Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity

Thomson, Emma C.; Rosen, Laura E.; Shepherd, James G.; Spreafico, Roberto; Filipe, Ana da Silva; Wojcechowskyj, Jason A.; Davis, Chris; Piccoli, Luca; Pascall, David; Dillen, Josh R; Lytras, Spyros; Czudnochowski, Nadine; Shah, Rajiv; Meury, Marcel; Jesudason, Natasha; Marco, Anna De; Li, Kathy; Bassi, Jessica; O’Toole, Áine; Pinto, Dora; Colquhoun, Rachel; Culap, Katja; Jackson, Ben; Zatta, Fabrizia; Rambaut, Andrew; Jaconi, Stefano; Sreenu, Vattipally B; Nix, Jay C.; Zhang, Ivy; Jarrett, Ruth F.; Glass, William G.; Beltramello, Martina; Nomikou, Kyriaki; Pizzuto, Matteo Samuele; Tong, L.; Cameroni, Elisabetta; Croll, Tristan I.; Johnson, Natasha; Iulio, Julia di; Wickenhagen, Arthur; Ceschi, Alessandro; Harbison, Aoife M; Mair, Daniel; Ferrari, Paolo; Smollett, Katherine; Sallusto, Federica; Carmichael, Stephen; Garzoni, Christian; Nichols, Jenna; Galli, Massimo; Hughes, Joseph; Riva, Agostino; Ho, Antonia; Schiuma, Marco; Semple, Malcolm G; Openshaw, Peter; Fadda, Elisa; Baillie, J Kenneth; Chodera, John D.; Rihn, Suzannah J.; Lycett, Samantha; Virgin, Herbert W.; Telenti, Amalio; Corti, Davide; Robertson, David L.; Snell, Gyorgy

doi:10.1016/j.cell.2021.01.037

Cited by 580 publications

(621 citation statements)

References 104 publications

(136 reference statements)

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“…Although our assays are limited to pseudotyped viruses there is an excellent correlation between pseudotyped and authentic SARS-CoV-2 neutralization assays 11 . In addition, similar results have been reported by others using vaccinee and convalescent plasmas and a variety of different pseudotype and authentic virus assays 16,30,[44][45][46][47][48] .…”

Section: Discussionsupporting

confidence: 87%

“…6a, and Table 5 and 5,6 ). To examine memory B cell antibodies for binding to circulating SARS-CoV-2 variants and antibody resistant mutants we performed ELISAs using mutant RBDs 7,8,13,16,29,30 . Twenty-two (26%) of the 84 antibodies tested showed at least 5-fold decreased binding to at least one of the mutant RBDs (Extended data Fig.…”

Section: Vaccine-elicited Sars-cov-2 Rbd-specific Monoclonal Antibodiesmentioning

confidence: 99%

See 1 more Smart Citation

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

Wang

Schmidt

Weisblum

et al. 2021

Nature

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Rafael C as el la s , T he od or a Hatziioannou, Paul D. Bieniasz & M ic hel C. Nussenzweig This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

show abstract

Section: Discussionsupporting

confidence: 87%

Section: Vaccine-elicited Sars-cov-2 Rbd-specific Monoclonal Antibodiesmentioning

confidence: 99%

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

Wang

Schmidt

Weisblum

et al. 2021

Nature

1,326

100

1,304

View full text Add to dashboard Cite

show abstract

“…Although our assays are limited to pseudotyped viruses there is an excellent correlation between pseudotyped and authentic SARS-CoV-2 neutralization assays 10 . In addition, similar results have been reported by others using vaccinee and convalescent plasmas and a variety of different pseudotype and authentic virus assays 15,31,45–49 .…”

Section: Discussionsupporting

confidence: 88%

“…6a, and Table 5 and 7,8 ). To examine memory B cell antibodies for binding to circulating SARS-CoV-2 variants and antibody resistant mutants we performed ELISAs using mutant RBDs 12,15,[28][29][30][31] . Twenty-two (26%) of the 84 antibodies tested showed at least 5-fold decreased binding to at least one of the mutant RBDs (Extended data Fig.…”

