Characterization and antiviral susceptibility of SARS-CoV-2 Omicron BA.2

Abstract

The recent emergence of SARS-CoV-2 Omicron (B.1.1.529 lineage) variants possessing numerous mutations has raised concerns of decreased effectiveness of current vaccines, therapeutic monoclonal antibodies and antiviral drugs for COVID-19 against these variants 1,2 . The original Omicron lineage, BA.1, prevailed in many countries, but more recently, BA.2 has become dominant in at least 68 countries 3 . Here we evaluated the replicative ability and pathogenicity of authentic infectious BA.2 isolates in immunocompetent and human ACE2-expressing mice and hamsters. In contrast to recent data with chimeric, recombinant SARS-CoV-2 strains expressing the spike proteins of BA.1 and BA.2 on an ancestral WK-521 backbone 4 , we observed similar infectivity and pathogenicity in mice and hamsters for BA.2 and BA.1, and less pathogenicity compared with early SARS-CoV-2 strains. We also observed a marked and significant reduction in the neutralizing activity of plasma from individuals who had recovered from COVID-19 and vaccine recipients against BA.2 compared to ancestral and Delta variant strains. In addition, we found that some therapeutic monoclonal antibodies (REGN10987 plus REGN10933, COV2-2196 plus COV2-2130, and S309) and antiviral drugs (molnupiravir, nirmatrelvir and S-217622) can restrict viral infection in the respiratory organs of BA.2-infected hamsters. These findings suggest that the replication and pathogenicity of BA.2 is similar to that of BA.1 in rodents and that several therapeutic monoclonal antibodies and antiviral compounds are effective against Omicron BA.2 variants.The Omicron variant of SARS-CoV-2, the virus responsible for COVID-19, was first detected in late November 2021 and has spread rapidly around the world. Omicron variants have been classified into four different sublineages: BA.1, BA.1.1, BA.2 and BA.3. The original Omicron lineage, BA.1, rapidly became the prevailing variant circulating in many countries; however, BA.2 variants have become dominant in at least 68 countries 3 . Moreover, the prevalence of BA.2 is increasing rapidly in several other countries including South Africa, Sweden, Austria, Singapore, Georgia and Sri Lanka (https://covariants.org/per-variant). Preliminary data indicate that the BA.2 variant may be more transmissible than the BA.1 variant 5,6 .Recently, we and others have shown that BA.1 variants are less pathogenic in animal models than previously circulating variants of concern 7-9 (VOC), consistent with preliminary clinical data in humans 10 . Moreover, other studies have reported that BA.1 variants show reduced sensitivity to vaccine-or infection-induced antibodies, as well as some therapeutic monoclonal antibodies [11][12][13][14][15] . The spike (S) protein of SARS-CoV-2 mediates viral receptor binding and membrane fusion, both of which are essential for viral infection of host cells. The S protein is also the principal antigen targeted by the host neutralizing antibody response 16 . Notably, mutations in the S protein, such as E484K, N501Y, D614G and P681H/R, have ...

Real-world effectiveness of molnupiravir and nirmatrelvir/ritonavir against mortality, hospitalization, and in-hospital outcomes among community-dwelling, ambulatory COVID-19 patients during the BA.2.2 wave in Hong Kong: an observational study

“…21 Relying on evidence derived from experimental studies, viral replication of Omicron variant is inhibited in treated cell lines, and infection restricted in hamsters treated with oral antivirals. [7][8][9][10]22,23 It is postulated that Omicron is similarly sensitive to both drugs as previous variants, given most mutations of the Omicron variant are located around the spike protein, and those involving the target enzymes (RdRp and M pro , respectively) are distant from their active sites. [7][8][9]22,23 As illustrated in the current study conducted amid a pandemic wave of Omicron BA.2 variant, early initiation of nirmatrelvir/ritonavir (within five days of symptom onset) in community-dwelling COVID-19 patients was associated with significant reduction in the risks of all-cause mortality by 75% and hospitalization by 31% compared to non-use, whereas a more modest effect was observed with molnupiravir in lowering the mortality risk by 39%.…”

“…In particular, the original trials were carried out mostly during the Delta wave whereas effectiveness against Omicron and its subvariants can only be inferred from laboratory studies so far. 7-10 Here we assessed the clinical effectiveness of molnupiravir and nirmatrelvir/ritonavir among community-dwelling COVID-19 outpatients in Hong Kong during the Omicron BA.2.2 wave in January to May 2022.…”

Comparative effectiveness of sotrovimab and molnupiravir for prevention of severe COVID-19 outcomes in non-hospitalised patients: an observational cohort study using the OpenSAFELY platform

“…Whether the beneficial effect of sotrovimab persists for other variant subtypes warrants further investigation [14][15][16][17]. For instance, the Omicron BA.2 sublineage was shown to exhibit marked resistance to sotrovimab in in vitro experiments [18,19], whereas an in vivo experiment found both molnupiravir and sotrovimab can restrict viral replication in the lungs of BA.2infected hamsters [20]. In addition, the patients included in this study are assumed to be only those who met the eligibility criteria made by NHS England [3], thus limiting further generalisation of our findings to people not in a known high-risk group.…”

Intranasal vaccination induced cross-protective secretory IgA antibodies against SARS-CoV-2 variants with reducing the potential risk of lung eosinophilic immunopathology

“…Thus, a nasal vaccine that could induce highly cross-protective secretory IgA antibodies in the nasal mucosa, which is the gateway to respiratory infection, would be a more effective, reasonable vaccine candidate. It has been shown that the Omicron variant, which is currently prevalent around the world, could replicate more effectively in the bronchi than in the lungs, compared with other variants and the ancestor [45–48]. Therefore, there is high chance that a nasal vaccine which could induce cross-protective IgA antibodies in the upper respiratory tract would be effective against the Omicron variant as well.…”