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Sebastian Einhauser
Institute for Medical Microbiology and Hygiene, University of Regensburg, 93053 Regensburg, Germany

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Journal article
Published: 11 August 2021
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The novel coronavirus SARS-CoV-2 is the seventh identified human coronavirus. Understanding the extent of pre-existing immunity induced by seropositivity to endemic seasonal coronaviruses and the impact of cross-reactivity on COVID-19 disease progression remains a key research question in immunity to SARS-CoV-2 and the immunopathology of COVID-2019 disease. This paper describes a panel of lentiviral pseudotypes bearing the spike (S) proteins for each of the seven human coronaviruses (HCoVs), generated under similar conditions optimized for high titre production allowing a high-throughput investigation of antibody neutralization breadth. Optimal production conditions and most readily available permissive target cell lines were determined for spike-mediated entry by each HCoV pseudotype: SARS-CoV-1, SARS-CoV-2 and HCoV-NL63 best transduced HEK293T/17 cells transfected with ACE2 and TMPRSS2, HCoV-229E and MERS-CoV preferentially entered HUH7 cells, and CHO cells were most permissive for the seasonal betacoronavirus HCoV-HKU1. Entry of ACE2 using pseudotypes was enhanced by ACE2 and TMPRSS2 expression in target cells, whilst TMPRSS2 transfection rendered HEK293T/17 cells permissive for HCoV-HKU1 and HCoV-OC43 entry. Additionally, pseudotype viruses were produced bearing additional coronavirus surface proteins, including the SARS-CoV-2 Envelope (E) and Membrane (M) proteins and HCoV-OC43/HCoV-HKU1 Haemagglutinin-Esterase (HE) proteins. This panel of lentiviral pseudotypes provides a safe, rapidly quantifiable and high-throughput tool for serological comparison of pan-coronavirus neutralizing responses; this can be used to elucidate antibody dynamics against individual coronaviruses and the effects of antibody cross-reactivity on clinical outcome following natural infection or vaccination.

ACS Style

Alexander Thomas Sampson; Jonathan Heeney; Diego Cantoni; Matteo Ferrari; Maria Suau Sans; Charlotte George; Cecilia Di Genova; Martin Mayora Neto; Sebastian Einhauser; Benedikt Asbach; Ralf Wagner; Helen Baxendale; Nigel Temperton; George Carnell. Coronavirus Pseudotypes for All Circulating Human Coronaviruses for Quantification of Cross-Neutralizing Antibody Responses. 2021, 1 .

AMA Style

Alexander Thomas Sampson, Jonathan Heeney, Diego Cantoni, Matteo Ferrari, Maria Suau Sans, Charlotte George, Cecilia Di Genova, Martin Mayora Neto, Sebastian Einhauser, Benedikt Asbach, Ralf Wagner, Helen Baxendale, Nigel Temperton, George Carnell. Coronavirus Pseudotypes for All Circulating Human Coronaviruses for Quantification of Cross-Neutralizing Antibody Responses. . 2021; ():1.

Chicago/Turabian Style

Alexander Thomas Sampson; Jonathan Heeney; Diego Cantoni; Matteo Ferrari; Maria Suau Sans; Charlotte George; Cecilia Di Genova; Martin Mayora Neto; Sebastian Einhauser; Benedikt Asbach; Ralf Wagner; Helen Baxendale; Nigel Temperton; George Carnell. 2021. "Coronavirus Pseudotypes for All Circulating Human Coronaviruses for Quantification of Cross-Neutralizing Antibody Responses." , no. : 1.

Journal article
Published: 10 August 2021 in Viruses
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The novel coronavirus SARS-CoV-2 is the seventh identified human coronavirus. Understanding the extent of pre-existing immunity induced by seropositivity to endemic seasonal coronaviruses and the impact of cross-reactivity on COVID-19 disease progression remains a key research question in immunity to SARS-CoV-2 and the immunopathology of COVID-2019 disease. This paper describes a panel of lentiviral pseudotypes bearing the spike (S) proteins for each of the seven human coronaviruses (HCoVs), generated under similar conditions optimized for high titre production allowing a high-throughput investigation of antibody neutralization breadth. Optimal production conditions and most readily available permissive target cell lines were determined for spike-mediated entry by each HCoV pseudotype: SARS-CoV-1, SARS-CoV-2 and HCoV-NL63 best transduced HEK293T/17 cells transfected with ACE2 and TMPRSS2, HCoV-229E and MERS-CoV preferentially entered HUH7 cells, and CHO cells were most permissive for the seasonal betacoronavirus HCoV-HKU1. Entry of ACE2 using pseudotypes was enhanced by ACE2 and TMPRSS2 expression in target cells, whilst TMPRSS2 transfection rendered HEK293T/17 cells permissive for HCoV-HKU1 and HCoV-OC43 entry. Additionally, pseudotype viruses were produced bearing additional coronavirus surface proteins, including the SARS-CoV-2 Envelope (E) and Membrane (M) proteins and HCoV-OC43/HCoV-HKU1 Haemagglutinin-Esterase (HE) proteins. This panel of lentiviral pseudotypes provides a safe, rapidly quantifiable and high-throughput tool for serological comparison of pan-coronavirus neutralizing responses; this can be used to elucidate antibody dynamics against individual coronaviruses and the effects of antibody cross-reactivity on clinical outcome following natural infection or vaccination.

