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1. Structural basis for receptor-binding domain mobility of the spike in SARS-CoV-2 BA.2.86 and JN.1

Author

Hisano Yajima, Yuki Anraku, Yu Kaku, Kanako Terakado Kimura, Arnon Plianchaisuk, Kaho Okumura, Yoshiko Nakada-Nakura, Yusuke Atarashi, Takuya Hemmi, Daisuke Kuroda, Yoshimasa Takahashi, Shunsuke Kita, Jiei Sasaki, Hiromi Sumita, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Jumpei Ito, Katsumi Maenaka, Kei Sato, and Takao Hashiguchi

Subjects
Science
Abstract

Abstract Since 2019, SARS-CoV-2 has undergone mutations, resulting in pandemic and epidemic waves. The SARS-CoV-2 spike protein, crucial for cellular entry, binds to the ACE2 receptor exclusively when its receptor-binding domain (RBD) adopts the up-conformation. However, whether ACE2 also interacts with the RBD in the down-conformation to facilitate the conformational shift to RBD-up remains unclear. Herein, we present the structures of the BA.2.86 and the JN.1 spike proteins bound to ACE2. Notably, we successfully observed the ACE2-bound down-RBD, indicating an intermediate structure before the RBD-up conformation. The wider and mobile angle of RBDs in the up-state provides space for ACE2 to interact with the down-RBD, facilitating the transition to the RBD-up state. The K356T, but not N354-linked glycan, contributes to both of infectivity and neutralizing-antibody evasion in BA.2.86. These structural insights the spike-protein dynamics would help understand the mechanisms underlying SARS-CoV-2 infection and its neutralization.

Published
2024
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2. Neutralizing immunity against coronaviruses in Tanzanian health care workers

Author

Godfrey Barabona, Isaac Ngare, Doreen Kamori, Lilian Nkinda, Yusuke Kosugi, Ambele Mawazo, Rayi Ekwabi, Gloria Kinasa, Harrison Chuwa, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Kei Sato, Bruno Sunguya, and Takamasa Ueno

Subjects
Medicine, Science
Abstract

Abstract The ongoing vaccination efforts and exposure to endemic and emerging coronaviruses can shape the population's immunity against this group of viruses. In this study, we investigated neutralizing immunity against endemic and emerging coronaviruses in 200 Tanzanian frontline healthcare workers (HCWs). Despite low vaccination rates (19.5%), we found a high SARS-CoV-2 seroprevalence (94.0%), indicating high exposure in these HCWs. Next, we determined the neutralization capacity of antisera against human coronavirus NL63, and 229E, SARS-CoV-1, MERS-CoV and SARS-CoV-2 (including Omicron subvariants: BA.1, BQ.1.1 and XBB.1.5) using pseudovirus neutralization assay. We observed a broad range of neutralizing activity in HCWs, but no neutralization activity detected against MERS-CoV. We also observed a strong correlation between neutralizing antibody titers for SARS-CoV-2 and SARS-CoV-1, but not between other coronaviruses. Cross-neutralization titers against the newer Omicron subvariants, BQ.1.1 and XBB.1.5, was significantly reduced compared to BA.1 and BA.2 subvariants. On the other hand, the exposed vaccinated HCWs showed relatively higher median cross-neutralization titers against both the newer Omicron subvariants and SARS-CoV-1, but did not reach statistical significance. In summary, our findings suggest a broad range of neutralizing potency against coronaviruses in Tanzanian HCWs with detectable neutralizing immunity against SARS-CoV-1 resulting from SARS-CoV-2 exposure.

Published
2024
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3. Virological characteristics of the SARS-CoV-2 Omicron XBB.1.5 variant

Author

Tomokazu Tamura, Takashi Irie, Sayaka Deguchi, Hisano Yajima, Masumi Tsuda, Hesham Nasser, Keita Mizuma, Arnon Plianchaisuk, Saori Suzuki, Keiya Uriu, Mst Monira Begum, Ryo Shimizu, Michael Jonathan, Rigel Suzuki, Takashi Kondo, Hayato Ito, Akifumi Kamiyama, Kumiko Yoshimatsu, Maya Shofa, Rina Hashimoto, Yuki Anraku, Kanako Terakado Kimura, Shunsuke Kita, Jiei Sasaki, Kaori Sasaki-Tabata, Katsumi Maenaka, Naganori Nao, Lei Wang, Yoshitaka Oda, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Terumasa Ikeda, Akatsuki Saito, Keita Matsuno, Jumpei Ito, Shinya Tanaka, Kei Sato, Takao Hashiguchi, Kazuo Takayama, and Takasuke Fukuhara

Subjects
Science
Abstract

Abstract Circulation of SARS-CoV-2 Omicron XBB has resulted in the emergence of XBB.1.5, a new Variant of Interest. Our phylogenetic analysis suggests that XBB.1.5 evolved from XBB.1 by acquiring the S486P spike (S) mutation, subsequent to the acquisition of a nonsense mutation in ORF8. Neutralization assays showed similar abilities of immune escape between XBB.1.5 and XBB.1. We determine the structural basis for the interaction between human ACE2 and the S protein of XBB.1.5, showing similar overall structures between the S proteins of XBB.1 and XBB.1.5. We provide the intrinsic pathogenicity of XBB.1 and XBB.1.5 in hamsters. Importantly, we find that the ORF8 nonsense mutation of XBB.1.5 resulted in impairment of MHC suppression. In vivo experiments using recombinant viruses reveal that the XBB.1.5 mutations are involved with reduced virulence of XBB.1.5. Together, our study identifies the two viral functions defined the difference between XBB.1 and XBB.1.5.

Published
2024
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4. Comparative pathogenicity of SARS-CoV-2 Omicron subvariants including BA.1, BA.2, and BA.5

Author

Tomokazu Tamura, Daichi Yamasoba, Yoshitaka Oda, Jumpei Ito, Tomoko Kamasaki, Naganori Nao, Rina Hashimoto, Yoichiro Fujioka, Rigel Suzuki, Lei Wang, Hayato Ito, Yukie Kashima, Izumi Kimura, Mai Kishimoto, Masumi Tsuda, Hirofumi Sawa, Kumiko Yoshimatsu, Yuki Yamamoto, Tetsuharu Nagamoto, Jun Kanamune, Yutaka Suzuki, Yusuke Ohba, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Isao Yokota, Keita Matsuno, Kazuo Takayama, Shinya Tanaka, Kei Sato, and Takasuke Fukuhara

Subjects
Biology (General), QH301-705.5
Abstract

Abstract The unremitting emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants necessitates ongoing control measures. Given its rapid spread, the new Omicron subvariant BA.5 requires urgent characterization. Here, we comprehensively analyzed BA.5 with the other Omicron variants BA.1, BA.2, and ancestral B.1.1. Although in vitro growth kinetics of BA.5 was comparable among the Omicron subvariants, BA.5 was much more fusogenic than BA.1 and BA.2. Airway-on-a-chip analysis showed that, among Omicron subvariants, BA.5 had enhanced ability to disrupt the respiratory epithelial and endothelial barriers. Furthermore, in our hamster model, in vivo pathogenicity of BA.5 was slightly higher than that of the other Omicron variants and less than that of ancestral B.1.1. Notably, BA.5 gains efficient virus spread compared with BA.1 and BA.2, leading to prompt immune responses. Our findings suggest that BA.5 has low pathogenicity compared with the ancestral strain but enhanced virus spread /inflammation compared with earlier Omicron subvariants.

