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Both natural infection with SARS-CoV-2 and immunization with vaccines induce protective immunity. However, the extent to which such immune responses protect against emerging variants is of increasing importance. Such variants of concern (VOC) include isolates of lineage B.1.1.7, first identified in the UK, and B.1.351, first identified in South Africa. Our data confirm that VOC, particularly those with substitutions at residues 484 and 417, escape neutralization by antibodies directed to the ACE2-binding Class 1 and the adjacent Class 2 epitopes but are susceptible to neutralization by the generally less potent antibodies directed to Class 3 and 4 epitopes on the flanks of the receptor-binding domain. To address the potential threat posed by VOC, we sampled a SARS-CoV-2 uninfected UK cohort recently vaccinated with BNT162b2 (Pfizer-BioNTech, two doses delivered 18-28 days apart), alongside a cohort sampled in the early convalescent stages after natural infection in the first wave of the pandemic in Spring 2020. We tested antibody and T cell responses against a reference isolate of the original circulating lineage, B, and the impact of sequence variation in the B.1.1.7 and B.1.351 VOC. Neutralization of the VOC compared to B isolate was reduced, and this was most evident for the B.1.351 isolate. This reduction in antibody neutralization was less marked in post-boost vaccine-induced responses compared to naturally induced immune responses and could be largely explained by the potency of the homotypic antibody response. After a single vaccination, which induced only modestly neutralizing homotypic antibody titres, neutralization against the VOC was completely abrogated in the majority of vaccinees. Importantly, high magnitude T cell responses were generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. These data indicate that VOC may evade protective neutralizing responses induced by prior infection, and to a lesser extent by immunization, particularly after a single vaccine dose, but the impact of the VOC on T cell responses appears less marked. The results emphasize the need to generate high potency immune responses through vaccination in order to provide protection against these and other emergent variants.
Donal T. Skelly; Adam C. Harding; Javier Gilbert-Jaramillo; Michael L. Knight; Stephanie Longet; Anthony Brown; Sandra Adele; Emily Adland; Helen Brown; Medawar Laboratory Team; Tom Tipton; Lizzie Stafford; Síle A. Johnson; Ali Amini; OPTIC Clinical Group; Tiong Kit Tan; Lisa Schimanski; Kuan-Ying A. Huang; Pramila Rijal; PITCH Study Group; CMORE/PHOSP-C Group; John Frater; Philip Goulder; Christopher P. Conlon; Katie Jeffery; Christina Dold; Andrew J. Pollard; Alex Sigal; Tulio de Oliveira; Alain R. Townsend; Paul Klenerman; Susanna J . Dunachie; Eleanor Barnes; Miles W. Carroll; William S. James. Two doses of SARS-CoV-2 vaccination induce more robust immune responses to emerging SARS-CoV-2 variants of concern than does natural infection. 2021, 1 .
AMA StyleDonal T. Skelly, Adam C. Harding, Javier Gilbert-Jaramillo, Michael L. Knight, Stephanie Longet, Anthony Brown, Sandra Adele, Emily Adland, Helen Brown, Medawar Laboratory Team, Tom Tipton, Lizzie Stafford, Síle A. Johnson, Ali Amini, OPTIC Clinical Group, Tiong Kit Tan, Lisa Schimanski, Kuan-Ying A. Huang, Pramila Rijal, PITCH Study Group, CMORE/PHOSP-C Group, John Frater, Philip Goulder, Christopher P. Conlon, Katie Jeffery, Christina Dold, Andrew J. Pollard, Alex Sigal, Tulio de Oliveira, Alain R. Townsend, Paul Klenerman, Susanna J . Dunachie, Eleanor Barnes, Miles W. Carroll, William S. James. Two doses of SARS-CoV-2 vaccination induce more robust immune responses to emerging SARS-CoV-2 variants of concern than does natural infection. . 2021; ():1.
Chicago/Turabian StyleDonal T. Skelly; Adam C. Harding; Javier Gilbert-Jaramillo; Michael L. Knight; Stephanie Longet; Anthony Brown; Sandra Adele; Emily Adland; Helen Brown; Medawar Laboratory Team; Tom Tipton; Lizzie Stafford; Síle A. Johnson; Ali Amini; OPTIC Clinical Group; Tiong Kit Tan; Lisa Schimanski; Kuan-Ying A. Huang; Pramila Rijal; PITCH Study Group; CMORE/PHOSP-C Group; John Frater; Philip Goulder; Christopher P. Conlon; Katie Jeffery; Christina Dold; Andrew J. Pollard; Alex Sigal; Tulio de Oliveira; Alain R. Townsend; Paul Klenerman; Susanna J . Dunachie; Eleanor Barnes; Miles W. Carroll; William S. James. 2021. "Two doses of SARS-CoV-2 vaccination induce more robust immune responses to emerging SARS-CoV-2 variants of concern than does natural infection." , no. : 1.
To prevent the emergence of zoonotic infectious diseases and reduce their epidemic potential, we need to understand their origins in nature. Bats in the order Chiroptera are widely distributed worldwide and are natural reservoirs of prominent zoonotic viruses, including Nipah virus, Marburg virus, and possibly SARS-CoV-2. In this study, we applied unbiased metagenomic and metatranscriptomic approaches to decipher the virosphere of frugivorous and insectivorous bat species captured in Guéckédou, Guinea, the epicenter of the West African Ebola virus disease epidemic in 2013–2016. Our study provides a snapshot of the viral diversity present in these bat species, with several novel viruses reported for the first time in bats, as well as some bat viruses closely related to known human or animal pathogens. In addition, analysis of Mops condylurus genomic DNA samples revealed the presence of an Ebola virus nucleoprotein (NP)-derived pseudogene inserted in its genome. These findings provide insight into the evolutionary traits of several virus families in bats and add evidence that nonretroviral integrated RNA viruses (NIRVs) derived from filoviruses may be common in bat genomes.
Roberto Hermida Lorenzo; Dániel Cadar; Fara Koundouno; Javier Juste; Alexandra Bialonski; Heike Baum; Juan García-Mudarra; Henry Hakamaki; András Bencsik; Emily Nelson; Miles Carroll; N’Faly Magassouba; Stephan Günther; Jonas Schmidt-Chanasit; César Muñoz Fontela; Beatriz Escudero-Pérez. Metagenomic Snapshots of Viral Components in Guinean Bats. Microorganisms 2021, 9, 599 .
AMA StyleRoberto Hermida Lorenzo, Dániel Cadar, Fara Koundouno, Javier Juste, Alexandra Bialonski, Heike Baum, Juan García-Mudarra, Henry Hakamaki, András Bencsik, Emily Nelson, Miles Carroll, N’Faly Magassouba, Stephan Günther, Jonas Schmidt-Chanasit, César Muñoz Fontela, Beatriz Escudero-Pérez. Metagenomic Snapshots of Viral Components in Guinean Bats. Microorganisms. 2021; 9 (3):599.
Chicago/Turabian StyleRoberto Hermida Lorenzo; Dániel Cadar; Fara Koundouno; Javier Juste; Alexandra Bialonski; Heike Baum; Juan García-Mudarra; Henry Hakamaki; András Bencsik; Emily Nelson; Miles Carroll; N’Faly Magassouba; Stephan Günther; Jonas Schmidt-Chanasit; César Muñoz Fontela; Beatriz Escudero-Pérez. 2021. "Metagenomic Snapshots of Viral Components in Guinean Bats." Microorganisms 9, no. 3: 599.
A novel coronavirus, SARS-CoV-2, has been identified as the causative agent of the current COVID-19 pandemic. Animal models, and in particular non-human primates, are essential to understand the pathogenesis of emerging diseases and to assess the safety and efficacy of novel vaccines and therapeutics. Here, we show that SARS-CoV-2 replicates in the upper and lower respiratory tract and causes pulmonary lesions in both rhesus and cynomolgus macaques. Immune responses against SARS-CoV-2 are also similar in both species and equivalent to those reported in milder infections and convalescent human patients. This finding is reiterated by our transcriptional analysis of respiratory samples revealing the global response to infection. We describe a new method for lung histopathology scoring that will provide a metric to enable clearer decision making for this key endpoint. In contrast to prior publications, in which rhesus are accepted to be the preferred study species, we provide convincing evidence that both macaque species authentically represent mild to moderate forms of COVID-19 observed in the majority of the human population and both species should be used to evaluate the safety and efficacy of interventions against SARS-CoV-2. Importantly, accessing cynomolgus macaques will greatly alleviate the pressures on current rhesus stocks.
Francisco J. Salguero; Andrew D. White; Gillian S. Slack; Susan A. Fotheringham; Kevin R. Bewley; Karen E. Gooch; Stephanie Longet; Holly E. Humphries; Robert J. Watson; Laura Hunter; Kathryn A. Ryan; Yper Hall; Laura Sibley; Charlotte Sarfas; Lauren Allen; Marilyn Aram; Emily Brunt; Phillip Brown; Karen R. Buttigieg; Breeze E. Cavell; Rebecca Cobb; Naomi S. Coombes; Alistair Darby; Owen Daykin-Pont; Michael J. Elmore; Isabel Garcia-Dorival; Konstantinos Gkolfinos; Kerry J. Godwin; Jade Gouriet; Rachel Halkerston; Debbie J. Harris; Thomas Hender; Catherine M. K. Ho; Chelsea L. Kennard; Daniel Knott; Stephanie Leung; Vanessa Lucas; Adam Mabbutt; Alexandra L. Morrison; Charlotte Nelson; Didier Ngabo; Jemma Paterson; Elizabeth J. Penn; Steve Pullan; Irene Taylor; Tom Tipton; Stephen Thomas; Julia A. Tree; Carrie Turner; Edith Vamos; Nadina Wand; Nathan R. Wiblin; Sue Charlton; Xiaofeng Dong; Bassam Hallis; Geoffrey Pearson; Emma L. Rayner; Andrew G. Nicholson; Simon G. Funnell; Julian A. Hiscox; Mike J. Dennis; Fergus V. Gleeson; Sally Sharpe; Miles W. Carroll. Comparison of rhesus and cynomolgus macaques as an infection model for COVID-19. Nature Communications 2021, 12, 1 -14.
