SARS-CoV-2 BA.2 poses greater global health risks than BA.1.

In a recent study published in the journal cellResearchers have investigated the distinction between the virological features of the Omicron subvariant BA.2.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Omicron’s latest concerns (VOCs) have three main strains: BA.1, BA.2, and BA.3. Although it is a monophyletic group, their genomic sequences are highly diversified. Several studies investigating various aspects of BA.2 suggest that this Omicron subvariant poses a higher risk to global public health than its predecessor, BA.1. The continued worldwide transmission of BA.2 in several countries, including India, the Philippines, Denmark, Singapore, Austria and South Africa, calls for an urgent need to study its virological properties in detail. It is embossed.

Interestingly, the SARS-CoV-2 spike (S) protein determines the virological characteristics of all its variants. It is cleaved into S1 and S2 subunits in the host cell, which binds to human angiotensin converting enzyme 2 (ACE2) and establishes SARS-CoV-2 infection.

BA.2 S has more than 30 new mutations compared to the original SARS-CoV-2 strain, resulting in significantly different virological characteristics. BA.2 also differs in amino acids from BA.1 and the other four SARS-CoV-2 VOCs, alpha, beta, gamma, delta, and the ancestral strain Wuhan-Hu-1, and is prominent among the Omicron subs. It suggests sequence diversity. -system.

study: Virological characteristics of SARS-CoV-2 Omicron BA.2 spikes.. Image Credit: Elsevier Inc.

About research

Researchers have constructed a Bayesian hierarchical model to represent the epidemic dynamics of the SARS-CoV-2 strain and to estimate the global mean number of effective reproductions for all SARS-CoV-2 strains. They conducted a neutralization experiment using a fake virus and Neutralizing antibody It is triggered by vaccination.

In addition, the researchers tested serum samples from individuals infected with BA.1. Evaluate their neutralizing activity. They tested 21 serum samples, 13 of which were collected from the fully vaccinated convalescent phase, one from the partially vaccinated convalescent phase, and 7 from the unvaccinated convalescent phase. rice field.

For them In vitro Used by researchers, researchers Reverse genetics Expresses green fluorescent protein (GFP) and produces recombinant SARS-CoV-2 containing ancestral B.1.1, Delta, BA.1 or BA.2 S genes, rB.1.1 S-GFP, rDeltaS To do. -GFP, rBA.1 S-GFP, rBA.2-GFP, respectively.Similarly, they ran In vivo Experiments with Syrian hamsters and mice.

Investigation result

The Bayesian model predicted that the number of effective reproductions of BA.2 would be 1.4 times higher than that of BA.1 on average worldwide. [95% confidence interval (CI)]..

Neutralization experiments with pseudoviruses showed that BA.2 evaded immunity similar to BA.1 but had significantly different antigenicity. BA.2 was as resistant as BA.1 to antisera induced by the messenger ribonucleic acid (mRNA) -1273, ChAdOx1, and BNT162b2 vaccines. The third dose of BNT162b2 (booster) neutralized both BA.1 and BA.2, but only at lower levels than B.1.1 and Delta.

The effect of BA.1 infected serum with complete vaccination was comparable to BA.1 and BA.2. Conversely, compared to BA.1, the BA.2 variant is 4.1 times more resistant to convalescent BA.1 infected sera received with a single vaccine and is unvaccinated with BA.1 infection. Suggests that it was unable to induce an efficient antiviral drug. Humoral immunity to BA.2.

In vitro Experiments have shown a marked and higher fusion of BA.2 S. Unlike Delta, the higher fusion of BA.2 S was not due to the highly efficient S cleavage. Furthermore, the biological basis of this mechanism remains unclear, but transmembrane serine protease 2 (TMPRSS2) Contributed to BA.2S-mediated cell-cell fusion and cell-free infection through various mechanisms of action.

In vivo, BA.2 was 2.9-fold more resistant to BA.1 infected convalescent hamster sera, similar to human sera. Even in mice, BA.2 was 6.4-fold more resistant to BA.1S immunized serum compared to BA.1. Animal studies have shown that BA.2-induced immunity is cross-reactive with BA.1.

Kawaoka et al. Showed similar pathogenicity of BA.1 and BA.2 subvariants in animal models. However, current studies have shown that BA.2 is highly pathogenic. The discrepancy increased the likelihood that the non-S region of the BA.2 genome would weaken the pathogenicity of the virus. In addition, the emergence of BA.1-BA.2 recombinants, such as the Omicron XE mutant, because recombinants containing the BA.2 S gene in the non-BA.2 genomic backbone may be more pathogenic. Pointed out.

rBA.1 S-GFP and rBA.2-GFP showed comparable proliferation in Vero E6 and TMPRSS2 cells. However, rBA.2-GFP replicated more efficiently than rBA.1S-GFP in Calu-3 cells and primary human nasal epithelial cells. In particular, rBA.2S-GFP forms 1.52-fold larger syncytium than rBA.1S-GFP, indicating different forms of infected cells.

The plaques formed after rBA.2 S-GFP infection were 1.27 times larger than the plaques formed after rBA.1 S-GFP infection. In contrast, veroE6 / TMPRSS2 cells infected with rBA.1S-GFP and rBA.2S-GFP had smaller plaque sizes than VeroE6 / TMPRSS2 cells infected with rB.1.1S-GFP.

BA.2 S was more efficient than BA.1 S in promoting viral replication in human nasal epithelial cells and mediating syncytium formation. In animal models such as Syrian hamsters, viruses containing BA.2S were more pathogenic. The load of SARS-CoV-2 ribonucleic acid (RNA) in the lungs of infected animals was higher. Similarly, the histopathological disorders associated with BA.2 were more severe.

In addition, BA.2 was almost 100% resistant to the therapeutic monoclonal antibodies casilivimab and imdevimab. Compared to the B.1.1 virus, BA.2 was 35 times more resistant to mAb sotrovimab. Even neutralizing antibodies induced in response to previous natural infections with alpha and delta VOCs did not neutralize both BA.1 and BA.2.

Conclusion

Current studies have emphasized that the Omicron / BA.2 subvariant may be most relevant to global health VOCs. The data showed that BA.2 has a higher effective reproduction number, fusion potential, and pathogenic potential than BA.1. It remained resistant to BA.1 evoked humoral immunity. Therefore, future studies need to comprehensively investigate the pathogenicity and virological characteristics of BA.2.