This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

The SARS-CoV-2 B.1.617.2 (Delta) variant 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 6-fold less sensitive to serum neutralising antibodies from recovered individuals, and 8-fold less sensitive to vaccine-elicited antibodies as compared to wild type (WT) Wuhan-1 bearing D614G. Serum neutralising titres against B.1.617.2 were lower in ChAdOx-1 versus BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies against the receptor binding domain (RBD) and N-terminal domain (NTD). B.1.617.2 demonstrated higher replication efficiency in both airway organoid and human airway epithelial systems compared to B.1.1.7, associated with B.1.617.2 spike in a predominantly cleaved state compared to B.1.1.7. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralising antibody as compared to WT spike. Additionally we observed that B.1.617.2 had higher replication and spike mediated entry as compared to B.1.617.1, potentially explaining B.1.617.2 dominance. In an analysis of over 130 SARS-CoV-2 infected healthcare workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx-1 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. India's first wave of SARS-CoV-2 infections in mid-2020 was relatively mild and was controlled by a nationwide lockdown. Since easing of restrictions, India has seen expansion in cases of COVID-19 since March

This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.Attenuated replication and pathogenicity of SARS-CoV-2 B.1.1.529 Omicron

This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

Severe acute respiratory syndrome coronavirus (SARS-CoV) is a highrisk infectious pathogen. In the proposed model of respiratory failure, SARS-CoV down-regulates its receptor, angiotensin-converting enzyme 2 (ACE2), but the mechanism involved is unknown. We found that the spike protein of SARS-CoV (SARS-S) induced TNF-␣-converting enzyme (TACE)-dependent shedding of the ACE2 ectodomain. The modulation of TACE activity by SARS-S depended on the cytoplasmic domain of ACE2, because deletion mutants of ACE2 lacking the carboxyl-terminal region did not induce ACE2 shedding or TNF-␣ production. In contrast, the spike protein of HNL63-CoV (NL63-S), a CoV that uses ACE2 as a receptor and mainly induces the common cold, caused neither of these cellular responses. Intriguingly, viral infection, judged by real-time RT-PCR analysis of SARS-CoV mRNA expression, was significantly attenuated by deletion of the cytoplasmic tail of ACE2 or knock-down of TACE expression by siRNA. These data suggest that cellular signals triggered by the interaction of SARS-CoV with ACE2 are positively involved in viral entry but lead to tissue damage. These findings may lead to the development of anti-SARS-CoV agents.shedding ͉ cytoplasmic tail ͉ HNL63-CoV ͉ TNF-␣ S evere acute respiratory syndrome coronavirus (SARS-CoV) is an infectious pathogen known to have caused acute respiratory distress in Ͼ8,000 patients with a mortality rate of Ϸ10% (1). Although outbreaks of SARS-CoV are now well controlled, the mechanism of severe respiratory failure in infected patients is unknown. Angiotensin-converting enzyme 2 (ACE2), an ACE homolog that functions as a positive regulator of the reninangiotensin system (RAS) (2, 3), was identified as a receptor of SARS-CoV (4). A possible indicator of a severe clinical outcome, the spike protein of SARS-CoV (SARS-S) was found to downregulate ACE2 expression (5). ACE2 knockout (KO) mice were also shown to be susceptible to severe respiratory failure after chemical challenge (5, 6), and ACE2 has been shown to moderate ACE-induced intracellular inflammation, suggesting that the mechanism of ACE2 down-regulation may explain the molecular basis of SARS-CoV-related severe respiratory distress.HNL63-CoV, a CoV (7) that causes the common cold, was recently found to use ACE2 for viral infection (8), and it was further shown that the spike protein of HNL63-CoV (NL63-S) binds ACE2 directly (9). NL63-S and SARS-S show 21% identity (10), whereas that between NL63-S and the spike protein of HCoV-229E, which uses CD13 [a completely different carboxy (C)-peptidase] as a cellular receptor (11), is 55%. It is important to note that, despite their phylogenetically distinct properties and their producing different clinical outcomes, SARS-CoV and HNL63-CoV both use ACE2.Based on these observations, we hypothesized that the functional modulation of ACE2 may be differentially induced by SARS-S and NL63-S. To test this prediction, we first clarified the mechanism of SARS-S-induced ACE2 down-regulation, and then compared the cellular respon...