Recurrent Emergence and Transmission of a SARS-CoV-2 Spike Deletion H69/V70

Kemp, Steven A; Meng, Bo; Ferriera, Isabella ATM; Datir, Rawlings; Harvey, William T.; Collier, Dami; Lytras, Spyros; Papa, Guido; Carabelli, Alessandro M.; Kenyon, Julia C.; Lever, Andrew M. L.; James, Leo C.; Robertson, David L.; Gupta, Ravindra

doi:10.2139/ssrn.3780277

Cited by 137 publications

(121 citation statements)

References 45 publications

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“…Analysis by TCRseq showed an increase in both breadth and depth across multiple epitopes of the SARS-CoV-2 spike protein. Recently, the SARS-CoV-2 spike genome has accumulated mutations, resulting in the emergence of SARS-CoV-2 variants, including the B.1.351 lineage that was first identified in South Africa, and the B.1.1.7 lineage that was first identified in the UK (34,35). Efficacy of AZD1222 against SARS-CoV-2 variants B.1.351 and B.1.1.7 investigated in Syrian hamsters showed that, despite an observed reduction in nAb titers against B.1.351 in AZD1222-vaccinated hamsters compared with those against B.1.1.7, there was evidence of protection in the lower respiratory tract against both variants post AZD1222 vaccination (36).…”

Section: Discussionmentioning

confidence: 99%

T-cell mediated immunity after AZD1222 vaccination: A polyfunctional spike-specific Th1 response with a diverse TCR repertoire

Swanson

Padilla

Hoyland

et al. 2021

Preprint

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AZD1222 (ChAdOx1 nCoV-19), a replication-deficient simian adenovirus-vectored vaccine, has demonstrated safety, efficacy, and immunogenicity against coronavirus disease 2019 (COVID-19) in clinical trials and real-world studies. We characterized CD4+ and CD8+ T-cell responses induced by AZD1222 vaccination in peripheral blood mononuclear cells (PBMCs) from 280 unique vaccine recipients aged 18-85 years who enrolled in the phase 2/3 COV002 trial. Total spike-specific CD4+ T cell helper type 1 (Th1) and CD8+ T-cell responses were significantly increased in AZD1222-vaccinated adults of all ages following two doses of AZD1222. CD4+ Th2 responses following AZD1222 vaccination were not detected. Furthermore, AZD1222-specific Th1 and CD8+ T cells both displayed a high degree of polyfunctionality in all adult age groups. T-cell receptor (TCR) β ; sequences from vaccinated participants mapped against TCR sequences known to react to SARS-CoV-2 revealed substantial breadth and depth across the SARS-CoV-2 spike protein for the AZD1222-induced CD4+ and CD8+ T-cell responses. Overall, AZD1222 vaccination induced a robust, polyfunctional Th1-dominated T-cell response, with broad CD4+ and CD8+ T-cell coverage across the SARS-CoV-2 spike protein.

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Section: Discussionmentioning

confidence: 99%

T-cell mediated immunity after AZD1222 vaccination: A polyfunctional spike-specific Th1 response with a diverse TCR repertoire

Swanson

Padilla

Hoyland

et al. 2021

Preprint

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“…In particular, there are three deletions, HV 69–70 and Y144 within the NTD (highlighted in orange in Figure 1 and Figure S2A ), and six mutations (N501Y, A570D, P681H, T716I, S982A and D1118H), besides D614G, from which the B.1.1.7 descends. Deletions HV 69–70 in the NTD have been found in multiple independent lineages of SARS-CoV-2 and have been associated with immune escape in immunocompromised patients and enhanced viral infectivity in vitro [ 29 ]. Major attention was given to mutations at position 501, as residue N501 within the RBD (green in Figure 1 and Figure S2C ) forms important contacts with ACE2 and experimental data suggests that mutations at this site have the potential to increase ACE2 receptor affinity [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Altered Local Interactions and Long-Range Communications in UK Variant (B.1.1.7) Spike Glycoprotein