Section: Vaccine-elicited Sars-cov-2 Rbd-specific Monoclonal Antibodiesmentioning

confidence: 99%

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

Wang

Schmidt

Weisblum

et al. 2021

Preprint

280

313

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To date severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected over 100 million individuals resulting in over two million deaths. Many vaccines are being deployed to prevent coronavirus disease 2019 (COVID-19) including two novel mRNA-based vaccines1,2. These vaccines elicit neutralizing antibodies and appear to be safe and effective, but the precise nature of the elicited antibodies is not known3–6. Here we report on the antibody and memory B cell responses in a cohort of 20 volunteers who received either the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines. Consistent with prior reports, 8 weeks after the second vaccine injection volunteers showed high levels of IgM, and IgG anti-SARS-CoV-2 spike protein (S) and receptor binding domain (RBD) binding titers3,5,6. Moreover, the plasma neutralizing activity, and the relative numbers of RBD-specific memory B cells were equivalent to individuals who recovered from natural infection7,8. However, activity against SARS-CoV-2 variants encoding E484K or N501Y or the K417N:E484K:N501Y combination was reduced by a small but significant margin. Consistent with these findings, vaccine-elicited monoclonal antibodies (mAbs) potently neutralize SARS-CoV-2, targeting a number of different RBD epitopes in common with mAbs isolated from infected donors. Structural analyses of mAbs complexed with S trimer suggest that vaccine- and virus-encoded S adopts similar conformations to induce equivalent anti-RBD antibodies. However, neutralization by 14 of the 17 most potent mAbs tested was reduced or abolished by either K417N, or E484K, or N501Y mutations. Notably, the same mutations were selected when recombinant vesicular stomatitis virus (rVSV)/SARS-CoV-2 S was cultured in the presence of the vaccine elicited mAbs. Taken together the results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy.

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“…Additional S variants such as N439K and S477N also rapidly increased in frequency in Europe over the summer and into the fall of 2020. Although S477N reportedly increases affinity for the entry receptor, ACE2 (Zahradník et al, 2021), and both mutations may impact antibody neutralization to some degree (Starr et al, 2020;Liu et al, 2021;Thomson et al, 2021), neither shows any signature of increased transmissibility over the S: D614G background from which they emerged, and neither have become prominent in the United States. Therefore, SARS-CoV-2 variants can emerge and increase greatly in number over time in the absence of any clear or sustained selective advantage.…”

Section: Caveatsmentioning

confidence: 97%

Emergence in late 2020 of multiple lineages of SARS-CoV-2 Spike protein variants affecting amino acid position 677

Hodcroft

Domman

Snyder³

et al. 2021

Preprint

122

116

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S) plays critical roles in host cell entry. Non-synonymous substitutions affecting S are not uncommon and have become fixed in a number of SARS-CoV-2 lineages. A subset of such mutations enable escape from neutralizing antibodies or are thought to enhance transmission through mechanisms such as increased affinity for the cell entry receptor, angiotensin-converting enzyme 2 (ACE2). Independent genomic surveillance programs based in New Mexico and Louisiana contemporaneously detected the rapid rise of numerous clade 20G (lineage B.1.2) infections carrying a Q677P substitution in S. The variant was first detected in the US on October 23, yet between 01 Dec 2020 and 19 Jan 2021 it rose to represent 27.8% and 11.3% of all SARS-CoV-2 genomes sequenced from Louisiana and New Mexico, respectively. Q677P cases have been detected predominantly in the south central and southwest United States; as of 03 Feb 2021, GISAID data show 499 viral sequences of this variant from the USA. Phylogenetic analyses revealed the independent evolution and spread of at least six distinct Q677H sub-lineages, with first collection dates ranging from mid-August to late November 2020. Four 677H clades from clade 20G (B.1.2), 20A (B.1.234), and 20B (B.1.1.220, and B.1.1.222) each contain roughly 100 or fewer sequenced cases, while a distinct pair of clade 20G clusters are represented by 754 and 298 cases, respectively. Although sampling bias and founder effects may have contributed to the rise of S:677 polymorphic variants, the proximity of this position to the polybasic cleavage site at the S1/S2 boundary are consistent with its potential functional relevance during cell entry, suggesting parallel evolution of a trait that may confer an advantage in spread or transmission. Taken together, our findings demonstrate simultaneous convergent evolution, thus providing an impetus to further evaluate S:677 polymorphisms for effects on proteolytic processing, cell tropism, and transmissibility.

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Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity

Cited by 580 publications

References 104 publications

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

Emergence in late 2020 of multiple lineages of SARS-CoV-2 Spike protein variants affecting amino acid position 677

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