson et al, 2016). Of note, LCA60 was shown to bind to an epitope overlapping with that of 3B11eN and to be 10-fold more potent in terms of viral neutralization (Corti et al, 2015).…”

“…Monoclonal antibodies were infused into the femoral vein in a volume of ≤1 ml depending on bodyweight. MERS-CoV-neutralizing activity in serum was determined at several timepoints after infusion using a microneutralization assay with 100 TCID 50 hCoV-EMC/2012 as described previously (de Wit et al, 2018). Serum samples collected on 1, 3 and 7 days after administration of LCA60 contained high levels of MERS-CoV neutralizing activity; no MERS-CoV neutralizing antibodies were detected in the control mAb-treated animals ( Fig.…”

“…Radiographs were used to score individual lung lobes for severity of pulmonary infiltrates by a clinical veterinarian blinded to treatment assignment 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 (E). On 6 dpi all animals were euthanized and tissue samples were collected from all 4 lung lobes, RNA was extracted, qRT-PCR targeting UpE performed, and viral load determined as TCID 50 equivalents per gram tissue as described previously (de Wit et al, 2018). Geometric mean viral loads and standard deviation are shown for each tissue (F).…”

“…Tissues of the respiratory tract, including samples of all four lung lobes, were collected for analysis. RNA was extracted from 30 mg tissue and used in a one-step realtime RT-PCR (qRT-PCR) detecting upE (Corman et al, 2012) as described previously (de Wit et al, 2018). There were no statistical differences in viral loads in LCA60-treated versus control mAb-treated animals (Fig.…”

“…Therapeutic efficacy of LCA60 was not assessed in the marmoset model here due to the moderate clinical benefit observed upon prophylactic treatment, but has been shown in a mouse model of MERS-CoV infection (Corti et al, 2015). However, therapeutic efficacy of several MERS-CoV neutralizing antibodies has been shown in mouse models (Agrawal et al, 2016;Corti et al, 2015;Li et al, 2015;Pascal et al, 2015;Qiu et al, 2016;Zhao et al, 2018), but so far the clinical benefit in nonhuman primate studies has been modest (Chen et al, 2017;de Wit et al, 2018;van Doremalen et al, 2017). Thus, LCA60 would likely be more efficacious as a therapeutic treatment in combination with other MERS-CoV-neutralizing antibodies or other antiviral treatments such as ribavirin, IFN and lopinavir that have shown therapeutic efficacy in nonhuman primates (Chan et al, 2015;Falzarano et al, 2013).…”