COVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models

Abstract

Effective treatments against Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Monoclonal antibodies have shown promising results in patients. Here, we evaluate the in vivo prophylactic and therapeutic effect of COVA1-18, a neutralizing antibody highly potent against the B.1.1.7 isolate. In both prophylactic and therapeutic settings, SARS-CoV-2 remains undetectable in the lungs of treated hACE2 mice. Therapeutic treatment also causes a reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg-1 one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 shows very strong antiviral activity in the upper respiratory compartments. Using a mathematical model, we estimate that COVA1-18 reduces viral infectivity by more than 95% in these compartments, preventing lymphopenia and extensive lung lesions. Our findings demonstrate that COVA1-18 has a strong antiviral activity in three preclinical models and could be a valuable candidate for further clinical evaluation.

Fig. 1. COVA1-18 avidity and SARS-CoV-2 protection in rodents.

a Biolayer interferometry sensorgrams comparing COVA1-18 IgG and Fab binding to RBD. K_Ds are indicated. Representative of 3 independent experiments. b Study design with n = 5 per group, except mouse control group (n = 3). Hamsters were infected with 10⁵ PFU on day 0 and treated on day 1. Mice received COVA1-18 24 h prior to or after exposure to 10⁴ PFU. Lung viral titers at 3 days post-infection are shown for mice (c) and hamsters (d). Bars indicate medians. Mann-Whitney unpaired two-tailed t-test, p values: *:0.0179, **:0.0079. Ctl. control group (black), KD dissociation constant, PFU Plaque forming unit, PrEP pre-exposure prophylaxis (dark blue), Ther. therapeutic (light blue).

Fig. 2. COVA1-18 serum and mucosal pharmacokinetic in infected cynomolgus macaques.

a Study design. Two groups of n = 5 were exposed to 10⁶ PFU of SARS-CoV-2 (intranasal and intratracheal routes). Treated animals received 10 mg kg⁻¹of COVA1-18 1 day before challenge. b COVA1-18 serum concentration (mean with range). COVA1-18 concentration reported as percent of total cynomolgus IgG in heat-inactivated (c) nasopharyngeal fluid, d tracheal fluid (means with range), e bronchoalveolar lavage (BAL) and f saliva (means ± SEMs) with n = 5, except for the control group in (f) where n = 1. g The two macaques from the pharmacokinetic study were euthanized at 24 h post-treatment and their organs analyzed to assess the biodistribution of COVA1-18. The concentration of COVA1-18 was normalized to the weight of each sample for every organ. Bars represent means. The red dashed line indicates challenge day. L left, PFU Plaque forming unit, PK pharmacokinetic, R right.

Fig. 3. COVA1-18 pre-exposure prophylaxis protects cynomolgus monkeys against SARS-CoV-2 challenge and clinical symptoms.

a Genomic (g)RNA and b subgenomic (sg)RNA loads determined by PCR in nasopharyngeal fluids (left), tracheal fluids (middle) and bronchoalveolar lavages (BAL) (right). Individual values are plotted for nasopharyngeal and tracheal samples and bars represent medians for BAL. For b, boxes and whiskers representation with min-max., median, 25th–75th percentile for n = 5 per group. c Chest CT scores were determined at 3 d.p.i. and at 2 or 5 d.p.i for historical controls (n = 8). d Absolute lymphocyte count in the blood (mean with range). Mann-Whitney unpaired two-tailed t-test, p values: * < 0.05, ** < 0.01. 1–18, COVA1-18; CT Computed Tomography, Ctl. control group, LoD limit of detection, LoQ limit of quantification.

Fig. 4. Modeling of viral dynamics and treatment efficacy.

a Individual prediction of the nasopharyngeal genomic (g)RNA and subgenomic (sg)RNA in control (top) and treated animals (bottom) with individual efficacy prediction indicated (green line). The dashed red line indicates the time of infection. gRNA (squares) and sgRNA (circles) data are indicated as plain (above LoQ) or open (below LoQ). b Model predictions of gRNA and sgRNA dynamics with 4 doses of COVA1-18 given 24 h prior to challenge (arrow). c Simulation as in (b) with COVA1-18 given 24 h post-infection. Black dotted lines indicate LoQ (limit of quantification), i.v. intravenous, PFU plaque forming units, PrEP Pre-exposure prophylaxis.