Virological characteristics of the novel SARS-CoV-2 Omicron variants including BA.2.12.1, BA.4 and BA.5【bioRxiv 2022年5月26日】


After the global spread of SARS-CoV-2 Omicron BA.2 lineage, some BA.2-related variants that acquire mutations in the L452 residue of spike protein, such as BA.2.9.1 and BA.2.13 (L452M), BA.2.12.1 (L452Q), and BA.2.11, BA.4 and BA.5 (L452R), emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these L452R/M/Q-bearing BA.2-related Omicron variants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1 and BA.2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. Furthermore, infection experiments using hamsters indicated that BA.4/5 is more pathogenic than BA.2. Altogether, our multiscale investigations suggest that the risk of L452R/M/Q-bearing BA.2-related Omicron variants, particularly BA.4 and BA.5, to global health is potentially greater than that of original BA.2.


Since the end of November 2021, the SARS-CoV-2 Omicron variant (B.1.1.529 and BA lineages) has spread worldwide and has outcompeted prior SARS-CoV-2 variants of concern (VOCs) such as Delta. After the surge of Omicron BA.1 variant, another Omicron variant, BA.2, outcompeted BA.1 and has become the most dominant variant in the world (Ito et al., 2022; UKHSA, 2022; Yamasoba et al., 2022a). Thereafter, as of May 2022, the Omicron subvariants that harbor the substitution at the L452 residue of spike (S) protein, such as BA.4 and BA.5, were frequently detected (Tegally et al., 2022; WHO, 2022). These observations suggest that these novel Omicron subvariants bearing mutations at the S L452 residue are more transmissible than Omicron BA.2. These recent developments have led the WHO to these Omicron subvariants bearing mutations at the S L452 residue, BA.4, BA.5, BA.2.12.1, BA.2.9.1 and BA.2.11, as VOC lineages under monitoring (VOC-LUM) on May 18, 2022 (WHO, 2022).

Resistance to antiviral humoral immunity can be mainly determined by the mutations in the S protein. For instance, Omicron BA.1 exhibits profound resistance to neutralizing antibodies induced by vaccination and natural SARS-CoV-2 infection as well as therapeutic monoclonal antibodies (Cao et al., 2021; Cele et al., 2021; Dejnirattisai et al., 2022; Garcia-Beltran et al., 2021; Liu et al., 2021; Meng et al., 2022; Planas et al., 2021; Takashita et al., 2022a; VanBlargan et al., 2022) and BA.2 (Bruel et al., 2022; Takashita et al., 2022b; Yamasoba et al., 2022a; Yamasoba et al., 2022b). In addition to immune evasion, the mutations in the S protein potentially modulate viral pathogenicity. Particularly, the fusogenicity of S protein in in vitro cell cultures is closely associated with viral pathogenicity in an experimental hamster model. For example, the Delta S is highly fusogenic in cell cultures and highly pathogenic in hamsters when compared to ancestral D614G-bearing B.1.1 S (Saito et al., 2022). In contrast, the Omicron BA.1 S is less fusogenic and pathogenic than B.1.1 S (Meng et al., 2022; Suzuki et al., 2022). Furthermore, we have recently demonstrated that the Omicron BA.2 S is more fusogenic and potentially confers the virus higher pathogenicity than Omicron BA.1 S (Yamasoba et al., 2022a).

Newly emerging SARS-CoV-2 variants need to be carefully and rapidly assessed for a potential increase in growth efficacy in the human population, pathogenicity and/or evasion from antiviral immunity. The substitution at the L452 residue of SARS-CoV-2 S protein was detected in Delta (L452R) and Lambda (L452Q) variants, which were previously classified as a VOC and a variant of interest (VOI), respectively (WHO, 2022). Importantly, we previously demonstrated that the L452R (Motozono et al., 2021) and L452Q (Kimura et al., 2022a) mutations increase viral infectivity by promoting the binding of S receptor binding domain (RBD) to human ACE2. We have recently characterized the virological features of SARS-CoV-2 Omicron BA.1 (Meng et al., 2022; Suzuki et al., 2022) and BA.2 (Yamasoba et al., 2022a). However, the impact of the substitution of S L452 residue on the virological characteristics of Omicron BA.2 remains unclear. Together with these findings, it is reasonable to assume that the novel BA.2-related Omicron variants bearing mutations at S L452 residue can be a potential risk for global health, and we herein elucidate the virological characteristics of these novel Omicron variants.