ACS Style

Alexander Sampson; Jonathan Heeney; Diego Cantoni; Matteo Ferrari; Maria Sans; Charlotte George; Cecilia Di Genova; Martin Mayora Neto; Sebastian Einhauser; Benedikt Asbach; Ralf Wagner; Helen Baxendale; Nigel Temperton; George Carnell. Coronavirus Pseudotypes for All Circulating Human Coronaviruses for Quantification of Cross-Neutralizing Antibody Responses. Viruses 2021, 13, 1579 .

AMA Style

Alexander Sampson, Jonathan Heeney, Diego Cantoni, Matteo Ferrari, Maria Sans, Charlotte George, Cecilia Di Genova, Martin Mayora Neto, Sebastian Einhauser, Benedikt Asbach, Ralf Wagner, Helen Baxendale, Nigel Temperton, George Carnell. Coronavirus Pseudotypes for All Circulating Human Coronaviruses for Quantification of Cross-Neutralizing Antibody Responses. Viruses. 2021; 13 (8):1579.

Chicago/Turabian Style

Alexander Sampson; Jonathan Heeney; Diego Cantoni; Matteo Ferrari; Maria Sans; Charlotte George; Cecilia Di Genova; Martin Mayora Neto; Sebastian Einhauser; Benedikt Asbach; Ralf Wagner; Helen Baxendale; Nigel Temperton; George Carnell. 2021. "Coronavirus Pseudotypes for All Circulating Human Coronaviruses for Quantification of Cross-Neutralizing Antibody Responses." Viruses 13, no. 8: 1579.

Journal article
Published: 10 June 2021 in Viruses
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SARS-CoV-2 infection fatality ratios (IFR) remain controversially discussed with implications for political measures. The German county of Tirschenreuth suffered a severe SARS-CoV-2 outbreak in spring 2020, with particularly high case fatality ratio (CFR). To estimate seroprevalence, underreported infections, and IFR for the Tirschenreuth population aged ≥14 years in June/July 2020, we conducted a population-based study including home visits for the elderly, and analyzed 4203 participants for SARS-CoV-2 antibodies via three antibody tests. Latent class analysis yielded 8.6% standardized county-wide seroprevalence, a factor of underreported infections of 5.0, and 2.5% overall IFR. Seroprevalence was two-fold higher among medical workers and one third among current smokers with similar proportions of registered infections. While seroprevalence did not show an age-trend, the factor of underreported infections was 12.2 in the young versus 1.7 for ≥85-year-old. Age-specific IFRs were <0.5% below 60 years of age, 1.0% for age 60–69, and 13.2% for age 70+. Senior care homes accounted for 45% of COVID-19-related deaths, reflected by an IFR of 7.5% among individuals aged 70+ and an overall IFR of 1.4% when excluding senior care home residents from our computation. Our data underscore senior care home infections as key determinant of IFR additionally to age, insufficient targeted testing in the young, and the need for further investigations on behavioral or molecular causes of the fewer infections among current smokers.

ACS Style

Ralf Wagner; David Peterhoff; Stephanie Beileke; Felix Günther; Melanie Berr; Sebastian Einhauser; Anja Schütz; Hans Niller; Philipp Steininger; Antje Knöll; Matthias Tenbusch; Clara Maier; Klaus Korn; Klaus Stark; André Gessner; Ralph Burkhardt; Michael Kabesch; Holger Schedl; Helmut Küchenhoff; Annette Pfahlberg; Iris Heid; Olaf Gefeller; Klaus Überla. Estimates and Determinants of SARS-Cov-2 Seroprevalence and Infection Fatality Ratio Using Latent Class Analysis: The Population-Based Tirschenreuth Study in the Hardest-Hit German County in Spring 2020. Viruses 2021, 13, 1118 .