Published
2023
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5. Virological characteristics correlating with SARS-CoV-2 spike protein fusogenicity

Author

MST Monira Begum, Kimiko Ichihara, Otowa Takahashi, Hesham Nasser, Michael Jonathan, Kenzo Tokunaga, Isao Yoshida, Mami Nagashima, Kenji Sadamasu, Kazuhisa Yoshimura, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Kei Sato, Terumasa Ikeda, Keita Matsuno, Naganori Nao, Hirofumi Sawa, Shinya Tanaka, Masumi Tsuda, Lei Wang, Yoshikata Oda, Zannatul Ferdous, Kenji Shishido, Takasuke Fukuhara, Tomokazu Tamura, Rigel Suzuki, Saori Suzuki, Hayato Ito, Jumpei Ito, Yu Kaku, Naoko Misawa, Arnon Plianchaisuk, Ziyi Guo, Alfredo Jr. Hinay, Keiya Uriu, Yusuke Kosugi, Shigeru Fujita, Jarel Elgin Mendoza Tolentino, Luo Chen, Lin Pan, Mai Suganami, Mika Chiba, Ryo Yoshimura, Kyoko Yasuda, Keiko Iida, Naomi Ohsumi, Adam Patrick Strange, Hiroyuki Asakura, So Nakagawa, Akifumi Takaori-Kondo, Kotaro Shirakawa, Kayoko Nagata, Ryosuke Nomura, Yoshihito Horisawa, Yusuke Tashiro, Yugo Kawai, Kazuo Takayama, Rina Hashimoto, Sayaka Deguchi, Yukio Watanabe, Ayaka Sakamoto, Naoko Yasuhara, Takao Hashiguchi, Tateki Suzuki, Kanako Kimura, Jiei Sasaki, Yukari Nakajima, Hisano Yajima, Takashi Irie, Ryoko Kawabata, Kaori Tabata, Ryo Shimizu, Yuka Mugita, Takamasa Ueno, Chihiro Motozono, Mako Toyoda, Akatsuki Saito, Maya Shofa, Yuki Shibatani, and Tomoko Nishiuchi

Subjects
SARS-CoV-2, fusogenicity, pathogenicity, S1/S2 cleavage efficiency, plaque size, pseudoviral infectivity, Microbiology, QR1-502
Abstract

IntroductionThe severe acute respiratory syndrome coronavirus (SARS-CoV-2) spike (S) protein is essential in mediating membrane fusion of the virus with the target cells. Several reports demonstrated that SARS-CoV-2 S protein fusogenicity is reportedly closely associated with the intrinsic pathogenicity of the virus determined using hamster models. However, the association between S protein fusogenicity and other virological parameters remains elusive.MethodsIn this study, we investigated the virological parameters (e.g., S1/S2 cleavage efficiency, plaque size, pseudoviral infectivity, pseudovirus entry efficiency, and viral replication kinetics) of eleven previous variants of concern (VOCs) and variants of interest (VOIs) correlating with S protein fusogenicity.Results and discussionS protein fusogenicity was found to be strongly correlated with S1/S2 cleavage efficiency and plaque size formed by clinical isolates. However, S protein fusogenicity was less associated with pseudoviral infectivity, pseudovirus entry efficiency, and viral replication kinetics. Taken together, our results suggest that S1/S2 cleavage efficiency and plaque size could be potential indicators to predict the intrinsic pathogenicity and S protein fusogenicity of newly emerged SARS-CoV-2 variants.

Published
2024
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6. Virological characteristics of the SARS-CoV-2 XBB variant derived from recombination of two Omicron subvariants

Author

Tomokazu Tamura, Jumpei Ito, Keiya Uriu, Jiri Zahradnik, Izumi Kida, Yuki Anraku, Hesham Nasser, Maya Shofa, Yoshitaka Oda, Spyros Lytras, Naganori Nao, Yukari Itakura, Sayaka Deguchi, Rigel Suzuki, Lei Wang, MST Monira Begum, Shunsuke Kita, Hisano Yajima, Jiei Sasaki, Kaori Sasaki-Tabata, Ryo Shimizu, Masumi Tsuda, Yusuke Kosugi, Shigeru Fujita, Lin Pan, Daniel Sauter, Kumiko Yoshimatsu, Saori Suzuki, Hiroyuki Asakura, Mami Nagashima, Kenji Sadamasu, Kazuhisa Yoshimura, Yuki Yamamoto, Tetsuharu Nagamoto, Gideon Schreiber, Katsumi Maenaka, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Takao Hashiguchi, Terumasa Ikeda, Takasuke Fukuhara, Akatsuki Saito, Shinya Tanaka, Keita Matsuno, Kazuo Takayama, and Kei Sato

Subjects
Science
Abstract

Abstract In late 2022, SARS-CoV-2 Omicron subvariants have become highly diversified, and XBB is spreading rapidly around the world. Our phylogenetic analyses suggested that XBB emerged through the recombination of two cocirculating BA.2 lineages, BJ.1 and BM.1.1.1 (a progeny of BA.2.75), during the summer of 2022. XBB.1 is the variant most profoundly resistant to BA.2/5 breakthrough infection sera to date and is more fusogenic than BA.2.75. The recombination breakpoint is located in the receptor-binding domain of spike, and each region of the recombinant spike confers immune evasion and increases fusogenicity. We further provide the structural basis for the interaction between XBB.1 spike and human ACE2. Finally, the intrinsic pathogenicity of XBB.1 in male hamsters is comparable to or even lower than that of BA.2.75. Our multiscale investigation provides evidence suggesting that XBB is the first observed SARS-CoV-2 variant to increase its fitness through recombination rather than substitutions.

Published
2023
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7. Convergent evolution of SARS-CoV-2 Omicron subvariants leading to the emergence of BQ.1.1 variant

Author

Jumpei Ito, Rigel Suzuki, Keiya Uriu, Yukari Itakura, Jiri Zahradnik, Kanako Terakado Kimura, Sayaka Deguchi, Lei Wang, Spyros Lytras, Tomokazu Tamura, Izumi Kida, Hesham Nasser, Maya Shofa, Mst Monira Begum, Masumi Tsuda, Yoshitaka Oda, Tateki Suzuki, Jiei Sasaki, Kaori Sasaki-Tabata, Shigeru Fujita, Kumiko Yoshimatsu, Hayato Ito, Naganori Nao, Hiroyuki Asakura, Mami Nagashima, Kenji Sadamasu, Kazuhisa Yoshimura, Yuki Yamamoto, Tetsuharu Nagamoto, Jin Kuramochi, Gideon Schreiber, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Akatsuki Saito, Keita Matsuno, Kazuo Takayama, Takao Hashiguchi, Shinya Tanaka, Takasuke Fukuhara, Terumasa Ikeda, and Kei Sato

Subjects
Science
Abstract

Abstract In late 2022, various Omicron subvariants emerged and cocirculated worldwide. These variants convergently acquired amino acid substitutions at critical residues in the spike protein, including residues R346, K444, L452, N460, and F486. Here, we characterize the convergent evolution of Omicron subvariants and the properties of one recent lineage of concern, BQ.1.1. Our phylogenetic analysis suggests that these five substitutions are recurrently acquired, particularly in younger Omicron lineages. Epidemic dynamics modelling suggests that the five substitutions increase viral fitness, and a large proportion of the fitness variation within Omicron lineages can be explained by these substitutions. Compared to BA.5, BQ.1.1 evades breakthrough BA.2 and BA.5 infection sera more efficiently, as demonstrated by neutralization assays. The pathogenicity of BQ.1.1 in hamsters is lower than that of BA.5. Our multiscale investigations illuminate the evolutionary rules governing the convergent evolution for known Omicron lineages as of 2022.

Published
2023
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8. Characterization of the evolutionary and virological aspects of mutations in the receptor binding motif of the SARS-CoV-2 spike protein

Author

Yuuka Masuda, Hesham Nasser, Jiri Zahradnik, Shuya Mitoma, Ryo Shimizu, Kayoko Nagata, Akifumi Takaori-Kondo, Gideon Schreiber, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Kotaro Shirakawa, Akatsuki Saito, Terumasa Ikeda, Jumpei Ito, and Kei Sato

Subjects
SARS-CoV-2, evolution, receptor binding motif, variants of concerns, epidemic dynamics modeling, Microbiology, QR1-502
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has substantially diversified during the pandemic, resulting in the successive emergence of variants characterized by various mutations. It has been observed that several epidemic variants, including those classified as variants of concern, share mutations at four key residues (L452R, T478K, E484K, and N501Y) within the receptor binding motif (RBM) region of the spike protein. However, the processes through which these four specific RBM mutations were acquired during the evolution of SARS-CoV-2, as well as the degree to which they enhance viral fitness, remain unclear. Moreover, the effect of these mutations on the properties of the spike protein is not yet fully understood. In this study, we performed a comprehensive phylogenetic analysis and showed that the four RBM mutations have been convergently acquired across various lineages throughout the evolutionary history of SARS-CoV-2. We also found a specific pattern in the order of acquisition for some of these mutations. Additionally, our epidemic dynamic modeling demonstrated that acquiring these mutations leads to an increase in the effective reproduction number of the virus. Furthermore, we engineered mutant spike proteins with all feasible combinations of the four mutations, and examined their properties to uncover the influence that these mutations have on viral characteristics. Our results provide insights into the roles these four mutations play in shaping the viral characteristics, epidemic proliferation, and evolutionary pathway of SARS-CoV-2.