AMA StyleFrancisco J. Salguero, Andrew D. White, Gillian S. Slack, Susan A. Fotheringham, Kevin R. Bewley, Karen E. Gooch, Stephanie Longet, Holly E. Humphries, Robert J. Watson, Laura Hunter, Kathryn A. Ryan, Yper Hall, Laura Sibley, Charlotte Sarfas, Lauren Allen, Marilyn Aram, Emily Brunt, Phillip Brown, Karen R. Buttigieg, Breeze E. Cavell, Rebecca Cobb, Naomi S. Coombes, Alistair Darby, Owen Daykin-Pont, Michael J. Elmore, Isabel Garcia-Dorival, Konstantinos Gkolfinos, Kerry J. Godwin, Jade Gouriet, Rachel Halkerston, Debbie J. Harris, Thomas Hender, Catherine M. K. Ho, Chelsea L. Kennard, Daniel Knott, Stephanie Leung, Vanessa Lucas, Adam Mabbutt, Alexandra L. Morrison, Charlotte Nelson, Didier Ngabo, Jemma Paterson, Elizabeth J. Penn, Steve Pullan, Irene Taylor, Tom Tipton, Stephen Thomas, Julia A. Tree, Carrie Turner, Edith Vamos, Nadina Wand, Nathan R. Wiblin, Sue Charlton, Xiaofeng Dong, Bassam Hallis, Geoffrey Pearson, Emma L. Rayner, Andrew G. Nicholson, Simon G. Funnell, Julian A. Hiscox, Mike J. Dennis, Fergus V. Gleeson, Sally Sharpe, Miles W. Carroll. Comparison of rhesus and cynomolgus macaques as an infection model for COVID-19. Nature Communications. 2021; 12 (1):1-14.
Chicago/Turabian StyleFrancisco J. Salguero; Andrew D. White; Gillian S. Slack; Susan A. Fotheringham; Kevin R. Bewley; Karen E. Gooch; Stephanie Longet; Holly E. Humphries; Robert J. Watson; Laura Hunter; Kathryn A. Ryan; Yper Hall; Laura Sibley; Charlotte Sarfas; Lauren Allen; Marilyn Aram; Emily Brunt; Phillip Brown; Karen R. Buttigieg; Breeze E. Cavell; Rebecca Cobb; Naomi S. Coombes; Alistair Darby; Owen Daykin-Pont; Michael J. Elmore; Isabel Garcia-Dorival; Konstantinos Gkolfinos; Kerry J. Godwin; Jade Gouriet; Rachel Halkerston; Debbie J. Harris; Thomas Hender; Catherine M. K. Ho; Chelsea L. Kennard; Daniel Knott; Stephanie Leung; Vanessa Lucas; Adam Mabbutt; Alexandra L. Morrison; Charlotte Nelson; Didier Ngabo; Jemma Paterson; Elizabeth J. Penn; Steve Pullan; Irene Taylor; Tom Tipton; Stephen Thomas; Julia A. Tree; Carrie Turner; Edith Vamos; Nadina Wand; Nathan R. Wiblin; Sue Charlton; Xiaofeng Dong; Bassam Hallis; Geoffrey Pearson; Emma L. Rayner; Andrew G. Nicholson; Simon G. Funnell; Julian A. Hiscox; Mike J. Dennis; Fergus V. Gleeson; Sally Sharpe; Miles W. Carroll. 2021. "Comparison of rhesus and cynomolgus macaques as an infection model for COVID-19." Nature Communications 12, no. 1: 1-14.
Both natural infection with SARS-CoV-2 and immunization with a number of vaccines induce protective immunity. However, the ability of such immune responses to recognize and therefore protect against emerging variants is a matter of increasing importance. Such variants of concern (VOC) include isolates of lineage B1.1.7, first identified in the UK, and B1.351, first identified in South Africa. Our data confirm that VOC, particularly those with substitutions at residues 484 and 417 escape neutralization by antibodies directed to the ACE2-binding Class 1 and the adjacent Class 2 epitopes but are susceptible to neutralization by the generally less potent antibodies directed to Class 3 and 4 epitopes on the flanks RBD. To address this potential threat, we sampled a SARS-CoV-2 uninfected UK cohort recently vaccinated with BNT162b2 (Pfizer-BioNTech, two doses delivered 18-28 days apart), alongside a cohort naturally infected in the first wave of the epidemic in Spring 2020. We tested antibody and T cell responses against a reference isolate (VIC001) representing the original circulating lineage B and the impact of sequence variation in these two VOCs. We identified a reduction in antibody neutralization against the VOCs which was most evident in the B1.351 variant. However, the majority of the T cell response was directed against epitopes conserved across all three strains. The reduction in antibody neutralization was less marked in post-boost vaccine-induced than in naturally-induced immune responses and could be largely explained by the potency of the homotypic antibody response. However, after a single vaccination, which induced only modestly neutralizing homotypic antibody titres, neutralization against the VOCs was completely abrogated in the majority of vaccinees. These data indicate that VOCs may evade protective neutralising responses induced by prior infection, and to a lesser extent by immunization, particularly after a single vaccine, but the impact of the VOCs on T cell responses appears less marked. The results emphasize the need to generate high potency immune responses through vaccination in order to provide protection against these and other emergent variants. We observed that two doses of vaccine also induced a significant increase in binding antibodies to spike of both SARS-CoV-1 & MERS, in addition to the four common coronaviruses currently circulating in the UK. The impact of antigenic imprinting on the potency of humoral and cellular heterotypic protection generated by the next generation of variant-directed vaccines remains to be determined.Authorship note: Donal T. Skelly and Adam C. Harding contributed equally; Miles W. Carroll and William S. James contributed equally
Donal T. Skelly; Adam C. Harding; Javier Gilbert-Jaramillo; Michael L. Knight; Stephanie Longet; Anthony Brown; Sandra Adele; Emily Adland; Helen Brown; Medawar Laboratory Team; Tom Tipton; Lizzie Stafford; Síle A. Johnson; Ali Amini; OPTIC Clinical Group; Tiong Kit Tan; Lisa Schimanski; Kuan-Ying A. Huang; Pramila Rijal; PITCH Study Group; CMORE/PHOSP-C Group; John Frater; Philip Goulder; Christopher P. Conlon; Katie Jeffery; Christina Dold; Andrew J. Pollard; Alain R. Townsend; Paul Klenerman; Susanna J . Dunachie; Eleanor Barnes; Miles W. Carroll; William S. James. Vaccine-induced immunity provides more robust heterotypic immunity than natural infection to emerging SARS-CoV-2 variants of concern. 2021, 1 .
AMA StyleDonal T. Skelly, Adam C. Harding, Javier Gilbert-Jaramillo, Michael L. Knight, Stephanie Longet, Anthony Brown, Sandra Adele, Emily Adland, Helen Brown, Medawar Laboratory Team, Tom Tipton, Lizzie Stafford, Síle A. Johnson, Ali Amini, OPTIC Clinical Group, Tiong Kit Tan, Lisa Schimanski, Kuan-Ying A. Huang, Pramila Rijal, PITCH Study Group, CMORE/PHOSP-C Group, John Frater, Philip Goulder, Christopher P. Conlon, Katie Jeffery, Christina Dold, Andrew J. Pollard, Alain R. Townsend, Paul Klenerman, Susanna J . Dunachie, Eleanor Barnes, Miles W. Carroll, William S. James. Vaccine-induced immunity provides more robust heterotypic immunity than natural infection to emerging SARS-CoV-2 variants of concern. . 2021; ():1.
Chicago/Turabian StyleDonal T. Skelly; Adam C. Harding; Javier Gilbert-Jaramillo; Michael L. Knight; Stephanie Longet; Anthony Brown; Sandra Adele; Emily Adland; Helen Brown; Medawar Laboratory Team; Tom Tipton; Lizzie Stafford; Síle A. Johnson; Ali Amini; OPTIC Clinical Group; Tiong Kit Tan; Lisa Schimanski; Kuan-Ying A. Huang; Pramila Rijal; PITCH Study Group; CMORE/PHOSP-C Group; John Frater; Philip Goulder; Christopher P. Conlon; Katie Jeffery; Christina Dold; Andrew J. Pollard; Alain R. Townsend; Paul Klenerman; Susanna J . Dunachie; Eleanor Barnes; Miles W. Carroll; William S. James. 2021. "Vaccine-induced immunity provides more robust heterotypic immunity than natural infection to emerging SARS-CoV-2 variants of concern." , no. : 1.
Ferrets were experimentally inoculated with SARS-CoV-2 (severe acute respiratory syndrome (SARS)-related coronavirus 2) to assess infection dynamics and host response. During the resulting subclinical infection, viral RNA was monitored between 2 and 21 days post-inoculation (dpi), and reached a peak in the upper respiratory cavity between 4 and 6 dpi. Viral genomic sequence analysis in samples from three animals identified the Y453F nucleotide substitution relative to the inoculum. Viral RNA was also detected in environmental samples, specifically in swabs of ferret fur. Microscopy analysis revealed viral protein and RNA in upper respiratory tract tissues, notably in cells of the respiratory and olfactory mucosae of the nasal turbinates, including olfactory neuronal cells. Antibody responses to the spike and nucleoprotein were detected from 21 dpi, but virus-neutralizing activity was low. A second intranasal inoculation (re-exposure) of two ferrets after a 17-day interval did not produce re-initiation of viral RNA shedding, but did amplify the humoral response in one animal. Therefore, ferrets can be experimentally infected with SARS-CoV-2 to model human asymptomatic infection.
Helen Everett; Fabian Lean; Alexander Byrne; Pauline van Diemen; Shelley Rhodes; Joe James; Benjamin Mollett; Vivien Coward; Paul Skinner; Caroline Warren; Kevin Bewley; Samantha Watson; Shellene Hurley; Kathryn Ryan; Yper Hall; Hugh Simmons; Alejandro Núñez; Miles Carroll; Ian Brown; Sharon Brookes. Intranasal Infection of Ferrets with SARS-CoV-2 as a Model for Asymptomatic Human Infection. Viruses 2021, 13, 113 .
AMA StyleHelen Everett, Fabian Lean, Alexander Byrne, Pauline van Diemen, Shelley Rhodes, Joe James, Benjamin Mollett, Vivien Coward, Paul Skinner, Caroline Warren, Kevin Bewley, Samantha Watson, Shellene Hurley, Kathryn Ryan, Yper Hall, Hugh Simmons, Alejandro Núñez, Miles Carroll, Ian Brown, Sharon Brookes. Intranasal Infection of Ferrets with SARS-CoV-2 as a Model for Asymptomatic Human Infection. Viruses. 2021; 13 (1):113.
