In a recent study posted to bioRxiv* preprint server, researchers characterized the clinical isolates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2.75 sub-variant.
SARS-CoV-2 Omicron emerged in November 2021 and has since evolved into several sub-lineages. Currently, the BA.5 lineage is the predominant variant in circulation. SARS-CoV-2 Omicron BA.2.75 (a sub-variant of the BA.2 lineage) appears more transmissible than BA.5 in India and Nepal. Moreover, the World Health Organization (WHO) has lately classified BA.2.75 as a variant of concern lineages under monitoring (VOC-LUM).
SARS-CoV-2 Omicron BA.1 has more than 30 modifications in the spike protein relative to the Wuhan Hu-1 strain. BA.2 differs from BA.1 at 27 positions in the spike protein, and BA.2.75 differs from BA.2 by nine amino acids. Evidence suggests that BA.2.75 spike has a higher affinity for human angiotensin-converting enzyme 2 (hACE2) than BA.2 spike. This raises concerns about the possibility of enhanced pathogenicity of BA.2.75.
The study and findings
In the present study, researchers evaluated the pathogenicity and replicative capacity of clinical isolates of SARS-CoV-2 Omicron BA.2.75 in animal models. Three clinical isolates of BA.2.75 (TY41-716, NCD1757, and NCD1759) were isolated in VeroE6 cells expressing transmembrane protease, serine 2 (TMPRSS2). The nine (additional) amino acid substitutions of BA.2.75 (relative to BA.2) were confirmed for the three clinical isolates.
First, the pathogenicity of the clinical isolates was studied in wild-type Syrian hamsters. Hamsters were infected with 105 plaque-forming units (PFU) of clinical isolates of BA.2.75, BA.2, BA.5, or B.1.617.2 (Delta) variant. Delta variant infection caused significant weight loss six days post-infection (dpi). Contrastingly, most hamsters infected with BA.2.75 isolates gained weight similar to BA.2-, BA.5, or mock-infected hamsters.
Pulmonary functions were assessed by measuring Penh and Rpef using a whole-body plethysmography system. Infecting hamsters with four Omicron isolates caused no substantial changes in Rpef or Penh relative to mock-infected animals. However, infection with TY41-716 isolate of BA.2.75 slightly increased Penh at 3 and 5 dpi. Delta infection resulted in significant changes in Rpef relative to the Omicron isolates.
Further, animals were infected with 105 PFU of Omicron (BA.2, BA.2.75, and BA.5) and Delta (B.1.617.2) isolates to evaluate infection levels in the respiratory tract. Hamsters were euthanized, and their lungs and nasal turbinates were collected. Plaque assays were performed to quantitate viral titers. Viral titers were significantly lower in the nasal turbinates in hamsters infected with BA.2, BA.2.75 (NCD1757, TY41-716), or BA.5 isolates than in Delta-infected animals.
Moreover, viral titers in BA.2.75-infected animals were higher than BA.2 or BA.5-infected animals, indicative of a higher replicative ability of BA.2.75 in the lungs of hamsters than previous Omicron variants. Histopathological examination of the lungs of infected hamsters was conducted. At 3 dpi, inflammation was not evident in the lungs of BA.5- or BA.2.75 (TY41-716)-infected hamsters; however, infiltration of neutrophils and mononuclear cells was noted in the peribronchial and peribronchiolar regions at 6 dpi.
Focal pneumonia was observed in the lungs of hamsters infected with BA.2.75 (TY41-716 and NCD1757 isolates) at 6 dpi. Lung inflammation was prominent for Delta-infected animals at 3 dpi with extensive pneumonia and focal alveolar hemorrhage at 6 dpi. Moreover, viral RNA and protein were detected in the lungs of BA.2.75-, BA.5-, or Delta-infected hamsters.
Furthermore, the authors evaluated the replicative fitness of BA.2.75. Wildtype hamsters were infected with 2 x 105 PFU of a mix comprising BA.2.75 and BA.5 in the following ratios: 1:1, 1:3, 1:19, or 1:199. The proportion of each Omicron sub-variant in the lungs and nasal turbinates was determined using next-generation sequencing (NGS) analysis. The authors found a higher proportion of BA.2.75 variant than BA.5 in the nasal turbinates of all infected hamsters regardless of the inoculum ratio. This was consistent for lung specimens from all except three hamsters.
In summary, the authors found no significant differences in the body weight of hamsters after infection with SARS-CoV-2 Omicron BA.2, BA.5, or BA.2.75. However, viral titers in the lungs of hamsters infected with BA.2.75 isolates were higher than those in BA.2- or BA.5-infected animals.
Notably, in BA.2.75-infected hamsters, the focal pneumonia was characterized by patchy inflammation interspersed in alveoli, suggesting that BA.2.75 could cause much more severe tissue damage than other Omicron variants. The findings showed that BA.2.75 replicates more efficiently in the lungs than BA.2 or BA.5.
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