Published
2023
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9. Structural Insight into the Resistance of the SARS-CoV-2 Omicron BA.4 and BA.5 Variants to Cilgavimab

Author

Shigeru Fujita, Yusuke Kosugi, Izumi Kimura, Daichi Yamasoba, The Genotype to Phenotype Japan (G2P-Japan) Consortium, and Kei Sato

Subjects
SARS-CoV-2, COVID-19, Omicron, BA.4, BA.5, cilgavimab, Microbiology, QR1-502
Abstract

We have recently revealed that the new SARS-CoV-2 Omicron sublineages BA.4 and BA.5 exhibit increased resistance to cilgavimab, a therapeutic monoclonal antibody, and the resistance to cilgavimab is attributed to the spike L452R substitution. However, it remains unclear how the spike L452R substitution renders resistance to cilgavimab. Here, we demonstrated that the increased resistance to cilgavimab of the spike L452R is possibly caused by the steric hindrance between cilgavimab and its binding interface on the spike. Our results suggest the importance of developing therapeutic antibodies that target SARS-CoV-2 variants harboring the spike L452R substitution.

Published
2022
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10. Virological characteristics of the SARS-CoV-2 BA.2.86 variant

Author

10759509, Tamura, Tomokazu, Mizuma, Keita, Nasser, Hesham, Deguchi, Sayaka, Padilla-Blanco, Miguel, Oda, Yoshitaka, Uriu, Keiya, Tolentino, Jarel E.M., Tsujino, Shuhei, Suzuki, Rigel, Kojima, Isshu, Nao, Naganori, Shimizu, Ryo, Wang, Lei, Tsuda, Masumi, Jonathan, Michael, Kosugi, Yusuke, Guo, Ziyi, Hinay, Alfredo A., Putri, Olivia, Kim, Yoonjin, Tanaka, Yuri L., Asakura, Hiroyuki, Nagashima, Mami, Sadamasu, Kenji, Yoshimura, Kazuhisa, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Saito, Akatsuki, Ito, Jumpei, Irie, Takashi, Tanaka, Shinya, Zahradnik, Jiri, Ikeda, Terumasa, Takayama, Kazuo, Matsuno, Keita, Fukuhara, Takasuke, Sato, Kei, 10759509, Tamura, Tomokazu, Mizuma, Keita, Nasser, Hesham, Deguchi, Sayaka, Padilla-Blanco, Miguel, Oda, Yoshitaka, Uriu, Keiya, Tolentino, Jarel E.M., Tsujino, Shuhei, Suzuki, Rigel, Kojima, Isshu, Nao, Naganori, Shimizu, Ryo, Wang, Lei, Tsuda, Masumi, Jonathan, Michael, Kosugi, Yusuke, Guo, Ziyi, Hinay, Alfredo A., Putri, Olivia, Kim, Yoonjin, Tanaka, Yuri L., Asakura, Hiroyuki, Nagashima, Mami, Sadamasu, Kenji, Yoshimura, Kazuhisa, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Saito, Akatsuki, Ito, Jumpei, Irie, Takashi, Tanaka, Shinya, Zahradnik, Jiri, Ikeda, Terumasa, Takayama, Kazuo, Matsuno, Keita, Fukuhara, Takasuke, and Sato, Kei

Abstract

In late 2023, several SARS-CoV-2 XBB descendants, notably EG.5.1, were predominant worldwide. However, a distinct SARS-CoV-2 lineage, the BA.2.86 variant, also emerged. BA.2.86 is phylogenetically distinct from other Omicron sublineages, accumulating over 30 amino acid mutations in its spike protein. Here, we examined the virological characteristics of the BA.2.86 variant. Our epidemic dynamics modeling suggested that the relative reproduction number of BA.2.86 is significantly higher than that of EG.5.1. Additionally, four clinically available antivirals were effective against BA.2.86. Although the fusogenicity of BA.2.86 spike is similar to that of the parental BA.2 spike, the intrinsic pathogenicity of BA.2.86 in hamsters was significantly lower than that of BA.2. Since the growth kinetics of BA.2.86 are significantly lower than those of BA.2 both in vitro and in vivo, the attenuated pathogenicity of BA.2.86 is likely due to its decreased replication capacity. These findings uncover the features of BA.2.86, providing insights for control and treatment.

Published
2024

11. Virological characteristics of the SARS-CoV-2 Omicron XBB.1.5 variant

Author

50632098, 10759509, Tamura, Tomokazu, Irie, Takashi, Deguchi, Sayaka, Yajima, Hisano, Tsuda, Masumi, Nasser, Hesham, Mizuma, Keita, Plianchaisuk, Arnon, Suzuki, Saori, Uriu, Keiya, Begum, Mst Monira, Shimizu, Ryo, Jonathan, Michael, Suzuki, Rigel, Kondo, Takashi, Ito, Hayato, Kamiyama, Akifumi, Yoshimatsu, Kumiko, Shofa, Maya, Hashimoto, Rina, Anraku, Yuki, Kimura, Kanako Terakado, Kita, Shunsuke, Sasaki, Jiei, Sasaki-Tabata, Kaori, Maenaka, Katsumi, Nao, Naganori, Wang, Lei, Oda, Yoshitaka, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Ikeda, Terumasa, Saito, Akatsuki, Matsuno, Keita, Ito, Jumpei, Tanaka, Shinya, Sato, Kei, Hashiguchi, Takao, Takayama, Kazuo, Fukuhara, Takasuke, 50632098, 10759509, Tamura, Tomokazu, Irie, Takashi, Deguchi, Sayaka, Yajima, Hisano, Tsuda, Masumi, Nasser, Hesham, Mizuma, Keita, Plianchaisuk, Arnon, Suzuki, Saori, Uriu, Keiya, Begum, Mst Monira, Shimizu, Ryo, Jonathan, Michael, Suzuki, Rigel, Kondo, Takashi, Ito, Hayato, Kamiyama, Akifumi, Yoshimatsu, Kumiko, Shofa, Maya, Hashimoto, Rina, Anraku, Yuki, Kimura, Kanako Terakado, Kita, Shunsuke, Sasaki, Jiei, Sasaki-Tabata, Kaori, Maenaka, Katsumi, Nao, Naganori, Wang, Lei, Oda, Yoshitaka, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Ikeda, Terumasa, Saito, Akatsuki, Matsuno, Keita, Ito, Jumpei, Tanaka, Shinya, Sato, Kei, Hashiguchi, Takao, Takayama, Kazuo, and Fukuhara, Takasuke

Abstract

Circulation of SARS-CoV-2 Omicron XBB has resulted in the emergence of XBB.1.5, a new Variant of Interest. Our phylogenetic analysis suggests that XBB.1.5 evolved from XBB.1 by acquiring the S486P spike (S) mutation, subsequent to the acquisition of a nonsense mutation in ORF8. Neutralization assays showed similar abilities of immune escape between XBB.1.5 and XBB.1. We determine the structural basis for the interaction between human ACE2 and the S protein of XBB.1.5, showing similar overall structures between the S proteins of XBB.1 and XBB.1.5. We provide the intrinsic pathogenicity of XBB.1 and XBB.1.5 in hamsters. Importantly, we find that the ORF8 nonsense mutation of XBB.1.5 resulted in impairment of MHC suppression. In vivo experiments using recombinant viruses reveal that the XBB.1.5 mutations are involved with reduced virulence of XBB.1.5. Together, our study identifies the two viral functions defined the difference between XBB.1 and XBB.1.5.

Published
2024

12. Comparative pathogenicity of SARS-CoV-2 Omicron subvariants including BA.1, BA.2, and BA.5

Author

10759509, Tamura, Tomokazu, Yamasoba, Daichi, Oda, Yoshitaka, Ito, Jumpei, Kamasaki, Tomoko, Nao, Naganori, Hashimoto, Rina, Fujioka, Yoichiro, Suzuki, Rigel, Wang, Lei, Ito, Hayato, Kashima, Yukie, Kimura, Izumi, Kishimoto, Mai, Tsuda, Masumi, Sawa, Hirofumi, Yoshimatsu, Kumiko, Yamamoto, Yuki, Nagamoto, Tetsuharu, Kanamune, Jun, Suzuki, Yutaka, Ohba, Yusuke, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Yokota, Isao, Matsuno, Keita, Takayama, Kazuo, Tanaka, Shinya, Sato, Kei, Fukuhara, Takasuke, 10759509, Tamura, Tomokazu, Yamasoba, Daichi, Oda, Yoshitaka, Ito, Jumpei, Kamasaki, Tomoko, Nao, Naganori, Hashimoto, Rina, Fujioka, Yoichiro, Suzuki, Rigel, Wang, Lei, Ito, Hayato, Kashima, Yukie, Kimura, Izumi, Kishimoto, Mai, Tsuda, Masumi, Sawa, Hirofumi, Yoshimatsu, Kumiko, Yamamoto, Yuki, Nagamoto, Tetsuharu, Kanamune, Jun, Suzuki, Yutaka, Ohba, Yusuke, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Yokota, Isao, Matsuno, Keita, Takayama, Kazuo, Tanaka, Shinya, Sato, Kei, and Fukuhara, Takasuke

Abstract

The unremitting emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants necessitates ongoing control measures. Given its rapid spread, the new Omicron subvariant BA.5 requires urgent characterization. Here, we comprehensively analyzed BA.5 with the other Omicron variants BA.1, BA.2, and ancestral B.1.1. Although in vitro growth kinetics of BA.5 was comparable among the Omicron subvariants, BA.5 was much more fusogenic than BA.1 and BA.2. Airway-on-a-chip analysis showed that, among Omicron subvariants, BA.5 had enhanced ability to disrupt the respiratory epithelial and endothelial barriers. Furthermore, in our hamster model, in vivo pathogenicity of BA.5 was slightly higher than that of the other Omicron variants and less than that of ancestral B.1.1. Notably, BA.5 gains efficient virus spread compared with BA.1 and BA.2, leading to prompt immune responses. Our findings suggest that BA.5 has low pathogenicity compared with the ancestral strain but enhanced virus spread /inflammation compared with earlier Omicron subvariants.