Chicago/Turabian StyleHelen Everett; Fabian Lean; Alexander Byrne; Pauline van Diemen; Shelley Rhodes; Joe James; Benjamin Mollett; Vivien Coward; Paul Skinner; Caroline Warren; Kevin Bewley; Samantha Watson; Shellene Hurley; Kathryn Ryan; Yper Hall; Hugh Simmons; Alejandro Núñez; Miles Carroll; Ian Brown; Sharon Brookes. 2021. "Intranasal Infection of Ferrets with SARS-CoV-2 as a Model for Asymptomatic Human Infection." Viruses 13, no. 1: 113.
Background Ebola virus disease (EVD) is an often-fatal infection where the effectiveness of medical countermeasures is uncertain. During the West African outbreak (2013–2016), several patients were treated with different types of anti-viral therapies including monoclonal antibody-based cocktails that had the potential to neutralise Ebola virus (EBOV). However, at the time, the efficacy of these therapies was uncertain. Given the scale of the outbreak, several clinical phenotypes came to the forefront including the ability of the same virus to cause recrudescence in the same patient—perhaps through persisting in immune privileged sites. Several key questions remained including establishing if monoclonal antibody therapy was effective in humans with severe EVD, whether virus escape mutants were selected during treatment, and what is the potential mechanism(s) of persistence. This was made possible through longitudinal samples taken from a UK patient with EVD. Methods Several different sample types, plasma and cerebrospinal fluid, were collected and sequenced using Illumina-based RNAseq. Sequence reads were mapped both to EBOV and the human genome and differential gene expression analysis used to identify changes in the abundance of gene transcripts as infection progressed. Digital Cell Quantitation analysis was used to predict the immune phenotype in samples derived from blood. Results The findings were compared to equivalent data from West African patients. The study found that both virus and host markers were predictive of a fatal outcome. This suggested that the extensive supportive care, and most likely the application of the medical countermeasure ZMab (a monoclonal antibody cocktail), contributed to survival of the UK patient. The switch from progression to a ‘fatal’ outcome to a ‘survival’ outcome could be seen in both the viral and host markers. The UK patient also suffered a recrudescence infection 10 months after the initial infection. Analysis of the sequencing data indicated that the virus entered a period of reduced or minimal replication, rather than other potential mechanisms of persistence—such as defective interfering genomes. Conclusions The data showed that comprehensive supportive care and the application of medical countermeasures are worth pursuing despite an initial unfavourable prognosis.
Andrew Bosworth; Natasha Y. Rickett; Xiaofeng Dong; Lisa F. P. Ng; Isabel García-Dorival; David A. Matthews; Tom Fletcher; Michael Jacobs; Emma C. Thomson; Miles W. Carroll; Julian A. Hiscox. Analysis of an Ebola virus disease survivor whose host and viral markers were predictive of death indicates the effectiveness of medical countermeasures and supportive care. Genome Medicine 2021, 13, 1 -18.
AMA StyleAndrew Bosworth, Natasha Y. Rickett, Xiaofeng Dong, Lisa F. P. Ng, Isabel García-Dorival, David A. Matthews, Tom Fletcher, Michael Jacobs, Emma C. Thomson, Miles W. Carroll, Julian A. Hiscox. Analysis of an Ebola virus disease survivor whose host and viral markers were predictive of death indicates the effectiveness of medical countermeasures and supportive care. Genome Medicine. 2021; 13 (1):1-18.
Chicago/Turabian StyleAndrew Bosworth; Natasha Y. Rickett; Xiaofeng Dong; Lisa F. P. Ng; Isabel García-Dorival; David A. Matthews; Tom Fletcher; Michael Jacobs; Emma C. Thomson; Miles W. Carroll; Julian A. Hiscox. 2021. "Analysis of an Ebola virus disease survivor whose host and viral markers were predictive of death indicates the effectiveness of medical countermeasures and supportive care." Genome Medicine 13, no. 1: 1-18.
There is a vital need for authentic COVID-19 animal models to enable the pre-clinical evaluation of candidate vaccines and therapeutics. Here we report a dose titration study of SARS-CoV-2 in the ferret model. After a high (5 × 106 pfu) and medium (5 × 104 pfu) dose of virus is delivered, intranasally, viral RNA shedding in the upper respiratory tract (URT) is observed in 6/6 animals, however, only 1/6 ferrets show similar signs after low dose (5 × 102 pfu) challenge. Following sequential culls pathological signs of mild multifocal bronchopneumonia in approximately 5–15% of the lung is seen on day 3, in high and medium dosed groups. Ferrets re-challenged, after virus shedding ceased, are fully protected from acute lung pathology. The endpoints of URT viral RNA replication & distinct lung pathology are observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease.
Kathryn A. Ryan; Kevin R. Bewley; Susan A. Fotheringham; Gillian S. Slack; Phillip Brown; Yper Hall; Nadina I. Wand; Anthony C. Marriott; Breeze E. Cavell; Julia A. Tree; Lauren Allen; Marilyn J. Aram; Thomas J. Bean; Emily Brunt; Karen R. Buttigieg; Daniel P. Carter; Rebecca Cobb; Naomi S. Coombes; Steve J. Findlay-Wilson; Kerry J. Godwin; Karen E. Gooch; Jade Gouriet; Rachel Halkerston; Debbie J. Harris; Thomas H. Hender; Holly E. Humphries; Laura Hunter; Catherine M. K. Ho; Chelsea L. Kennard; Stephanie Leung; Stephanie Longet; Didier Ngabo; Karen L. Osman; Jemma Paterson; Elizabeth J. Penn; Steven T. Pullan; Emma Rayner; Oliver Skinner; Kimberley Steeds; Irene Taylor; Tom Tipton; Stephen Thomas; Carrie Turner; Robert J. Watson; Nathan R. Wiblin; Sue Charlton; Bassam Hallis; Julian A. Hiscox; Simon Funnell; Mike J. Dennis; Catherine J. Whittaker; Michael G. Catton; Julian Druce; Francisco J. Salguero; Miles W. Carroll. Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity. Nature Communications 2021, 12, 1 -13.
AMA StyleKathryn A. Ryan, Kevin R. Bewley, Susan A. Fotheringham, Gillian S. Slack, Phillip Brown, Yper Hall, Nadina I. Wand, Anthony C. Marriott, Breeze E. Cavell, Julia A. Tree, Lauren Allen, Marilyn J. Aram, Thomas J. Bean, Emily Brunt, Karen R. Buttigieg, Daniel P. Carter, Rebecca Cobb, Naomi S. Coombes, Steve J. Findlay-Wilson, Kerry J. Godwin, Karen E. Gooch, Jade Gouriet, Rachel Halkerston, Debbie J. Harris, Thomas H. Hender, Holly E. Humphries, Laura Hunter, Catherine M. K. Ho, Chelsea L. Kennard, Stephanie Leung, Stephanie Longet, Didier Ngabo, Karen L. Osman, Jemma Paterson, Elizabeth J. Penn, Steven T. Pullan, Emma Rayner, Oliver Skinner, Kimberley Steeds, Irene Taylor, Tom Tipton, Stephen Thomas, Carrie Turner, Robert J. Watson, Nathan R. Wiblin, Sue Charlton, Bassam Hallis, Julian A. Hiscox, Simon Funnell, Mike J. Dennis, Catherine J. Whittaker, Michael G. Catton, Julian Druce, Francisco J. Salguero, Miles W. Carroll. Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity. Nature Communications. 2021; 12 (1):1-13.
Chicago/Turabian StyleKathryn A. Ryan; Kevin R. Bewley; Susan A. Fotheringham; Gillian S. Slack; Phillip Brown; Yper Hall; Nadina I. Wand; Anthony C. Marriott; Breeze E. Cavell; Julia A. Tree; Lauren Allen; Marilyn J. Aram; Thomas J. Bean; Emily Brunt; Karen R. Buttigieg; Daniel P. Carter; Rebecca Cobb; Naomi S. Coombes; Steve J. Findlay-Wilson; Kerry J. Godwin; Karen E. Gooch; Jade Gouriet; Rachel Halkerston; Debbie J. Harris; Thomas H. Hender; Holly E. Humphries; Laura Hunter; Catherine M. K. Ho; Chelsea L. Kennard; Stephanie Leung; Stephanie Longet; Didier Ngabo; Karen L. Osman; Jemma Paterson; Elizabeth J. Penn; Steven T. Pullan; Emma Rayner; Oliver Skinner; Kimberley Steeds; Irene Taylor; Tom Tipton; Stephen Thomas; Carrie Turner; Robert J. Watson; Nathan R. Wiblin; Sue Charlton; Bassam Hallis; Julian A. Hiscox; Simon Funnell; Mike J. Dennis; Catherine J. Whittaker; Michael G. Catton; Julian Druce; Francisco J. Salguero; Miles W. Carroll. 2021. "Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity." Nature Communications 12, no. 1: 1-13.
Background The novel human coronavirus SARS-CoV-2 is a major ongoing global threat with huge economic burden. Like all respiratory viruses, SARS-CoV-2 initiates infection in the upper respiratory tract (URT). Infected individuals are often asymptomatic, yet highly infectious and readily transmit virus. A therapy that restricts initial replication in the URT has the potential to prevent progression of severe lower respiratory tract disease as well as limiting person-to-person transmission. Methods SARS-CoV-2 Victoria/01/2020 was passaged in Vero/hSLAM cells and virus titre determined by plaque assay. Challenge virus was delivered by intranasal instillation to female ferrets at 5.0 × 106 pfu/ml. Treatment groups received intranasal INNA-051, developed by Ena Respiratory. SARS-CoV-2 RNA was detected using the 2019-nCoV CDC RUO Kit and QuantStudio™ 7 Flex Real-Time PCR System. Histopathological analysis was performed using cut tissues stained with haematoxylin and eosin (H&E). Findings We show that prophylactic intra-nasal administration of the TLR2/6 agonist INNA-051 in a SARS-CoV-2 ferret infection model effectively reduces levels of viral RNA in the nose and throat. After 5 days post-exposure to SARS-CoV-2, INNA-051 significantly reduced virus in throat swabs (p=p=0.0107) up to a 15 fold (93% reduction) in comparison to untreated animals. Interpretation The results of our study support clinical development of a therapy based on prophylactic TLR2/6 innate immune activation in the URT, to reduce SARS-CoV-2 transmission and provide protection against COVID-19. Funding This work was funded by Ena Respiratory, Melbourne, Australia.
