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BMC Medicine
Published in: BMC Medicine 1/2022

01-12-2022 | Vaccination | Research article

Human serum from SARS-CoV-2-vaccinated and COVID-19 patients shows reduced binding to the RBD of SARS-CoV-2 Omicron variant

Authors: Maren Schubert, Federico Bertoglio, Stephan Steinke, Philip Alexander Heine, Mario Alberto Ynga-Durand, Henrike Maass, Josè Camilla Sammartino, Irene Cassaniti, Fanglei Zuo, Likun Du, Janin Korn, Marko Milošević, Esther Veronika Wenzel, Fran Krstanović, Saskia Polten, Marina Pribanić-Matešić, Ilija Brizić, Fausto Baldanti, Lennart Hammarström, Stefan Dübel, Alan Šustić, Harold Marcotte, Monika Strengert, Alen Protić, Antonio Piralla, Qiang Pan-Hammarström, Luka Čičin-Šain, Michael Hust

Published in: BMC Medicine | Issue 1/2022

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Abstract

Background

The COVID-19 pandemic is caused by the betacoronavirus SARS-CoV-2. In November 2021, the Omicron variant was discovered and immediately classified as a variant of concern (VOC), since it shows substantially more mutations in the spike protein than any previous variant, especially in the receptor-binding domain (RBD). We analyzed the binding of the Omicron RBD to the human angiotensin-converting enzyme-2 receptor (ACE2) and the ability of human sera from COVID-19 patients or vaccinees in comparison to Wuhan, Beta, or Delta RBD variants.

Methods

All RBDs were produced in insect cells. RBD binding to ACE2 was analyzed by ELISA and microscale thermophoresis (MST). Similarly, sera from 27 COVID-19 patients, 81 vaccinated individuals, and 34 booster recipients were titrated by ELISA on RBDs from the original Wuhan strain, Beta, Delta, and Omicron VOCs. In addition, the neutralization efficacy of authentic SARS-CoV-2 wild type (D614G), Delta, and Omicron by sera from 2× or 3× BNT162b2-vaccinated persons was analyzed.

Results

Surprisingly, the Omicron RBD showed a somewhat weaker binding to ACE2 compared to Beta and Delta, arguing that improved ACE2 binding is not a likely driver of Omicron evolution. Serum antibody titers were significantly lower against Omicron RBD compared to the original Wuhan strain. A 2.6× reduction in Omicron RBD binding was observed for serum of 2× BNT162b2-vaccinated persons. Neutralization of Omicron SARS-CoV-2 was completely diminished in our setup.