Published
2023

13. Convergent evolution of SARS-CoV-2 Omicron subvariants leading to the emergence of BQ.1.1 variant

Author

80833334, 10759509, 50632098, Ito, Jumpei, Suzuki, Rigel, Uriu, Keiya, Itakura, Yukari, Zahradnik, Jiri, Kimura, Kanako Terakado, Deguchi, Sayaka, Wang, Lei, Lytras, Spyros, Tamura, Tomokazu, Kida, Izumi, Nasser, Hesham, Shofa, Maya, Begum, Mst Monira, Tsuda, Masumi, Oda, Yoshitaka, Suzuki, Tateki, Sasaki, Jiei, Sasaki-Tabata, Kaori, Fujita, Shigeru, Yoshimatsu, Kumiko, Ito, Hayato, Nao, Naganori, Asakura, Hiroyuki, Nagashima, Mami, Sadamasu, Kenji, Yoshimura, Kazuhisa, Yamamoto, Yuki, Nagamoto, Tetsuharu, Kuramochi, Jin, Schreiber, Gideon, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Saito, Akatsuki, Matsuno, Keita, Takayama, Kazuo, Hashiguchi, Takao, Tanaka, Shinya, Fukuhara, Takasuke, Ikeda, Terumasa, Sato, Kei, 80833334, 10759509, 50632098, Ito, Jumpei, Suzuki, Rigel, Uriu, Keiya, Itakura, Yukari, Zahradnik, Jiri, Kimura, Kanako Terakado, Deguchi, Sayaka, Wang, Lei, Lytras, Spyros, Tamura, Tomokazu, Kida, Izumi, Nasser, Hesham, Shofa, Maya, Begum, Mst Monira, Tsuda, Masumi, Oda, Yoshitaka, Suzuki, Tateki, Sasaki, Jiei, Sasaki-Tabata, Kaori, Fujita, Shigeru, Yoshimatsu, Kumiko, Ito, Hayato, Nao, Naganori, Asakura, Hiroyuki, Nagashima, Mami, Sadamasu, Kenji, Yoshimura, Kazuhisa, Yamamoto, Yuki, Nagamoto, Tetsuharu, Kuramochi, Jin, Schreiber, Gideon, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Saito, Akatsuki, Matsuno, Keita, Takayama, Kazuo, Hashiguchi, Takao, Tanaka, Shinya, Fukuhara, Takasuke, Ikeda, Terumasa, and Sato, Kei

Abstract

In late 2022, various Omicron subvariants emerged and cocirculated worldwide. These variants convergently acquired amino acid substitutions at critical residues in the spike protein, including residues R346, K444, L452, N460, and F486. Here, we characterize the convergent evolution of Omicron subvariants and the properties of one recent lineage of concern, BQ.1.1. Our phylogenetic analysis suggests that these five substitutions are recurrently acquired, particularly in younger Omicron lineages. Epidemic dynamics modelling suggests that the five substitutions increase viral fitness, and a large proportion of the fitness variation within Omicron lineages can be explained by these substitutions. Compared to BA.5, BQ.1.1 evades breakthrough BA.2 and BA.5 infection sera more efficiently, as demonstrated by neutralization assays. The pathogenicity of BQ.1.1 in hamsters is lower than that of BA.5. Our multiscale investigations illuminate the evolutionary rules governing the convergent evolution for known Omicron lineages as of 2022.

Published
2023

14. Virological characteristics of the SARS-CoV-2 XBB variant derived from recombination of two Omicron subvariants

Author

50632098, 10759509, Tamura, Tomokazu, Ito, Jumpei, Uriu, Keiya, Zahradnik, Jiri, Kida, Izumi, Anraku, Yuki, Nasser, Hesham, Shofa, Maya, Oda, Yoshitaka, Lytras, Spyros, Nao, Naganori, Itakura, Yukari, Deguchi, Sayaka, Suzuki, Rigel, Wang, Lei, Begum, MST Monira, Kita, Shunsuke, Yajima, Hisano, Sasaki, Jiei, Sasaki-Tabata, Kaori, Shimizu, Ryo, Tsuda, Masumi, Kosugi, Yusuke, Fujita, Shigeru, Pan, Lin, Sauter, Daniel, Yoshimatsu, Kumiko, Suzuki, Saori, Asakura, Hiroyuki, Nagashima, Mami, Sadamasu, Kenji, Yoshimura, Kazuhisa, Yamamoto, Yuki, Nagamoto, Tetsuharu, Schreiber, Gideon, Maenaka, Katsumi, The Genotype to Phenotype Japan (G2P-Japan), Hashiguchi, Takao, Ikeda, Terumasa, Fukuhara, Takasuke, Saito, Akatsuki, Tanaka, Shinya, Matsuno, Keita, Takayama, Kazuo, Sato, Kei, 50632098, 10759509, Tamura, Tomokazu, Ito, Jumpei, Uriu, Keiya, Zahradnik, Jiri, Kida, Izumi, Anraku, Yuki, Nasser, Hesham, Shofa, Maya, Oda, Yoshitaka, Lytras, Spyros, Nao, Naganori, Itakura, Yukari, Deguchi, Sayaka, Suzuki, Rigel, Wang, Lei, Begum, MST Monira, Kita, Shunsuke, Yajima, Hisano, Sasaki, Jiei, Sasaki-Tabata, Kaori, Shimizu, Ryo, Tsuda, Masumi, Kosugi, Yusuke, Fujita, Shigeru, Pan, Lin, Sauter, Daniel, Yoshimatsu, Kumiko, Suzuki, Saori, Asakura, Hiroyuki, Nagashima, Mami, Sadamasu, Kenji, Yoshimura, Kazuhisa, Yamamoto, Yuki, Nagamoto, Tetsuharu, Schreiber, Gideon, Maenaka, Katsumi, The Genotype to Phenotype Japan (G2P-Japan), Hashiguchi, Takao, Ikeda, Terumasa, Fukuhara, Takasuke, Saito, Akatsuki, Tanaka, Shinya, Matsuno, Keita, Takayama, Kazuo, and Sato, Kei

Abstract

In late 2022, SARS-CoV-2 Omicron subvariants have become highly diversified, and XBB is spreading rapidly around the world. Our phylogenetic analyses suggested that XBB emerged through the recombination of two cocirculating BA.2 lineages, BJ.1 and BM.1.1.1 (a progeny of BA.2.75), during the summer of 2022. XBB.1 is the variant most profoundly resistant to BA.2/5 breakthrough infection sera to date and is more fusogenic than BA.2.75. The recombination breakpoint is located in the receptor-binding domain of spike, and each region of the recombinant spike confers immune evasion and increases fusogenicity. We further provide the structural basis for the interaction between XBB.1 spike and human ACE2. Finally, the intrinsic pathogenicity of XBB.1 in male hamsters is comparable to or even lower than that of BA.2.75. Our multiscale investigation provides evidence suggesting that XBB is the first observed SARS-CoV-2 variant to increase its fitness through recombination rather than substitutions.