Pamela C. Proud; Daphne Tsitoura; Robert J. Watson; Brendon Y. Chua; Marilyn J. Aram; Kevin R. Bewley; Breeze E. Cavell; Rebecca Cobb; Stuart Dowall; Susan A. Fotheringham; Catherine M.K. Ho; Vanessa Lucas; Didier Ngabo; Emma Rayner; Kathryn A. Ryan; Gillian S. Slack; Stephen Thomas; Nadina I. Wand; Paul Yeates; Christophe Demaison; Weiguang Zeng; Ian Holmes; David C. Jackson; Nathan W. Bartlett; Francesca Mercuri; Miles W. Carroll. Prophylactic intranasal administration of a TLR2/6 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model. EBioMedicine 2020, 63, 103153 -103153.
AMA StylePamela C. Proud, Daphne Tsitoura, Robert J. Watson, Brendon Y. Chua, Marilyn J. Aram, Kevin R. Bewley, Breeze E. Cavell, Rebecca Cobb, Stuart Dowall, Susan A. Fotheringham, Catherine M.K. Ho, Vanessa Lucas, Didier Ngabo, Emma Rayner, Kathryn A. Ryan, Gillian S. Slack, Stephen Thomas, Nadina I. Wand, Paul Yeates, Christophe Demaison, Weiguang Zeng, Ian Holmes, David C. Jackson, Nathan W. Bartlett, Francesca Mercuri, Miles W. Carroll. Prophylactic intranasal administration of a TLR2/6 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model. EBioMedicine. 2020; 63 ():103153-103153.
Chicago/Turabian StylePamela C. Proud; Daphne Tsitoura; Robert J. Watson; Brendon Y. Chua; Marilyn J. Aram; Kevin R. Bewley; Breeze E. Cavell; Rebecca Cobb; Stuart Dowall; Susan A. Fotheringham; Catherine M.K. Ho; Vanessa Lucas; Didier Ngabo; Emma Rayner; Kathryn A. Ryan; Gillian S. Slack; Stephen Thomas; Nadina I. Wand; Paul Yeates; Christophe Demaison; Weiguang Zeng; Ian Holmes; David C. Jackson; Nathan W. Bartlett; Francesca Mercuri; Miles W. Carroll. 2020. "Prophylactic intranasal administration of a TLR2/6 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model." EBioMedicine 63, no. : 103153-103153.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Sequencing the viral genome as the outbreak progresses is important, particularly in the identification of emerging isolates with different pathogenic potential and to identify whether nucleotide changes in the genome will impair clinical diagnostic tools such as real-time PCR assays. Although single nucleotide polymorphisms and point mutations occur during the replication of coronaviruses, one of the biggest drivers in genetic change is recombination. This can manifest itself in insertions and/or deletions in the viral genome. Therefore, sequencing strategies that underpin molecular epidemiology and inform virus biology in patients should take these factors into account. A long amplicon/read length-based RT-PCR sequencing approach focused on the Oxford Nanopore MinION/GridION platforms was developed to identify and sequence the SARS-CoV-2 genome in samples from patients with or suspected of COVID-19. The protocol, termed Rapid Sequencing Long Amplicons (RSLAs) used random primers to generate cDNA from RNA purified from a sample from a patient, followed by single or multiplex PCRs to generate longer amplicons of the viral genome. The base protocol was used to identify SARS-CoV-2 in a variety of clinical samples and proved sensitive in identifying viral RNA in samples from patients that had been declared negative using other nucleic acid-based assays (false negative). Sequencing the amplicons revealed that a number of patients had a proportion of viral genomes with deletions.
Shona C. Moore; Rebekah Penrice-Randall; Muhannad Alruwaili; Nadine Randle; Stuart Armstrong; Catherine Hartley; Sam Haldenby; Xiaofeng Dong; Abdulrahman Alrezaihi; Mai Almsaud; Eleanor Bentley; Jordan Clark; Isabel García-Dorival; Paul Gilmore; Ximeng Han; Benjamin Jones; Lisa Luu; Parul Sharma; Ghada Shawli; Yani Sun; Qin Zhao; Steven T. Pullan; Daniel P. Carter; Kevin Bewley; Jake Dunning; En-Min Zhou; Tom Solomon; Michael Beadsworth; James Cruise; Derrick W. Crook; David A. Matthews; Andrew D. Davidson; Zana Mahmood; Waleed Aljabr; Julian Druce; Richard Vipond; Lisa Ng; Laurent Renia; Peter J. M. Openshaw; J. Kenneth Baillie; Miles W. Carroll; James Stewart; Alistair Darby; Malcolm Semple; Lance Turtle; Julian A. Hiscox. Amplicon-Based Detection and Sequencing of SARS-CoV-2 in Nasopharyngeal Swabs from Patients With COVID-19 and Identification of Deletions in the Viral Genome That Encode Proteins Involved in Interferon Antagonism. Viruses 2020, 12, 1164 .
AMA StyleShona C. Moore, Rebekah Penrice-Randall, Muhannad Alruwaili, Nadine Randle, Stuart Armstrong, Catherine Hartley, Sam Haldenby, Xiaofeng Dong, Abdulrahman Alrezaihi, Mai Almsaud, Eleanor Bentley, Jordan Clark, Isabel García-Dorival, Paul Gilmore, Ximeng Han, Benjamin Jones, Lisa Luu, Parul Sharma, Ghada Shawli, Yani Sun, Qin Zhao, Steven T. Pullan, Daniel P. Carter, Kevin Bewley, Jake Dunning, En-Min Zhou, Tom Solomon, Michael Beadsworth, James Cruise, Derrick W. Crook, David A. Matthews, Andrew D. Davidson, Zana Mahmood, Waleed Aljabr, Julian Druce, Richard Vipond, Lisa Ng, Laurent Renia, Peter J. M. Openshaw, J. Kenneth Baillie, Miles W. Carroll, James Stewart, Alistair Darby, Malcolm Semple, Lance Turtle, Julian A. Hiscox. Amplicon-Based Detection and Sequencing of SARS-CoV-2 in Nasopharyngeal Swabs from Patients With COVID-19 and Identification of Deletions in the Viral Genome That Encode Proteins Involved in Interferon Antagonism. Viruses. 2020; 12 (10):1164.
Chicago/Turabian StyleShona C. Moore; Rebekah Penrice-Randall; Muhannad Alruwaili; Nadine Randle; Stuart Armstrong; Catherine Hartley; Sam Haldenby; Xiaofeng Dong; Abdulrahman Alrezaihi; Mai Almsaud; Eleanor Bentley; Jordan Clark; Isabel García-Dorival; Paul Gilmore; Ximeng Han; Benjamin Jones; Lisa Luu; Parul Sharma; Ghada Shawli; Yani Sun; Qin Zhao; Steven T. Pullan; Daniel P. Carter; Kevin Bewley; Jake Dunning; En-Min Zhou; Tom Solomon; Michael Beadsworth; James Cruise; Derrick W. Crook; David A. Matthews; Andrew D. Davidson; Zana Mahmood; Waleed Aljabr; Julian Druce; Richard Vipond; Lisa Ng; Laurent Renia; Peter J. M. Openshaw; J. Kenneth Baillie; Miles W. Carroll; James Stewart; Alistair Darby; Malcolm Semple; Lance Turtle; Julian A. Hiscox. 2020. "Amplicon-Based Detection and Sequencing of SARS-CoV-2 in Nasopharyngeal Swabs from Patients With COVID-19 and Identification of Deletions in the Viral Genome That Encode Proteins Involved in Interferon Antagonism." Viruses 12, no. 10: 1164.
Summary Background The 2013–16 Ebola virus disease epidemic in west Africa caused international alarm due to its rapid and extensive spread resulting in a significant death toll and social unrest within the affected region. The large number of cases provided an opportunity to study the long-term kinetics of Zaire ebolavirus-specific immune response of survivors in addition to known contacts of those infected with the virus. Methods In this observational cohort study, we worked with leaders of Ebola virus disease survivor associations in two regions of Guinea, Guéckédou and Coyah, to recruit survivors of Ebola virus disease, contacts from households of individuals known to have had Ebola virus disease, and individuals who were not knowingly associated with infected individuals or had not had Ebola virus disease symptoms to serve as negative controls. We did Zaire ebolavirus glycoprotein-specific T cell analysis on peripheral blood mononuclear cells (PBMCs) on location in Guinea and transported plasma and PBMCs back to Europe for antibody quantification by ELISA, functional neutralising antibody analysis using live Zaire ebolavirus, and T cell phenotype studies. We report on the longitudinal cellular and humoral response among Ebola virus disease survivors and highlight potentially paucisymptomatic infection. Findings We recruited 117 survivors of Ebola virus disease, 66 contacts, and 23 negative controls. The mean neutralising antibody titre among the Ebola virus disease survivors 3–14 months after infection was 1/174 (95% CI 1/136—1/223). Individual results varied greatly from 1/10 to more than 1/1000 but were on average ten times greater than that induced after 1 month by single dose Ebola virus vaccines. Following reactivation with glycoprotein peptide, the mean T cell responses among 116 Ebola virus disease survivors as measured by ELISpot was 305 spot-forming units (95% CI 257–353). The dominant CD8+ polyfunctional T cell phenotype, as measured among 53 Ebola virus disease survivors, was interferon γ+, tumour necrosis factor+, interleukin-2–, and the mean response was 0·046% of total CD8+ T cells (95% CI 0·021–0·071). Additionally, both neutralising antibody and T cell responses were detected in six (9%) of 66 Ebola virus disease contacts. We also noted that four (3%) of 117 individuals with Ebola virus disease infections did not have circulating Ebola virus-specific antibodies 3 months after infection. Interpretation The continuous high titre of neutralising antibodies and increased T cell response might support the concept of long-term protective immunity in survivors. The existence of antibody and T cell responses in contacts of individuals with Ebola virus disease adds further evidence to the existence of sub-clinical Ebola virus infection. Funding US Food & Drug Administration, Horizon 2020 EU EVIDENT, Wellcome, UK Department for International Development. Translation For the French translation of the abstract see Supplementary Materials section.
Ruth Thom; Thomas Tipton; Thomas Strecker; Yper Hall; Joseph Akoi Bore; Piet Maes; Fara Raymond Koundouno; Sarah Katharina Fehling; Verena Krähling; Kimberley Steeds; Anitha Varghese; Graham Bailey; Mary Matheson; Saidou Kouyate; Moussa Coné; Balla Moussa Keita; Sekou Kouyate; Amento Richard Ablam; Lies Laenen; Valentijn Vergote; Malcolm Guiver; Joseph Timothy; Barry Atkinson; Lisa Ottowell; Kevin S Richards; Andrew Bosworth; Stephanie Longet; Jack Mellors; Delphine Pannetier; Sophie Duraffour; César Muñoz-Fontela; Oumou Sow; Lamine Koivogui; Edmund Newman; Stephan Becker; Armand Sprecher; Herve Raoul; Julian Hiscox; Ana Maria Henao-Restrepo; Keita Sakoba; N'faly Magassouba; Stephan Günther; Mandy Kader Konde; Miles W Carroll. Longitudinal antibody and T cell responses in Ebola virus disease survivors and contacts: an observational cohort study. The Lancet Infectious Diseases 2020, 21, 507 -516.