Conclusion

These results indicate an immune escape focused on neutralizing antibodies. Nevertheless, a boost vaccination increased the level of anti-RBD antibodies against Omicron, and neutralization of authentic Omicron SARS-CoV-2 was at least partially restored. This study adds evidence that current vaccination protocols may be less efficient against the Omicron variant.
Appendix
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Literature
1.
Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet Lond Engl. 2020;395:565–74.CrossRef
2.
Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–3.CrossRef
3.
4.
Leung K, Shum MH, Leung GM, Lam TT, Wu JT. Early transmissibility assessment of the N501Y mutant strains of SARS-CoV-2 in the United Kingdom, October to November 2020. Euro Surveill Bull Eur Sur Mal Transm Eur Commun Dis Bull. 2021;26.
5.
Mwenda M, Saasa N, Sinyange N, Busby G, Chipimo PJ, Hendry J, et al. Detection of B.1.351 SARS-CoV-2 variant strain - Zambia, December 2020. MMWR Morb Mortal Wkly Rep. 2021;70:280–2.CrossRef
6.
Muñoz M, Patiño LH, Ballesteros N, Paniz-Mondolfi A, Ramírez JD. Characterizing SARS-CoV-2 genome diversity circulating in South American countries: signatures of potentially emergent lineages? Int J Infect Dis IJID Off Publ Int Soc Infect Dis. 2021;105:329–32.
7.
Wall EC, Wu M, Harvey R, Kelly G, Warchal S, Sawyer C, et al. Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination. Lancet Lond Engl. 2021;397:2331–3.CrossRef
8.
9.
Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh C-L, Abiona O, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020;367:1260–3.CrossRef
10.
Bošnjak B, Stein SC, Willenzon S, Cordes AK, Puppe W, Bernhardt G, et al. Low serum neutralizing anti-SARS-CoV-2 S antibody levels in mildly affected COVID-19 convalescent patients revealed by two different detection methods. Cell Mol Immunol. 2021;18:936–44.CrossRef
11.
Mengist HM, Kombe Kombe AJ, Mekonnen D, Abebaw A, Getachew M, Jin T. Mutations of SARS-CoV-2 spike protein: implications on immune evasion and vaccine-induced immunity. Semin Immunol. 2021;55:101533.
12.
Bertoglio F, Fühner V, Ruschig M, Heine PA, Abassi L, Klünemann T, et al. A SARS-CoV-2 neutralizing antibody selected from COVID-19 patients binds to the ACE2-RBD interface and is tolerant to most known RBD mutations. Cell Rep. 2021;36:109433.
13.
14.
Wilhelm A, Widera M, Grikscheit K, Toptan T, Schenk B, Pallas C, et al. Reduced neutralization of SARS-CoV-2 Omicron variant by vaccine sera and monoclonal antibodies. medRxiv. 2021;2021.12.07.21267432. (medRxiv preprint).
15.
Hoffmann M, Krüger N, Schulz S, Cossmann A, Rocha C, Kempf A, et al. The Omicron variant is highly resistant against antibody-mediated neutralization: implications for control of the COVID-19 pandemic. Cell. 2021;185(3):447–456.e11.CrossRef
16.
Muik A, Lui BG, Wallisch A-K, Bacher M, Mühl J, Reinholz J, et al. Neutralization of SARS-CoV-2 omicron by BNT162b2 mRNA vaccine-elicited human sera. Science. 2022;375(6581):678–80.CrossRef
17.
18.
Bleckmann M, Fritz MH-Y, Bhuju S, Jarek M, Schürig M, Geffers R, et al. Genomic analysis and isolation of RNA polymerase II dependent promoters from Spodoptera frugiperda. PLoS One. 2015;10:e0132898.CrossRef
19.
Zheng L, Baumann U, Reymond J-L. An efficient one-step site-directed and site-saturation mutagenesis protocol. Nucleic Acids Res. 2004;32:e115.CrossRef
20.
Korn J, Schäckermann D, Kirmann T, Bertoglio F, Steinke S, Heisig J, et al. Baculovirus-free insect cell expression system for high yield antibody and antigen production. Sci Rep. 2020;10:21393.CrossRef
21.
Bertoglio F, Meier D, Langreder N, Steinke S, Rand U, Simonelli L, et al. SARS-CoV-2 neutralizing human recombinant antibodies selected from pre-pandemic healthy donors binding at RBD-ACE2 interface. Nat Commun. 2021;12:1577.CrossRef
22.
Bertoglio F, Fühner V, Ruschig M, Heine PA, Abassi L, Klünemann T, et al. A SARS-CoV-2 neutralizing antibody selected from COVID-19 patients binds to the ACE2-RBD interface and is tolerant to most known RBD mutations. Cell Rep. 2021;36:109433.CrossRef
23.
Wenzel EV, Bosnak M, Tierney R, Schubert M, Brown J, Dübel S, et al. Human antibodies neutralizing diphtheria toxin in vitro and in vivo. Sci Rep. 2020;10:571.CrossRef
24.
Cassaniti I, Bergami F, Percivalle E, Gabanti E, Sammartino JC, Ferrari A, et al. Humoral and cell-mediated response against SARS-CoV-2 variants elicited by mRNA vaccine BNT162b2 in healthcare workers: a longitudinal observational study. Clin Microbiol Infect. 2022;28:301.e1–8.CrossRef
25.
Percivalle E, Cambiè G, Cassaniti I, Nepita EV, Maserati R, Ferrari A, et al. Prevalence of SARS-CoV-2 specific neutralising antibodies in blood donors from the Lodi Red Zone in Lombardy, Italy, as at 06 April 2020. Euro Surveill Bull Eur Sur Mal Transm Eur Commun Dis Bull. 2020;25.
26.
27.
