Virological characteristics of the SARS-CoV-2 Omicron BA.2 spike

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:10.1016/j.cell.2022.04.035

Cited by 329 publications

(557 citation statements)

References 69 publications

Supporting

Mentioning

475

Contrasting

Unclassified

Order By: Relevance

“…We then introduced the Delta NTD into the both BA.1 and BA.2 to examine whether the Delta NTD could also confer increased fusion to Omicron, a known poor cell-cell fusion spike (Figure 5B). Although BA.2 showed faster fusion than BA.1, consistent with a recently published study (Yamasoba et al, 2022), both Omicron and the Delta-NTD fused Omicron chimeras showed poor spike-mediated fusion and that most importantly the difference between Omicron and its counterpart was negligible. Intriguingly, this phenotype correlates with inefficient cleavage of spike even after the cleavage-enhancing Delta NTD was fused into an Omicron spike background.…”

Section: Resultssupporting

confidence: 90%

See 1 more Smart Citation

SARS-CoV-2 Spike N-Terminal Domain modulates TMPRSS2-dependent viral entry and fusogenicity

Meng

Datir

Choi

et al. 2022

Preprint

View full text Add to dashboard Cite

Over 20 mutations have been identified in the N-Terminal Domain (NTD) of SARS-CoV-2 spike and yet few of them are fully characterised. Here we first examined the contribution of the NTD to infection and cell-cell fusion by constructing different VOC-based chimeric spikes bearing B.1617 lineage (Delta and Kappa variants) NTDs and generating spike pseudotyped lentivirus (PV). We found the Delta NTD on a Kappa or WT background increased spike S1/S2 cleavage efficiency and virus entry, specifically in Calu-3 lung cells and airway organoids, through use of TMPRSS2. Delta was previously shown to have fast cell-cell fusion kinetics and increased fusogenicity that could be conferred to WT and Kappa variant spikes by transfer of the Delta NTD. Moving to contemporary variants, we found that BA.2 had higher entry efficiency in a range of cell types as compared to BA.1. BA.2 showed higher fusogenic activity than BA.1, but the BA.2 NTD could not confer higher fusion to BA.1 spike. There was low efficiency of TMPRSS2 usage by both BA.1 and BA.2, and chimeras of Omicron BA.1 and BA.2 spikes with a Delta NTD did not result in more efficient use of TMRPSS2 or cell-cell fusogenicity. We conclude that the NTD allosterically modulates S1/S2 cleavage and spike-mediated functions such as entry and cell-cell fusion in a spike context dependent manner, and allosteric interactions may be lost when combining regions from more distantly related spike proteins. These data may explain the lack of dominant SARS-CoV-2 inter-variant recombinants bearing breakpoints within spike.

show abstract

Section: Resultssupporting

confidence: 90%

“…Although BA.2 showed faster fusion than BA.1, consistent with a recently published study (Yamasoba et al, 2022), both Omicron and the Delta-NTD fused Omicron chimeras showed poor spike-mediated fusion and that most importantly the difference between Omicron and its counterpart was negligible.…”

Section: Ntd Mutations and Deletions Impact Entry Efficiencysupporting

confidence: 89%

SARS-CoV-2 Spike N-Terminal Domain modulates TMPRSS2-dependent viral entry and fusogenicity

Meng

Datir

Choi

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Since the end of November 2021, the SARS-CoV-2 Omicron variant (B.1.1.529 and BA lineages) has spread worldwide and has outcompeted prior SARS-CoV-2 variants of concern (VOCs) such as Delta. After the surge of Omicron BA.1 variant, another Omicron variant, BA.2, outcompeted BA.1 and has become the most dominant variant in the world (Ito et al, 2022; UKHSA, 2022; Yamasoba et al, 2022a). Thereafter, as of May 2022, the Omicron subvariants that harbor the substitution at the L452 residue of spike (S) protein, such as BA.4 and BA.5, were frequently detected (Tegally et al, 2022; WHO, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…Resistance to antiviral humoral immunity can be mainly determined by the mutations in the S protein. For instance, Omicron BA.1 exhibits profound resistance to neutralizing antibodies induced by vaccination and natural SARS-CoV-2 infection as well as therapeutic monoclonal antibodies (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) and BA.2 (Bruel et al, 2022; Takashita et al, 2022b; Yamasoba et al ., 2022a; Yamasoba et al, 2022b). In addition to immune evasion, the mutations in the S protein potentially modulate viral pathogenicity.…”

