N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2

McCallum, Matthew; Marco, Anna De; Lempp, Florian A.; Tortorici, M. Alejandra; Pinto, Dora; Walls, Alexandra C.; Beltramello, Martina; Chen, Alex; Liu, Zhuoming; Zatta, Fabrizia; Zepeda, Samantha K; Iulio, Julia di; Bowen, John E.; Montiel-Ruiz, Martin; Zhou, Jiayi; Rosen, Laura E.; Bianchi, Siro; Guarino, Barbara; Fregni, Chiara Silacci; Abdelnabi, Rana; Foo, Shi-Yan Caroline; Rothlauf, Paul W.; Bloyet, Louis-Marie; Benigni, Fabio; Cameroni, Elisabetta; Neyts, Johan; Riva, Agostino; Snell, Gyorgy; Telenti, Amalio; Whelan, Sean P. J.; Virgin, Herbert W.; Corti, Davide; Pizzuto, Matteo Samuele; Veesler, David

doi:10.1101/2021.01.14.426475

Cited by 257 publications

(434 citation statements)

References 90 publications

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“…The human mAbs studied in this paper (COV2-2196, COV2-2072, COV2-2050, COV2-2381, COV2-2130, COVOX-384, COVOX-40, S309, S2E12, S2H58, S2X333, VIR-7381 and S2X259) were isolated from blood samples from individuals in North America or Europe with previous laboratory-confirmed symptomatic SARS-CoV or SARS-CoV-2 infection. The original clinical studies to obtain specimens after written informed consent were previously described 3,5,7,47,48 and approved by the Institutional Review Board of Vanderbilt University Medical Center, the Institutional Review Board of the University of Washington, the Research Ethics Board of the University of Toronto and the Canton Ticino Ethics Committee (Switzerland). Chimeric mAb 1B07 with a murine Fv and human Fc (human IgG1) were isolated from C57BL/6 mice immunized with recombinant spike and RBD proteins and described previously 20 .…”

Section: Methodsmentioning

confidence: 99%

Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies

Chen

Zhang

Case

et al. 2021

Nat Med

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902

962

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evere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic infecting more than 111 million people and causing 2.4 million deaths. Clinical disease in humans ranges from asymptomatic infection to pneumonia, severe respiratory compromise, multi-organ failure and systemic inflammatory syndromes. The rapid expansion and prolonged nature of the COVID-19 pandemic and its accompanying morbidity, mortality and destabilizing socioeconomic effects have made the development of SARS-CoV-2 therapeutics and vaccines an urgent global health priority 1. Indeed, the emergency use authorization and rapid deployment of antibody-based countermeasures, including mAbs, immune plasma therapy and messenger RNA, and inactivated and viral-vectored vaccines has provided hope for curtailing disease and ending the pandemic. The spike protein of the SARS-CoV-2 virion binds the cell-surface receptor angiotensin-converting enzyme 2 (ACE2) to promote entry into human cells 2. Because the spike protein is critical for viral entry, it has been targeted for vaccine development and therapeutic antibody interventions. SARS-CoV-2 S proteins are cleaved to yield S1 and S2 fragments. The S1 protein includes the N-terminal (NTD) and receptor-binding (RBD) domains, whereas the S2 protein promotes membrane fusion. The RBD is recognized by many potently neutralizing monoclonal antibodies 3-7 , protein-based inhibitors 8 and serum antibodies 9. The current suite of antibody therapeutics and vaccines was designed with a spike protein based on strains circulating during the early phases of the pandemic in 2020. More recently, variants with enhanced transmissibility have emerged in the United Kingdom (B.1.1.7), South Africa (B.1.351), Brazil (B.1.1.248) and elsewhere with multiple substitutions in the spike protein, including in the NTD and the receptor-binding motif (RBM) of the RBD. Preliminary studies with pseudoviruses suggest that neutralization by some antibodies and immune sera may be diminished against variants expressing mutations in the spike gene 10-13. Given these

