As of November, 2023, SARS-CoV-2 XBB variants, including EG.5.1 (XBB.1.9.2.5.1), the currently predominant lineage, have been circulating worldwide, according to Nextstrain datasets. The EG.5.1 strain has a characteristic amino acid substitution in the spike protein (S; S:F456L), which allows the strain to escape humoral immunity (appendix p 16).1Kaku Y Kosugi Y Uriu K et al.Antiviral efficacy of the SARS-CoV-2 XBB breakthrough infection sera against omicron subvariants including EG.5.Lancet Infect Dis. 2023; 23: e395-e396Summary Full Text Full Text PDF PubMed Google Scholar EG.5.1 has further evolved, and its descendant lineage harbouring the S:L455F (ie, EG.5.1+S:L455F) variant has emerged and has been named HK.3 (XBB.1.9.2.5.1.1.3). HK.3 was initially discovered in east Asia and is rapidly spreading worldwide. Notably, the XBB subvariants bearing both S:L455F and S:F456L substitutions, including HK.3, are defined as FLip variants. These FLip variants, including JG.3 (XBB.1.9.2.5.1.3.3), JF.1 (XBB.1.16.6.1), and GK.3 (XBB.1.5.70.3) have emerged concurrently, suggesting that the acquisition of these two substitutions confers a growth advantage to XBB in the human population.2Ito J Suzuki R Uriu K et al.Convergent evolution of SARS-CoV-2 omicron subvariants leading to the emergence of BQ.1.1 variant.Nat Commun. 2023; 14: 2671Crossref PubMed Scopus (19) Google Scholar,3Bloom JD Neher RA Fitness effects of mutations to SARS-CoV-2 proteins.Virus Evol. 2023; 9vead055Crossref Scopus (2) Google Scholar We investigated the virological properties of HK.3 as a representative of the FLip variants. We estimated the relative effective reproduction number (Re) of HK.3 on the basis of genome surveillance data obtained from 13 countries reporting the substantial presence of HK.3 with a Bayesian hierarchical multinomial logistic regression model (appendix pp 9–14, 16).4Yamasoba D Kimura I Nasser H et al.Virological characteristics of the SARS-CoV-2 omicron BA.2 spike.Cell. 2022; 185: 2103-2115.e19Summary Full Text Full Text PDF PubMed Scopus (149) Google Scholar The global mean Re for HK.3 was 1·29 times higher than that of XBB.1.5 and 1·12 higher than that of EG.5.1, suggesting that HK.3 might soon become the predominant lineage worldwide. As of Oct 15, 2023, the HK.3 variant has outcompeted EG.5.1 in countries such as Australia, China, South Korea, and Singapore (appendix p 16). Next, to identify whether the enhanced infectivity of HK.3 contributes to its higher Re, we constructed lentivirus-based pseudoviruses carrying the S proteins XBB.1.5, EG.5.1, HK.3, and an XBB.1.5 derivative, XBB.1.5+L455F. Although the S:L455F substitution significantly increased the infectivity of XBB.1.5, the infectivity of HK.3 (identical to EG.5.1+S:L455F) was similar to that of EG.5.1 (appendix p 16). The difference in the effect of S:L455F between XBB.1.5 and EG.5.1 might be attributed to the epistatic effects due to the S protein structures of XBB.1.5 and EG.5.1. These results suggest that the increased Re of HK.3 is not owing to the increased infectivity caused by S:L455F. We then performed a neutralisation assay using breakthrough infection serum samples (XBB.1.5 [n=20], XBB.1.9 [n=15], XBB.1.16 [n=20], or EG.5.1 [n=18]) to address whether HK.3 evades the antiviral response of humoral immunity induced by breakthrough infection of these variants. The 50% neutralisation titre (NT50) for all breakthrough infection serum samples tested against XBB.1.5+S:L455F was significantly lower than that observed against the parental XBB.1.5 strain (appendix p 16). Notably, the NT50 for EG.5.1 breakthrough infection serum samples against HK.3 was significantly lower (1·6 times, p=0·0003) than that observed against EG.5.1 (appendix p 16). Thus, the increased Re of HK.3 might be partly attributed to the enhanced immune evasion from humoral immunity elicited by breakthrough infection subvariants of XBB, including EG.5.1, its ancestor. S:L455F is a key mutation leading to this immune evasion. JI has received consulting fees and honoraria for lectures from Takeda Pharmaceutical. KSat has received consulting fees from Moderna Japan and Takeda Pharmaceutical and has received honoraria for lectures from Gilead Sciences, Moderna Japan, and Shionogi & Co. All other authors declare no competing interests. YKo, AP, and OP contributed equally. This work was supported in part by the Japan Agency for Medical Research and Development (AMED) Strategic Center of Biomedical Advanced Vaccine Research and Development for Preparedness and Response (SCARDA) Japan Initiative for World-leading Vaccine Research and Development Centers UTOPIA (JP223fa627001, to KSat), AMED SCARDA Programme on R&D of New Generation Vaccine including New Modality Application (JP223fa727002, to KSat); AMED Research Programme on Emerging and Re-emerging Infectious Diseases (JP22fk0108146, to KSat; JP21fk0108494, to G2P-Japan Consortium and KSat; JP21fk0108425, to KSat; JP21fk0108432, to KSat; JP22fk0108511, to G2P-Japan Consortium and KSat; JP22fk0108516, to KSat; JP22fk0108506, to KSat); AMED Research Programme on HIV/AIDS (JP22fk0410039, to KSat); JST PRESTO (JPMJPR22R1, to JI); JST CREST (JPMJCR20H4, to KSat); JSPS KAKENHI Grant-in-Aid for Early-Career Scientists (23K14526, to JI); JSPS Core-to-Core Program (A. Advanced Research Networks) (JPJSCCA20190008, to KSat); JSPS Research Fellow DC2 (22J11578, to KU); JSPS Research Fellow DC1 (23KJ0710, to YKo); The Tokyo Biochemical Research Foundation (to KSat); and The Mitsubishi Foundation (to KSat). Members of the G2P-Japan Consortium are listed in the appendix (p 18). Download .pdf (.63 MB) Help with pdf files Supplementary appendix
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.
