TY - JOUR
T1 - Neutralization of SARS-CoV-2 requires antibodies against conformational receptor-binding domain epitopes
AU - Gattinger, Pia
AU - Niespodziana, Katarzyna
AU - Stiasny, Karin
AU - Sahanic, Sabina
AU - Tulaeva, Inna
AU - Borochova, Kristina
AU - Dorofeeva, Yulia
AU - Schlederer, Thomas
AU - Sonnweber, Thomas
AU - Hofer, Gerhard
AU - Kiss, Renata
AU - Kratzer, Bernhard
AU - Trapin, Doris
AU - Tauber, Peter A
AU - Rottal, Arno
AU - Körmöczi, Ulrike
AU - Feichter, Melanie
AU - Weber, Milena
AU - Focke-Tejkl, Margarete
AU - Löffler-Ragg, Judith
AU - Mühl, Bernhard
AU - Kropfmüller, Anna
AU - Keller, Walter
AU - Stolz, Frank
AU - Henning, Rainer
AU - Tancevski, Ivan
AU - Puchhammer-Stöckl, Elisabeth
AU - Pickl, Winfried F
AU - Valenta, Rudolf
N1 - Funding Information:
This study was supported by grants from Österreichische Forschungsförderungsgesellschaft, Grant number: 35721032; Austrian Science Fund, Grant numbers: DK‐W1248 and P29398; Viravaxx AG; Medizinisch‐Wissenschaftlichen Fonds des Bürgermeisters der Bundeshauptstadt Wien, Grant numbers: COVID001 and COVID006. ITa was awarded an Investigator‐Initiated Study (IIS) grant by Boehringer Ingelheim (IIS 1199‐0424). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Funding Information:
This study was supported by grants from ?sterreichische Forschungsf?rderungsgesellschaft, Grant number: 35721032; Austrian Science Fund, Grant numbers: DK-W1248 and P29398; Viravaxx AG; Medizinisch-Wissenschaftlichen Fonds des B?rgermeisters der Bundeshauptstadt Wien, Grant numbers: COVID001 and COVID006. ITa was awarded an Investigator-Initiated Study (IIS) grant by Boehringer Ingelheim (IIS 1199-0424). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript We wish to thank Jutta Hutecek, Paul Ettel, Fritz Tuppy, Katharina Grabmeier-Pfistershammer, Lisabeth Pimenov for excellent technical assistance. Furthermore, we are grateful to Brian Seed (Harvard) and Theodore Jardetzky (Stanford) for critically reading the manuscript and useful suggestions. We wish to acknowledge the help of Doris Werjant-Locmele and Anna Guentcheva regarding the recruitment and administration of study subjects. We are grateful to all individuals who participated in our study.
Publisher Copyright:
© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.
PY - 2022/1
Y1 - 2022/1
N2 - BACKGROUND: The determinants of successful humoral immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of critical importance for the design of effective vaccines and the evaluation of the degree of protective immunity conferred by exposure to the virus. As novel variants emerge, understanding their likelihood of suppression by population antibody repertoires has become increasingly important.METHODS: In this study, we analyzed the SARS-CoV-2 polyclonal antibody response in a large population of clinically well-characterized patients after mild and severe COVID-19 using a panel of microarrayed structurally folded and unfolded SARS-CoV-2 proteins, as well as sequential peptides, spanning the surface spike protein (S) and the receptor-binding domain (RBD) of the virus.RESULTS: S- and RBD-specific antibody responses were dominated by immunoglobulin G (IgG), mainly IgG1 , and directed against structurally folded S and RBD and three distinct peptide epitopes in S2. The virus neutralization activity of patients´ sera was highly correlated with IgG antibodies specific for conformational but not sequential RBD epitopes and their ability to prevent RBD binding to its human receptor angiotensin-converting enzyme 2 (ACE2). Twenty percent of patients selectively lacked RBD-specific IgG. Only immunization with folded, but not with unfolded RBD, induced antibodies against conformational epitopes with high virus-neutralizing activity. Conformational RBD epitopes required for protection do not seem to be altered in the currently emerging virus variants.CONCLUSION: These results are fundamental for estimating the protective activity of antibody responses after natural infection or vaccination and for the design of vaccines, which can induce high levels of SARS-CoV-2-neutralizing antibodies conferring sterilizing immunity.
AB - BACKGROUND: The determinants of successful humoral immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of critical importance for the design of effective vaccines and the evaluation of the degree of protective immunity conferred by exposure to the virus. As novel variants emerge, understanding their likelihood of suppression by population antibody repertoires has become increasingly important.METHODS: In this study, we analyzed the SARS-CoV-2 polyclonal antibody response in a large population of clinically well-characterized patients after mild and severe COVID-19 using a panel of microarrayed structurally folded and unfolded SARS-CoV-2 proteins, as well as sequential peptides, spanning the surface spike protein (S) and the receptor-binding domain (RBD) of the virus.RESULTS: S- and RBD-specific antibody responses were dominated by immunoglobulin G (IgG), mainly IgG1 , and directed against structurally folded S and RBD and three distinct peptide epitopes in S2. The virus neutralization activity of patients´ sera was highly correlated with IgG antibodies specific for conformational but not sequential RBD epitopes and their ability to prevent RBD binding to its human receptor angiotensin-converting enzyme 2 (ACE2). Twenty percent of patients selectively lacked RBD-specific IgG. Only immunization with folded, but not with unfolded RBD, induced antibodies against conformational epitopes with high virus-neutralizing activity. Conformational RBD epitopes required for protection do not seem to be altered in the currently emerging virus variants.CONCLUSION: These results are fundamental for estimating the protective activity of antibody responses after natural infection or vaccination and for the design of vaccines, which can induce high levels of SARS-CoV-2-neutralizing antibodies conferring sterilizing immunity.
KW - Antibodies, Viral
KW - COVID-19
KW - Epitopes
KW - Humans
KW - SARS-CoV-2
KW - Spike Glycoprotein, Coronavirus/genetics
UR - http://www.scopus.com/inward/record.url?scp=85115336445&partnerID=8YFLogxK
U2 - 10.1111/all.15066
DO - 10.1111/all.15066
M3 - Journal article
C2 - 34453317
SN - 0105-4538
VL - 77
SP - 230
EP - 242
JO - Allergy: European Journal of Allergy and Clinical Immunology
JF - Allergy: European Journal of Allergy and Clinical Immunology
IS - 1
ER -