Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera

Xie, Xuping; Liu, Yang; Liu, Jianying; Zhang, Xianwen; Zou, Jing; Fontes-Garfias, Camila R.; Xia, Hongjie; Swanson, Kena A.; Cutler, Mark; Cooper, David A.; Menachery, Vineet D.; Weaver, Scott C.; Dormitzer, Philip R.; Shi, Pei Yong

doi:10.1038/s41591-021-01270-4

Cited by 579 publications

(439 citation statements)

References 14 publications

(12 reference statements)

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“…It was difficult to assess the impact of the P681H and other mutations on the NTD mAbs, as these mAbs neutralized the D614G virus poorly at baseline in Vero-hACE2-TMPRSS2 cells; (2) The K417N mutation resulted in ~27-fold reduction in neutralization by mAb COVOX-40 but did not negatively affect other mAbs in our panel. If anything, several class 1 mAbs and also SARS2-44 showed slightly improved inhibitory activity (P = 0.002, two-tailed Wilcoxon matched-pairs signed-rank test) with this mutation; (3) Mutation at N501Y reduced the neutralizing activity of COVOX-40, SARS2-31 and SARS2-10 slightly but did not alter the potency of other mAbs substantively; this result is consistent with data showing that human convalescent sera efficiently neutralize viruses with N501Y substitutions [22][23][24] ; (4) The E484K mutation negatively impacted the potency of several class 1 antibodies. Compared to the D614G virus, mAbs COV2-2196, COV2-3025, COV2-2381 and S2E12 showed four to fivefold reduced activity against the E484K virus and COV2-2050, 1B07, COVOX-384 and S2H58 lost virtually all neutralizing potential; (5) The combination of E484K and N501Y mutations, which is present in the circulating South African B.1.351 and Brazilian B.1.1.248 strains, showed even greater effects (6-to 13-fold reductions) on the activity of class 1 mAbs COV2-2196, COV2-3025, COV2-2381 and S2E12 mAbs; (6) When we tested class 1 mAbs for inhibition of the Wash SA-B.1.351 virus containing the full South African spike sequence, as expected, several mAbs (COV2-2050, 1B07, COVOX-384 and S2H58) lost activity in both Vero-hACE2-TMPRSS2 and Vero-TMPRSS2 cells.…”

Section: Resultssupporting

confidence: 85%

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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904

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: Resultssupporting

confidence: 85%

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

904

962

View full text Add to dashboard Cite

show abstract

“…Though the notorious N501Y mutation was not identified in our samples, five samples contained mutation E484K that is found in lineages from various countries and present in the ‘Brazil’ variant B.1.1.28. E484K is located in the receptor-binding ridge epitope and was shown to provide marked resistance to neutralizing antibodies in multiple studies [8, 11, 12].…”

Section: Resultsmentioning

confidence: 99%

Acquisition of the L452R mutation in the ACE2-binding interface of Spike protein triggers recent massive expansion of SARS-Cov-2 variants

