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Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography	The antibody response to SARS-CoV-2 Beta underscores the antigenic distance to other variants Chang Liu , Daming Zhou , Rungtiwa Nutalai , Helen M. E. Duyvesteyn , Aekkachai Tuekprakhon , Helen M. Ginn , Wanwisa Dejnirattisai , Piyada Supasa , Alexander J. Mentzer , Beibei Wang , James Brett Case , Yuguang Zhao , Donal T. Skelly , Rita E. Chen , Sile Ann Johnson , Thomas G. Ritter , Chris Mason , Tariq Malik , Nigel Temperton , Neil G. Paterson , Mark A. Williams , David R. Hall , Daniel K. Clare , Andrew Howe , Philip J. R. Goulder , Elizabeth E. Fry , Michael S. Diamond , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell Host & Microbe DOI: 10.1016/j.chom.2021.11.013 Diamond Proposal Number(s): [27009] Open Access Show Abstract ▼ Abstract: Alpha-B.1.1.7, Beta-B.1.351, Gamma-P.1 and Delta-B.1.617.2 variants of SARS-CoV-2 express multiple mutations in the spike protein (S). These may alter the antigenic structure of S, causing escape from natural or vaccine-induced immunity. Beta is particularly difficult to neutralize using serum induced by early pandemic SARS-CoV-2 strains and is most antigenically separated from Delta. To understand this, we generated 674 mAbs from Beta infected individuals and performed a detailed structure-function analysis of the 27 most potent mAbs: one binding the spike N-terminal domain (NTD), the rest the receptor binding domain (RBD). Two of these RBD-binding mAbs recognise a neutralizing epitope conserved between SARS-CoV-1 and -2, whilst 18 target mutated residues in Beta: K417N, E484K, and N501Y. There is a major response to N501Y including a public IgVH4-39 sequence, with E484K and K417N also targeted. Recognition of these key residues underscores why serum from Beta cases poorly neutralizes early pandemic and Delta viruses.	Nov 2021
I03-Macromolecular Crystallography	Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum Chang Liu , Helen M. Ginn , Wanwisa Dejnirattisai , Piyada Supasa , Beibei Wang , Aekkachai Tuekprakhon , Rungtiwa Nutalai , Daming Zhou , Alexander J. Mentzer , Yuguang Zhao , Helen M. E. Duyvesteyn , César López-Camacho , Jose Slon-Campos , Thomas Walter , Donal Skelly , Sile Ann Johnson , Thomas G. Ritter , Chris Mason , Sue Ann Costa Clemens , Felipe Gomes Naveca , Valdinete Nascimento , Fernanda Nascimento , Cristiano Fernandes Da Costa , Paola Cristina Resende , Alex Pauvolid-Correa , Marilda M. Siqueira , Christina Dold , Nigel Temperton , Tao Dong , Andrew J. Pollard , Julian C. Knight , Derrick Crook , Teresa Lambe , Elizabeth Clutterbuck , Sagida Bibi , Amy Flaxman , Mustapha Bittaye , Sandra Belij-Rammerstorfer , Sarah C. Gilbert , Tariq Malik , Miles W. Carroll , Paul Klenerman , Eleanor Barnes , Susanna J. Dunachie , Vicky Baillie , Natali Serafin , Zanele Ditse , Kelly Da Silva , Neil G. Paterson , Mark A. Williams , David R. Hall , Shabir Madhi , Marta C. Nunes , Philip Goulder , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell DOI: 10.1016/j.cell.2021.06.020 Diamond Proposal Number(s): [27009] Show Abstract ▼ Abstract: SARS-CoV-2 has undergone progressive change with variants conferring advantage rapidly becoming dominant lineages e.g. B.1.617. With apparent increased transmissibility variant B.1.617.2 has contributed to the current wave of infection ravaging the Indian subcontinent and has been designated a variant of concern in the UK. Here we study the ability of monoclonal antibodies, convalescent and vaccine sera to neutralize B.1.617.1 and B.1.617.2 and complement this with structural analyses of Fab/RBD complexes and map the antigenic space of current variants. Neutralization of both viruses is reduced when compared with ancestral Wuhan related strains but there is no evidence of widespread antibody escape as seen with B.1.351. However, B.1.351 and P.1 sera showed markedly more reduction in neutralization of B.1.617.2 suggesting that individuals previously infected by these variants may be more susceptible to reinfection by B.1.617.2. This observation provides important new insight for immunisation policy with future variant vaccines in non-immune populations.	Jun 2021
