Japanese Study Indicates that Covid-19 BA.2.75 Is More Pathogenic

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A new study by researchers from Japan have found that the BA.2.75 variant that is expected to follow after the BA.5 surges along with possibly another new emerging variant ie BA.4.6, is not only more transmissible than the BA.5 variant but also more pathogenic than the original BA.2 variant.

The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.08.07.503115v1

By the end of 2021, five SARS-CoV-2 variants-of-concern (VOCs) were classified by the WHO (WHO, 2022). These are the Alpha [also known as lineage B.1.1.7 based on the PANGO classification (https://cov-lineages.org); clade 20I based on the Nextstrain classification (https://nextstrain.org)], Beta (lineage B.1.351; clade 20H), Gamma (lineage P.1; clade 20J), Delta (lineages
B.1.617.2 and AY; clades 21I and 21J), and Omicron (lineages B.1.1.529 and BA; clade 21K) variants.

Since these five VOCs are phylogenetically unrelated to each other, SARS-CoV-2 evolution until the end of 2021 was posed by the antigenic shift. At the beginning of 2022, Omicron BA.1 variant (clade 21K) outcompeted the other variants and spread globally. Thereafter, BA.2 (clade 21L) and BA.4/5 (clades 22A and 22B) continuously emerged from South Africa, while BA.2.12.1 (clade 22C) emerged in the USA.

As of the beginning of August 2022, Omicron BA.5 (clade 22B) is the most predominant SARS-CoV-2 variant in the world. In contrast to the five VOCs detected in 2021, the Omicron subvariants are phylogenetically related. Therefore, the evolution of SARS-CoV-2 Omicron subvariants since the end of 2021 is posed by the antigenic drift.

Newly emerging SARS-CoV-2 variants need to be carefully and rapidly assessed for a potential increase in their growth efficiency in the human population [i.e., relative effective reproduction number (Re)], their evasion from antiviral immunity, and their pathogenicity. Resistance to antiviral humoral immunity can be mainly determined by substitutions in the spike (S) protein.

For instance, Omicron BA.1 (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) , BA.2 (Bruel et al., 2022; Takashita et al., 2022b; Yamasoba et al., 2022c), and BA.5 (Arora et al., 2022; Cao et al., 2022; Gruell et al., 2022; Hachmann et al., 2022; Khan et al., 2022; Kimura et al., 2022c; Lyke et al., 2022; Qu et al., 2022; Tuekprakhon et al., 2022; Wang et al., 2022; Yamasoba et al., 2022c) exhibit profound resistance to neutralizing antibodies induced by vaccination, natural SARS-CoV-2 infection, and therapeutic monoclonal antibodies.

Particularly, newly spreading SARS-CoV-2 variants tend to be resistant to the humoral immunity induced by the infection with prior variant; for instance, BA.2 is resistant to BA.1 breakthrough infection sera (Qu et al., 2022; Tuekprakhon et al., 2022; Yamasoba et al., 2022b), and BA.5 is resistant to BA.2 breakthrough infection sera (Hachmann et al., 2022; Kimura et al., 2022c; Wang et al., 2022).

Therefore, acquiring immune resistance to previously dominant variant is a key factor in outcompeting previous variants, thereby obtaining relatively increased Re compared to the previously dominant variant. Viral pathogenicity is also closely associated with the phenotype of viral S protein. Particularly, we have proposed

that the fusogenicity of viral S protein in in vitro cell cultures is associated with viral pathogenicity in vivo (Kimura et al., 2022c; Saito et al., 2022; Suzuki et al., 2022; Yamasoba et al., 2022b).

As mentioned above, major SARS-CoV-2 phenotypes can be defined by the function of the viral S protein. SARS-CoV-2 S protein bears two major domains, receptor binding domain (RBD) and N-terminal domain (NTD) [reviewed in (Harvey et al., 2021; Mittal et al., 2022)].

RBD is crucial for the binding to human angiotensin-converting enzyme 2 (ACE2) receptor for the cell attachment and entry, and therefore, this domain has been considered a major target for neutralizing antibodies to block viral infection [reviewed in (Barnes et al., 2020; Harvey et al., 2021; Jackson et al., 2022)].

On the other hand, NTD is an immunodominant domain that can be recognized by antibodies, and some antibodies targeting NTD potentially neutralize viral infection (Cerutti et al., 2021; Chi et al., 2020; Liu et al., 2020; Lok, 2021; McCallum et al., 2021; Suryadevara et al., 2021; Voss et al., 2021), despite our limited understanding of its virological function.

The Omicron BA.2.75 variant, a new BA.2 subvariant, was first detected in India in May 2022 (WHO, 2022). Because an early preliminary investigation suggested the potential increase in the relative Re value of BA.2.75 compared to BA.5 and the original BA.2 (GitHub, 2022), BA.2.75 has been flagged as the most concerning variant that can potentially outcompete BA.5 and be the next predominant variant in the future.

In fact, on July 19, 2022, the WHO classified this variant as a VOC lineage under monitoring (VOC-LUM) together with the other BA.2 subvariants, including BA.5, which bear the substitution at the L452 residue in their S proteins (WHO, 2022). On July 23, 2022, Nextstrain (https://nextstrain.org) classified BA.2.75 as a new clade, 22D.

Compared to the BA.2 S, BA.4/5 bears four mutations in its S protein (Kimura et al., 2022c; Yamasoba et al., 2022b). On the other hand, the majority of BA.2.75 S bears nine mutations: K147E, W152R, F157L, I210V, and G257S substitutions are located in the NTD, while D339H, G446S, N460K, and R493Q substitutions are located in the RBD.

The mutation number in the BA.2.75 S is larger than that in the BA.4/5 S, and notably, some of the substitutions detected in the BA.2.75 S show the signs of convergent evolution (Zahradnik et al., 2022). These notions raise the possibility that the phenotype of BA.2.75 S is critically different from previous BA.2 subvariants.

In fact, we have recently revealed that the S protein of BA.2.75 exhibits different sensitivity towards several therapeutic monoclonal antibodies from those of BA.2 and BA.5 (Yamasoba et al., 2022a). However, the virological phenotype of BA.2.75, including its Re, potential evasion from antiviral humoral immunity, sensitivity to currently recommended antiviral small compounds, virological properties of its S protein, and intrinsic pathogenicity remains unclear. Here, we elucidate the features of newly emerging SARS-CoV-2 Omicron BA.2.75 subvariant.

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