Omicron BA.2 Variant Is A Major Health Threat As It Is More Fusogenic – Pathogenic And Causes Severe Outcomes

A new detailed study on the characteristics of the Omicron BA.2 variant by Japanese researchers from the University of Tokyo, Kobe University, Kumamoto University, Hokkaido University and Kyoto University has alarmingly found that the new variant is completely different from the initial Omicron BA.1 variant and is far more fusogenic and pathogenic and poses a serious health threat as it now spreading globally at an exponential rate due to its increased transmissibility.

The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.02.14.480335v1

Virological characteristics of newly emerging SARS-CoV-2 variants, such as transmissibility, pathogenicity and resistance to the vaccine-induced immunity and antiviral drugs, is an urgent global health concern.

In February 2022, the Omicron variant (B.1.1.529 and BA lineages) spreads worldwide and represents the most recently recognised variant of concern². Omicron was first reported from South Africa at the end of November 2021¹. Then, a variant of Omicron, the BA.1 lineage, has rapidly spread worldwide and outcompeted other variants such as Delta.

As of February 2022, another variant of Omicron, the BA.2 lineage, has detected in multiple countries such as Denmark and UK³. Notably, BA.2 has initiated outcompeting BA.1³, suggesting that BA.2 is more transmissible than BA.1.

In a few months since the emergence of BA.1, we and others revealed the virological characteristics of BA.1^4-19. For instance, BA.1 is highly resistant to the vaccine-induced humoral immunity and antiviral drugs^4-11,16-19.

Also, the spike (S) protein of BA.1 is less efficiently cleaved by furin and less fusogenic than those of Delta and an ancestral SARS-CoV-2 belonging to the B.1.1 lineage^11,12. Further, the pathogenicity of BA.1 is attenuated when compared to Delta and an ancestral B.1.1 virus^12-14. However, the virological characteristics of BA.2 remains unaddressed.

Phylogenetic and epidemic dynamics of BA.2

As of February 2022, Omicron is classified into three main lineages, BA.1, BA.2, BA.3, and a sublineage of BA.1, BA1.1, which harbours the R346K substitution in S (Fig. 1a). Although these lineages are monophyletic, their sequences have been greatly diversified.

For example, BA.1 differs from BA.2 by 50 amino acids, which is approximately twice as much as the numbers of amino acid differences between four VOCs (Alpha, Beta, Gamma and Delta) and Wuhan-Hu-1, a prototypic SARS-CoV-2 isolate (Fig. 1b).

Phylodynamics analysis suggests that BA.1 emerged first, followed by BA.2 and BA.3 (Extended Data Fig. 1). In addition to BA.1, the earlier strains of BA.2, BA.3, and BA.1.1 were isolated from Gauteng Province, South Africa, the place of the earliest Omicron (BA.1) epidemic (Extended Data Fig. 1)²⁰. These results suggest that the remarkable diversification of Omicron occurred in Gauteng Province and all Omicron lineages emerged there.

Although BA.1 spread worldwide earlier than BA.2, the lineage frequency of BA.2 increased and exceeded that of BA.1 since January 2022 in multiple countries, such as Philippines, India, Denmark, Singapore, Austria, and South Africa (Fig. 1c and Extended Data Fig. 2). To quantify the growth advantage of BA.2 in the human population, we constructed a Bayesian model representing the epidemic dynamics of SARS-CoV-2 lineages.

This hierarchical model can estimate the global average of the relative effective reproduction numbers of viral lineages (Fig. 1d) as well as those in each country (Extended Data Fig. 2). The effective reproduction number of BA.2 is 1.40-fold higher than that of BA.1 on average in the world [95% confidence interval (CI), 1.29–1.52; Fig. 1d].

Furthermore, the effective reproduction number of BA.2 was even higher than that of BA.1.1, which spread more rapidly than BA.1 in several countries such as the UK and USA (Fig. 1d and Extended Data Fig. 2d). These results suggest that the BA.2 epidemic will more expand around the world, raising the importance of elucidating virological features of BA.2 in depth.

Immune resistance of BA.2

Since the sequence of BA.2, particularly in S protein, is substantially different from that of BA.1 (Fig. 1b and Fig. 2a), it is reasonable to assume that the virological properties of BA.2, such as immune resistance and pathogenicity, are different from those of BA.1.

To reveal the virological features of BA.2, we set out to perform neutralisation assay using pseudoviruses and the neutralising antibodies elicited by vaccination. Consistent with recent studies^4-11,16-19, BA.1 is highly resistant to the antisera elicited by mRNA-1273 and ChAdOx1 vaccines (Fig. 2b,c).

Similar to BA.1, BA.2 was also highly resistant to the vaccine-induced antisera (Fig. 2b,c). Also, BA.2 was almost completely resistant to two therapeutic monoclonal antibodies, Casirivimab and Imdevimab, and was 35-fold more resistant to another therapeutic antibody, Sotrovimab, when compared to the ancestral D614G-bearing B.1.1 virus (Fig. 2d).

Moreover, both BA.1 and BA.2 were highly resistant to the convalescent sera who had infected with early pandemic virus (before May 2020; Fig. 2e), Alpha (Extended data Fig. 3a) and Delta (Extended data Fig. 3b). These data suggest that, similar to BA.1, BA.2 is highly resistant to the antisera induced by vaccination and infection with other SARS-CoV-2 variants as well as three antiviral therapeutic antibodies.

We then tested the 17 sera infected with BA.1: 13 convalescents were fully vaccinated (2 shots), 1 convalescent was 1-dose vaccinated, and 3 convalescents were not vaccinated. BA.1 convalescent sera exhibited the strongest antiviral effect against BA.1 (Fig. 2f).

Although BA.2 was 1.4-fold more resistant to the BA.1-infected sera than BA.1, there was no statistical difference (Fig. 2f; P=0.091 by Wilcoxon signed-rank test). Importantly, the BA.1 convalescent sera with full vaccination exhibited significantly stronger antiviral effects against all variants tested than unvaccinated or 1-dose vaccinated convalescents (Extended Data Fig. 3c).

To address the possibility that the BA.1-induced humoral immunity is less effective against BA.2, we used the convalescent sera obtained from infected hamsters at 16 days postinfection (d.p.i.). Similar to the results of convalescent human sera (Fig. 2e and Extended Data Fig. 2b), both BA.1 and BA.2 exhibited pronounced resistances against B.1.1- and Delta-infected convalescent hamster sera (Fig. 2g and Extended Data Fig. 3d).

Interestingly, BA.2 was significantly (2.9-fold) more resistant to BA.1-infected convalescent hamster sera than BA.1 (Fig. 2g). To further verify the resistance of BA.2 against BA.1-induced immunity, mice were immunised with the cells expressing the S proteins of ancestral B.1.1 and BA.1 and obtained murine antisera.

Again, the neutralisation assay using murine sera showed that BA.2 is more significantly (6.4-fold) resistant to the BA.1 S-immunised sera than BA.1 (Fig. 2h). These findings suggest that BA.1-induced humoral immunity is less effective against BA.2.