AMA StyleRuth Thom, Thomas Tipton, Thomas Strecker, Yper Hall, Joseph Akoi Bore, Piet Maes, Fara Raymond Koundouno, Sarah Katharina Fehling, Verena Krähling, Kimberley Steeds, Anitha Varghese, Graham Bailey, Mary Matheson, Saidou Kouyate, Moussa Coné, Balla Moussa Keita, Sekou Kouyate, Amento Richard Ablam, Lies Laenen, Valentijn Vergote, Malcolm Guiver, Joseph Timothy, Barry Atkinson, Lisa Ottowell, Kevin S Richards, Andrew Bosworth, Stephanie Longet, Jack Mellors, Delphine Pannetier, Sophie Duraffour, César Muñoz-Fontela, Oumou Sow, Lamine Koivogui, Edmund Newman, Stephan Becker, Armand Sprecher, Herve Raoul, Julian Hiscox, Ana Maria Henao-Restrepo, Keita Sakoba, N'faly Magassouba, Stephan Günther, Mandy Kader Konde, Miles W Carroll. Longitudinal antibody and T cell responses in Ebola virus disease survivors and contacts: an observational cohort study. The Lancet Infectious Diseases. 2020; 21 (4):507-516.
Chicago/Turabian StyleRuth Thom; Thomas Tipton; Thomas Strecker; Yper Hall; Joseph Akoi Bore; Piet Maes; Fara Raymond Koundouno; Sarah Katharina Fehling; Verena Krähling; Kimberley Steeds; Anitha Varghese; Graham Bailey; Mary Matheson; Saidou Kouyate; Moussa Coné; Balla Moussa Keita; Sekou Kouyate; Amento Richard Ablam; Lies Laenen; Valentijn Vergote; Malcolm Guiver; Joseph Timothy; Barry Atkinson; Lisa Ottowell; Kevin S Richards; Andrew Bosworth; Stephanie Longet; Jack Mellors; Delphine Pannetier; Sophie Duraffour; César Muñoz-Fontela; Oumou Sow; Lamine Koivogui; Edmund Newman; Stephan Becker; Armand Sprecher; Herve Raoul; Julian Hiscox; Ana Maria Henao-Restrepo; Keita Sakoba; N'faly Magassouba; Stephan Günther; Mandy Kader Konde; Miles W Carroll. 2020. "Longitudinal antibody and T cell responses in Ebola virus disease survivors and contacts: an observational cohort study." The Lancet Infectious Diseases 21, no. 4: 507-516.
Respiratory viruses such as coronaviruses represent major ongoing global threats, causing epidemics and pandemics with huge economic burden. Rapid spread of virus through populations poses an enormous challenge for outbreak control. Like all respiratory viruses, the most recent novel human coronavirus SARS-CoV-2, initiates infection in the upper respiratory tract (URT). Infected individuals are often asymptomatic, yet highly infectious and readily transmit virus. A therapy that restricts initial replication in the URT has the potential to prevent progression of severe lower respiratory tract disease as well as limiting person-to-person transmission.We show that prophylactic intra-nasal administration of the TLR2/6 agonist INNA-051 in a SARS-CoV-2 ferret infection model effectively reduces levels of viral RNA in the nose and throat. The results of our study support clinical development of a therapy based on prophylactic TLR2/6 innate immune activation in the URT to reduce SARS-CoV-2 transmission and provide protection against COVID-19.
Pamela C. Proud; Daphne Tsitoura; Robert J. Watson; Brendon Y Chua; Marilyn J. Aram; Kevin R. Bewley; Breeze E. Cavell; Rebecca Cobb; Stuart Dowall; Susan A. Fotheringham; Catherine M. K. Ho; Vanessa Lucas; Didier Ngabo; Emma Rayner; Kathryn A. Ryan; Gillian S. Slack; Stephen Thomas; Nadina I. Wand; Paul Yeates; Christophe Demaison; David C. Jackson; Nathan W. Bartlett; Francesca Mercuri; Miles W. Carroll. Prophylactic intranasal administration of a TLR2 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model. 2020, 1 .
AMA StylePamela C. Proud, Daphne Tsitoura, Robert J. Watson, Brendon Y Chua, Marilyn J. Aram, Kevin R. Bewley, Breeze E. Cavell, Rebecca Cobb, Stuart Dowall, Susan A. Fotheringham, Catherine M. K. Ho, Vanessa Lucas, Didier Ngabo, Emma Rayner, Kathryn A. Ryan, Gillian S. Slack, Stephen Thomas, Nadina I. Wand, Paul Yeates, Christophe Demaison, David C. Jackson, Nathan W. Bartlett, Francesca Mercuri, Miles W. Carroll. Prophylactic intranasal administration of a TLR2 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model. . 2020; ():1.
Chicago/Turabian StylePamela C. Proud; Daphne Tsitoura; Robert J. Watson; Brendon Y Chua; Marilyn J. Aram; Kevin R. Bewley; Breeze E. Cavell; Rebecca Cobb; Stuart Dowall; Susan A. Fotheringham; Catherine M. K. Ho; Vanessa Lucas; Didier Ngabo; Emma Rayner; Kathryn A. Ryan; Gillian S. Slack; Stephen Thomas; Nadina I. Wand; Paul Yeates; Christophe Demaison; David C. Jackson; Nathan W. Bartlett; Francesca Mercuri; Miles W. Carroll. 2020. "Prophylactic intranasal administration of a TLR2 agonist reduces upper respiratory tract viral shedding in a SARS-CoV-2 challenge ferret model." , no. : 1.
Summary LamPORE is a novel diagnostic platform for the detection of SARS-CoV-2 RNA that combines loop-mediated isothermal amplification with nanopore sequencing, which could potentially be used to analyse thousands of samples per day on a single instrument. We evaluated the performance of LamPORE against RT-PCR using RNA extracted from spiked respiratory samples and from stored nose and throat swabs collected at two UK hospitals. The limit of detection of LamPORE was 7-10 genome copies/µl of extracted RNA. This is above the limit achievable by RT-PCR but was not associated with a significant reduction of sensitivity in clinical samples. Positive clinical specimens came mostly from patients with acute symptomatic infection, and among these LamPORE had a diagnostic sensitivity of 99.1% (226/228 [95% CI 96.9–99.9%]). Among negative clinical specimens, including 153 with other respiratory pathogens detected, LamPORE had a diagnostic specificity of 99.6% (278/279 [98.0–100.0%]). Overall, 1.4% (7/514 [0.5–2.9]) of samples produced an indeterminate result on first testing, and repeat LamPORE testing on the same RNA extract had a reproducibility of 96.8% (478/494 [94.8–98.1]). This indicates that LamPORE has a similar performance to RT-PCR for the diagnosis of SARS-CoV-2 infection in symptomatic patients, and offers a promising approach to high-throughput testing.
Leon Peto; Gillian Rodger; Daniel P Carter; Karen L Osman; Mehmet Yavuz; Katie Johnson; Mohammad Raza; Matthew D Parker; Matthew D Wyles; Monique Andersson; Anita Justice; Alison Vaughan; Sarah Hoosdally; Nicole Stoesser; Philippa C Matthews; David W Eyre; Timothy Ea Peto; Miles W Carroll; Thushan I de Silva; Derrick W Crook; Cariad M Evans; Steven T Pullan. Diagnosis of SARS-CoV-2 infection with LamPORE, a high-throughput platform combining loop-mediated isothermal amplification and nanopore sequencing. 2020, 1 .
AMA StyleLeon Peto, Gillian Rodger, Daniel P Carter, Karen L Osman, Mehmet Yavuz, Katie Johnson, Mohammad Raza, Matthew D Parker, Matthew D Wyles, Monique Andersson, Anita Justice, Alison Vaughan, Sarah Hoosdally, Nicole Stoesser, Philippa C Matthews, David W Eyre, Timothy Ea Peto, Miles W Carroll, Thushan I de Silva, Derrick W Crook, Cariad M Evans, Steven T Pullan. Diagnosis of SARS-CoV-2 infection with LamPORE, a high-throughput platform combining loop-mediated isothermal amplification and nanopore sequencing. . 2020; ():1.
Chicago/Turabian StyleLeon Peto; Gillian Rodger; Daniel P Carter; Karen L Osman; Mehmet Yavuz; Katie Johnson; Mohammad Raza; Matthew D Parker; Matthew D Wyles; Monique Andersson; Anita Justice; Alison Vaughan; Sarah Hoosdally; Nicole Stoesser; Philippa C Matthews; David W Eyre; Timothy Ea Peto; Miles W Carroll; Thushan I de Silva; Derrick W Crook; Cariad M Evans; Steven T Pullan. 2020. "Diagnosis of SARS-CoV-2 infection with LamPORE, a high-throughput platform combining loop-mediated isothermal amplification and nanopore sequencing." , no. : 1.
A novel coronavirus, SARS-CoV-2, has been identified as the causative agent of the current COVID-19 pandemic. Animal models, and in particular non-human primates, are essential to understand the pathogenesis of emerging diseases and to the safety and efficacy of novel vaccines and therapeutics. Here, we show that SARS-CoV-2 replicates in the upper and lower respiratory tract and causes pulmonary lesions in both rhesus and cynomolgus macaques, resembling the mild clinical cases of COVID-19 in humans. Immune responses against SARS-CoV-2 were also similar in both species and equivalent to those reported in milder infections and convalescent human patients. Importantly, we have devised a new method for lung histopathology scoring that will provide a metric to enable clearer decision making for this key endpoint. In contrast to prior publications, in which rhesus are accepted to be the optimal study species, we provide convincing evidence that both macaque species authentically represent mild to moderate forms of COVID-19 observed in the majority of the human population and both species should be used to evaluate the safety and efficacy of novel and repurposed interventions against SARS-CoV-2. Accessing cynomolgus macaques will greatly alleviate the pressures on current rhesus stocks.