Published
2023

15. Convergent evolution of SARS-CoV-2 Omicron subvariants leading to the emergence of BQ.1.1 variant

Author

Ito, Jumpei, Suzuki, Rigel, Uriu, Keiya, Itakura, Yukari, Zahradnik, Jiri, Kimura, Kanako Terakado, Deguchi, Sayaka, Wang, Lei, Lytras, Spyros, Tamura, Tomokazu, Kida, Izumi, Nasser, Hesham, Shofa, Maya, Begum, Mst Monira, Tsuda, Masumi, Oda, Yoshitaka, Suzuki, Tateki, Sasaki, Jiei, Sasaki-Tabata, Kaori, Fujita, Shigeru, Yoshimatsu, Kumiko, Ito, Hayato, Nao, Naganori, Asakura, Hiroyuki, Nagashima, Mami, Sadamasu, Kenji, Yoshimura, Kazuhisa, Yamamoto, Yuki, Nagamoto, Tetsuharu, Kuramochi, Jin, Schreiber, Gideon, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Saito, Akatsuki, Matsuno, Keita, Takayama, Kazuo, Hashiguchi, Takao, Tanaka, Shinya, Fukuhara, Takasuke, Ikeda, Terumasa, and Sato, Kei

Subjects
SARS-CoV-2, Virus–host interactions
Abstract

In late 2022, various Omicron subvariants emerged and cocirculated worldwide. These variants convergently acquired amino acid substitutions at critical residues in the spike protein, including residues R346, K444, L452, N460, and F486. Here, we characterize the convergent evolution of Omicron subvariants and the properties of one recent lineage of concern, BQ.1.1. Our phylogenetic analysis suggests that these five substitutions are recurrently acquired, particularly in younger Omicron lineages. Epidemic dynamics modelling suggests that the five substitutions increase viral fitness, and a large proportion of the fitness variation within Omicron lineages can be explained by these substitutions. Compared to BA.5, BQ.1.1 evades breakthrough BA.2 and BA.5 infection sera more efficiently, as demonstrated by neutralization assays. The pathogenicity of BQ.1.1 in hamsters is lower than that of BA.5. Our multiscale investigations illuminate the evolutionary rules governing the convergent evolution for known Omicron lineages as of 2022., SARS-CoV-2オミクロン株の進化パターンの一端を解明 --スパイクタンパク質の収斂進化が適応度の高い変異株の出現に繋がる--. 京都大学プレスリリース. 2023-05-15.

Published
2023

16. Virological characteristics of the SARS-CoV-2 XBB variant derived from recombination of two Omicron subvariants

Author

Tamura, Tomokazu, Ito, Jumpei, Uriu, Keiya, Zahradnik, Jiri, Kida, Izumi, Anraku, Yuki, Nasser, Hesham, Shofa, Maya, Oda, Yoshitaka, Lytras, Spyros, Nao, Naganori, Itakura, Yukari, Deguchi, Sayaka, Suzuki, Rigel, Wang, Lei, Begum, MST Monira, Kita, Shunsuke, Yajima, Hisano, Sasaki, Jiei, Sasaki-Tabata, Kaori, Shimizu, Ryo, Tsuda, Masumi, Kosugi, Yusuke, Fujita, Shigeru, Pan, Lin, Sauter, Daniel, Yoshimatsu, Kumiko, Suzuki, Saori, Asakura, Hiroyuki, Nagashima, Mami, Sadamasu, Kenji, Yoshimura, Kazuhisa, Yamamoto, Yuki, Nagamoto, Tetsuharu, Schreiber, Gideon, Maenaka, Katsumi, The Genotype to Phenotype Japan (G2P-Japan), Hashiguchi, Takao, Ikeda, Terumasa, Fukuhara, Takasuke, Saito, Akatsuki, Tanaka, Shinya, Matsuno, Keita, Takayama, Kazuo, and Sato, Kei

Subjects
SARS-CoV-2, Virus–host interactions, Viral evolution
Abstract

In late 2022, SARS-CoV-2 Omicron subvariants have become highly diversified, and XBB is spreading rapidly around the world. Our phylogenetic analyses suggested that XBB emerged through the recombination of two cocirculating BA.2 lineages, BJ.1 and BM.1.1.1 (a progeny of BA.2.75), during the summer of 2022. XBB.1 is the variant most profoundly resistant to BA.2/5 breakthrough infection sera to date and is more fusogenic than BA.2.75. The recombination breakpoint is located in the receptor-binding domain of spike, and each region of the recombinant spike confers immune evasion and increases fusogenicity. We further provide the structural basis for the interaction between XBB.1 spike and human ACE2. Finally, the intrinsic pathogenicity of XBB.1 in male hamsters is comparable to or even lower than that of BA.2.75. Our multiscale investigation provides evidence suggesting that XBB is the first observed SARS-CoV-2 variant to increase its fitness through recombination rather than substitutions., オミクロンXBB株の進化経路とウイルス学的特性の解明 --遺伝子組換えによる更なる免疫逃避能力の獲得--. 京都大学プレスリリース. 2023-05-22.

Published
2023

17. SARS-CoV-2 B.1.617 mutations L452 and E484Q are not synergistic for antibody evasion

Author

Ferreira, Isabella, Kemp, Steven, Datir, Rawlings, Saito, Akatsuki, Meng, Bo, Rakshit, Partha, Takaori-Kondo, Akifumi, Kosugi, Yusuke, Uriu, Keiya, Kimura, Izumi, Shirakawa, Kotaro, Abdullahi, Adam, The CITIID-NIHR BioResource COVID-19 Collaboration, The Indian SARS-CoV-2 Genomics Consortium (INSACOG), Agarwal, Anurag, Ozono, Seiya, Tokunaga, Kenzo, Genotype to Phenotype Japan (G2P-Japan) Consortium, Sato, Kei, and Gupta, Ravindra K.

Subjects
infectivity, SARS-CoV-2, COVID-19, Indian variant, covid-19 vaccines, vaccines, evasion, fitness, resistance, spike mutation, antibodies, pathogenicity, antibody escape, neutralizing antibodies, mutation, B.1.617
Abstract

The SARS-CoV-2 B.1.617 variant emerged in the Indian state of Maharashtra in late 2020. There have been fears that two key mutations seen in the receptor binding domain L452R and E484Q would have additive effects on evasion of neutralising antibodies. We report that spike bearing L452R and E484Q confers modestly reduced sensitivity to BNT162b2 mRNA vaccine-elicited antibodies following either first or second dose. The effect is similar in magnitude to the loss of sensitivity conferred by L452R or E484Q alone. These data demonstrate reduced sensitivity to vaccine elicited neutralising antibodies by L452R and E484Q but lack of synergistic loss of sensitivity., SARS-CoV-2 B.1.617系統（俗称「インド株」）のL452R変異とE484Q変異は 中和抗体感受性の低下において、相加的な抵抗性を示さない. 京都大学プレスリリース. 2021-08-24.

Published
2021

18. Virological characteristics of the SARS-CoV-2 Omicron BA.2.75 variant

Author

80728270, 50632098, 10759509, Saito, Akatsuki, Tamura, Tomokazu, Zahradnik, Jiri, Deguchi, Sayaka, Tabata, Koshiro, Anraku, Yuki, Kimura, Izumi, Ito, Jumpei, Yamasoba, Daichi, Nasser, Hesham, Toyoda, Mako, Nagata, Kayoko, Uriu, Keiya, Kosugi, Yusuke, Fujita, Shigeru, Shofa, Maya, Monira Begum, M.S.T., Shimizu, Ryo, Oda, Yoshitaka, Suzuki, Rigel, Ito, Hayato, Nao, Naganori, Wang, Lei, Tsuda, Masumi, Yoshimatsu, Kumiko, Kuramochi, Jin, Kita, Shunsuke, Sasaki-Tabata, Kaori, Fukuhara, Hideo, Maenaka, Katsumi, Yamamoto, Yuki, Nagamoto, Tetsuharu, Asakura, Hiroyuki, Nagashima, Mami, Sadamasu, Kenji, Yoshimura, Kazuhisa, Ueno, Takamasa, Schreiber, Gideon, Takaori-Kondo, Akifumi, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Shirakawa, Kotaro, Sawa, Hirofumi, Irie, Takashi, Hashiguchi, Takao, Takayama, Kazuo, Matsuno, Keita, Tanaka, Shinya, Ikeda, Terumasa, Fukuhara, Takasuke, Sato, Kei, 80728270, 50632098, 10759509, Saito, Akatsuki, Tamura, Tomokazu, Zahradnik, Jiri, Deguchi, Sayaka, Tabata, Koshiro, Anraku, Yuki, Kimura, Izumi, Ito, Jumpei, Yamasoba, Daichi, Nasser, Hesham, Toyoda, Mako, Nagata, Kayoko, Uriu, Keiya, Kosugi, Yusuke, Fujita, Shigeru, Shofa, Maya, Monira Begum, M.S.T., Shimizu, Ryo, Oda, Yoshitaka, Suzuki, Rigel, Ito, Hayato, Nao, Naganori, Wang, Lei, Tsuda, Masumi, Yoshimatsu, Kumiko, Kuramochi, Jin, Kita, Shunsuke, Sasaki-Tabata, Kaori, Fukuhara, Hideo, Maenaka, Katsumi, Yamamoto, Yuki, Nagamoto, Tetsuharu, Asakura, Hiroyuki, Nagashima, Mami, Sadamasu, Kenji, Yoshimura, Kazuhisa, Ueno, Takamasa, Schreiber, Gideon, Takaori-Kondo, Akifumi, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Shirakawa, Kotaro, Sawa, Hirofumi, Irie, Takashi, Hashiguchi, Takao, Takayama, Kazuo, Matsuno, Keita, Tanaka, Shinya, Ikeda, Terumasa, Fukuhara, Takasuke, and Sato, Kei

