SARS-CoV-2 B.1.1.7 and B.1.351 spike variants bind human ACE2 with increased affinity

Ramanathan, Muthukumar; Ferguson, Ian; Miao, Weili; Khavari, Paul A.

doi:10.1016/s1473-3099(21)00262-0

Cited by 188 publications

(148 citation statements)

References 5 publications

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“…Of note, these Spike proteins also differ in their N-terminal sequences (NTD), which is thought to also contribute to the Spike RBD-ACE2 interaction. Some of these mutations have been associated with increased virus transmissibility [42][43][44]. [46][47][48][49][50], the current study revealed rank-ordered neutralization capability against a series of additional Spike variants with distinct mutations in RBD.…”

Section: Cross-reactivity Of Vaccine-induced Nabmentioning

confidence: 76%

Control of SARS-CoV-2 infection after Spike DNA or Spike DNA+Protein co-immunization in rhesus macaques

Rosati

Agarwal

et al. 2021

Preprint

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The speed of development, versatility and efficacy of mRNA-based vaccines have been amply demonstrated in the case of SARS-CoV-2. DNA vaccines represent an important alternative since they induce both humoral and cellular immune responses in animal models and in human trials. We tested the immunogenicity and protective efficacy of DNA-based vaccine regimens expressing different prefusion-stabilized SARS-CoV-2 Spike antigens upon intramuscular injection followed by electroporation in rhesus macaques. Different Spike DNA vaccine regimens induced antibodies that potently neutralized SARS-CoV-2 in vitro and elicited robust T cell responses. The DNA-only vaccine regimens were compared to a regimen that included co-immunization of Spike DNA and protein in the same anatomical site, the latter of which showed significant higher antibody responses. All vaccine regimens led to control of SARS-CoV-2 intranasal/intratracheal challenge and absence of virus dissemination to the lower respiratory tract. Vaccine-induced binding and neutralizing antibody titers and antibody-dependent cellular phagocytosis inversely correlated with transient virus levels in the nasal mucosa. Importantly, the Spike DNA+Protein co-immunization regimen induced the highest binding and neutralizing antibodies and showed the strongest control against SARS-CoV-2 challenge in rhesus macaques.

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Section: Cross-reactivity Of Vaccine-induced Nabmentioning

confidence: 76%

Control of SARS-CoV-2 infection after Spike DNA or Spike DNA+Protein co-immunization in rhesus macaques

Rosati

Agarwal

et al. 2021

Preprint

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“…The copyright holder for this preprint this version posted July 6, 2021. ; https://doi.org/10.1101/2021.07.01.21259404 doi: medRxiv preprint (Martin et al, 2021). Likewise, both VOCs Alpha and Gamma share the mutation N501Y, also implicated in immune escape and enhancement of the affinity between the RBD and human angiotensin converting enzyme 2 (ACE2), the cellular receptor used by SARS-CoV-2 for cell entry (Lan et al, 2020;Ramanathan et al, 2021). These functional effects, joint to the fast observed rise in frequency and number of cases across diverse epidemiological settings (Barbosa et al, 2021;Franceschi et al, 2021;Moreira et al, 2021a;Naveca et al, 2021) -including the one herein reported -provide evidence that the VOC Gamma has a fitness advantage over previously circulating lineages.…”