Francisco J. Salguero; Andrew D. White; Gillian S. Slack; Susan A. Fotheringham; Kevin R. Bewley; Karen E. Gooch; Stephanie Longet; Holly E. Humphries; Robert J. Watson; Laura Hunter; Kathryn A. Ryan; Yper Hall; Laura Sibley; Charlotte Sarfas; Lauren Allen; Marilyn Aram; Emily Brunt; Phillip Brown; Karen R. Buttigieg; Breeze E. Cavell; Rebecca Cobb; Naomi S. Coombes; Owen Daykin-Pont; Michael J. Elmore; Konstantinos Gkolfinos; Kerry J. Godwin; Jade Gouriet; Rachel Halkerston; Debbie J. Harris; Thomas Hender; Catherine M.K. Ho; Chelsea L. Kennard; Daniel Knott; Stephanie Leung; Vanessa Lucas; Adam Mabbutt; Alexandra L. Morrison; Didier Ngabo; Jemma Paterson; Elizabeth J. Penn; Steve Pullan; Irene Taylor; Tom Tipton; Stephen Thomas; Julia A. Tree; Carrie Turner; Nadina Wand; Nathan R. Wiblin; Sue Charlton; Bassam Hallis; Geoffrey Pearson; Emma L. Rayner; Andrew G. Nicholson; Simon G. Funnell; Mike J. Dennis; Fergus V. Gleeson; Sally Sharpe; Miles W. Carroll. Comparison of Rhesus and Cynomolgus macaques as an authentic model for COVID-19. 2020, 1 .
AMA StyleFrancisco J. Salguero, Andrew D. White, Gillian S. Slack, Susan A. Fotheringham, Kevin R. Bewley, Karen E. Gooch, Stephanie Longet, Holly E. Humphries, Robert J. Watson, Laura Hunter, Kathryn A. Ryan, Yper Hall, Laura Sibley, Charlotte Sarfas, Lauren Allen, Marilyn Aram, Emily Brunt, Phillip Brown, Karen R. Buttigieg, Breeze E. Cavell, Rebecca Cobb, Naomi S. Coombes, Owen Daykin-Pont, Michael J. Elmore, Konstantinos Gkolfinos, Kerry J. Godwin, Jade Gouriet, Rachel Halkerston, Debbie J. Harris, Thomas Hender, Catherine M.K. Ho, Chelsea L. Kennard, Daniel Knott, Stephanie Leung, Vanessa Lucas, Adam Mabbutt, Alexandra L. Morrison, Didier Ngabo, Jemma Paterson, Elizabeth J. Penn, Steve Pullan, Irene Taylor, Tom Tipton, Stephen Thomas, Julia A. Tree, Carrie Turner, Nadina Wand, Nathan R. Wiblin, Sue Charlton, Bassam Hallis, Geoffrey Pearson, Emma L. Rayner, Andrew G. Nicholson, Simon G. Funnell, Mike J. Dennis, Fergus V. Gleeson, Sally Sharpe, Miles W. Carroll. Comparison of Rhesus and Cynomolgus macaques as an authentic model for COVID-19. . 2020; ():1.
Chicago/Turabian StyleFrancisco J. Salguero; Andrew D. White; Gillian S. Slack; Susan A. Fotheringham; Kevin R. Bewley; Karen E. Gooch; Stephanie Longet; Holly E. Humphries; Robert J. Watson; Laura Hunter; Kathryn A. Ryan; Yper Hall; Laura Sibley; Charlotte Sarfas; Lauren Allen; Marilyn Aram; Emily Brunt; Phillip Brown; Karen R. Buttigieg; Breeze E. Cavell; Rebecca Cobb; Naomi S. Coombes; Owen Daykin-Pont; Michael J. Elmore; Konstantinos Gkolfinos; Kerry J. Godwin; Jade Gouriet; Rachel Halkerston; Debbie J. Harris; Thomas Hender; Catherine M.K. Ho; Chelsea L. Kennard; Daniel Knott; Stephanie Leung; Vanessa Lucas; Adam Mabbutt; Alexandra L. Morrison; Didier Ngabo; Jemma Paterson; Elizabeth J. Penn; Steve Pullan; Irene Taylor; Tom Tipton; Stephen Thomas; Julia A. Tree; Carrie Turner; Nadina Wand; Nathan R. Wiblin; Sue Charlton; Bassam Hallis; Geoffrey Pearson; Emma L. Rayner; Andrew G. Nicholson; Simon G. Funnell; Mike J. Dennis; Fergus V. Gleeson; Sally Sharpe; Miles W. Carroll. 2020. "Comparison of Rhesus and Cynomolgus macaques as an authentic model for COVID-19." , no. : 1.
Background Viral load is a major contributor to outcome in patients with Ebola virus disease (EVD), with high values leading to a fatal outcome. Evidence from the 2013–2016 Ebola virus (EBOV) outbreak indicated that different genotypes of the virus can have different phenotypes in patients. Additionally, due to the error-prone nature of viral RNA synthesis in an individual patient, the EBOV genome exists around a dominant viral genome sequence. The minor variants within a patient may contribute to the overall phenotype in terms of viral protein function. To investigate the effects of these minor variants, blood samples from patients with acute EVD were deeply sequenced. Results We examine the minor variant frequency between patients with acute EVD who survived infection with those who died. Non-synonymous differences in viral proteins were identified that have implications for viral protein function. The greatest frequency of substitution was identified at three codon sites in the L gene—which encodes the viral RNA-dependent RNA polymerase (RdRp). Recapitulating this in an assay for virus replication, these substitutions result in aberrant viral RNA synthesis and correlate with patient outcome. Conclusions Together, these findings support the notion that in patients who survived EVD, in some cases, the genetic variability of the virus resulted in deleterious mutations that affected viral protein function, leading to reduced viral load. Such mutations may also lead to persistent strains of the virus and be associated with recrudescent infections.
Xiaofeng Dong; Jordana Munoz-Basagoiti; Natasha Y. Rickett; Georgios Pollakis; William A. Paxton; Stephan Günther; Romy Kerber; Lisa F. P. Ng; Michael J. Elmore; N’Faly Magassouba; Miles W. Carroll; David A. Matthews; Julian A. Hiscox. Variation around the dominant viral genome sequence contributes to viral load and outcome in patients with Ebola virus disease. Genome Biology 2020, 21, 1 -20.
AMA StyleXiaofeng Dong, Jordana Munoz-Basagoiti, Natasha Y. Rickett, Georgios Pollakis, William A. Paxton, Stephan Günther, Romy Kerber, Lisa F. P. Ng, Michael J. Elmore, N’Faly Magassouba, Miles W. Carroll, David A. Matthews, Julian A. Hiscox. Variation around the dominant viral genome sequence contributes to viral load and outcome in patients with Ebola virus disease. Genome Biology. 2020; 21 (1):1-20.
Chicago/Turabian StyleXiaofeng Dong; Jordana Munoz-Basagoiti; Natasha Y. Rickett; Georgios Pollakis; William A. Paxton; Stephan Günther; Romy Kerber; Lisa F. P. Ng; Michael J. Elmore; N’Faly Magassouba; Miles W. Carroll; David A. Matthews; Julian A. Hiscox. 2020. "Variation around the dominant viral genome sequence contributes to viral load and outcome in patients with Ebola virus disease." Genome Biology 21, no. 1: 1-20.
Ebola virus (EBOV) is an enveloped, single-stranded RNA virus that can cause Ebola virus disease (EVD). It is thought that EVD survivors are protected against subsequent infection with EBOV and that neutralising antibodies to the viral surface glycoprotein (GP) are potential correlates of protection. Serological studies are vital to assess neutralising antibodies targeted to EBOV GP; however, handling of EBOV is limited to containment level 4 laboratories. Pseudotyped viruses can be used as alternatives to live viruses, which require high levels of bio-containment, in serological and viral entry assays. However, neutralisation capacity can differ among pseudotyped virus platforms. We evaluated the suitability of EBOV GP pseudotyped human immunodeficiency virus type 1 (HIV-1) and vesicular stomatitis virus (VSV) to measure the neutralising ability of plasma from EVD survivors, when compared to results from a live EBOV neutralisation assay. The sensitivity, specificity and correlation with live EBOV neutralisation were greater for the VSV-based pseudotyped virus system, which is particularly important when evaluating EBOV vaccine responses and immuno-therapeutics. Therefore, the EBOV GP pseudotyped VSV neutralisation assay reported here could be used to provide a better understanding of the putative correlates of protection against EBOV.
Kimberley Steeds; Yper Hall; Gillian S. Slack; Stephanie Longet; Thomas Strecker; Sarah Katharina Fehling; Edward Wright; Joseph Akoi Bore; Fara Raymond Koundouno; Mandy Kader Konde; Roger Hewson; Julian A. Hiscox; Georgios Pollakis; Miles W. Carroll. Pseudotyping of VSV with Ebola virus glycoprotein is superior to HIV-1 for the assessment of neutralising antibodies. Scientific Reports 2020, 10, 14289 .
AMA StyleKimberley Steeds, Yper Hall, Gillian S. Slack, Stephanie Longet, Thomas Strecker, Sarah Katharina Fehling, Edward Wright, Joseph Akoi Bore, Fara Raymond Koundouno, Mandy Kader Konde, Roger Hewson, Julian A. Hiscox, Georgios Pollakis, Miles W. Carroll. Pseudotyping of VSV with Ebola virus glycoprotein is superior to HIV-1 for the assessment of neutralising antibodies. Scientific Reports. 2020; 10 (1):14289.
Chicago/Turabian StyleKimberley Steeds; Yper Hall; Gillian S. Slack; Stephanie Longet; Thomas Strecker; Sarah Katharina Fehling; Edward Wright; Joseph Akoi Bore; Fara Raymond Koundouno; Mandy Kader Konde; Roger Hewson; Julian A. Hiscox; Georgios Pollakis; Miles W. Carroll. 2020. "Pseudotyping of VSV with Ebola virus glycoprotein is superior to HIV-1 for the assessment of neutralising antibodies." Scientific Reports 10, no. 1: 14289.
There is dire need for an effective and affordable vaccine against SARS-CoV-2 to tackle the ongoing pandemic. In this study, we describe a modular virus-like particle vaccine candidate displaying the SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) using SpyTag/SpyCatcher technology (RBD-SpyVLP). Low doses of RBD-SpyVLP in a prime-boost regimen induced a strong neutralising antibody response in mice and pigs that was superior to convalescent human sera. We evaluated antibody quality using ACE2 blocking and neutralisation of cell infection by pseudovirus or wild-type SARS-CoV-2. Using competition assays with a monoclonal antibody panel, we showed that RBD-SpyVLP induced a polyclonal antibody response that recognised all key epitopes on the RBD, reducing the likelihood of selecting neutralisation-escape mutants. The induction of potent and polyclonal antibody responses by RBD-SpyVLP provides strong potential to address clinical and logistic challenges of the COVID-19 pandemic. Moreover, RBD-SpyVLP is highly resilient, thermostable and can be lyophilised without losing immunogenicity, to facilitate global distribution and reduce cold-chain dependence.