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Section: Methodsmentioning

confidence: 99%

Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies

Chen

Zhang

Case

et al. 2021

Nat Med

Self Cite

902

962

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“…Whereas the L18F mutation is fixed in all currently sampled V3 lineage sequences, it has occurred (and persisted in descendent variants) at least twice in the V1 lineage and at least four times in the V2 lineage. S/18 falls within multiple different predicted CTL epitopes 41 and the L18F mutation is known to reduce viral sensitivity to some neutralizing monoclonal antibodies 29 . An F at residue S/18 is also observed in 10% of other known Sarbecoviruses and the L18F mutation is the tenth most common in currently sampled SARS-CoV-2 genomes.…”

Section: Signals Of Ongoing Mutational Convergence At Signature Mutatmentioning

confidence: 99%

The emergence and ongoing convergent evolution of the N501Y lineages coincides with a major global shift in the SARS-CoV-2 selective landscape

Martin

Weaver

Tegally

et al. 2021

Preprint

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The emergence and rapid rise in prevalence of three independent SARS-CoV-2 '501Y lineages', B.1.1.7, B.1.351 and P.1, in the last three months of 2020 has prompted renewed concerns about the evolutionarily capacity of SARS-CoV-2 to adapt to both rising population immunity and public health interventions such as vaccines and social distancing. Viruses giving rise to the different 501Y lineages have, presumably under intense natural selection following a shift in host environment, independently acquired multiple unique and convergent mutations. As a consequence all have gained epidemiological and immunological properties that will likely complicate the control of COVID-19. Here, by examining patterns of mutations that arose in SARS-CoV-2 genomes during the pandemic we find evidence of a major change in the selective forces acting on immunologically important SARS-CoV-2 genes (such as N and S) that likely coincided with the emergence of the 501Y lineages. In addition to involving continuing sequence diversification, we find evidence that a significant portion of the ongoing adaptive evolution of the 501Y lineages also involves further convergence between the lineages. Our findings highlight the importance of monitoring how members of these known 501Y lineages, and others still undiscovered, are convergently evolving similar strategies to ensure their persistence in the face of mounting infection and vaccine induced host immune recognition.

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“…In addition, a chronically infected immune suppressed individual was recently reported in Russia with emergence of Y453F, along with Δ H69/V70 13 . Deletions in other parts of the N-Terminal Domain (NTD) have been reported to arise in chronic infections 7 and to reduce sensitivity to NTD-specific neutralising antibodies 14,15 .…”

Section: Introductionmentioning

confidence: 99%

Recurrent emergence and transmission of a SARS-CoV-2 spike deletion H69/V70

Kemp

Meng

Ferriera

et al. 2020

Preprint

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SARS-CoV-2 Spike amino acid replacements in the receptor binding domain (RBD) occur relatively frequently and some have a consequence for immune recognition. Here we report recurrent emergence and significant onward transmission of a six-nucleotide deletion in the S gene, which results in loss of two amino acids: H69 and V70. Of particular note this deletion, 𝚫H69/V70, often co-occurs with the receptor binding motif amino acid replacements N501Y, N439K and Y453F. One of the 𝚫H69/V70+ N501Y lineages, B.1.1.7, is comprised of over 4000 SARS-CoV-2 genome sequences from the UK and includes eight other S gene mutations: RBD (N501Y and A570D), S1 (𝚫H69/V70 and 𝚫144/145) and S2 (P681H, T716I, S982A and D1118H). Some of these mutations have presumably arisen as a result of the virus evolving from immune selection pressure in infected individuals and at least one, lineage B.1.1.7, potentially from a chronic infection. Given our recent evidence that delH69/V70 enhances viral infectivity (Kemp et al. 2020), its effect on virus fitness appears to be independent to the RBD changes. Enhanced surveillance for the delH69/V70 deletion with and without RBD mutations should be considered as a priority. Permissive mutations such as delH69/V70 have the potential to enhance the ability of SARS-CoV-2 to generate new variants, including vaccine escape variants, that would have otherwise significantly reduced viral infectivity.

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N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2

Cited by 257 publications

References 90 publications

Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies

Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies

The emergence and ongoing convergent evolution of the N501Y lineages coincides with a major global shift in the SARS-CoV-2 selective landscape

Recurrent emergence and transmission of a SARS-CoV-2 spike deletion H69/V70

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