Comparative pathogenicity of SARS-CoV-2 Omicron subvariants including BA.1, BA.2, and BA.5

Abstract

Unremitting emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants imposes us to continuous control measurement. Given the rapid spread, new Omicron subvariant named BA.5 is urgently required for characterization. Here we analyzed BA.5 with the other Omicron variants BA.1, BA.2, and ancestral B.1.1 comprehensively. Although in vitro growth kinetics of BA.5 is comparable among the Omicron subvariants, BA.5 become much more fusogenic than BA.1 and BA.2. The airway-on-a-chip analysis showed that the ability of BA.5 to disrupt the respiratory epithelial and endothelial barriers is enhanced among Omicron subvariants. Furthermore, in our hamster model, in vivo replication of BA.5 is comparable with that of the other Omicrons and less than that of the ancestral B.1.1. Importantly, inflammatory response against BA.5 is strong compared with BA.1 and BA.2. Our data suggest that BA.5 is still low pathogenic compared to ancestral strain but evolved to induce enhanced inflammation when compared to prior Omicron subvariants.

Virological characteristics of the SARS-CoV-2 Omicron BA.2.75

“…To evaluate the sensitivity of BA.2.75 to three antiviral drugs, Remdesivir, EIDD-1931 (an active metabolite of Molnupiravir) and Nirmatrelvir (also known as PF-07321332), we used a clinical isolate of BA.2.75 (strain TY41-716; GISAID ID: EPI_ISL_13969765). As controls, we also used clinical isolates of B.1.1 (strain TKYE610670; GISAID ID: EPI_ISL_479681) (Suzuki et al ., 2022), BA.2 (strain TY40-385; GISAID ID: EPI_ISL_9595859) (Kimura et al ., 2022c), BA.5 (strain TKYS14631; GISAID ID: EPI_ISL_12812500) (Tamura et al, 2022). These viruses were inoculated into human airway organoids (AO), a physiologically relevant model (Sano et al, 2022), and treated with three antiviral drugs.…”

“…Here we revealed that both BA.5 and BA.2.75 are more fusogenic than BA.2 in the in vitro cell culture systems ( Figures 3 and 4 ). Given that the recombinant SARS-CoV-2 bearing the BA.5 S (Kimura et al ., 2022c) as well as a clinical isolate of BA.5 (Tamura et al ., 2022) exhibited relatively higher pathogenicity than BA.2 in hamsters, it is hypothesized that BA.2.75 is also intrinsically more pathogenic than BA.2. To address this possibility, we intranasally inoculated a BA.2.75 isolate into hamsters.…”

“…When we compare the histopathological scores of Omicron subvariants, the scores indicating hemorrhage or congestion and total histology scores of BA.5 and BA.2.75 were significantly greater than those of BA.2 ( Figures 5F and 5G ). Similar to our recent studies (Kimura et al ., 2022c; Tamura et al ., 2022), BA.5 is intrinsically more pathogenic than BA.2, and notably, our results suggest that BA.2.75 exhibits more significant inflammation than BA.2. To clarify the area of pneumonia, the inflammatory area, which is mainly composed of the type II pneumocytes with some inflammatory cell types, such as neutrophils, lymphocytes, and macrophages, is termed the area of type II pneumocytes and was morphometrically analyzed ( Figure S4D ).…”

“…The air-liquid interface culture of airway and alveolar epithelial cells ( Figures 4E and 4F ) were differentiated from human iPSC-derived lung progenitor cells as previously described (Gotoh et al, 2014; Kimura et al ., 2022c; Konishi et al, 2016; Tamura et al ., 2022; Yamamoto et al, 2017). Briefly, lung progenitor cells were stepwise induced from human iPSCs referring a 21-days and 4-steps protocol (Yamamoto et al ., 2017).…”

“…After 1 hour, the AO differentiation medium was added to the top channel. In the infection experiments (Figures 4G-4I), the AO differentiation medium containing either B.1.1, Delta, BA.2, BA.5 or BA.2.75 isolate (500 TCID 50 ) was inoculated from the Animal experiments Animal experiments (Figure 5) were performed as previously described (Kimura et al, 2022b;Kimura et al, 2022c;Saito et al, 2022;Suzuki et al, 2022;Tamura et al, 2022;Yamasoba et al, 2022b). Syrian hamsters (male, 4 weeks old) were purchased from Japan SLC Inc. (Shizuoka, Japan).…”