Section: Introductionmentioning

confidence: 99%

Virological characteristics of the novel SARS-CoV-2 Omicron variants including BA.2.12.1, BA.4 and BA.5

Kimura

Yamasoba

Tamura

et al. 2022

Preprint

Self Cite

166

View full text Add to dashboard Cite

After the global spread of SARS-CoV-2 Omicron BA.2 lineage, some BA.2-related variants that acquire mutations in the L452 residue of spike protein, such as BA.2.9.1 and BA.2.13 (L452M), BA.2.12.1 (L452Q), and BA.2.11, BA.4 and BA.5 (L452R), emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these L452R/M/Q-bearing BA.2-related Omicron variants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1 and BA.2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. Furthermore, infection experiments using hamsters indicated that BA.4/5 is more pathogenic than BA.2. Altogether, our multiscale investigations suggest that the risk of L452R/M/Q-bearing BA.2-related Omicron variants, particularly BA.4 and BA.5, to global health is potentially greater than that of original BA.2.HighlightsSpike L452R/Q/M mutations increase the effective reproduction number of BA.2BA.4/5 is resistant to the immunity induced by BA.1 and BA.2 infectionsBA.2.12.1 and BA.4/5 more efficiently spread in human lung cells than BA.2BA.4/5 is more pathogenic than BA.2 in hamsters

show abstract

“…The Omicron BA.2 spike was recently shown to be more pathogenic and more efficient in mediating syncytia formation than the BA.1 spike ( 13 ). The ability of scFv76 to prevent SARS-CoV-2 Omicron BA.1 or BA.2 spike-induced fusion of pulmonary cells was than tested in vitro .…”

Section: Resultsmentioning

confidence: 99%

Spike mutation resilient scFv76 antibody counteracts SARS-CoV-2 lung damage upon aerosol delivery

Milazzo

Chaves-Sanjuán

Minenkova

et al. 2022

Preprint

View full text Add to dashboard Cite

Uneven worldwide vaccination coverage against SARS-CoV-2 and emergence of variants escaping immunity call for broadly-effective and easily-deployable therapeutics. We previously described the human single-chain scFv76 antibody, which recognizes SARS-CoV-2 Alfa, Beta, Gamma and Delta variants. We now show that scFv76 also neutralizes infectivity and fusogenic activity of Omicron BA.1 and BA.2 variants. Cryo-EM analysis reveals that scFv76 binds to a well-conserved SARS-CoV-2 spike epitope, providing the structural basis for its broad-spectrum activity. Moreover, we demonstrate that nebulized scFv76 exhibits therapeutic efficacy in a severe hACE2 transgenic mouse model of COVID-19 pneumonia, as shown by body weight and pulmonary viral load data. Counteraction of infection correlates with the inhibition of lung inflammation observed by histopathology and expression of inflammatory cytokines and chemokines. Biomarkers of pulmonary endothelial damage were also significantly reduced in scFv76-treated mice. Altogether the results support the use of nebulized scFv76 for COVID-19 induced by any SARS-CoV-2 variants emerged so far.

show abstract

Virological characteristics of the SARS-CoV-2 Omicron BA.2 spike

Cited by 329 publications

References 69 publications

SARS-CoV-2 Spike N-Terminal Domain modulates TMPRSS2-dependent viral entry and fusogenicity

SARS-CoV-2 Spike N-Terminal Domain modulates TMPRSS2-dependent viral entry and fusogenicity

Virological characteristics of the novel SARS-CoV-2 Omicron variants including BA.2.12.1, BA.4 and BA.5

Spike mutation resilient scFv76 antibody counteracts SARS-CoV-2 lung damage upon aerosol delivery

Contact Info

Product

Resources

About