SARS-CoV-2 Omicron virus causes attenuated disease in mice and hamsters

Abstract

The recent emergence of B.1.1.529, the Omicron variant^1,2, has raised concerns of escape from protection by vaccines and therapeutic antibodies. A key test for potential countermeasures against B.1.1.529 is their activity in preclinical rodent models of respiratory tract disease. Here, using the collaborative network of the SARS-CoV-2 Assessment of Viral Evolution (SAVE) programme of the National Institute of Allergy and Infectious Diseases (NIAID), we evaluated the ability of several B.1.1.529 isolates to cause infection and disease in immunocompetent and human ACE2 (hACE2)-expressing mice and hamsters. Despite modelling data indicating that B.1.1.529 spike can bind more avidly to mouse ACE2 (refs. ^3,4), we observed less infection by B.1.1.529 in 129, C57BL/6, BALB/c and K18-hACE2 transgenic mice than by previous SARS-CoV-2 variants, with limited weight loss and lower viral burden in the upper and lower respiratory tracts. In wild-type and hACE2 transgenic hamsters, lung infection, clinical disease and pathology with B.1.1.529 were also milder than with historical isolates or other SARS-CoV-2 variants of concern. Overall, experiments from the SAVE/NIAID network with several B.1.1.529 isolates demonstrate attenuated lung disease in rodents, which parallels preliminary human clinical data.

Fig. 1. B.1.1.529 is less pathogenic in mice.

a, Left: weight change in mock-infected mice (n = 4) or mice inoculated with B.1.1.529 + A701V (n = 5), B.1.1.529 (n = 3) or B.1.351 (n = 3). Middle: weight change in mice inoculated with B.1.1.529 or B.1.351 (n = 5) (**P = 0.0075, ***P = 0.0006, ****P < 0.0001). Right: weight change in mice inoculated with B.1.1.529 (n = 4), B.1.1.7 (n = 10) or B.1.351 (n = 18). Comparison between B.1.351 and B.1.1.529: *P = 0.0151, ***P = 0.0003 (3 dpi) and 0.0006 (4 dpi). Mean ± s.e.m. b, Viral RNA level in mice inoculated with B.1.1.529 or B.1.351 (n = 5) (**P = 0.0079). c, Infectious virus titre in mice inoculated with B.1.1.529 + A701V, B.1.1.529 or B.1.351 (n = 3). d, Infectious virus titre in mice inoculated with B.1.1.529 or B.1.351 (n = 5) (**P = 0.0079). e, Pulmonary function analysis as measured by whole-body plethysmography. Mean ± s.e.m. Comparison between B.1.617.2 and B.1.351: **P = 0.0095 (n = 5 each). f, Left, weight change in mice inoculated with WA1/2020 D614G (10³ FFU; n = 6), B.1.1.529 (10³ FFU; n = 3), B.1.1.529 (10⁴ PFU; n = 6) or B.1.1.529 (10⁵ FFU; n = 3). Right, weight change in mice inoculated with 10⁴ PFU of B.1.1.529 +A701V (n = 6) or B.1.351 (n = 6), or mock-infected, age-matched mice (n = 4). Mean ± s.e.m. g, Infectious virus titre in lungs of mice inoculated with WA1/2020 D614G (n = 8) or B.1.1.529 (n = 7) (****P < 0.0001). h, Infectious virus titre in mice inoculated with B.1.1.529 + A701V or B.1.351 (n = 3). i, Heat map of concentration of cytokines and chemokines in lungs of infected mice. Results are from one (a–f, h, i) or two (g) experiments. The dotted line is the limit of detection. Statistical analysis (a, e: two-way analysis of variance (ANOVA) with multiple comparisons test; b, d, g: two-tailed Mann–Whitney test) was performed on datasets with four or more data points. See Supplementary Table 1 for more information. CCL4, chemokine (C-C motif) ligand 4; IL-18, interleukin-18; CXCL2, chemokine (C-X-C motif) ligand 2; TNF, tumour necrosis factor; GM-CSF, granulocyte–macrophage CSF; IFNγ, interferon-γ. Source data

Fig. 2. B.1.1.529 is less pathogenic in wild-type and hACE2-transgenic Syrian hamsters.

