The furin cleavage site in the SARS-CoV-2 spike protein is required for transmission in ferrets

Peacock, Thomas P.; Goldhill, Daniel H.; Zhou, Jie; Baillon, Laury; Frise, Rebecca; Swann, Olivia C.; Kugathasan, Ruthiran; Penn, Rebecca; Brown, Jonathan C.; Sanchez-David, Raul Y.; Braga, Luca; Williamson, Maia Kavanagh; Hassard, Jack A.; Staller, Ecco; Hanley, Brian; Osborn, Michael; Giacca, Mauro; Davidson, Andrew D.; Matthews, David A.; Barclay, William

doi:10.1038/s41564-021-00908-w

Cited by 638 publications

(753 citation statements)

References 68 publications

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“…Virus infectivity and fusogenicity mediated by the PBCS is a key determinant of pathogenicity and transmissibility 9,24 and there are indications that giant cells/syncitia formation are associated with fatal disease 25 . Spike cleavage and stability of cleaved spike are likely therefore to be critical parameters for future SARS-CoV-2 variants of concern.…”

Section: Discussionmentioning

confidence: 99%

“…over Wuhan-1 D614G wild type in nearly all cells tested (Figure 2e). SARS-CoV-2 infection in clinically relevant cells is TMPRSS2 dependent and requires fusion at the plasma membrane, potentially to avoid restriction factors in endosomes 9 . We found that B.1.617.2 was marginally less sensitive to the TMPRSS2 inhibitor Camostat (Figure 2f).…”

Section: B16172 Spike Has Enhanced Entry Efficiency Associated With Cleaved Spikementioning

confidence: 99%

“…The plasma membrane route of entry, and indeed transmissibility in animal models, is critically dependent on the polybasic cleavage site (PBCS) between S1 and S2 9,11,12 and cleavage of spike prior to virion release from producer cells; this contrasts with the endosomal entry route, which does not require spike cleavage in producer cells. 9,13,14 . Mutations at P681 in the PBCS have been observed in multiple SARS-CoV-2 lineages, most notably in the B.1.1.7 Alpha variant 15 .…”

Section: B16172 Spike Confers Increased Syncytium Formationmentioning

confidence: 99%

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SARS-CoV-2 B.1.617.2 Delta variant emergence and vaccine breakthrough

Mlčochová¹,

Kemp²,

Dhar

et al. 2021

Preprint

112

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The SARS-CoV-2 B.1.617.2 (Delta) variant was first identified in the state of Maharashtra in late 2020 and has spread throughout India, displacing the B.1.1.7 (Alpha) variant and other pre-existing lineages. Mathematical modelling indicates that the growth advantage is most likely explained by a combination of increased transmissibility and immune evasion. Indeed in vitro, the delta variant is less sensitive to neutralising antibodies in sera from recovered individuals, with higher replication efficiency as compared to the Alpha variant. In an analysis of vaccine breakthrough in over 100 healthcare workers across three centres in India, the Delta variant not only dominates vaccine-breakthrough infections with higher respiratory viral loads compared to non-delta infections (Ct value of 16.5 versus 19), but also generates greater transmission between HCW as compared to B.1.1.7 or B.1.617.1 (p=0.02). In vitro, the Delta variant shows 8 fold approximately reduced sensitivity to vaccine-elicited antibodies compared to wild type Wuhan-1 bearing D614G. Serum neutralising titres against the SARS-CoV-2 Delta variant were significantly lower in participants vaccinated with ChadOx-1 as compared to BNT162b2 (GMT 3372 versus 654, p<0001). These combined epidemiological and in vitro data indicate that the dominance of the Delta variant in India has been most likely driven by a combination of evasion of neutralising antibodies in previously infected individuals and increased virus infectivity. Whilst severe disease in fully vaccinated HCW was rare, breakthrough transmission clusters in hospitals associated with the Delta variant are concerning and indicate that infection control measures need continue in the post-vaccination era.

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Section: Discussionmentioning

confidence: 99%

Section: B16172 Spike Has Enhanced Entry Efficiency Associated With Cleaved Spikementioning

confidence: 99%

Section: B16172 Spike Confers Increased Syncytium Formationmentioning

confidence: 99%

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SARS-CoV-2 B.1.617.2 Delta variant emergence and vaccine breakthrough

Mlčochová¹,

Kemp²,

Dhar

et al. 2021

Preprint

112

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“…Thus, for our analysis we assume the presence of a single virus in a single sample. This approach will not detect evolution of viral quasi-species within individuals but allows for the characterization of dominant spreading mutations in populations 33 .…”

Section: Supplemental Materials Methodsmentioning

confidence: 99%

Predicting the mutational drivers of future SARS-CoV-2 variants of concern

Maher

Bartha

Weaver

et al. 2021

Preprint

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SARS-CoV-2 evolution threatens vaccine- and natural infection-derived immunity, and the efficacy of therapeutic antibodies. Herein we sought to predict Spike amino acid changes that could contribute to future variants of concern. We tested the importance of features comprising epidemiology, evolution, immunology, and neural network-based protein sequence modeling. This resulted in identification of the primary biological drivers of SARS-CoV-2 intra-pandemic evolution. We found evidence that resistance to population-level host immunity has increasingly shaped SARS-CoV-2 evolution over time. We identified with high accuracy mutations that will spread, at up to four months in advance, across different phases of the pandemic. Behavior of the model was consistent with a plausible causal structure wherein epidemiological variables integrate the effects of diverse and shifting drivers of viral fitness. We applied our model to forecast mutations that will spread in the future, and characterize how these mutations affect the binding of therapeutic antibodies. These findings demonstrate that it is possible to forecast the driver mutations that could appear in emerging SARS-CoV-2 variants of concern. This modeling approach may be applied to any pathogen with genomic surveillance data, and so may address other rapidly evolving pathogens such as influenza, and unknown future pandemic viruses.

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“…The P681H and P618R mutations facilitate easier access of the human proteases to the furin cleavage site, thus increasing SARS-CoV-2 transmission and infection [187,188].…”

Section: Sars-cov-2 Variantsmentioning

confidence: 99%

COVID-19: Unmasking Emerging SARS-CoV-2 Variants, Vaccines and Therapeutic Strategies

Raman

Patel

Ranjan

2021

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic which has been a topic of major concern to global human health. The challenge to restrain the COVID-19 pandemic is further compounded by the emergence of several SARS-CoV-2 variants viz. B.1.1.7, B.1.351, P1 and, B.1.617., which show in-creased transmissibility and resistance towards vaccines and therapies. Importantly, the likelihood of susceptibility to SARS-CoV-2 infection among individuals with dysregulated immune response or comorbidities needs greater attention. Herein, we provide a comprehensive perspective regarding ongoing vaccine (mRNA, protein-based, viral vector based etc.) and therapeutic (mono-clonal antibodies, small molecules, plasma therapy, etc.) modalities designed to curb the COVID-19 pandemic. We also discuss in detail the challenges posed by different SARS-CoV-2 variants of concern (VOC) identified across the globe and their effects on therapeutic and prophylactic interventions.

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The furin cleavage site in the SARS-CoV-2 spike protein is required for transmission in ferrets

Cited by 638 publications

References 68 publications

SARS-CoV-2 B.1.617.2 Delta variant emergence and vaccine breakthrough

SARS-CoV-2 B.1.617.2 Delta variant emergence and vaccine breakthrough

Predicting the mutational drivers of future SARS-CoV-2 variants of concern

COVID-19: Unmasking Emerging SARS-CoV-2 Variants, Vaccines and Therapeutic Strategies

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