Abstract

The SARS-CoV-2 Omicron BA.2.75 variant emerged in May 2022. BA.2.75 is a BA.2 descendant but is phylogenetically distinct from BA.5, the currently predominant BA.2 descendant. Here, we show that BA.2.75 has a greater effective reproduction number and different immunogenicity profile than BA.5. We determined the sensitivity of BA.2.75 to vaccinee and convalescent sera as well as a panel of clinically available antiviral drugs and antibodies. Antiviral drugs largely retained potency but antibody sensitivity varied depending on several key BA.2.75-specific substitutions. The BA.2.75 spike exhibited a profoundly higher affinity for its human receptor, ACE2. Additionally, the fusogenicity, growth efficiency in human alveolar epithelial cells, and intrinsic pathogenicity in hamsters of BA.2.75 were greater than those of BA.2. Our multilevel investigations suggest that BA.2.75 acquired virological properties independent of BA.5, and the potential risk of BA.2.75 to global health is greater than that of BA.5.

Published
2022

19. Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts tropism and fusogenicity

Author

80728270, Meng, Bo, Abdullahi, Adam, Ferreira, Isabella A. T. M., Goonawardane, Niluka, Saito, Akatsuki, Kimura, Izumi, Yamasoba, Daichi, Gerber, Pehuén Pereyra, Fatihi, Saman, Rathore, Surabhi, Zepeda, Samantha K., Papa, Guido, Kemp, Steven A., Ikeda, Terumasa, Toyoda, Mako, Tan, Toong Seng, Kuramochi, Jin, Mitsunaga, Shigeki, Ueno, Takamasa, Shirakawa, Kotaro, Takaori-Kondo, Akifumi, Brevini, Teresa, Mallery, Donna L., Charles, Oscar J., The CITIID-NIHR BioResource COVID-19 Collaboration, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Ecuador-COVID19 Consortium, Bowen, John E., Joshi, Anshu, Walls, Alexandra C., Jackson, Laurelle, Martin, Darren, Smith, Kenneth G. C., Bradley, John, Briggs, John A. G., Choi, Jinwook, Madissoon, Elo, Meyer, Kerstin, Mlcochova, Petra, Ceron-Gutierrez, Lourdes, Doffinger, Rainer, Teichmann, Sarah A., Fisher, Andrew J., Pizzuto, Matteo S., de Marco, Anna, Corti, Davide, Hosmillo, Myra, Lee, Joo Hyeon, James, Leo C., Thukral, Lipi, Veesler, David, Sigal, Alex, Sampaziotis, Fotios, Goodfellow, Ian G., Matheson, Nicholas J., Sato, Kei, Gupta, Ravindra K., 80728270, Meng, Bo, Abdullahi, Adam, Ferreira, Isabella A. T. M., Goonawardane, Niluka, Saito, Akatsuki, Kimura, Izumi, Yamasoba, Daichi, Gerber, Pehuén Pereyra, Fatihi, Saman, Rathore, Surabhi, Zepeda, Samantha K., Papa, Guido, Kemp, Steven A., Ikeda, Terumasa, Toyoda, Mako, Tan, Toong Seng, Kuramochi, Jin, Mitsunaga, Shigeki, Ueno, Takamasa, Shirakawa, Kotaro, Takaori-Kondo, Akifumi, Brevini, Teresa, Mallery, Donna L., Charles, Oscar J., The CITIID-NIHR BioResource COVID-19 Collaboration, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Ecuador-COVID19 Consortium, Bowen, John E., Joshi, Anshu, Walls, Alexandra C., Jackson, Laurelle, Martin, Darren, Smith, Kenneth G. C., Bradley, John, Briggs, John A. G., Choi, Jinwook, Madissoon, Elo, Meyer, Kerstin, Mlcochova, Petra, Ceron-Gutierrez, Lourdes, Doffinger, Rainer, Teichmann, Sarah A., Fisher, Andrew J., Pizzuto, Matteo S., de Marco, Anna, Corti, Davide, Hosmillo, Myra, Lee, Joo Hyeon, James, Leo C., Thukral, Lipi, Veesler, David, Sigal, Alex, Sampaziotis, Fotios, Goodfellow, Ian G., Matheson, Nicholas J., Sato, Kei, and Gupta, Ravindra K.

Abstract

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and bears multiple spike mutations2. Here we show that Omicron spike has higher affinity for ACE2 compared to Delta as well as a marked change of antigenicity conferring significant evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralising antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralisation. Importantly, antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lower airway organoids, lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared to Delta. Replication differences mapped to entry efficiency using spike pseudotyped virus (PV) assays. The defect for Omicron PV to enter specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and knock down of TMPRSS2 impacted Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently utilises the cellular protease TMPRSS2 that promotes cell entry via plasma membrane fusion, with greater dependency on cell entry via the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to utilise TMPRSS2, syncytium formation by the Omicron spike was markedly impaired compared to the Delta spike. Omicron’s less efficient spike cleavage at S1/S2 is associated with shift in cellular tropism away from TMPRSS2 expressing cells, with implications for altered pathogenesis.

Published
2022

20. The SARS-CoV-2 Lambda variant exhibits enhanced infectivity and immune resistance

Author

80728270, Kimura, Izumi, Kosugi, Yusuke, Wu, Jiaqi, Zahradnik, Jiri, Yamasoba, Daichi, Butlertanaka, Erika P., Tanaka, Yuri L., Uriu, Keiya, Liu, Yafei, Morizako, Nanami, Shirakawa, Kotaro, Kazuma, Yasuhiro, Nomura, Ryosuke, Horisawa, Yoshihito, Tokunaga, Kenzo, Ueno, Takamasa, Takaori-Kondo, Akifumi, Schreiber, Gideon, Arase, Hisashi, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Motozono, Chihiro, Saito, Akatsuki, Nakagawa, So, Sato, Kei, 80728270, Kimura, Izumi, Kosugi, Yusuke, Wu, Jiaqi, Zahradnik, Jiri, Yamasoba, Daichi, Butlertanaka, Erika P., Tanaka, Yuri L., Uriu, Keiya, Liu, Yafei, Morizako, Nanami, Shirakawa, Kotaro, Kazuma, Yasuhiro, Nomura, Ryosuke, Horisawa, Yoshihito, Tokunaga, Kenzo, Ueno, Takamasa, Takaori-Kondo, Akifumi, Schreiber, Gideon, Arase, Hisashi, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Motozono, Chihiro, Saito, Akatsuki, Nakagawa, So, and Sato, Kei

Abstract

SARS-CoV-2 Lambda, a variant of interest, has spread in some South American countries; however, its virological features and evolutionary traits remain unknown. In this study, we use pseudoviruses and reveal that the spike protein of the Lambda variant is more infectious than that of other variants due to the T76I and L452Q mutations. The RSYLTPGD246-253N mutation, a unique 7-amino-acid deletion in the N-terminal domain of the Lambda spike protein, is responsible for evasion from neutralizing antibodies and further augments antibody-mediated enhancement of infection. Although this mutation generates a nascent N-linked glycosylation site, the additional N-linked glycan is dispensable for the virological property conferred by this mutation. Since the Lambda variant has dominantly spread according to the increasing frequency of the isolates harboring the RSYLTPGD246-253N mutation, our data suggest that the RSYLTPGD246-253N mutation is closely associated with the substantial spread of the Lambda variant in South America.