a, Weight change in uninfected age-matched hamsters (n = 3) or in hamsters inoculated with B.1.1.529 or B.1.617.2 (n = 4). Mean ± s.e.m. b, Weight change in uninfected age-matched hamsters (n = 9) or in hamsters inoculated with B.1.1.529 (n = 10) or WA1/2020 D614G (n = 6). Mean ± s.e.m. (red, *P = 0.0293; red, **P = 0.0046 and 0.0014; black, **P = 0.0021; black, ***P = 0.0001). c, Weight change in hamsters inoculated with 10³, 10⁴, 10⁵ or 10⁶ PFU of B.1.1.529 or 10³ PFU of B.1.617.2 (n = 4). Mean ± s.e.m. Comparison between B.1.617.2 and B.1.1.529 (10³ PFU): *P = 0.0476, **P = 0.0041, 0.0041, 0.0047 and 0.0019, respectively. d, Weight change in hamsters inoculated with B.1.1.529 (n = 5) or WA1/2020 (n = 9). Mean ± s.e.m. (****P < 0.0001). e, Viral RNA level in hamsters inoculated with WA1/2020 D614G or B.1.1.529 (n = 15) (*P = 0.015, ***P < 0.0003). f, Infectious virus titre in hamsters inoculated with B.1.617.2 or B.1.1.529 (n = 4) (*P = 0.0286; NS, not significant). g, Nasal wash viral RNA level in hamsters inoculated with WA1/2020 (n = 8) or B.1.1.529 (n = 3). TCID₅₀, median tissue culture infectious dose. h, Pulmonary function analysis by whole-body plethysmography. Mean ± s.e.m. (Penh and Rpef, comparison between B.1.617.2 and B.1.1.529: *P = 0.0263 (3 dpi), *P = 0.0186 (5 dpi), ***P = 0.0005 (7 dpi), ****P < 0.0001) (n = 4). i, Micro-CT images of the lungs of mock-infected (n = 3) or B.1.617.2- (n = 4) and B.1.1.529-infected (n = 4) hamsters at 7 dpi. Multifocal nodules (black arrows), ground-glass opacity (white arrowheads) and pneumomediastinum (white asterisk) are indicated. j, CT score for uninfected hamsters (n = 3) or those inoculated with B.1.617.2 or B.1.1.529 (n = 4) (****P < 0.0001). k, Weight change in hACE2 hamsters inoculated with HP-095 D614G or B.1.1.529 (n = 4). Error bars indicate s.e.m. l, Survival of hACE2 hamsters after inoculation with HP-095 D614G or B.1.1.529 (n = 4) (*P = 0.029). m, Infectious virus titre of hACE2 hamsters inoculated with HP-095 D614G or B.1.1.529; n = 3 (3 dpi), n = 4 (5 dpi) (*P = 0.0286). The results are from one (a, c, d, f–m) or two to three independent (b, e) experiments. Dotted lines represent the limit of detection. Statistical analysis (b–d, h: two-way ANOVA with multiple comparisons test; e, j: two-tailed t-test, f, m: two-tailed Mann–Whitney test, l: log-rank test) was performed on datasets with four or more data points. See Supplementary Table 1 for more information. Source data

Fig. 3. Pathological findings in the lungs of SARS-CoV-2-infected Syrian hamsters.

Hamsters were inoculated with 10³ PFU of B.1.617.2 or B.1.1.529 and euthanized at 3 and 6 dpi (n = 4). a, Macroscopic images of the lungs obtained at 6 dpi. Yellow arrows indicate haemorrhage. b, Lung sections from animals infected with B.1.617.2 or B.1.1.529. Scale bars, 200 µm. Focal alveolar haemorrhage in B.1.617.2-infected animals at 6 dpi is outlined and shown at higher magnification in the inset (scale bar, 100 µm). Black arrow indicates focal inflammation. c, Histopathological score of pneumonia based on the percentage of alveolitis in a given section using the following scoring: 0, no pathological change; 1, affected area (≤10%); 2, affected area (<50%, >10%); 3, affected area (≥50%); an additional point was added when pulmonary edema and/or alveolar haemorrhage was observed. Data are median score (n = 4; *P = 0.0286; two-tailed Mann–Whitney test). d, RNA in situ hybridization for SARS-CoV-2 viral RNA. Representative images for the alveoli and bronchi of hamsters infected with B.1.617.2 or B.1.1.529 (n = 4) virus at 3 or 6 dpi are shown. Scale bars, 20 µm. See Supplementary Table 1 for more information. Source data