Tiong Kit Tan; Pramila Rijal; Rolle Rahikainen; Anthony Keeble; Lisa Schimanski; Saira Hussain; Ruth Harvey; Jack Hayes; Jane Edwards; Rebecca McLean; Veronica Martini; Miriam Pedrera; Nazia Thakur; Carina Conceicao; Isabelle Dietrich; Holly Shelton; Anna Barbara Ludi; G Wilsden; Clare Browning; Adrian Zagrajek; Dagmara Bialy; Sushant Bhat; Phoebe Stevenson-Leggett; Philippa Hollinghurst; Matthew Tully; Katy Moffat; Chris Chiu; Ryan Waters; Ashley Gray; Mehreen Azhar; Valerie Mioulet; Joseph Newman; Amin S Asfor; Alison Burman; Sylvia Crossley; John Hammond; Elma Tchilian; Bryan Charleston; Dalan Bailey; Tobias J Tuthill; Simon Graham; Tomas Malinauskas; Jiandong Huo; Julia Tree; Karen Buttigieg; Ray Owens; Miles Carroll; Rod Daniels; John McCauley; Kuan-Ying A Huang; Mark Howarth; Alain Townsend. A COVID-19 vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain induces potent neutralising antibody responses. 2020, 1 .
AMA StyleTiong Kit Tan, Pramila Rijal, Rolle Rahikainen, Anthony Keeble, Lisa Schimanski, Saira Hussain, Ruth Harvey, Jack Hayes, Jane Edwards, Rebecca McLean, Veronica Martini, Miriam Pedrera, Nazia Thakur, Carina Conceicao, Isabelle Dietrich, Holly Shelton, Anna Barbara Ludi, G Wilsden, Clare Browning, Adrian Zagrajek, Dagmara Bialy, Sushant Bhat, Phoebe Stevenson-Leggett, Philippa Hollinghurst, Matthew Tully, Katy Moffat, Chris Chiu, Ryan Waters, Ashley Gray, Mehreen Azhar, Valerie Mioulet, Joseph Newman, Amin S Asfor, Alison Burman, Sylvia Crossley, John Hammond, Elma Tchilian, Bryan Charleston, Dalan Bailey, Tobias J Tuthill, Simon Graham, Tomas Malinauskas, Jiandong Huo, Julia Tree, Karen Buttigieg, Ray Owens, Miles Carroll, Rod Daniels, John McCauley, Kuan-Ying A Huang, Mark Howarth, Alain Townsend. A COVID-19 vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain induces potent neutralising antibody responses. . 2020; ():1.
Chicago/Turabian StyleTiong Kit Tan; Pramila Rijal; Rolle Rahikainen; Anthony Keeble; Lisa Schimanski; Saira Hussain; Ruth Harvey; Jack Hayes; Jane Edwards; Rebecca McLean; Veronica Martini; Miriam Pedrera; Nazia Thakur; Carina Conceicao; Isabelle Dietrich; Holly Shelton; Anna Barbara Ludi; G Wilsden; Clare Browning; Adrian Zagrajek; Dagmara Bialy; Sushant Bhat; Phoebe Stevenson-Leggett; Philippa Hollinghurst; Matthew Tully; Katy Moffat; Chris Chiu; Ryan Waters; Ashley Gray; Mehreen Azhar; Valerie Mioulet; Joseph Newman; Amin S Asfor; Alison Burman; Sylvia Crossley; John Hammond; Elma Tchilian; Bryan Charleston; Dalan Bailey; Tobias J Tuthill; Simon Graham; Tomas Malinauskas; Jiandong Huo; Julia Tree; Karen Buttigieg; Ray Owens; Miles Carroll; Rod Daniels; John McCauley; Kuan-Ying A Huang; Mark Howarth; Alain Townsend. 2020. "A COVID-19 vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain induces potent neutralising antibody responses." , no. : 1.
The last seven years have seen the greatest surge of Ebola virus disease (EVD) cases in equatorial Africa, including the 2013–2016 epidemic in West Africa and the recent epidemics in the Democratic Republic of Congo (DRC). The vaccine clinical trials that took place in West Africa and the DRC, as well as follow-up studies in collaboration with EVD survivor communities, have for the first time allowed researchers to compare immune memory induced by natural infection and vaccination. These comparisons may be relevant to evaluate the putative effectiveness of vaccines and candidate medical countermeasures such as convalescent plasma transfer. In this study, we compared the long-term functionality of anti-EBOV glycoprotein (GP) antibodies from EVD survivors with that from volunteers who received the recombinant vesicular stomatitis virus vectored vaccine (rVSV-ZEBOV) during the Phase I clinical trial in Hamburg. Our study highlights important differences between EBOV vaccination and natural infection and provides a framework for comparison with other vaccine candidates.
Till Koch; Monika Rottstegge; Paula Ruibal; Sergio Gomez-Medina; Emily V. Nelson; Beatriz Escudero-Pérez; Matthias Pillny; My Linh Ly; Fara Raymond Koundouno; Joseph Akoi Bore; N’Faly Magassouba; Christine Dahlke; Stephan Günther; Miles W. Carroll; Marylyn M. Addo; César Muñoz-Fontela. Ebola Virus Disease Survivors Show More Efficient Antibody Immunity than Vaccines Despite Similar Levels of Circulating Immunoglobulins. Viruses 2020, 12, 915 .
AMA StyleTill Koch, Monika Rottstegge, Paula Ruibal, Sergio Gomez-Medina, Emily V. Nelson, Beatriz Escudero-Pérez, Matthias Pillny, My Linh Ly, Fara Raymond Koundouno, Joseph Akoi Bore, N’Faly Magassouba, Christine Dahlke, Stephan Günther, Miles W. Carroll, Marylyn M. Addo, César Muñoz-Fontela. Ebola Virus Disease Survivors Show More Efficient Antibody Immunity than Vaccines Despite Similar Levels of Circulating Immunoglobulins. Viruses. 2020; 12 (9):915.
Chicago/Turabian StyleTill Koch; Monika Rottstegge; Paula Ruibal; Sergio Gomez-Medina; Emily V. Nelson; Beatriz Escudero-Pérez; Matthias Pillny; My Linh Ly; Fara Raymond Koundouno; Joseph Akoi Bore; N’Faly Magassouba; Christine Dahlke; Stephan Günther; Miles W. Carroll; Marylyn M. Addo; César Muñoz-Fontela. 2020. "Ebola Virus Disease Survivors Show More Efficient Antibody Immunity than Vaccines Despite Similar Levels of Circulating Immunoglobulins." Viruses 12, no. 9: 915.
Objectives Stage 1: To evaluate the safety and efficacy of candidate agents as add-on therapies to standard of care (SoC) in patients hospitalised with COVID-19 in a screening stage. Stage 2: To confirm the efficacy of candidate agents selected on the basis of evidence from Stage 1 in patients hospitalised with COVID-19 in an expansion stage. Trial design ACCORD is a seamless, Phase 2, adaptive, randomised controlled platform study, designed to rapidly test candidate agents in the treatment of COVID-19. Designed as a master protocol with each candidate agent being included via its own sub-protocol, initially randomising equally between each candidate and a single contemporaneous SoC arm (which can adapt into 2:1). Candidate agents currently include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin. For each candidate a total of 60 patients will be recruited in Stage 1. If Stage 1 provides evidence of efficacy and acceptable safety the candidate will enter Stage 2 where a total of approximately 126 patients will be recruited into each study arm sub-protocol. Enrollees and outcomes will not be shared across the Stages; the endpoint, analysis and sample size for Stage 2 may be adjusted based on evidence from Stage 1. Additional arms may be added as new potential candidate agents are identified via candidate agent specific sub-protocols. Participants The study will include hospitalised adult patients (≥18 years) with confirmed SARS-CoV-2 infection, the virus that causes COVID-19, that clinically meet Grades 3 (hospitalised – mild disease, no oxygen therapy), Grades 4 (hospitalised, oxygen by mask or nasal prongs) and 5 (hospitalised, non-invasive ventilation or high flow oxygen) of the WHO Working Group on the Clinical Characteristics of COVID-19 9-point category ordinal scale. Participants will be recruited from England, Northern Ireland, Wales and Scotland. Intervention and comparator Comparator is current standard of care (SoC) for the treatment of COVID-19. Current candidate experimental arms include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin with others to be added over time. Bemcentinib could potentially reduce viral infection and blocks SARS-CoV-2 spike protein; MEDI3506 is a clinic-ready anti-IL-33 monoclonal antibody with the potential to treat respiratory failure caused by COVID; acalabrutinib is a BTK inhibitor which is anti-viral and anti-inflammatory; zilucoplan is a complement C5 inhibitor which may block the severe inflammatory response in COVID-19 and; nebulised heparin has been shown to bind with the spike protein. ACCORD is linked with the UK national COVID therapeutics task force to help prioritise candidate agents. Main outcomes Time to sustained clinical improvement of at least 2 points (from randomisation) on the WHO 9-point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the “responder” for the response rate analyses). Randomisation An electronic randomization will be performed by Cenduit using Interactive Response Technology (IRT). Randomisation will be stratified by baseline severity grade. Randomisation will proceed with an equal allocation to each arm and a contemporaneous SoC arm (e.g. 1:1 if control and 1 experimental arm; 1:1:1 if two experimental candidate arms etc) but will be reviewed as the trial progresses and may be changed to 2:1 in favour of the candidate agents. Blinding (masking) The trial is open label and no blinding is currently planned in the study. Numbers to be randomised (sample size) This will be in the order of 60 patients per candidate agent for Stage 1, and 126 patients for Stage 2. However, sample size re-estimation may be considered after Stage 1. It is estimated that up to 1800 patients will participate in the overall study. Trial Status Master protocol version ACCORD-2-001 - Master Protocol (Amendment 1) 22nd April 2020, the trial has full regulatory approval and recruitment is ongoing in the bemcentinib (first patient recruited 6/5/2020), MEDI3506 (first patient recruited 19/5/2020), acalabrutinib (first patient recruited 20/5/2020) and zilucoplan (first patient recruited 19/5/2020) candidates (and SoC). The recruitment dates of each arm will vary between candidate agents as they are added or dropped from the trial, but will have recruited and reported within a year. Trial registration EudraCT 2020-001736-95, registered 28th April 2020. Full protocol The full protocol (Master Protocol with each of the candidate sub-protocols) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
Tom Wilkinson; Rupert Dixon; Clive Page; Miles Carroll; Gareth Griffiths; Ling-Pei Ho; Anthony De Soyza; Timothy Felton; Keir E. Lewis; Karen Phekoo; James D. Chalmers; Anthony Gordon; Lorcan McGarvey; Jillian Doherty; Robert C. Read; Manu Shankar-Hari; Nuria Martinez-Alier; Michael O’Kelly; Graeme Duncan; Roelize Walles; James Sykes; Charlotte Summers; Dave Singh; On Behalf Of The Accord Collaborators. ACCORD: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients: A structured summary of a study protocol for a randomised controlled trial. Trials 2020, 21, 1 -3.