Published
2022

21. The SARS-CoV-2 Lambda variant exhibits enhanced infectivity and immune resistance

Author

Kimura, Izumi, Kosugi, Yusuke, Wu, Jiaqi, Zahradnik, Jiri, Yamasoba, Daichi, Butlertanaka, Erika P., Tanaka, Yuri L., Uriu, Keiya, Liu, Yafei, Morizako, Nanami, Shirakawa, Kotaro, Kazuma, Yasuhiro, Nomura, Ryosuke, Horisawa, Yoshihito, Tokunaga, Kenzo, Ueno, Takamasa, Takaori-Kondo, Akifumi, Schreiber, Gideon, Arase, Hisashi, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Motozono, Chihiro, Saito, Akatsuki, Nakagawa, So, and Sato, Kei

Subjects
Adult, Male, Lambda, Glycosylation, SARS-CoV-2, Immunity, COVID-19, C.37, Middle Aged, Antibodies, Viral, spike protein, Antibodies, Neutralizing, General Biochemistry, Genetics and Molecular Biology, Cell Line, HEK293 Cells, Report, Mutation, Spike Glycoprotein, Coronavirus, Humans, Female, Aged
Abstract

SARS-CoV-2 Lambda, a variant of interest, has spread in some South American countries; however, its virological features and evolutionary traits remain unknown. In this study, we use pseudoviruses and reveal that the spike protein of the Lambda variant is more infectious than that of other variants due to the T76I and L452Q mutations. The RSYLTPGD246-253N mutation, a unique 7-amino-acid deletion in the N-terminal domain of the Lambda spike protein, is responsible for evasion from neutralizing antibodies and further augments antibody-mediated enhancement of infection. Although this mutation generates a nascent N-linked glycosylation site, the additional N-linked glycan is dispensable for the virological property conferred by this mutation. Since the Lambda variant has dominantly spread according to the increasing frequency of the isolates harboring the RSYLTPGD246-253N mutation, our data suggest that the RSYLTPGD246-253N mutation is closely associated with the substantial spread of the Lambda variant in South America., Graphical Abstract, Kimura et al. reveal the characteristics of SARS-CoV-2 Lambda variant of interest. Lambda spike is more infectious than that of other variants due to the T76I and L452Q mutations. The RSYLTPGD246-253N mutation is responsible for evasion from neutralizing antibodies and further augments antibody-mediated enhancement of infection.

Published
2022

22. Virological characteristics of the SARS-CoV-2 Omicron BA.2.75 variant

Author

Saito, Akatsuki, Tamura, Tomokazu, Zahradnik, Jiri, Deguchi, Sayaka, Tabata, Koshiro, Anraku, Yuki, Kimura, Izumi, Ito, Jumpei, Yamasoba, Daichi, Nasser, Hesham, Toyoda, Mako, Nagata, Kayoko, Uriu, Keiya, Kosugi, Yusuke, Fujita, Shigeru, Shofa, Maya, Monira Begum, M.S.T., Shimizu, Ryo, Oda, Yoshitaka, Suzuki, Rigel, Ito, Hayato, Nao, Naganori, Wang, Lei, Tsuda, Masumi, Yoshimatsu, Kumiko, Kuramochi, Jin, Kita, Shunsuke, Sasaki-Tabata, Kaori, Fukuhara, Hideo, Maenaka, Katsumi, Yamamoto, Yuki, Nagamoto, Tetsuharu, Asakura, Hiroyuki, Nagashima, Mami, Sadamasu, Kenji, Yoshimura, Kazuhisa, Ueno, Takamasa, Schreiber, Gideon, Takaori-Kondo, Akifumi, The Genotype to Phenotype Japan (G2P-Japan) Consortium, Shirakawa, Kotaro, Sawa, Hirofumi, Irie, Takashi, Hashiguchi, Takao, Takayama, Kazuo, Matsuno, Keita, Tanaka, Shinya, Ikeda, Terumasa, Fukuhara, Takasuke, and Sato, Kei

Subjects
SARS-CoV-2, Omicron, antiviral drug resistance, COVID-19, Antibodies, Viral, Antibodies, Neutralizing, Antiviral Agents, Microbiology, Virology, Spike Glycoprotein, Coronavirus, Humans, BA.2.75, transmissibility, pathogenicity, Parasitology, immune resistance, COVID-19 Serotherapy
Abstract

The SARS-CoV-2 Omicron BA.2.75 variant emerged in May 2022. BA.2.75 is a BA.2 descendant but is phylogenetically distinct from BA.5, the currently predominant BA.2 descendant. Here, we show that BA.2.75 has a greater effective reproduction number and different immunogenicity profile than BA.5. We determined the sensitivity of BA.2.75 to vaccinee and convalescent sera as well as a panel of clinically available antiviral drugs and antibodies. Antiviral drugs largely retained potency but antibody sensitivity varied depending on several key BA.2.75-specific substitutions. The BA.2.75 spike exhibited a profoundly higher affinity for its human receptor, ACE2. Additionally, the fusogenicity, growth efficiency in human alveolar epithelial cells, and intrinsic pathogenicity in hamsters of BA.2.75 were greater than those of BA.2. Our multilevel investigations suggest that BA.2.75 acquired virological properties independent of BA.5, and the potential risk of BA.2.75 to global health is greater than that of BA.5., SARS-CoV-2オミクロンBA.2.75株（通称ケンタウロス）のウイルス学的性状の解明. 京都大学プレスリリース. 2022-10-12.

Published
2022
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23. SARS-CoV-2 B.1.617 mutations L452 and E484Q are not synergistic for antibody evasion

Author

80728270, Ferreira, Isabella, Kemp, Steven, Datir, Rawlings, Saito, Akatsuki, Meng, Bo, Rakshit, Partha, Takaori-Kondo, Akifumi, Kosugi, Yusuke, Uriu, Keiya, Kimura, Izumi, Shirakawa, Kotaro, Abdullahi, Adam, The CITIID-NIHR BioResource COVID-19 Collaboration, The Indian SARS-CoV-2 Genomics Consortium (INSACOG), Agarwal, Anurag, Ozono, Seiya, Tokunaga, Kenzo, Genotype to Phenotype Japan (G2P-Japan) Consortium, Sato, Kei, Gupta, Ravindra K., 80728270, Ferreira, Isabella, Kemp, Steven, Datir, Rawlings, Saito, Akatsuki, Meng, Bo, Rakshit, Partha, Takaori-Kondo, Akifumi, Kosugi, Yusuke, Uriu, Keiya, Kimura, Izumi, Shirakawa, Kotaro, Abdullahi, Adam, The CITIID-NIHR BioResource COVID-19 Collaboration, The Indian SARS-CoV-2 Genomics Consortium (INSACOG), Agarwal, Anurag, Ozono, Seiya, Tokunaga, Kenzo, Genotype to Phenotype Japan (G2P-Japan) Consortium, Sato, Kei, and Gupta, Ravindra K.

Abstract

The SARS-CoV-2 B.1.617 variant emerged in the Indian state of Maharashtra in late 2020. There have been fears that two key mutations seen in the receptor binding domain L452R and E484Q would have additive effects on evasion of neutralising antibodies. We report that spike bearing L452R and E484Q confers modestly reduced sensitivity to BNT162b2 mRNA vaccine-elicited antibodies following either first or second dose. The effect is similar in magnitude to the loss of sensitivity conferred by L452R or E484Q alone. These data demonstrate reduced sensitivity to vaccine elicited neutralising antibodies by L452R and E484Q but lack of synergistic loss of sensitivity.

Published
2021

24. Increased flexibility of the SARS-CoV-2 RNA-binding site causes resistance to remdesivir.

Author

Shiho Torii, Kwang Su Kim, Jun Koseki, Rigel Suzuki, Shoya Iwanami, Yasuhisa Fujita, Yong Dam Jeong, Jumpei Ito, Hiroyuki Asakura, Mami Nagashima, Kenji Sadamasu, Kazuhisa Yoshimura, Genotype to Phenotype Japan (G2P-Japan) Consortium, Kei Sato, Yoshiharu Matsuura, Teppei Shimamura, Shingo Iwami, and Takasuke Fukuhara

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

Mutations continue to accumulate within the SARS-CoV-2 genome, and the ongoing epidemic has shown no signs of ending. It is critical to predict problematic mutations that may arise in clinical environments and assess their properties in advance to quickly implement countermeasures against future variant infections. In this study, we identified mutations resistant to remdesivir, which is widely administered to SARS-CoV-2-infected patients, and discuss the cause of resistance. First, we simultaneously constructed eight recombinant viruses carrying the mutations detected in in vitro serial passages of SARS-CoV-2 in the presence of remdesivir. We confirmed that all the mutant viruses didn't gain the virus production efficiency without remdesivir treatment. Time course analyses of cellular virus infections showed significantly higher infectious titers and infection rates in mutant viruses than wild type virus under treatment with remdesivir. Next, we developed a mathematical model in consideration of the changing dynamic of cells infected with mutant viruses with distinct propagation properties and defined that mutations detected in in vitro passages canceled the antiviral activities of remdesivir without raising virus production capacity. Finally, molecular dynamics simulations of the NSP12 protein of SARS-CoV-2 revealed that the molecular vibration around the RNA-binding site was increased by the introduction of mutations on NSP12. Taken together, we identified multiple mutations that affected the flexibility of the RNA binding site and decreased the antiviral activity of remdesivir. Our new insights will contribute to developing further antiviral measures against SARS-CoV-2 infection.