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.
Abstract The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants has led to concerns that ancestral SARS-CoV-2-based vaccines may not be effective against newly emerging Omicron subvariants. The concept of “imprinted immunity” suggests that individuals vaccinated with ancestral virus-based vaccines may not develop effective immunity against newly emerging Omicron subvariants, such as BQ.1.1 and XBB.1. In this study, we investigated this possibility using hamsters. Although natural infection induced effective antiviral immunity, breakthrough infections in hamsters with BQ.1.1 and XBB.1 Omicron subvariants after receiving the 3-dose mRNA-lipid nanoparticle vaccine resulted in only faintly induced humoral immunity, supporting the possibility of imprinted immunity.
A total of 593 cats consisting of 144 adults and 449 kittens obtained from Animal Protection Center, Prefecture of Kanagawa, were examined. Of these, 51 (8.6%) had Campylobacter, 12 (2.1%) had Yersinia, and 8 (1.4%) had Salmonella. In adult cats, the respective recovery rates of the 3 bacteria were 9.0, 5.8, and 2.1% and in kittens, 8.5, 0.9, and 1.1%. Of 64 Campylobacter strains, 48 from 36 cats were identified as C. jejuni and 16 from 16 cats were as C. coli. Of 12 Yersinia strains, 6 were identified as Y. enterocolitica, 5 were as Y. frederiksenii, and 1 was as Y. pseudotuberculosis. Biovars (Wauters) of the 6 Y. enterocolitica strains were biovar 1 (5 strains) and biovar 2 (1 strain) and their serovars were 06 (1 strain), 07 (1 strain), 014 (1 strain), and ungroupable other than 01 to 033 (3 strains). Eight Salmonella strains were all identified as S. choleraesuis subsp. choleraesuis and belonged to 4 serovars, agona (3 strains), blockley (3 strains), braenderup (1 strain), and typhimurium (1 strain). These results indicate that Campylobacter is carried in the healthy pet cats more frequently than Yersinia and Salmonella.
The efficiency of infection receptor use is the first step in determining the species tropism of viruses. After the coronavirus disease 2019 pandemic, a number of SARS-CoV-2-related coronaviruses (SC2r-CoVs) were identified in
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.
