Virological characteristics of SARS-CoV-2 BA.2 variant

Yamasoba, Daichi; Kimura, Izumi; Nasser, Hesham; Morioka, Yuhei; Nao, Naganori; Ito, Jumpei; Uriu, Keiya; Tsuda, Masumi; Zahradník, Jiří; Shirakawa, Kotaro; Suzuki, Rigel; Kishimoto, Mai; Kosugi, Yusuke; Kobiyama, Kouji; Hara, Teppei; Toyoda, Mako; Tanaka, Yuri; Butlertanaka, Erika P.; Shimizu, Ryo; Ito, Hayato; Wang, Lei; Oda, Yoshitaka; Orba, Yasuko; Sasaki, Michihito; Nagata, Kayoko; Yoshimatsu, Kumiko; Asakura, Hiroyuki; Nagashima, Mami; Sadamasu, Kenji; Yoshimura, Kazuhisa; Kuramochi, Jin; Seki, Masanori; Fujiki, Ryoji; Kaneda, Atsushi; Shimada, Tadanaga; Nakada, Taka‐aki; Sakao, Seiichiro; Suzuki, Takuji; Ueno, Takamasa; Takaori‐Kondo, Akifumi; Ishii, Ken J.; Schreiber, Gideon; Sawa, Hirofumi; Saito, Akatsuki; Irie, Takashi; Tanaka, Shinya; Matsuno, Keita; Fukuhara, Takasuke; Ikeda, Terumasa; Sato, Kei

doi:10.1101/2022.02.14.480335

Cited by 113 publications

(250 citation statements)

References 52 publications

(187 reference statements)

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“…A recent study using in vitro neutralization assays reported that there were differences in the reactivity of several mAbs against these different Omicron sublineages 38 . These observations suggest that BA.2 are antigenically distinct from BA.1 and BA.1.1, which is consistent with the data performed convalescent hamster sera 3 .…”

Section: Discussionsupporting

confidence: 92%

“…Our study suggests that the pathogenicity and replicative ability of the BA.2 variant is comparable to that of BA.1 variants in animal models. In contrast, a recent study showed that a recombinant, chimeric SARS-CoV-2 possessing the BA.2 S gene in the background of an ancestral SARS-CoV-2 strain is more pathogenic than a recombinant virus bearing the BA.1 S gene in the same background 3 , suggesting that the differences in the BA.1 and BA.2 S genes are responsible for the difference in pathogenicity between these chimeric viruses; based on these data, the authors concluded that BA.2 is more pathogenic than BA.1. However, in natural isolates, the genomes of BA.1 and BA2 also differ at locations other than the S gene, and these differences could have epistatic or independent effects that offset differences in pathogenic potential of the S gene 43 .…”

Section: Discussionmentioning

confidence: 83%

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

Kawaoka

Uraki

Kiso

et al. 2022

Preprint

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The recent emergence of SARS-CoV-2 Omicron variants possessing large numbers of mutations has raised concerns of decreased effectiveness of current vaccines, therapeutic monoclonal antibodies, and antiviral drugs for COVID-19 against these variants1,2. While the original Omicron lineage, BA.1, has become dominant in many countries, BA.2 has been detected in at least 67 countries and has become dominant in the Philippines, India, and Denmark. Here, we evaluated the replicative ability and pathogenicity of an authentic infectious BA.2 isolate in immunocompetent and human ACE2 (hACE2)-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 backbone3, we observed similar infectivity and pathogenicity in mice and hamsters between BA.2 and BA.1, and less pathogenicity compared to early SARS-CoV-2 strains. We also observed a marked and significant reduction in the neutralizing activity of plasma from COVID-19 convalescent individuals and vaccine recipients against BA.2 compared to ancestral and Delta variant strains. In addition, we found that some therapeutic monoclonal antibodies (REGN10987/REGN10933, COV2-2196/COV2-2130, and S309) and antiviral drugs (molnupiravir, nirmatrelvir, and S-217622) can restrict viral infection in the respiratory organs of hamsters infected with BA.2. These findings suggest that the replication and pathogenicity of BA.2 is comparable to that of BA.1 in rodents and that several therapeutic monoclonal antibodies and antiviral compounds are effective against Omicron/BA.2 variants.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 83%

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

Kawaoka

Uraki

Kiso

et al. 2022

Preprint

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“…In vaccine-boosted individuals, BA.1, BA.1.1 and BA.2 showed no significant difference in plasma neutralization resistance (Fig. 1a-b), which is concordant with several recent research 4,16 . However, this does not necessarily mean BA.2 displays similar antigenicity with BA.1 and BA.1.1.…”