Krios II-Titan Krios II at Diamond	Native-like SARS-CoV-2 spike glycoprotein expressed by ChAdOx1 nCoV-19/AZD1222 vaccine Yasunori Watanabe , Luiza Mendonca , Elizabeth R. Allen , Andrew Howe , Mercede Lee , Joel D. Allen , Himanshi Chawla , David Pulido , Francesca Donnellan , Hannah Davies , Marta Ulaszewska , Sandra Belij-Rammerstorfer , Susan Morris , Anna-Sophia Krebs , Wanwisa Dejnirattisai , Juthathip Mongkolsapaya , Piyada Supasa , Gavin R. Screaton , Catherine M. Green , Teresa Lambe , Peijun Zhang , Sarah C. Gilbert , Max Crispin Acs Central Science DOI: 10.1021/acscentsci.1c00080 Diamond Proposal Number(s): [18477, 21005, 21004] Show Abstract ▼ Abstract: Vaccine development against the SARS-CoV-2 virus focuses on the principal target of the neutralizing immune response, the spike (S) glycoprotein. Adenovirus-vectored vaccines offer an effective platform for the delivery of viral antigen, but it is important for the generation of neutralizing antibodies that they produce appropriately processed and assembled viral antigen that mimics that observed on the SARS-CoV-2 virus. Here, we describe the structure, conformation, and glycosylation of the S protein derived from the adenovirus-vectored ChAdOx1 nCoV-19/AZD1222 vaccine. We demonstrate native-like post-translational processing and assembly, and reveal the expression of S proteins on the surface of cells adopting the trimeric prefusion conformation. The data presented here confirm the use of ChAdOx1 adenovirus vectors as a leading platform technology for SARS-CoV-2 vaccines.	Apr 2021
I03-Macromolecular Crystallography	Antibody evasion by the P.1 strain of SARS-CoV-2 Wanwisa Dejnirattisai , Daming Zhou , Piyada Supasa , Chang Liu , Alexander J. Mentzer , Helen M. Ginn , Yuguang Zhao , Helen M. E. Duyvesteyn , Aekkachai Tuekprakhon , Rungtiwa Nutalai , Beibei Wang , Guido Paesen , César López-Camacho , Jose Slon-Campos , Thomas S. Walter , Donal Skelly , Sue Ann Costa Clemens , Felipe Gomes Naveca , Valdinete Nascimento , Fernanda Nascimento , Cristiano Fernandes Da Costa , Paola C. Resende , Alex Pauvolid-Correa , Marilda M. Siqueira , Christina Dold , Robert Levin , Tao Dong , Andrew J. Pollard , Julian C. Knight , Derrick Crook , Teresa Lambe , Elizabeth Clutterbuck , Sagida Bibi , Amy Flaxman , Mustapha Bittaye , Sandra Belij-Rammerstorfer , Sarah Gilbert , Miles W. Carroll , Paul Klenerman , Eleanor Barnes , Susanna J. Dunachie , Neil G. Paterson , Mark A. Williams , David R. Hall , Ruben J. G. Hulswit , Thomas A. Bowden , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell DOI: 10.1016/j.cell.2021.03.055 Diamond Proposal Number(s): [27009] Open Access Show Abstract ▼ Abstract: Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations: P.1 from Brazil, B.1.351 from South Africa and B.1.1.7 from the UK (12, 10 and 9 changes in the spike respectively). All have mutations in the ACE2 binding site with P.1 and B.1.351 having a virtually identical triplet: E484K, K417N/T and N501Y, which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine induced antibody responses than B.1.351 suggesting that changes outside the RBD impact neutralisation. Monoclonal antibody 222 neutralises all three variants despite interacting with two of the ACE2 binding site mutations, we explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.	Mar 2021