Section: -Discussionmentioning

confidence: 99%

Epidemiological dynamics of SARS-CoV-2 VOC Gamma in Rio de Janeiro, Brazil

Moreira

D’arc

Mariani

et al. 2021

Preprint

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The emergence and widespread circulation of SARS-CoV-2 variants of concern (VOC) or interest (VOI) imposes an enhanced threat to global public health. In Brazil, one of the countries most severely impacted throughout the pandemic, a complex dynamics involving variants co-circulation and turnover events has been recorded with the emergence and spread of VOC Gamma in Manaus in late 2020. In this context, we present a genomic epidemiology investigation based on samples collected between December 2020 and May 2021 in the second major Brazilian metropolis, Rio de Janeiro. By sequencing 244 novel genomes through all epidemiological weeks in this period, we were able to document the introduction and rapid dissemination of VOC Gamma in the city, driving the rise of the third local epidemic wave. Molecular clock analysis indicates this variant has circulated locally since the first weeks of 2021 and only seven weeks were necessary for it to achieve a frequency above 70%, consistent with rates of growth observed in Manaus and other states. Moreover, a Bayesian phylogeographic reconstruction indicates VOC Gamma spread throughout Brazil between December 2020 and January 2021, and that it was introduced in Rio de Janeiro through at least 13 events coming from nearly all regions of the country. Comparative analysis of RT-qPCR cycle threshold (Ct) values provide further evidence that VOC Gamma induces higher viral loads (N1 target; mean reduction of Ct: 2.7, 95% CI = 2.0 - 3.4). This analysis corroborates the previously proposed mechanistic basis for this variant enhanced transmissibility and distinguished epidemiological behavior. Our results document the evolution of VOC Gamma and provide independent assessment of scenarios previously studied in Manaus, therefore contributing to the better understanding of the epidemiological dynamics currently being surveyed in other Brazilian regions.

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“…In this work, we report that the SARS-CoV-2 gained the novel S1-NTD in its genome. Most of the studies focused on the rapid spread of the SARS-CoV-2 due to its S1-RBD diversity to binds with the human ACE2 receptor and the presence of a specific furin cleavage site (FCS) 4,[29][30][31][32][33][34][35] . However, the furin cleavage site is not only present in SARS-CoV-2, but also present in MERS-CoV, HKU1, and HCoV-OC43 4,32,34,36 , and the SARS-CoV-2 without FCS also can infect target cells efficiently in the presence of trypsin or human airway trypsin-like protease (HAT) 37 .…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 gained the unique spike protein S1-N-Terminal Domain from the promising pangolins mixing vessel: A novel clue for the pandemic outbreak

Desingu¹,

Nagarajan²

2021

Preprint

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The clue behind the emergence of SARS-CoV-2 remains a huge debate among the virologist, policymakers, and general public, while the gain-of-function hypothesizes mostly focused on the furin cleavage site and receptor-binding domain (RBD) of the spike (S) protein. Here, we report that the SARS-CoV-2 gained the novel human-specific spike protein S1-N-Terminal Domain (S1-NTD) (Type-I) which is present only in SARS-CoV-2. Interestingly, SARS-CoV-2-rB-CoV showed unique bat-specific Type-II and Type-III-S1-NTD, which is not present in other SARS coronaviruses, including SARS-CoV-2 variants. We also found widespread recombination and selection pressure in the S1-NTDs of the bat viruses. In addition, the Pangolin/GX/2018 and Pangolin/Guangdong/2019 lineages showed close identity (73-79%) with the Type-I-S1-NTD and Type-II-S1-NTD respectively. This justifies that the pangolin is the mixing vessel (intermediate host) to exchange the bat-specific Type-II-S1-NTD in the SARS-CoV-2-rB-CoV into Type-I-like-S1-NTD in pangolin through recombination. Furthermore, the pangolin virus with Type-I-like-S1-NTD jumped into humans which then transformed into SARS-CoV-2 with Type-I-S1-NTD by host selection pressure. Remarkably, we characterized the bat/Cambodia virus as a recombinant SARS-CoV-2/RatG13 with the S1-NTD of bat-SARS-like viruses; while only bat/RatG13 with Type-I-S1-NTD established a huge pandemic outbreak. Additionally, recent SARS-CoV-2 S1-NTD specific neutralizing antibody-based studies support the role of S1-NTD in the post-attachment of the virus; fusion, virus dissemination, and cell-cell fusion thereby prevent the onset of infection; and most of the SARS-CoV-2 variants with increased transmissibility were linked to the S1-NTD mutations. Collectively, our results strongly suggest that the gain of Type-I-S1-NTD in the SARS-CoV-2 is the reason for the pandemic outbreak.

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SARS-CoV-2 B.1.1.7 and B.1.351 spike variants bind human ACE2 with increased affinity

Cited by 188 publications

References 5 publications

Control of SARS-CoV-2 infection after Spike DNA or Spike DNA+Protein co-immunization in rhesus macaques

Control of SARS-CoV-2 infection after Spike DNA or Spike DNA+Protein co-immunization in rhesus macaques

Epidemiological dynamics of SARS-CoV-2 VOC Gamma in Rio de Janeiro, Brazil

SARS-CoV-2 gained the unique spike protein S1-N-Terminal Domain from the promising pangolins mixing vessel: A novel clue for the pandemic outbreak

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