Tchesnokova

Kulakesara

Larson

et al. 2021

Preprint

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The recent rise in mutational variants of SARS-CoV-2, especially with changes in the Spike protein, is of significant concern due to the potential ability for these mutations to increase viral infectivity, virulence and/or ability to escape protective antibodies. Here, we investigated genetic variations in a 414-583 amino acid region of the Spike protein, partially encompassing the ACE2 receptor-binding domain (RBD), across a subset of 570 nasopharyngeal samples isolated between April 2020 and February 2021, from Washington, California, Arizona, Colorado, Minnesota and Illinois. We found that samples isolated since November have an increased number of amino acid mutations in the region, with L452R being the dominant mutation. This mutation is associated with a recently discovered CAL.20C viral variant from clade 20C, lineage B.1.429, that since November-December 2020 is associated with multiple outbreaks and is undergoing massive expansion across California. In some samples, however, we found a distinct L452R-carrying variant of the virus that, upon detailed analysis of the GISAID database genomes, is also circulating primarily in California, but emerged even more recently. The newly identified variant derives from the clade 20A (lineage B.1.232) and is named CAL.20A. We also found that the SARS-CoV-2 strain that caused the only recorded case of infection in an ape - gorillas in the San Diego Zoo, reported in January 2021 - is CAL.20A. In contrast to CAL.20C that carries two additional to L452R mutations in the Spike protein, L452R is the only mutation found in CAL.20A. According to the phylogenetic analysis, however, emergence of CAL.20C was also specifically triggered by acquisition of the L452R mutation. Further analysis of GISAID-deposited genomes revealed that several independent L452R-carrying lineages have recently emerged across the globe, with over 90% of the isolates reported between December 2020 -February 2021. Taken together, these results indicate that the L452R mutation alone is of significant adaptive value to SARS-CoV-2 and, apparently, the positive selection for this mutation became particularly strong only recently, possibly reflecting viral adaptation to the containment measures or increasing population immunity. While the functional impact of L452R has not yet been extensively evaluated, leucine-452 is positioned in the receptor-binding motif of RBD, in the interface of direct contact with the ACE2 receptor. Its replacement with arginine is predicted to result in both a much stronger binding to the receptor and escape from neutralizing antibodies. If true, this in turn might lead to significantly increased infectivity of the L452R variants, warranting their close surveillance and in-depth functional studies.

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“…These studies revealed the link between certain mutations and particular phenotypes such as (i) an enhanced transmission potential associated with D614G, 31 (ii) an increase in virulence associated with N501Y, 39 and (iii) an impact of E484K on neutralization by post-vaccination sera. 40,41 We set out to study the infection and pathogenesis of two prototypic VoC B.1.1.7 and B.1.351 (local isolates from the UK and the South African lineages) in the Syrian hamster model using original low passage clinical isolates.…”

Section: Discussionmentioning

confidence: 99%

Comparative infectivity and pathogenesis of emerging SARS-CoV-2 variants in Syrian hamsters

Abdelnabi

Boudewijns

Foo

et al. 2021

Preprint

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Within one year after its emergence, more than 108 million people contracted SARS-CoV-2 and almost 2.4 million succumbed to COVID-19. New SARS-CoV-2 variants of concern (VoC) are emerging all over the world, with the threat of being more readily transmitted, being more virulent, or escaping naturally acquired and vaccine-induced immunity. At least three major prototypic VoC have been identified, i.e. the UK (B.1.1.7), South African (B.1.351) and Brazilian (B.1.1.28.1), variants. These are replacing formerly dominant strains and sparking new COVID-19 epidemics and new spikes in excess mortality. We studied the effect of infection with prototypic VoC from both B.1.1.7 and B.1.351 lineages in Syrian golden hamsters to assess their relative infectivity and pathogenicity in direct comparison to two basal SARS-CoV-2 strains isolated in early 2020. A very efficient infection of the lower respiratory tract of hamsters by these VoC is observed. In line with clinical evidence from patients infected with these VoC, no major differences in disease outcome were observed as compared to the original strains as was quantified by (i) histological scoring, (ii) micro-computed tomography, and (iii) analysis of the expression profiles of selected antiviral and pro-inflammatory cytokine genes. Noteworthy however, in hamsters infected with VoC B.1.1.7, a particularly strong elevation of proinflammatory cytokines was detected. Overall, we established relevant preclinical infection models that will be pivotal to assess the efficacy of current and future vaccine(s) (candidates) as well as therapeutics (small molecules and antibodies) against two important SARS-CoV-2 VoC.

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Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera

Cited by 579 publications

References 14 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

Acquisition of the L452R mutation in the ACE2-binding interface of Spike protein triggers recent massive expansion of SARS-Cov-2 variants

Comparative infectivity and pathogenesis of emerging SARS-CoV-2 variants in Syrian hamsters

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