SARS-CoV-2 BA.5 Variant Has Evolved To Be Worse Than Alpha or Delta


Emerging data is showing that the SARS-CoV-2 BA.5 variant and its emerging sub-variants are able to utilize the TMPRSS2 more effectively than the even the previous Alpha or Delta variants and implies that we can expect more disease severity and increased mortality in those infected with this new variant and its sub-variants.

The B.5 and its emerging sub-variants are nothing like the earlier Omicron BA.1 and BA.2 variants that were not able to utilize the TMPRSS2 effectively due to lack of certain critical mutations including the L452R mutation.

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It should also be noted that the BA.5 variant replicates very effciently and rapidly in the human host lungs compared to previous variants.

Viral transmissibility, immune resistance and pathogenicity characterize the potential risk of new SARS-CoV-2 variant to global health. In this study, we investigated the virological characteristics of five “novel Omicron variants”, BA.2.9.1, BA.2.11, BA.2.12.1, BA.4 and BA.5. In these five variants, BA.4/5 renders highest potential risk in terms of the growth efficacy in the human population, resistance to antiviral humoral immunity, and pathogenicity in an experimental animal model.

As a common characteristic of the five BA.2-related Omicron variants focused in this study, the S proteins of these variants bear a mutation at the residue 452: BA.2.11 and BA.4/5, BA.2.9.1, and BA.2.12.1 respectively possess R, M and Q instead of parental L residue.

The L452R and L452Q substitutions were present in previous a VOC and a VOI such as the Delta and Lambda variants (WHO, 2022), and in our previous studies (Kimura et al., 2022a; Motozono et al., 2021),we demonstrated that the L452R/Q mutation increases the binding affinity of S RBD to human ACE2, and thereby, increases pseudovirus infectivity.

Here we demonstrated that the L452R mutation increases binding affinity to human ACE2 and pseudovirus infectivity even in the BA.2 S backbone. Therefore, together with our previous reports (Kimura et al., 2022a; Motozono et al., 2021), Additionally, the S proteins of BA.4 and BA.5 harbor the HV69-70del mutation, which was detected in the Alpha variant, a prior VOC.

Consistent with a previous study (Meng et al., 2021), we demonstrated that the insertion of HV69-70del mutation increases pseudovirus infectivity. Altogether, multiple mutations in the S protein of BA.4/5 contribute to enhanced growth capacity in human lung cell culture and the lung of an experimental animal model.

In our previous studies that focused on Delta (Saito et al., 2022), Omicron BA.1 (Suzuki et al., 2022) and Omicron BA.2 (Yamasoba et al., 2022a), we suggested close association between viral fusogenicity in in vitro cell cultures and pathogenicity in vivo. For instance, a less fusogenic virus such as Omicron BA.1 was less pathogenic, while a more fusogenic virus such as Delta was more pathogenic (Saito et al., 2022; Suzuki et al., 2022).

Here we demonstrated that the Omicron BA.4/5 variant is more fusogenic and pathogenic than the Omicron BA.2 variant. Consistent with previous findings (Saito et al., 2022; Suzuki et al., 2022; Yamasoba et al., 2022a), our data support the possibility that higher fusogenic virus tends to exhibit potentially higher pathogenicity at least in experimental animal models. Therefore, measuring the fusogenicity of viral S protein can be a rapid surrogate marker to assume potential viral pathogenicity.

A simplistic assumption without conclusive evidence implies that SARS-CoV-2 will evolve to attenuate its pathogenicity. However, we argue against this notion with at least three observations. First, the Delta variant exhibited relatively higher pathogenicity than the ancestral B.1 virus in an experimental animal model (Saito et al., 2022).

Clinical studies also provide evidence suggesting the higher virulence of the Delta variant than other prior variants including the Alpha variant (Ong et al., 2021; Sheikh et al., 2021; Twohig et al., 2022). Second, although the Omicron BA.1 variant was less pathogenic than Delta and ancestral B.1.1 virus (Suzuki et al., 2022), the S protein of a subsequently spread variant, Omicron BA.2, acquired the potential to exhibit higher pathogenicity than that of Omicron BA.1 (Yamasoba et al., 2022a). Third, here we demonstrated that the Omicron BA.4/5 are more potentially pathogenic than Omicron BA.2. Therefore, our observations strongly suggest that SARS-CoV-2 does not necessarily evolve to attenuate its pathogenicity.


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