Section: Mainsupporting

confidence: 92%

Omicron BA.2 specifically evades broad sarbecovirus neutralizing antibodies

Cao

Yisimayi

Jian

et al. 2022

Preprint

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Constantly emerging SARS-CoV-2 variants, such as Omicron BA.1, BA.1.1 and BA.2, pose a severe challenge to COVID-19 control. Broad-spectrum antibody therapeutics and vaccines are needed for defending against future SARS-CoV-2 variants and sarbecovirus pandemics; however, we have yet to gain a comprehensive understanding of the epitopes capable of inducing broad sarbecovirus neutralization. Here, we report the identification of 241 anti-RBD broad sarbecovirus neutralizing antibodies isolated from 44 SARS-CoV-2 vaccinated SARS convalescents. Neutralizing efficacy of these antibodies against D614G, SARS-CoV-1, Omicron variants (BA.1, BA.1.1, BA.2), RATG13 and Pangolin-GD is tested, and their binding capability to 21 sarbecovirus RBDs is measured. High-throughput yeast-display mutational screening was further applied to determine each antibody's RBD escaping mutation profile, and unsupervised epitope clustering based on escaping mutation hotspots was performed. A total of 6 clusters of broad sarbecovirus neutralizing antibodies with diverse breadth and epitopes were identified, namely Group E1 (S309, BD55-3152 site), E3 (S2H97 site), F1 (CR3022, S304 site), F2 (DH1047, BD55-3500 site), F3 (ADG-2, BD55-3372 site) and B' (S2K146 site). Members of E1, F2 and F3 demonstrate the highest neutralization potency; yet, Omicron, especially BA.2, has evolved multiple mutations (G339D, N440K, T376A, D405N, R408S) to escape antibodies of these groups. Nevertheless, broad sarbecovirus neutralizing antibodies that survived Omicron would serve as favorable therapeutic candidates. Furthermore, structural analyses of selected drug candidates propose two non-competing antibody pairing strategies, E1-F2 and E1-F3, as broad-spectrum antibody cocktails. Together, our work provides a comprehensive epitope map of broad sarbecovirus neutralizing antibodies and offers critical instructions for designing broad-spectrum vaccines.

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“…We investigated whether these variants produce less aberrant 5′ end svRNAs in human cells. Compared with the parental strain, the Omicron variants BA.1 and BA.2 (termed BA.1 and BA.2) replicated less well in Calu-3 cells as reported previously (Yamasoba et al, 2022), with the most drastic difference observed at 33ºC rather than 37ºC (Figure 7A). IFN-b expression was markedly attenuated, although nally achieving a substantial level at 120 hpi at 37ºC but not 33ºC (Figure 7B), whereas IL-6 expression was less reduced in Omicron-infected cells (Figure 7C).…”

Section: Resultssupporting

confidence: 75%

Stimulation of dysregulated IFN-β responses by aberrant SARS-CoV-2 small viral RNAs

Arai

Yamanaka

Okamoto

et al. 2022

Preprint

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Patients with severe COVID-19 exhibit a cytokine storm characterized by greatly elevated levels of cytokines during worsening disease. Despite this, the interferon (IFN) response is delayed, contributing to disease progression. Here, we report that SARS-CoV-2 generates excessive amounts of small viral RNAs (svRNAs) encoding exact 5′ ends of positive-sense genes in human cells, whereas significantly fewer similar svRNAs are produced by endemic human coronaviruses (OC43 and 229E). SARS-CoV-2 5′ end svRNAs are RIG-I agonists associated with IFN-beta expression in later stages of infection. The first 60-nt ends bearing duplex structures and 5′-triphosphates are responsible for immune-stimulation. The 5′ end svRNAs were also produced during infection ex vivo and in vivo. The delta variant retains the robust 5′ end svRNA production of the parental strain, whereas omicron (BA.1 and BA.2) produces little of these erroneous svRNAs. We propose that RIG-I activation by accumulated 5′ end svRNAs overcomes the initial IFN antagonistic ability of viral proteins and contributes to drive late over-exuberant IFN production leading to the development of severe COVID-19 and suggest that evolutionary modification of SARS-CoV-2 5′ end svRNA production may correlate with the reduced disease severity likely seen with omicron (BA.1 and BA.2).

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Virological characteristics of SARS-CoV-2 BA.2 variant

Cited by 113 publications

References 52 publications

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

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

Omicron BA.2 specifically evades broad sarbecovirus neutralizing antibodies

Stimulation of dysregulated IFN-β responses by aberrant SARS-CoV-2 small viral RNAs

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