In a recent study published in the journal Natureresearchers assessed the pathogenicity and infectivity of the Omicron BA.2 variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in hamsters and mice.
The emergence of the Omicron BA.1, BA.2 and BA.1.1 strains has heightened concerns about the decrease efficiency of vaccines against coronavirus disease 2019 (COVID-19). This has accelerated the development of antiviral agents and monoclonal antibodies (mAbs) to expand the therapeutic landscape for COVID-19.
Study: Characterization and antiviral susceptibility of SARS-CoV-2 Omicron/BA.2. Image creditNIAID
About the study
In the current study, researchers assessed the pathogenicity and infectivity of BA.2 in hamsters and mice against SARS-CoV-2 variants D614G WA1/2020 D614G, Beta and Omicron BA.1.
BA.2 variants such as HP353, NCD1288, TY40-385 and HP354 have been isolated in VeroE6/TMPRSS2 (transmembrane serine protease 2) cell lines. Isolates TY40-385 and NCD1288 were obtained from Indian travelers arriving in Japan, while isolates HP354 and HP353 were obtained from Japanese residents.
BALB/c mice were inoculated intranasally with 105 plate forming units (PFU) of BA.1 or BA.2. Subsequently, changes in their weight and lung function were assessed. Their Rpef and Penh values were measured by whole body plethysmography (WBP) to identify lung changes. In addition, lung and nasal tissues from mouse horns were subjected to histopathological analysis, on the spot hybridization and immunohistochemical analysis and their cytokine and chemokine levels were assessed.
Similar analyzes were performed on transgenic K18 mice and hamsters expressing human angiotensin converting enzyme 2 (hACE2) for comparative evaluation of D614G, Beta, BA.1 and BA.2 variants. In addition, computed tomography (micro-CT) analysis and next-generation sequencing (NGS) were performed.
Neutralization of BA.2 was assessed in COVID-19 convalescents and BNT162b2 vaccinates by concentration reduction neutralization assays (FRNT) and titers were compared to those of D614G, Delta, BA.1 and BA variants. .1.1. Additionally, FRNT assays using antisera from SARS-CoV-2 infected hamsters were performed to assess the antigenic properties of the three Omicron variants. The therapeutic efficacies of Food and Drug Administration (FDA)-cleared mAbs and antiviral agents against BA.1 and BA.2 were also evaluated.
Results
Two days post-infection (dpi), BALB/c mice infected with BA.1 and BA.2 showed no change in weight or lung function, in contrast to significantly higher Penh values and Rpef values lower in mice infected with Beta. mouse. BA.2 lung titers (6.9 logten PFU/g) were higher than BA.1 titers (6.4 logten PFU/g). At five dpi, BA.2 lung titers decreased 33-fold compared to BA.1 at five dpi. Nevertheless, the BA.1 and BA.2 titers in the nasal turbinates remained similar.
Histopathological analysis showed minimal inflammatory infiltrate in the pulmonary alveolar and peribronchial/bronchiolar spaces in BA.1 and BA.2 infected mice. On the spot hybridization analysis revealed the presence of SARS-CoV-2 ribonucleic acid (RNA) in the alveolar and bronchiolar epithelium of mice infected with BA.1 and BA.2. Immunohistochemical analysis showed a similar distribution of SARS-CoV-2 antigen and RNA in mice infected with BA.1 or BA.2. Analyzes indicated comparable infectivity of BA.1 and BA.2, although lower than Beta.
Compared to mice infected with BA.1, those infected with BA.2 showed significantly higher expression of inflammatory chemokines and cytokines, such as interleukin-1 beta (IL-1β), interferon-gamma ( IFN-ꓬ) and macrophages. inflammatory protein beta-1 (MIP-1β). However, the inflammatory expression was significantly lower than in beta infections, indicating the low replication capacity of BA.2.
At three days per inch, hACE2-expressing K18 mice showed significantly lower BA.1 and BA.2 titers and RNA in the lungs and nasal turbinates than D614G titers. BA.2-induced expression of chemokines and cytokines [IL-1β, MIP-1α, and tumor necrosis factor-alpha (TNF-α)] were higher than those induced by BA.1 but lower than those induced by D614G. This indicates lower pathogenicity for BA.1 and BA.2 than for D614G.
Syrian hamsters showed no difference in weight or lung function when inoculated with 103 or 105 PFU doses of SARS-CoV-2 strains. At three dpi and 103 inoculations, nasal turbinate and pulmonary BA.1 titers were significantly higher than BA.2 titers. However, at 105 inoculation doses, BA.1 and BA.2 lung titers were similar. Moreover, no significant difference was detected in hamsters infected with BA.1 and BA.2 in the on the spot hybridization, histopathological analysis and immunohistochemical analysis. The results indicate that BA.1 and BA.2 have comparable pathogenicity.
Micro-CT analysis showed pneumonia-like pathologic changes in BA.1 and BA.2 infected hamsters with higher CT severity scores among those infected with BA.2. NGS analysis showed a predominance of BA.1 in the lungs and nasal turbinates of hamsters at both inoculation doses.
All K18 transgenic hamsters (including the M51 cell line) inoculated with 103 D614G’s PFU died at five days per inch, while most BA.1 and BA.2 infected hamsters survived. Lung BA.2 titers were 100-fold and 10,000-fold lower than the corresponding BA.1 and D614G titers, respectively. However, all strains showed comparable titers in nasal turbinates.
FRNT analysis showed that vaccination with BNT162b2 caused a more significant reduction in BA.1 and BA.1.1 titers compared to BA.2 titers. Vaccines infected with delta showed an elevated FRNT of 50% (FRNT50) values against Delta but low FRNT50 values against the three Omicron strains. Vaccines infected with Omicron showed FRNT50 values 2.9 times to 3.6 times lower against Omicron strains than Delta.
Hamster antisera to Omicron strains showed markedly low FRNT50 titers against D614G and Delta strains. Additionally, 17.4-fold and 11.7-fold lower neutralization of BA.1.1 and BA.1 and compared to BA.2, respectively, was observed. This indicates that BA.2 differs antigenically from D614G, Delta, BA.1 and BA.1.1 strains.
Among the mAbs, COV2-2196/COV2-2130, S309 and REGN10987/REGN10933 inhibited lung replication of SARS-CoV-2 in BA.2-infected hamsters. Of the antiviral drugs, all significantly decreased lung BA.2 titers. Additionally, S-217622 reduced BA.2 titers in the nasal turbinates.
Overall, the study results showed that the pathogenicity and infectivity of BA.2 was comparable to BA.1 but lower than that of other SARS-CoV-2 variants.
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