I03-Macromolecular Crystallography	Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera Piyada Supasa , Daming Zhou , Wanwisa Dejnirattisai , Chang Liu , Alexander J. Mentzer , Helen M. Ginn , Yuguang Zhao , Helen M. E. Duyvesteyn , Rungtiwa Nutalai , Aekkachai Tuekprakhon , Beibei Wang , Guido Paesen , Jose Slon-Campos , César López-Camacho , Bassam Hallis , Naomi Coombes , Kevin Bewley , Sue Charlton , Thomas S. Walter , Eleanor Barnes , Susanna J. Dunachie , Donal Skelly , Sheila F. Lumley , Natalie Baker , Imam Shaik , Holly Humphries , Kerry Godwin , Nick Gent , Alex Sienkiewicz , Christina Dold , Robert Levin , Tao Dong , Andrew J. Pollard , Julian C. Knight , Paul Klenerman , Derrick Crook , Teresa Lambe , Elizabeth Clutterbuck , Sagida Bibi , Amy Flaxman , Mustapha Bittaye , Sandra Belij-Rammerstorfer , Sarah Gilbert , David R. Hall , Mark Williams , Neil G. Paterson , William James , Miles W. Carroll , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell DOI: 10.1016/j.cell.2021.02.033 Diamond Proposal Number(s): [27009] Open Access Show Abstract ▼ Abstract: SARS-CoV-2 has caused over 2M deaths in little over a year. Vaccines are being deployed at scale, aiming to generate responses against the virus spike. The scale of the pandemic and error-prone virus replication is leading to the appearance of mutant viruses and potentially escape from antibody responses. Variant B.1.1.7, now dominant in the UK, with increased transmission, harbours 9 amino-acid changes in the spike, including N501Y in the ACE2 interacting-surface. We examine the ability of B.1.1.7 to evade antibody responses elicited by natural SARS-CoV-2 infection or vaccination. We map the impact of N501Y by structure/function analysis of a large panel of well-characterised monoclonal antibodies. B.1.1.7 is harder to neutralize than parental virus, compromising neutralization by some members of a major class of public antibodies through light chain contacts with residue 501. However, widespread escape from monoclonal antibodies or antibody responses generated by natural infection or vaccination was not observed.	Feb 2021
I03-Macromolecular Crystallography	Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine induced sera Daming Zhou , Wanwisa Dejnirattisai , Piyada Supasa , Chang Liu , Alexander J. Mentzer , Helen M. Ginn , Yuguang Zhao , Helen M. E. Duyvesteyn , Aekkachai Tuekprakhon , Rungtiwa Nutalai , Beibei Wang , Guido C. Paesen , Cesar Lopez-Camacho , Jose Slon-Campos , Bassam Hallis , Naomi Coombes , Kevin Bewley , Sue Charlton , Thomas S. Walter , Donal Skelly , Sheila F. Lumley , Christina Dold , Robert Levin , Tao Dong , Andrew J. Pollard , Julian C. Knight , Derrick Crook , Teresa Lambe , Elizabeth Clutterbuck , Sagida Bibi , Amy Flaxman , Mustapha Bittaye , Sandra Belij-Rammerstorfer , Sarah Gilbert , William James , Miles W. Carroll , Paul Klenerman , Eleanor Barnes , Susanna J. Dunachie , Elizabeth E. Fry , Juthathip Mongkolspaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell DOI: 10.1016/j.cell.2021.02.037 Diamond Proposal Number(s): [27009] Open Access Show Abstract ▼ Abstract: The race to produce vaccines against SARS-CoV-2 began when the first sequence was published, and this forms the basis for vaccines currently deployed globally. Independent lineages of SARS-CoV-2 have recently been reported: UK–B.1.1.7, South Africa–B.1.351 and Brazil–P.1. These variants have multiple changes in the immunodominant spike protein which facilitates viral cell entry via the Angiotensin converting enzyme-2 (ACE2) receptor. Mutations in the receptor recognition site on the spike are of great concern for their potential for immune escape. Here we describe a structure-function analysis of B.1.351 using a large cohort of convalescent and vaccinee serum samples. The receptor binding domain mutations provide tighter ACE2 binding and widespread escape from monoclonal antibody neutralization largely driven by E484K although K417N and N501Y act together against some important antibody classes. In a number of cases it would appear that convalescent and some vaccine serum offers limited protection against this variant.	Feb 2021