AMA Style

Ralf Wagner, David Peterhoff, Stephanie Beileke, Felix Günther, Melanie Berr, Sebastian Einhauser, Anja Schütz, Hans Niller, Philipp Steininger, Antje Knöll, Matthias Tenbusch, Clara Maier, Klaus Korn, Klaus Stark, André Gessner, Ralph Burkhardt, Michael Kabesch, Holger Schedl, Helmut Küchenhoff, Annette Pfahlberg, Iris Heid, Olaf Gefeller, Klaus Überla. Estimates and Determinants of SARS-Cov-2 Seroprevalence and Infection Fatality Ratio Using Latent Class Analysis: The Population-Based Tirschenreuth Study in the Hardest-Hit German County in Spring 2020. Viruses. 2021; 13 (6):1118.

Chicago/Turabian Style

Ralf Wagner; David Peterhoff; Stephanie Beileke; Felix Günther; Melanie Berr; Sebastian Einhauser; Anja Schütz; Hans Niller; Philipp Steininger; Antje Knöll; Matthias Tenbusch; Clara Maier; Klaus Korn; Klaus Stark; André Gessner; Ralph Burkhardt; Michael Kabesch; Holger Schedl; Helmut Küchenhoff; Annette Pfahlberg; Iris Heid; Olaf Gefeller; Klaus Überla. 2021. "Estimates and Determinants of SARS-Cov-2 Seroprevalence and Infection Fatality Ratio Using Latent Class Analysis: The Population-Based Tirschenreuth Study in the Hardest-Hit German County in Spring 2020." Viruses 13, no. 6: 1118.

Preprint content
Published: 06 June 2021
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Approximately 75% of the UK population has received only one dose of a 2-dose COVID-19 vaccine regime in the face of circulating SARS-CoV-2 Variants of Concern (VOCs). We aimed to determine the levels of vaccine-induced neutralising antibodies to SARS-CoV-2 variants B.1.1.7, B.1.351 and P.1. To do so, we undertook a single-centre cross-sectional study of health care workers (HCWs) and outpatients with immunodeficiencies (IDP) based at the same critical care tertiary NHS Trust, following a single dose of either BNT162b2 or AZD1222 vaccines. Data revealed low neutralising antibodies (nAbs) in IDPs, with only 5% and 3% showing detectable neutralisation of B.1.1.7 and B.1.351, respectively. In contrast, healthy HCWs without a prior SARS-CoV-2 infection demonstrated a wide range of nAb titres post-vaccination with responses significantly lower than HCWs with prior SARS-CoV-2 infection. Neutralisation of VOCs with the E484K mutation (B.1.351 and P.1) were consistently lower in HCWs in the absence of evidence of prior SARS-CoV-2 infection (p<0.001). Notably, in vaccinated HCWs with prior SARS-CoV-2 infection, there was a significant increase of neutralising titres post-vaccination to all variants, compared to their pre-vaccination neutralisation titres. This underscores the importance of vaccination to boost neutralising antibody breadth to VOCs, and also provides support for the hypothesis that repeated immunisations will boost protective immunity in individuals without prior SARS-CoV-2 exposure.

ACS Style

Angalee Nadesalingam; Diego Cantoni; David A Wells; Ernest T Aguinam; Matteo Ferrari; Peter Smith; Andrew Chan; George Carnell; Luis Ohlendorf; Sebastian Einhauser; Ralf Wagner; Nigel Temperton; Javier Castillo-Olivares; Helen Baxendale; Jonathan L Heeney; the HICC consortium. Breadth of neutralising antibody responses to SARS-CoV-2 variants of concern is augmented by vaccination following prior infection: studies in UK healthcare workers and immunodeficient patients. 2021, 1 .

AMA Style

Angalee Nadesalingam, Diego Cantoni, David A Wells, Ernest T Aguinam, Matteo Ferrari, Peter Smith, Andrew Chan, George Carnell, Luis Ohlendorf, Sebastian Einhauser, Ralf Wagner, Nigel Temperton, Javier Castillo-Olivares, Helen Baxendale, Jonathan L Heeney, the HICC consortium. Breadth of neutralising antibody responses to SARS-CoV-2 variants of concern is augmented by vaccination following prior infection: studies in UK healthcare workers and immunodeficient patients. . 2021; ():1.

Chicago/Turabian Style

Angalee Nadesalingam; Diego Cantoni; David A Wells; Ernest T Aguinam; Matteo Ferrari; Peter Smith; Andrew Chan; George Carnell; Luis Ohlendorf; Sebastian Einhauser; Ralf Wagner; Nigel Temperton; Javier Castillo-Olivares; Helen Baxendale; Jonathan L Heeney; the HICC consortium. 2021. "Breadth of neutralising antibody responses to SARS-CoV-2 variants of concern is augmented by vaccination following prior infection: studies in UK healthcare workers and immunodeficient patients." , no. : 1.

