Broad sarbecovirus neutralization by a human monoclonal antibody

Tortorici, M. Alejandra; Czudnochowski, Nadine; Starr, Tyler N; Marzi, Roberta; Walls, Alexandra C.; Zatta, Fabrizia; Bowen, John E.; Jaconi, Stefano; Iulio, Julia di; Wang, Zhaoqian; Marco, Anna De; Zepeda, Samantha K; Pinto, Dora; Liu, Zhuoming; Beltramello, Martina; Bartha, István; Housley, Michael P.; Lempp, Florian A.; Rosen, Laura E.; Dellota, Exequiel; Kaiser, Hannah; Montiel-Ruiz, Martin; Zhou, Jiayi; Addetia, Amin; Guarino, Barbara; Culap, Katja; Sprugasci, Nicole; Saliba, Christian; Vetti, Eneida; Giacchetto-Sasselli, Isabella; Fregni, Chiara Silacci; Abdelnabi, Rana; Foo, Caroline S.; Havenar-Daughton, Colin; Schmid, Michael; Benigni, Fabio; Cameroni, Elisabetta; Neyts, Johan; Telenti, Amalio; Virgin, Herbert W.; Whelan, Sean P. J.; Snell, Gyorgy; Bloom, Jesse D; Corti, Davide; Veesler, David; Pizzuto, Matteo Samuele

doi:10.1038/s41586-021-03817-4

Cited by 220 publications

(238 citation statements)

References 87 publications

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“…Indeed, individual affinity-matured antibodies can impose a requirement for multiple viral substitutions for antibody escape and enable substantial activity against VOC. Some human monoclonal antibodies also have activity against divergent sarbecoviruses 24,29 . Thus, affinity maturation, the availability of numerous epitope targets and the generation of high levels of circulating antibodies may explain why polyclonal plasma from individuals who have been both infected and subsequently vaccinated could effectively neutralize the otherwise highly neutralization resistant PMS20 spike, as well as sarbecoviruses whose NTD and/or RBD domains are divergent from SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

High genetic barrier to escape from human polyclonal SARS-CoV-2 neutralizing antibodies

Schmidt

Weisblum

Rutkowska

et al. 2021

Preprint

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The number and variability of the neutralizing epitopes targeted by polyclonal antibodies in SARS-CoV-2 convalescent and vaccinated individuals are key determinants of neutralization breadth and, consequently, the genetic barrier to viral escape. Using chimeric viruses and antibody-selected viral mutants, we show that multiple neutralizing epitopes, within and outside the viral receptor binding domain (RBD), are variably targeted by polyclonal plasma antibodies and coincide with sequences that are enriched for diversity in natural SARS-CoV-2 populations. By combining plasma-selected spike substitutions, we generated synthetic polymutant spike proteins that resisted polyclonal antibody neutralization to a similar degree as currently circulating variants of concern (VOC). Importantly, by aggregating VOC-associated and plasma-selected spike substitutions into a single polymutant spike protein, we show that 20 naturally occurring mutations in SARS-CoV-2 spike are sufficient to confer near-complete resistance to the polyclonal neutralizing antibodies generated by convalescents and mRNA vaccine recipients. Strikingly however, plasma from individuals who had been infected and subsequently received mRNA vaccination, neutralized this highly resistant SARS-CoV-2 polymutant, and also neutralized diverse sarbecoviruses. Thus, optimally elicited human polyclonal antibodies against SARS-CoV-2 should be resilient to substantial future SARS-CoV-2 variation and may confer protection against future sarbecovirus pandemics.

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Section: Discussionmentioning

confidence: 99%

High genetic barrier to escape from human polyclonal SARS-CoV-2 neutralizing antibodies

Schmidt

Weisblum

Rutkowska

et al. 2021

Preprint

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“…E484Q, L452R, and T478K mutations are part of antigenic site I which we previously showed to be immunodominant (16)(17)(18). Both the B.1.351 (beta) and P.1 (gamma) variants of concern harbor the E484K mutation which is associated with a reduction of vaccine-elicited neutralizing Ab titers and mAb neutralization (38,41,57).…”

mentioning

confidence: 93%

“…The S2 subunit contains the fusion machinery and undergoes large-scale conformational changes to drive fusion of the virus and host membranes (14), enabling genome delivery and initiation of infection. Abs that bind to specific sites on the RBD (15)(16)(17)(18)(19)(20)(21)(22), the NTD (23)(24)(25)(26), or the fusion machinery stem helix (27)(28)(29)(30)(31) interfere with receptor attachment or membrane fusion. Serum neutralizing Ab titers are a correlate of protection against SARS-CoV-2 in non-human primates (32)(33)(34)(35).…”