Published
2023
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25. SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Author

Mlcochova, Petra, Kemp, Steven A., Dhar, Mahesh Shanker, Papa, Guido, Meng, Bo, Ferreira, Isabella A. T. M., Datir, Rawlings, Collier, Dami A., Albecka, Anna, Singh, Sujeet, Pandey, Rajesh, Brown, Jonathan, Zhou, Jie, Goonawardane, Niluka, Mishra, Swapnil, Whittaker, Charles, Mellan, Thomas, Marwal, Robin, Datta, Meena, Sengupta, Shantanu, Ponnusamy, Kalaiarasan, Radhakrishnan, Venkatraman Srinivasan, Abdullahi, Adam, Charles, Oscar, Chattopadhyay, Partha, Devi, Priti, Caputo, Daniela, Peacock, Tom, Wattal, Chand, Goel, Neeraj, Satwik, Ambrish, Vaishya, Raju, Agarwal, Meenakshi, Chauhan, Himanshu, Dikid, Tanzin, Gogia, Hema, Lall, Hemlata, Verma, Kaptan, Singh, Manoj K., Soni, Namita, Meena, Namonarayan, Madan, Preeti, Singh, Priyanka, Sharma, Ramesh, Sharma, Rajeev, Kabra, Sandhya, Kumar, Sattender, Kumari, Swati, Sharma, Uma, Chaudhary, Urmila, Sivasubbu, Sridhar, Scaria, Vinod, Oberoi, J. K., Raveendran, Reena, Datta, S., Das, Saumitra, Maitra, Arindam, Chinnaswamy, Sreedhar, Biswas, Nidhan Kumar, Parida, Ajay, Raghav, Sunil K., Prasad, Punit, Sarin, Apurva, Mayor, Satyajit, Ramakrishnan, Uma, Palakodeti, Dasaradhi, Seshasayee, Aswin Sai Narain, Thangaraj, K., Bashyam, Murali Dharan, Dalal, Ashwin, Bhat, Manoj, Shouche, Yogesh, Pillai, Ajay, Abraham, Priya, Potdar, Varsha Atul, Cherian, Sarah S., Desai, Anita Sudhir, Pattabiraman, Chitra, Manjunatha, M. V., Mani, Reeta S., Udupi, Gautam Arunachal, Nandicoori, Vinay, Tallapaka, Karthik Bharadwaj, Sowpati, Divya Tej, Kawabata, Ryoko, Morizako, Nanami, Sadamasu, Kenji, Asakura, Hiroyuki, Nagashima, Mami, Yoshimura, Kazuhisa, Ito, Jumpei, Kimura, Izumi, Uriu, Keiya, Kosugi, Yusuke, Suganami, Mai, Oide, Akiko, Yokoyama, Miyabishara, Chiba, Mika, Saito, Akatsuki, Butlertanaka, Erika P., Tanaka, Yuri L., Ikeda, Terumasa, Motozono, Chihiro, Nasser, Hesham, Shimizu, Ryo, Yuan, Yue, Kitazato, Kazuko, Hasebe, Haruyo, Nakagawa, So, Wu, Jiaqi, Takahashi, Miyoko, Fukuhara, Takasuke, Shimizu, Kenta, Tsushima, Kana, Kubo, Haruko, Shirakawa, Kotaro, Kazuma, Yasuhiro, Nomura, Ryosuke, Horisawa, Yoshihito, Takaori-Kondo, Akifumi, Tokunaga, Kenzo, Ozono, Seiya, Baker, Stephen, Dougan, Gordon, Hess, Christoph, Kingston, Nathalie, Lehner, Paul J., Lyons, Paul A., Matheson, Nicholas J., Owehand, Willem H., Saunders, Caroline, Summers, Charlotte, Thaventhiran, James E. D., Toshner, Mark, Weekes, Michael P., Maxwell, Patrick, Shaw, Ashley, Bucke, Ashlea, Calder, Jo, Canna, Laura, Domingo, Jason, Elmer, Anne, Fuller, Stewart, Harris, Julie, Hewitt, Sarah, Kennet, Jane, Jose, Sherly, Kourampa, Jenny, Meadows, Anne, O'Brien, Criona, Price, Jane, Publico, Cherry, Rastall, Rebecca, Ribeiro, Carla, Rowlands, Jane, Ruffolo, Valentina, Tordesillas, Hugo, Bullman, Ben, Dunmore, Benjamin J., Fawke, Stuart, Graf, Stefan, Hodgson, Josh, Huang, Christopher, Hunter, Kelvin, Jones, Emma, Legchenko, Ekaterina, Matara, Cecilia, Martin, Jennifer, Mescia, Federica, O'Donnell, Ciara, Pointon, Linda, Pond, Nicole, Shih, Joy, Sutcliffe, Rachel, Tilly, Tobias, Treacy, Carmen, Tong, Zhen, Wood, Jennifer, Wylot, Marta, Bergamaschi, Laura, Betancourt, Ariana, Bower, Georgie, Cossetti, Chiara, De Sa, Aloka, Epping, Madeline, Gleadall, Nick, Grenfell, Richard, Hinch, Andrew, Huhn, Oisin, Jackson, Sarah, Jarvis, Isobel, Krishna, Ben, Lewis, Daniel, Marsden, Joe, Nice, Francesca, Okecha, Georgina, Omarjee, Ommar, Perera, Marianne, Potts, Martin, Richoz, Nathan, Romashova, Veronika, Yarkoni, Natalia Savinykh, Sharma, Rahul, Stefanucci, Luca, Stephens, Jonathan, Strezlecki, Mateusz, Turner, Lori, De Bie, Eckart M. D. D., Bunclark, Katherine, Josipovic, Masa, Mackay, Michael, Rossi, Sabrina, Selvan, Mayurun, Spencer, Sarah, Yong, Cissy, Allison, John, Butcher, Helen, Clapham-Riley, Debbie, Dewhurst, Eleanor, Furlong, Anita, Graves, Barbara, Gray, Jennifer, Ivers, Tasmin, Kasanicki, Mary, Le Gresley, Emma, Linger, Rachel, Meloy, Sarah, Muldoon, Francesca, Ovington, Nigel, Papadia, Sofia, Phelan, Isabel, Stark, Hannah, Stirrups, Kathleen E., Townsend, Paul, Walker, Neil, Webster, Jennifer, Scholtes, Ingrid, Hein, Sabine, King, Rebecca, Mavousian, Antranik, Lee, Joo Hyeon, Bassi, Jessica, Silacci-Fegni, Chiara, Saliba, Christian, Pinto, Dora, Irie, Takashi, Yoshida, Isao, Hamilton, William L., Sato, Kei, Bhatt, Samir, Flaxman, Seth, James, Leo C., Corti, Davide, Piccoli, Luca, Barclay, Wendy S., Rakshit, Partha, Agrawal, Anurag, Gupta, Ravindra K., (INSACOG), Indian SARS-CoV-2 Genomics Consortium, Consortium, Genotype to Phenotype Japan (G2P-Japan), Collaboration, CITIID-NIHR BioResource COVID-19, Gupta, Ravindra K [0000-0001-9751-1808], Apollo - University of Cambridge Repository, and Gupta, Ravindra K. [0000-0001-9751-1808]

Subjects
Male, COVID-19 Vaccines, medicine.drug_class, Health Personnel, India, Monoclonal antibody, Virus Replication, Antibodies, Cell Line, Cell Fusion, Immune system, 13/100, medicine, Humans, Neutralizing antibody, Antibodies, Neutralizing, Female, Kinetics, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Vaccination, Immune Evasion, Neutralizing, 631/326/596/4130, Syncytium, Multidisciplinary, Cell fusion, biology, article, Vaccine efficacy, 631/250/254, Virology, Spike Glycoprotein, Coronavirus, 13/31, biology.protein, Antibody, Infection
Abstract

The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era., A study of SARS-CoV-2 variants examining their transmission, infectivity, and potential resistance to therapies provides insights into the biology of the Delta variant and its role in the global pandemic.

Published
2022
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