Article
Published: 26 May 2021
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Background The rise of SARS-CoV-2 variants has made the pursuit to define correlates of protection more troublesome, despite the availability of the World Health Organisation (WHO) International Standard for anti-SARS-CoV-2 Immunoglobulin sera, a key reagent used to standardise laboratory findings into an international unitage. Methods Using pseudotyped virus, we examine the capacity of convalescent sera, from a well-defined cohort of healthcare workers (HCW) and Patients infected during the first wave from a national critical care centre in the UK to neutralise B.1.1.298, variants of interest (VOI) B.1.617.1 (Kappa), and four VOCs, B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta), including the B.1.617.2 K417N, informally known as Delta Plus. We utilised the WHO International Standard for anti-SARS-CoV-2 Immunoglobulin to report neutralisation antibody levels in International Units per mL. Findings Our data demonstrate a significant reduction in the ability of first wave convalescent sera to neutralise the VOCs. Patients and HCWs with more severe COVID-19 were found to have higher antibody titres and to neutralise the VOCs more effectively than individuals with milder symptoms. Using an estimated threshold for 50% protection, 54 IU/mL, we found most asymptomatic and mild cases did not produce titres above this threshold. Interpretation Expressing our data in IU/ml, we provide a benchmark pre-vaccine standardised dataset that compares disease severity with neutralising antibody titres. Our data may now be compared across multiple laboratories. The continued use and aggregation of standardised data will eventually assist in defining correlates of protection. Funding UKRI and NIHR; grant number G107217 Research in context Evidence before this study During the first wave outbreak, much focus was placed on the role of neutralising antibodies and titres generated upon infection to ancestral SARS-CoV-2. Due to the large amounts of different assays used to elucidate the antibody-mediated immunity and laboratory to laboratory, large amounts of invaluable data could not be directly compared in order to define a correlate of protection, due to variability in the results. The WHO International Standard for anti-SARS-CoV-2 Immunoglobulin sera was made in order to standardise future data so that comparisons may take place. Added value of this study Our study compares the neutralisation capacity of sera from patients and healthcare workers (HCWs) from the ancestral strain of SARS-CoV-2 against new variants, including the current variants of concern in circulation. We also provide data in International Units per mL, a standardised unitage, for infected individuals that have a clinical severity score, allowing us to assess levels of neutralising antibodies across different severities of COVID-19 disease. By providing a method to calibrate most of the variants of concern so that the WHO International Standard for anti-SARS-CoV-2 Immunoglobulin reagent could be used to standardise our results, therefore making them comparable to other laboratories who also standardised their data in an identical manner. Implications of all the available evidence Continual use and accumulation of standardised data would eventually lead to defining the correlates of protection against SARS-CoV-2. This could help to inform medical staff to identify which individuals would be a greater risk of a potential reinfection to SARS-CoV-2.

ACS Style

Diego Cantoni; Martin Mayora-Neto; Angalee Nadesalingham; David A. Wells; George W. Carnell; Luis Ohlendorf; Matteo Ferarri; Phil Palmer; Andrew C.Y. Chan; Peter Smith; Emma M. Bentley; Sebastian Einhauser; Ralf Wagner; Mark Page; Gianmarco Raddi; Helen Baxendale; Javier Castillo-Olivares; Jonathan Heeney; Nigel Temperton. Neutralisation hierarchy of SARS-CoV-2 Variants of Concern using standardised, quantitative neutralisation assays reveals a correlation with disease severity; towards deciphering protective antibody thresholds. 2021, 1 .

AMA Style

Diego Cantoni, Martin Mayora-Neto, Angalee Nadesalingham, David A. Wells, George W. Carnell, Luis Ohlendorf, Matteo Ferarri, Phil Palmer, Andrew C.Y. Chan, Peter Smith, Emma M. Bentley, Sebastian Einhauser, Ralf Wagner, Mark Page, Gianmarco Raddi, Helen Baxendale, Javier Castillo-Olivares, Jonathan Heeney, Nigel Temperton. Neutralisation hierarchy of SARS-CoV-2 Variants of Concern using standardised, quantitative neutralisation assays reveals a correlation with disease severity; towards deciphering protective antibody thresholds. . 2021; ():1.

Chicago/Turabian Style

Diego Cantoni; Martin Mayora-Neto; Angalee Nadesalingham; David A. Wells; George W. Carnell; Luis Ohlendorf; Matteo Ferarri; Phil Palmer; Andrew C.Y. Chan; Peter Smith; Emma M. Bentley; Sebastian Einhauser; Ralf Wagner; Mark Page; Gianmarco Raddi; Helen Baxendale; Javier Castillo-Olivares; Jonathan Heeney; Nigel Temperton. 2021. "Neutralisation hierarchy of SARS-CoV-2 Variants of Concern using standardised, quantitative neutralisation assays reveals a correlation with disease severity; towards deciphering protective antibody thresholds." , no. : 1.