mentioning

confidence: 99%

“…S3). The RBD is the main target of serum neutralizing activity in convalescent and vaccinated individuals and comprises several antigenic sites recognized by neutralizing Abs with a range of neutralization potencies and breadth (15)(16)(17)(18)(49)(50)(51). The B.1.617.1 S and B.1.617.2 S structures resolve the complete RBD and provide high-resolution blueprints of the residue substitutions found in these two variants (Fig 2C-D).…”

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confidence: 99%

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Molecular basis of immune evasion by the delta and kappa SARS-CoV-2 variants

McCallum

Walls

Sprouse

et al. 2021

Preprint

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110

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Worldwide SARS-CoV-2 transmission leads to the recurrent emergence of variants, such as the recently described B.1.617.1 (kappa), B.1.617.2 (delta) and B.1.617.2+ (delta+). The B.1.617.2 (delta) variant of concern is causing a new wave of infections in many countries, mostly affecting unvaccinated individuals, and has become globally dominant. We show that these variants dampen the in vitro potency of vaccine-elicited serum neutralizing antibodies and provide a structural framework for describing the impact of individual mutations on immune evasion. Mutations in the B.1.617.1 (kappa) and B.1.617.2 (delta) spike glycoproteins abrogate recognition by several monoclonal antibodies via alteration of key antigenic sites, including an unexpected remodeling of the B.1.617.2 (delta) N-terminal domain. The binding affinity of the B.1.617.1 (kappa) and B.1.617.2 (delta) receptor-binding domain for ACE2 is comparable to the ancestral virus whereas B.1.617.2+ (delta+) exhibits markedly reduced affinity. We describe a previously uncharacterized class of N-terminal domain-directed human neutralizing monoclonal antibodies cross-reacting with several variants of concern, revealing a possible target for vaccine development.

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“…The large majority of neutralizing antibodies bind the receptor binding motif (RBM), within the RBD, and a smaller fraction target the NTD 3,7 . Neutralizing antibodies against the S2 subunit have been described, however they have very low potency 3,8 . Neutralizing antibodies generated after infection derive in large part from germline IGHV3-53 and the closely related IGHV3-66 with very few somatic mutations 9,10 .…”

Section: Introductionmentioning

confidence: 99%

Hybrid immunity improves B cell frequency, antibody potency and breadth against SARS-CoV-2 and variants of concern

Andreano

Paciello

Piccini

et al. 2021

Preprint

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To understand the nature of the antibody response to SARS-CoV-2 vaccination, we analyzed at single cell level the B cell responses of five naïve and five convalescent people immunized with the BNT162b2 mRNA vaccine. Convalescents had higher frequency of spike protein specific memory B cells and by cell sorting delivered 3,532 B cells, compared with 2,352 from naïve people. Of these, 944 from naïve and 2,299 from convalescents produced monoclonal antibodies against the spike protein and 411 of them neutralized the original Wuhan SARS-CoV-2 virus. More than 75% of the monoclonal antibodies from naïve people lost their neutralization activity against the B.1.351 (beta) and B.1.1.248 (gamma) variants while this happened only for 61% of those from convalescents. The overall loss of neutralization was lower for the B.1.1.7 (alpha) and B.1.617.2 (delta) variants, however it was always significantly higher in those of naïve people. In part this was due to the IGHV2-5;IGHJ4-1 germline, which was found only in convalescents and generated potent and broadly neutralizing antibodies. Overall, vaccination of seropositive people increases the frequency of B cells encoding antibodies with high potency and that are not susceptible to escape by any of the four variants of concern. Our data suggest that people that are seropositive following infection or primary vaccination will produce antibodies with increased potency and breadth and will be able to better control SARS-CoV-2 emerging variants.

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Broad sarbecovirus neutralization by a human monoclonal antibody

Cited by 220 publications

References 87 publications

High genetic barrier to escape from human polyclonal SARS-CoV-2 neutralizing antibodies

High genetic barrier to escape from human polyclonal SARS-CoV-2 neutralizing antibodies

Molecular basis of immune evasion by the delta and kappa SARS-CoV-2 variants

Hybrid immunity improves B cell frequency, antibody potency and breadth against SARS-CoV-2 and variants of concern

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