AMA StyleTom Wilkinson, Rupert Dixon, Clive Page, Miles Carroll, Gareth Griffiths, Ling-Pei Ho, Anthony De Soyza, Timothy Felton, Keir E. Lewis, Karen Phekoo, James D. Chalmers, Anthony Gordon, Lorcan McGarvey, Jillian Doherty, Robert C. Read, Manu Shankar-Hari, Nuria Martinez-Alier, Michael O’Kelly, Graeme Duncan, Roelize Walles, James Sykes, Charlotte Summers, Dave Singh, On Behalf Of The Accord Collaborators. ACCORD: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients: A structured summary of a study protocol for a randomised controlled trial. Trials. 2020; 21 (1):1-3.
Chicago/Turabian StyleTom Wilkinson; Rupert Dixon; Clive Page; Miles Carroll; Gareth Griffiths; Ling-Pei Ho; Anthony De Soyza; Timothy Felton; Keir E. Lewis; Karen Phekoo; James D. Chalmers; Anthony Gordon; Lorcan McGarvey; Jillian Doherty; Robert C. Read; Manu Shankar-Hari; Nuria Martinez-Alier; Michael O’Kelly; Graeme Duncan; Roelize Walles; James Sykes; Charlotte Summers; Dave Singh; On Behalf Of The Accord Collaborators. 2020. "ACCORD: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients: A structured summary of a study protocol for a randomised controlled trial." Trials 21, no. 1: 1-3.
Clinical development of the COVID-19 vaccine candidate ChAdOx1 nCoV-19, a replication-deficient simian adenoviral vector expressing the full-length SARS-CoV-2 spike (S) protein was initiated in April 2020 following non-human primate studies using a single immunisation. Here, we compared the immunogenicity of one or two doses of ChAdOx1 nCoV-19 in both mice and pigs. Whilst a single dose induced antigen-specific antibody and T cells responses, a booster immunisation enhanced antibody responses, particularly in pigs, with a significant increase in SARS-CoV-2 neutralising titres.
Simon P. Graham; Rebecca K. McLean; Alexandra J. Spencer; Sandra Belij-Rammerstorfer; Daniel Wright; Marta Ulaszewska; Jane C. Edwards; Jack W. P. Hayes; Veronica Martini; Nazia Thakur; Carina Conceicao; Isabelle Dietrich; Holly Shelton; Ryan Waters; Anna Ludi; Ginette Wilsden; Clare Browning; Dagmara Bialy; Sushant Bhat; Phoebe Stevenson-Leggett; Philippa Hollinghurst; Ciaran Gilbride; David Pulido; Katy Moffat; Hannah Sharpe; Elizabeth Allen; Valerie Mioulet; Chris Chiu; Joseph Newman; Amin S. Asfor; Alison Burman; Sylvia Crossley; Jiandong Huo; Raymond J. Owens; Miles Carroll; John A. Hammond; Elma Tchilian; Dalan Bailey; Bryan Charleston; Sarah C. Gilbert; Tobias J. Tuthill; Teresa Lambe. Evaluation of the immunogenicity of prime-boost vaccination with the replication-deficient viral vectored COVID-19 vaccine candidate ChAdOx1 nCoV-19. 2020, 1 .
AMA StyleSimon P. Graham, Rebecca K. McLean, Alexandra J. Spencer, Sandra Belij-Rammerstorfer, Daniel Wright, Marta Ulaszewska, Jane C. Edwards, Jack W. P. Hayes, Veronica Martini, Nazia Thakur, Carina Conceicao, Isabelle Dietrich, Holly Shelton, Ryan Waters, Anna Ludi, Ginette Wilsden, Clare Browning, Dagmara Bialy, Sushant Bhat, Phoebe Stevenson-Leggett, Philippa Hollinghurst, Ciaran Gilbride, David Pulido, Katy Moffat, Hannah Sharpe, Elizabeth Allen, Valerie Mioulet, Chris Chiu, Joseph Newman, Amin S. Asfor, Alison Burman, Sylvia Crossley, Jiandong Huo, Raymond J. Owens, Miles Carroll, John A. Hammond, Elma Tchilian, Dalan Bailey, Bryan Charleston, Sarah C. Gilbert, Tobias J. Tuthill, Teresa Lambe. Evaluation of the immunogenicity of prime-boost vaccination with the replication-deficient viral vectored COVID-19 vaccine candidate ChAdOx1 nCoV-19. . 2020; ():1.
Chicago/Turabian StyleSimon P. Graham; Rebecca K. McLean; Alexandra J. Spencer; Sandra Belij-Rammerstorfer; Daniel Wright; Marta Ulaszewska; Jane C. Edwards; Jack W. P. Hayes; Veronica Martini; Nazia Thakur; Carina Conceicao; Isabelle Dietrich; Holly Shelton; Ryan Waters; Anna Ludi; Ginette Wilsden; Clare Browning; Dagmara Bialy; Sushant Bhat; Phoebe Stevenson-Leggett; Philippa Hollinghurst; Ciaran Gilbride; David Pulido; Katy Moffat; Hannah Sharpe; Elizabeth Allen; Valerie Mioulet; Chris Chiu; Joseph Newman; Amin S. Asfor; Alison Burman; Sylvia Crossley; Jiandong Huo; Raymond J. Owens; Miles Carroll; John A. Hammond; Elma Tchilian; Dalan Bailey; Bryan Charleston; Sarah C. Gilbert; Tobias J. Tuthill; Teresa Lambe. 2020. "Evaluation of the immunogenicity of prime-boost vaccination with the replication-deficient viral vectored COVID-19 vaccine candidate ChAdOx1 nCoV-19." , no. : 1.
The COVID-19 pandemic has had unprecedented health and economic impact, but currently there are no approved therapies. We have isolated an antibody, EY6A, from a late-stage COVID-19 patient and show it neutralises SARS-CoV-2 and cross-reacts with SARS-CoV-1. EY6A Fab binds tightly (KD of 2 nM) the receptor binding domain (RBD) of the viral Spike glycoprotein and a 2.6Å crystal structure of an RBD/EY6A Fab complex identifies the highly conserved epitope, away from the ACE2 receptor binding site. Residues of this epitope are key to stabilising the pre-fusion Spike. Cryo-EM analyses of the pre-fusion Spike incubated with EY6A Fab reveal a complex of the intact trimer with three Fabs bound and two further multimeric forms comprising destabilized Spike attached to Fab. EY6A binds what is probably a major neutralising epitope, making it a candidate therapeutic for COVID-19.
Daming Zhou; Helen M E Duyvesteyn; Cheng-Pin Chen; Chung-Guei Huang; Ting-Hua Chen; Shin-Ru Shih; Yi-Chun Lin; Chien-Yu Cheng; Shu-Hsing Cheng; Yhu-Chering Huang; Tzou-Yien Lin; Che Ma; Jiandong Huo; Loic Carrique; Tomas Malinauskas; Reinis R Ruza; Pranav Nm Shah; Tiong Kit Tan; Pramila Rijal; Robert F. Donat; Kerry Godwin; Karen Buttigieg; Julia Tree; Julika Radecke; Neil G Paterson; Piyasa Supasa; Juthathip Mongkolsapaya; Gavin R Screaton; Miles W. Carroll; Javier G. Jaramillo; Michael Knight; William S James; Raymond J Owens; James H. Naismith; Alain Townsend; Elizabeth E Fry; Yuguang Zhao; Jingshan Ren; David I Stuart; Kuan-Ying A. Huang. Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient. bioRxiv 2020, 1 .
AMA StyleDaming Zhou, Helen M E Duyvesteyn, Cheng-Pin Chen, Chung-Guei Huang, Ting-Hua Chen, Shin-Ru Shih, Yi-Chun Lin, Chien-Yu Cheng, Shu-Hsing Cheng, Yhu-Chering Huang, Tzou-Yien Lin, Che Ma, Jiandong Huo, Loic Carrique, Tomas Malinauskas, Reinis R Ruza, Pranav Nm Shah, Tiong Kit Tan, Pramila Rijal, Robert F. Donat, Kerry Godwin, Karen Buttigieg, Julia Tree, Julika Radecke, Neil G Paterson, Piyasa Supasa, Juthathip Mongkolsapaya, Gavin R Screaton, Miles W. Carroll, Javier G. Jaramillo, Michael Knight, William S James, Raymond J Owens, James H. Naismith, Alain Townsend, Elizabeth E Fry, Yuguang Zhao, Jingshan Ren, David I Stuart, Kuan-Ying A. Huang. Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient. bioRxiv. 2020; ():1.
Chicago/Turabian StyleDaming Zhou; Helen M E Duyvesteyn; Cheng-Pin Chen; Chung-Guei Huang; Ting-Hua Chen; Shin-Ru Shih; Yi-Chun Lin; Chien-Yu Cheng; Shu-Hsing Cheng; Yhu-Chering Huang; Tzou-Yien Lin; Che Ma; Jiandong Huo; Loic Carrique; Tomas Malinauskas; Reinis R Ruza; Pranav Nm Shah; Tiong Kit Tan; Pramila Rijal; Robert F. Donat; Kerry Godwin; Karen Buttigieg; Julia Tree; Julika Radecke; Neil G Paterson; Piyasa Supasa; Juthathip Mongkolsapaya; Gavin R Screaton; Miles W. Carroll; Javier G. Jaramillo; Michael Knight; William S James; Raymond J Owens; James H. Naismith; Alain Townsend; Elizabeth E Fry; Yuguang Zhao; Jingshan Ren; David I Stuart; Kuan-Ying A. Huang. 2020. "Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient." bioRxiv , no. : 1.