Delta spike P681R mutation enhances SARS-CoV-2 fitness over Alpha variant

Abstract

SARS-CoV-2 Delta variant has rapidly replaced the Alpha variant around the world. The mechanism that drives this global replacement has not been defined. Here we report that Delta spike mutation P681R plays a key role in the Alpha-to-Delta variant replacement. In a replication competition assay, Delta SARS-CoV-2 efficiently outcompeted the Alpha variant in human lung epithelial cells and primary human airway tissues. Delta SARS-CoV-2 bearing the Alpha-spike glycoprotein replicated less efficiently than the wild-type Delta variant, suggesting the importance of Delta spike in enhancing viral replication. The Delta spike has accumulated mutation P681R located at a furin cleavage site that separates the spike 1 (S1) and S2 subunits. Reverting the P681R mutation to wild-type P681 significantly reduced the replication of Delta variant, to a level lower than the Alpha variant. Mechanistically, the Delta P681R mutation enhanced the cleavage of the full-length spike to S1 and S2, leading to increased infection via cell surface entry. In contrast, the Alpha spike also has a mutation at the same amino acid (P681H), but the spike cleavage from purified Alpha virions was reduced compared to the Delta spike. Collectively, our results indicate P681R as a key mutation in enhancing Delta variant replication via increased S1/S2 cleavage. Spike mutations that potentially affect furin cleavage efficiency must be closely monitored for future variant surveillance.

Longitudinal analysis of SARS-CoV-2 vaccine breakthrough infections reveal limited infectious virus shedding and restricted tissue distribution

“…Finally, enrollment in this study concluded before the arrival of the Delta variant at either study site. It remains unclear how well the effects of vaccination on viral infection dynamics that we describe apply to Delta variant breakthrough infections, given the unique features 12 and enhanced transmissibility 13 of this variant relative to the viruses we captured here.…”

“…Finally, enrollment in this study concluded before the arrival of the Delta variant at either study site. It remains unclear how well the effects of vaccination on viral infection dynamics that we describe apply to Delta variant breakthrough infections, given the unique features 12 and enhanced transmissibility 13 of this variant relative to the viruses we captured here. Overall, our data suggest that vaccinated individuals are less likely to be shedding infectious virus at a given viral genome load and shed for a shorter period of time compared to unvaccinated and report fewer days of symptoms.…”

Spike Protein NTD mutation G142D in SARS-CoV-2 Delta VOC lineages is associated with frequent back mutations, increased viral loads, and immune evasion

“…SARS-CoV-2 viral loads are significantly higher in both vaccinated and unvaccinated individuals infected by Delta VOC (1). At least in part this appears to be driven by increased infectivity due to the furin cleavage enhancing P681R mutation (2). Other potential mechanisms have been proposed, including reduced immune recognition resulting from diminished neutralizing antibody binding to spike protein epitopes, particularly in the receptor binding domain (RBD) of the spike protein (3).…”

Biological Significance of the Genomic Variation and Structural Dynamics of SARS-CoV-2 B.1.617

“…It was observed that the variants carrying spike L452R change are likely to be more transmissible and infective and less susceptible to the neutralizing antibodies from convalescent patients and vaccine recipients (Deng et al, 2021). The variant bearing P681R, such as B.1.617.2, has an increased furin-mediated cleavage at the S1/S2 cleavage site that would lead to enhanced viral fusogenicity and exhibit a higher pathogenicity (Liu et al, 2021b;Peacock et al, 2021;Saito et al, 2021). It was also observed that in the hamster model, B.1.617.1 has a higher pathogenicity than has B.1 (Yadav et al, 2021a).…”