Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants

Xu, Jiegou; Xu, Kai; Jung, Seolkyoung; Conte, Andrea; Lieberman, Jenna Ariel; Muecksch, Frauke; Lorenzi, Julio C. C.; Park, Solji; Schmidt, Fabian; Wang, Zijun; Huang, Yaoxing; Luo, Yang; Nair, Manoj S.; Wang, Pengfei; Schulz, Jonathan; Tessarollo, Lino; Bylund, Tatsiana; Chuang, Gwo-Yu; Olia, Adam S.; Stephens, Tyler; Teng, I-Ting; Tsybovsky, Yaroslav; Zhou, Tongqing; Munster, Vincent J.; Ho, David D.; Hatziioannou, Théodora; Bieniasz, Paul D.; Nussenzweig, Michel C.; Kwong, Peter D.; Casellas, Rafael

doi:10.1038/s41586-021-03676-z

Cited by 174 publications

(199 citation statements)

References 46 publications

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“…At least two recent studies reported that antibodies could be detected up to 11 months after infection and provided evidence that that these antibodies originated in memory B cells, not plasmablasts(Tong et al, 2021; Turner et al, 2021a). Generation of SARS-CoV-2 memory B cells(De Gasparo et al, 2021; Schoof et al, 2020; Xu et al, 2021) is likely necessary for long-term protection since that is the mechanism by which most anti-viral vaccines work(Iwasaki, 2016).…”

Section: Discussionmentioning

confidence: 99%

Large-scale study of antibody titer decay following BNT162b2 mRNA vaccine or SARS-CoV-2 infection

Israel

Shenhar

Green

et al. 2021

Preprint

110

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BackgroundImmune protection following either vaccination or infection with SARS-CoV-2 decreases over time.ObjectiveTo determine the kinetics of SARS-CoV-2 IgG antibodies following administration of two doses of BNT162b2 vaccine, or SARS-CoV-2 infection in unvaccinated individuals.MethodsAntibody titers were measured between January 31, 2021, and July 31, 2021 in two mutually exclusive groups: i) vaccinated individuals who received two doses of BNT162b2 vaccine and had no history of previous infection with COVID-19 and ii) SARS-CoV-2 convalescents who had not received the vaccine.ResultsA total of 2,653 individuals fully vaccinated by two doses of vaccine during the study period and 4,361 convalescent patients were included. Higher SARS-CoV-2 IgG antibody titers were observed in vaccinated individuals (median 1581 AU/mL IQR [533.8-5644.6]) after the second vaccination, than in convalescent individuals (median 355.3 AU/mL IQR [141.2-998.7]; p<0.001). In vaccinated subjects, antibody titers decreased by up to 40% each subsequent month while in convalescents they decreased by less than 5% per month. Six months after BNT162b2 vaccination 16.1% subjects had antibody levels below the seropositivity threshold of <50 AU/mL, while only 10.8% of convalescent patients were below <50 AU/mL threshold after 9 months from SARS-CoV-2 infection.ConclusionsThis study demonstrates individuals who received the Pfizer-BioNTech mRNA vaccine have different kinetics of antibody levels compared to patients who had been infected with the SARS-CoV-2 virus, with higher initial levels but a much faster exponential decrease in the first group.FundingThis research was internally funded by Leumit Health Services (LHS) and was supported in part by the Intramural Research Program, National Institutes of Health, National Cancer Institute, Center for Cancer Research.The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.Impact statementLarge scale study display the kinetics of SARS-CoV-2 IgG antibodies present in individuals vaccinated with two doses of mRNA vaccine vs. unvaccinated patients who had recovered from the disease: initial levels of antibody are much higher in vaccinated patients, but decrease faster.

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Section: Discussionmentioning

confidence: 99%

Large-scale study of antibody titer decay following BNT162b2 mRNA vaccine or SARS-CoV-2 infection

Israel

Shenhar

Green

et al. 2021

Preprint

110

View full text Add to dashboard Cite

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“…The ternary structure may also be considered as illustrative of the potential behavior of a bispecific construct linking two nanobodies. The bivalent or multivalent binding by antibody or nanobody would be expected to increase neutralization potential ( 19 , 45 , 46 , 47 ). Superposition of Sb14–RBD–Sb68 or Sb45–RBD–Sb68 on V HH -E–RBD–V HH -U indicates that Sb14, Sb45, and V HH -E represent class 1 and class 2 in recognizing the epitopic region but do so in somewhat different orientations ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Structures of synthetic nanobody–SARS-CoV-2 receptor-binding domain complexes reveal distinct sites of interaction

Ahmad

Jiang

Boyd

et al. 2021

Journal of Biological Chemistry

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Combating the worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the emergence of new variants demands understanding of the structural basis of the interaction of antibodies with the SARS-CoV-2 receptor-binding domain (RBD). Here we report five X-ray crystal structures of sybodies (synthetic nanobodies) including those of binary and ternary complexes of Sb16–RBD, Sb45–RBD, Sb14–RBD–Sb68, and Sb45–RBD–Sb68, as well as unliganded Sb16. These structures reveal that Sb14, Sb16, and Sb45 bind the RBD at the angiotensin converting enzyme 2 (ACE2) interface, and that the Sb16 interaction is accompanied by a large conformational adjustment of complementarity determining region 2 (CDR2). In contrast, Sb68 interacts at the periphery of the SARS-CoV-2 RBC/ACE2 interface. We also determined cryo-EM structures of Sb45 bound to the SARS-CoV-2 spike (S) protein. Superposition of the X-ray structures of sybodies onto the trimeric S protein cryo-EM map indicates that some sybodies may bind in both "up" and "down" configurations, but others may not. Differences in sybody recognition of several recently identified RBD variants are explained by these structures.

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“…Secondly, while conventional antibodies that comprise two disulphide-linked polypeptides, heavy and light chain, typically require mammalian cells for production, nanobodies can be manufactured using readily available microbial systems. The potency of nanobodies against SARS-CoV-2 7 infection has been demonstrated in cell-based assays [8][9][10][11][12][13][14][15][16] and most recently in animal studies 17,18 . Several strategies for engineering VHH into a multivalent species are known.…”

mentioning

confidence: 99%

A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19

et al. 2021

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SARS-CoV-2 remains a global threat to human health particularly as escape mutants emerge. There is an unmet need for effective treatments against COVID-19 for which neutralizing single domain antibodies (nanobodies) have significant potential. Their small size and stability mean that nanobodies are compatible with respiratory administration. We report four nanobodies (C5, H3, C1, F2) engineered as homotrimers with pmolar affinity for the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Crystal structures show C5 and H3 overlap the ACE2 epitope, whilst C1 and F2 bind to a different epitope. Cryo Electron Microscopy shows C5 binding results in an all down arrangement of the Spike protein. C1, H3 and C5 all neutralize the Victoria strain, and the highly transmissible Alpha (B.1.1.7 first identified in Kent, UK) strain and C1 also neutralizes the Beta (B.1.35, first identified in South Africa). Administration of C5-trimer via the respiratory route showed potent therapeutic efficacy in the Syrian hamster model of COVID-19 and separately, effective prophylaxis. The molecule was similarly potent by intraperitoneal injection.

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Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants

Cited by 174 publications

References 46 publications

Large-scale study of antibody titer decay following BNT162b2 mRNA vaccine or SARS-CoV-2 infection

Large-scale study of antibody titer decay following BNT162b2 mRNA vaccine or SARS-CoV-2 infection

Structures of synthetic nanobody–SARS-CoV-2 receptor-binding domain complexes reveal distinct sites of interaction

A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19

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