Heinrich L, Tissot N, Hartmann DJ, Cohen R. Comparison of the results obtained by ELISA and surface plasmon resonance for the determination of antibody affinity. J Immunol Methods. 2010;352:13–22.CrossRef
28.
Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H, et al. Structural basis of receptor recognition by SARS-CoV-2. Nature. 2020;581:221–4.CrossRef
29.
Shah M, Woo HG. Omicron: a heavily mutated SARS-CoV-2 variant exhibits stronger binding to ACE2 and potently escape approved COVID-19 therapeutic antibodies; 2021.
30.
Fratev F. The high transmission of SARS-CoV-2 Omicron (B.1.1.529) variant is not only due to its hACE2 binding: a free energy of perturbation study. bioRxiv. 2021;2021.12.04.471246. (bioRxiv preprint).
31.
Glocker MO, Opuni KFM, Thiesen H-J. Compared with SARS-CoV2 wild type’s spike protein, the SARS-CoV2 omicron’s receptor binding motif has adopted a more SARS-CoV1 and/or bat/civet-like structure. bioRxiv. 2021;2021.12.14.472585. (bioRxiv preprint).
32.
Han P, Su C, Zhang Y, Bai C, Zheng A, Qiao C, et al. Molecular insights into receptor binding of recent emerging SARS-CoV-2 variants. Nat Commun. 2021;12:6103.CrossRef
33.
Zhao H, Lu L, Peng Z, Chen L-L, Meng X, Zhang C, et al. SARS-CoV-2 Omicron variant shows less efficient replication and fusion activity when compared with Delta variant in TMPRSS2-expressed cells. Emerg Microbes Infect. 2022;11:277–83.CrossRef
34.
Belouzard S, Chu VC, Whittaker GR. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc Natl Acad Sci U S A. 2009;106:5871–6.CrossRef
35.
Pachetti M, Marini B, Benedetti F, Giudici F, Mauro E, Storici P, et al. Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant. J Transl Med. 2020;18:179.CrossRef
36.
Hörnich BF, Großkopf AK, Schlagowski S, Tenbusch M, Kleine-Weber H, Neipel F, et al. SARS-CoV-2 and SARS-CoV spike-mediated cell-cell fusion differ in their requirements for receptor expression and proteolytic activation. J Virol. 2021;95:e00002–21.CrossRef
37.
Butt AA, Dargham SR, Chemaitelly H, Al Khal A, Tang P, Hasan MR, et al. Severity of illness in persons infected with the SARS-CoV-2 Delta variant vs Beta variant in Qatar. JAMA Intern Med. 2022;182:197–205.CrossRef
38.
Wu L, Zhou L, Mo M, Liu T, Wu C, Gong C, et al. SARS-CoV-2 Omicron RBD shows weaker binding affinity than the currently dominant Delta variant to human ACE2. Signal Transduct Target Ther. 2022;7:1–3.CrossRef
39.
Dejnirattisai W, Huo J, Zhou D, Zahradník J, Supasa P, Liu C, et al. SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses. Cell. 2022;185:467–484.e15.CrossRef
40.
Harvey WT, Carabelli AM, Jackson B, Gupta RK, Thomson EC, Harrison EM, et al. SARS-CoV-2 variants, spike mutations and immune escape. Nat Rev Microbiol. 2021;19:409–24.CrossRef
41.
Ng KW, Faulkner N, Wrobel AG, Gamblin SJ, Kassiotis G. Heterologous humoral immunity to human and zoonotic coronaviruses: aiming for the Achilles heel. Semin Immunol. 2021;55:101507.
42.
Zahradník J, Marciano S, Shemesh M, Zoler E, Harari D, Chiaravalli J, et al. SARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution. Nat Microbiol. 2021;6:1188–98.CrossRef
43.
Marcotte H, Piralla A, Zuo F, Du L, Cassaniti I, Wan H, et al. Immunity to SARS-CoV-2 up to 15 months after infection. iScience. 2022;25(2):103743.
44.
45.
Dulovic A, Kessel B, Harries M, Becker M, Ortmann J, Griesbaum J, et al. Comparative magnitude and persistence of SARS-CoV-2 vaccination responses on a population level in Germany. medRxiv. 2021;2021.12.01.21266960. (medRxiv preprint).
46.
Cele S, Karim F, Lustig G, James SE, Hermanus T, Wilkinson E, et al. SARS-CoV-2 evolved during advanced HIV disease immunosuppression has Beta-like escape of vaccine and Delta infection elicited immunity. medRxiv. 2021;2021.09.14.21263564. (medRxiv preprint).
47.
Sievers BL, Chakraborty S, Xue Y, Gelbart T, Gonzalez JC, Cassidy AG, et al. Antibodies elicited by SARS-CoV-2 infection or mRNA vaccines have reduced neutralizing activity against Beta and Omicron pseudoviruses. Sci Transl Med. 2022:eabn7842. (in press).
48.
49.
50.
Tao K, Tzou PL, Nouhin J, Gupta RK, de Oliveira T, Kosakovsky Pond SL, et al. The biological and clinical significance of emerging SARS-CoV-2 variants. Nat Rev Genet. 2021;22:757–73.CrossRef
Metadata
Title
Human serum from SARS-CoV-2-vaccinated and COVID-19 patients shows reduced binding to the RBD of SARS-CoV-2 Omicron variant
Authors
Maren Schubert
Federico Bertoglio
Stephan Steinke
Philip Alexander Heine
Mario Alberto Ynga-Durand
Henrike Maass
Josè Camilla Sammartino
Irene Cassaniti
Fanglei Zuo
Likun Du
Janin Korn
Marko Milošević
Esther Veronika Wenzel
Fran Krstanović
Saskia Polten
Marina Pribanić-Matešić
Ilija Brizić
Fausto Baldanti
Lennart Hammarström
Stefan Dübel
Alan Šustić
Harold Marcotte
Monika Strengert
Alen Protić
Antonio Piralla
Qiang Pan-Hammarström
Luka Čičin-Šain
Michael Hust
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02312-5

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