BackgroundAlthough several SARS-CoV-2-related coronaviruses (SC2r-CoVs) were discovered in bats and pangolins, the differences in virological characteristics between SARS-CoV-2 and SC2r-CoVs remain poorly understood. Recently, BANAL-20-236 (B236) was isolated from a rectal swab of Malayan horseshoe bat and was found to lack a furin cleavage site (FCS) in the spike (S) protein. The comparison of its virological characteristics with FCS-deleted SARS-CoV-2 (SC2ΔFCS) has not been conducted yet.MethodsWe prepared human induced pluripotent stem cell (iPSC)-derived airway and lung epithelial cells and colon organoids as human organ-relevant models. B236, SARS-CoV-2, and artificially generated SC2ΔFCS were used for viral experiments. To investigate the pathogenicity of B236 in vivo, we conducted intranasal infection experiments in hamsters.FindingsIn human iPSC-derived airway epithelial cells, the growth of B236 was significantly lower than that of the SC2ΔFCS. A fusion assay showed that the B236 and SC2ΔFCS S proteins were less fusogenic than the SARS-CoV-2 S protein. The infection experiment in hamsters showed that B236 was less pathogenic than SARS-CoV-2 and even SC2ΔFCS. Interestingly, in human colon organoids, the growth of B236 was significantly greater than that of SARS-CoV-2.InterpretationCompared to SARS-CoV-2, we demonstrated that B236 exhibited a tropism toward intestinal cells rather than respiratory cells. Our results are consistent with a previous report showing that B236 is enterotropic in macaques. Altogether, our report strengthens the assumption that SC2r-CoVs in horseshoe bats replicate primarily in the intestinal tissues rather than respiratory tissues.FundingThis study was supported in part by AMED ASPIRE (JP23jf0126002, to Keita Matsuno, Kazuo Takayama, and Kei Sato); AMED SCARDA Japan Initiative for World-leading Vaccine Research and Development Centers "UTOPIA" (JP223fa627001, to Kei Sato), AMED SCARDA Program on R&D of new generation vaccine including new modality application (JP223fa727002, to Kei Sato); AMED SCARDA Hokkaido University Institute for Vaccine Research and Development (HU-IVReD) (JP223fa627005h0001, to Takasuke Fukuhara, and Keita Matsuno); AMED Research Program on Emerging and Re-emerging Infectious Diseases (JP21fk0108574, to Hesham Nasser; JP21fk0108493, to Takasuke Fukuhara; JP22fk0108617 to Takasuke Fukuhara; JP22fk0108146, to Kei Sato; JP21fk0108494 to G2P-Japan Consortium, Keita Matsuno, Shinya Tanaka, Terumasa Ikeda, Takasuke Fukuhara, and Kei Sato; JP21fk0108425, to Kazuo Takayama and Kei Sato; JP21fk0108432, to Kazuo Takayama, Takasuke Fukuhara and Kei Sato; JP22fk0108534, Terumasa Ikeda, and Kei Sato; JP22fk0108511, to Yuki Yamamoto, Terumasa Ikeda, Keita Matsuno, Shinya Tanaka, Kazuo Takayama, Takasuke Fukuhara, and Kei Sato; JP22fk0108506, to Kazuo Takayama and Kei Sato); AMED Research Program on HIV/AIDS (JP22fk0410055, to Terumasa Ikeda; and JP22fk0410039, to Kei Sato); AMED Japan Program for Infectious Diseases Research and Infrastructure (JP22wm0125008 to Keita Matsuno); AMED CREST (JP21gm1610005, to Kazuo Takayama; JP22gm1610008, to Takasuke Fukuhara; JST PRESTO (JPMJPR22R1, to Jumpei Ito); JST CREST (JPMJCR20H4, to Kei Sato); JSPS KAKENHI Fund for the Promotion of Joint International Research (International Leading Research) (JP23K20041, to G2P-Japan Consortium, Keita Matsuno, Takasuke Fukuhara and Kei Sato); JST SPRING (JPMJSP2108 to Shigeru Fujita); JSPS KAKENHI Grant-in-Aid for Scientific Research C (22K07103, to Terumasa Ikeda); JSPS KAKENHI Grant-in-Aid for Scientific Research B (21H02736, to Takasuke Fukuhara); JSPS KAKENHI Grant-in-Aid for Early-Career Scientists (22K16375, to Hesham Nasser; 20K15767, to Jumpei Ito); JSPS Core-to-Core Program (A. Advanced Research Networks) (JPJSCCA20190008, to Kei Sato); JSPS Research Fellow DC2 (22J11578, to Keiya Uriu); JSPS Research Fellow DC1 (23KJ0710, to Yusuke Kosugi); JSPS Leading Initiative for Excellent Young Researchers (LEADER) (to Terumasa Ikeda); World-leading Innovative and Smart Education (WISE) Program 1801 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (to Naganori Nao); Ministry of Health, Labour and Welfare (MHLW) under grant 23HA2010 (to Naganori Nao and Keita Matsuno); The Cooperative Research Program (Joint Usage/Research Center program) of Institute for Life and Medical Sciences, Kyoto University (to Kei Sato); International Joint Research Project of the Institute of Medical Science, the University of Tokyo (to Terumasa Ikeda and Takasuke Fukuhara); The Tokyo Biochemical Research Foundation (to Kei Sato); Takeda Science Foundation (to Terumasa Ikeda and Takasuke Fukuhara); Mochida Memorial Foundation for Medical and Pharmaceutical Research (to Terumasa Ikeda); The Naito Foundation (to Terumasa Ikeda); Hokuto Foundation for Bioscience (to Tomokazu Tamura); Hirose Foundation (to Tomokazu Tamura); and Mitsubishi Foundation (to Kei Sato).
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.
Most studies investigating the characteristics of emerging SARS-CoV-2 variants have been focusing on mutations in the spike proteins that affect viral infectivity, fusogenicity, and pathogenicity. However, few studies have addressed how naturally occurring mutations in the non-
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