Borocci

Cerchia

Grottesi

et al. 2021

IJMS

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The COVID-19 pandemic is caused by SARS-CoV-2. Currently, most of the research efforts towards the development of vaccines and antibodies against SARS-CoV-2 were mainly focused on the spike (S) protein, which mediates virus entry into the host cell by binding to ACE2. As the virus SARS-CoV-2 continues to spread globally, variants have emerged, characterized by multiple mutations of the S glycoprotein. Herein, we employed microsecond-long molecular dynamics simulations to study the impact of the mutations of the S glycoprotein in SARS-CoV-2 Variant of Concern 202012/01 (B.1.1.7), termed the “UK variant”, in comparison with the wild type, with the aim to decipher the structural basis of the reported increased infectivity and virulence. The simulations provided insights on the different dynamics of UK and wild-type S glycoprotein, regarding in particular the Receptor Binding Domain (RBD). In addition, we investigated the role of glycans in modulating the conformational transitions of the RBD. The overall results showed that the UK mutant experiences higher flexibility in the RBD with respect to wild type; this behavior might be correlated with the increased transmission reported for this variant. Our work also adds useful structural information on antigenic “hotspots” and epitopes targeted by neutralizing antibodies.

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“…Notably, the viruses that emerged in the United Kingdom (B.1.1.7 lineage) and separately in South Africa (B.1.351 lineage, also known as 501Y.V2) are reported to increase the transmission of the virus and host immune evasion. 6 , 7 In the spike protein alone, the B.1.1.7 variant has amino acid deletions at H69, V70, and Y144 and mutations N501Y, A570D, P681H, T716I, S982A, and D1118H, while the South African variant has mutations L18F, D80A, D215G, R246I, K417N, E484K, N501Y, and A701V. 8 The N501Y mutation at the receptor binding domain (RBD) that directly interacts with the human receptor ACE2, as shown in Figure 1 , is found to be common in both of these mutants and is assumed to increase virus infectivity and transmittivity.…”

Section: Introductionmentioning

confidence: 99%

Structural and Dynamical Differences in the Spike Protein RBD in the SARS-CoV-2 Variants B.1.1.7 and B.1.351

et al. 2021

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The novel coronavirus (SARS-CoV-2) pandemic that started in late 2019 is responsible for hundreds of millions of cases worldwide and millions of fatalities. Though vaccines are available, the virus is mutating to form new strains among which are the variants B.1.1.7 and B.1.351 that demonstrate increased transmissivity and infectivity. In this study, we performed molecular dynamics simulations to explore the role of the mutations in the interaction of the virus spike protein receptor binding domain (RBD) with the host receptor ACE2. We find that the hydrogen bond networks are rearranged in the variants and also that new hydrogen bonds are established between the RBD and ACE2 as a result of mutations. We investigated three variants: the wild-type (WT), B.1.1.7, and B.1.351. We find that the B.1.351 variant (also known as 501Y.V2) shows larger flexibility in the RBD loop segment involving residue K484, yet the RBD–ACE2 complex shows higher stability. Mutations that allow a more flexible interface that can result in a more stable complex may be a factor contributing to the increased infectivity of the mutated variants.

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Recurrent Emergence and Transmission of a SARS-CoV-2 Spike Deletion H69/V70

Cited by 137 publications

References 45 publications

T-cell mediated immunity after AZD1222 vaccination: A polyfunctional spike-specific Th1 response with a diverse TCR repertoire

T-cell mediated immunity after AZD1222 vaccination: A polyfunctional spike-specific Th1 response with a diverse TCR repertoire

Altered Local Interactions and Long-Range Communications in UK Variant (B.1.1.7) Spike Glycoprotein

Structural and Dynamical Differences in the Spike Protein RBD in the SARS-CoV-2 Variants B.1.1.7 and B.1.351

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