Krios IV-Titan Krios IV at Diamond	Flavivirus maturation leads to the formation of an occupied lipid pocket in the surface glycoproteins Max Renner , Wanwisa Dejnirattisai , Loic Carrique , Itziar Serna Martin , Dimple Karia , Serban L. Ilca , Shu F. Ho , Abhay Kotecha , Jeremy R. Keown , Juthathip Mongkolsapaya , Gavin R. Screaton , Jonathan M. Grimes Nature Communications 12 DOI: 10.1038/s41467-021-21505-9 Diamond Proposal Number(s): [20223] Open Access Show Abstract ▼ Abstract: Flaviviruses such as Dengue (DENV) or Zika virus (ZIKV) assemble into an immature form within the endoplasmatic reticulum (ER), and are then processed by furin protease in the trans-Golgi. To better grasp maturation, we carry out cryo-EM reconstructions of immature Spondweni virus (SPOV), a human flavivirus of the same serogroup as ZIKV. By employing asymmetric localised reconstruction we push the resolution to 3.8 Å, enabling us to refine an atomic model which includes the crucial furin protease recognition site and a conserved Histidine pH-sensor. For direct comparison, we also solve structures of the mature forms of SPONV and DENV to 2.6 Å and 3.1 Å, respectively. We identify an ordered lipid that is present in only the mature forms of ZIKV, SPOV, and DENV and can bind as a consequence of rearranging amphipathic stem-helices of E during maturation. We propose a structural role for the pocket and suggest it stabilizes mature E.	Feb 2021
I03-Macromolecular Crystallography Krios I-Titan Krios I at Diamond	The antigenic anatomy of SARS-CoV-2 receptor binding domain Wanwisa Dejnirattisai , Daming Zhou , Helen M. Ginn , Helen M. E. Duyvesteyn , Piyada Supasa , James Brett Case , Yuguang Zhao , Thomas Walter , Alexander J. Mentzer , Chang Liu , Beibei Wang , Guido C. Paesen , Jose Slon-Campos , César López-Camacho , Natasha M. Kafai , Adam L. Bailey , Rita E. Chen , Baoling Ying , Craig Thompson , Jai Bolton , Alex Fyfe , Sunetra Gupta , Tiong Kit Tan , Javier Gilbert-Jaramillo , William James , Michael Knight , Miles W. Carroll , Donal Skelly , Christina Dold , Yanchun Peng , Robert Levin , Tao Dong , Andrew J. Pollard , Julian C. Knight , Paul Klenerman , Nigel Temperton , David R. Hall , Mark A. Williams , Neil G. Paterson , Felicity Bertram , C. Alistair Siebert , Daniel K. Clare , Andrew Howe , Julika Radecke , Yun Song , Alain R. Townsend , Kuan-Ying A. Huang , Elizabeth E. Fry , Juthathip Mongkolsapaya , Michael S. Diamond , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell DOI: 10.1016/j.cell.2021.02.032 Diamond Proposal Number(s): [27009, 26983] Open Access Show Abstract ▼ Abstract: Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike, and focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data driven method to map RBD binding sites. We find that although antibody binding sites are widely dispersed, neutralizing antibody binding is focused, with nearly all highly inhibitory mAbs (IC50<0.1μg/ml) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryo-electron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models.	Feb 2021
	Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19 Yanchun Peng , Alexander J. Mentzer , Guihai Liu , Xuan Yao , Zixi Yin , Danning Dong , Wanwisa Dejnirattisai , Timothy Rostron , Piyada Supasa , Chang Liu , César López-Camacho , Jose Slon-Campos , Yuguang Zhao , David I. Stuart , Guido C. Paesen , Jonathan M. Grimes , Alfred A. Antson , Oliver W. Bayfield , Dorothy E. D. P. Hawkins , De-Sheng Ker , Beibei Wang , Lance Turtle , Krishanthi Subramaniam , Paul Thomson , Ping Zhang , Christina Dold , Jeremy Ratcliff , Peter Simmonds , Thushan De Silva , Paul Sopp , Dannielle Wellington , Ushani Rajapaksa , Yi-Ling Chen , Mariolina Salio , Giorgio Napolitani , Wayne Paes , Persephone Borrow , Benedikt M. Kessler , Jeremy W. Fry , Nikolai F. Schwabe , Malcolm G. Semple , J. Kenneth Baillie , Shona C. Moore , Peter J. M. Openshaw , M. Azim Ansari , Susanna Dunachie , Eleanor Barnes , John Frater , Georgina Kerr , Oliver Gould , Teresa Lockett , Robert Levin , Yonghong Zhang , Ronghua Jing , Ling-Pei Ho , Richard J. Cornall , Christopher P. Conlon , Paul Klenerman , Gavin R. Screaton , Juthathip Mongkolsapaya , Andrew Mcmichael , Julian C. Knight , Graham Ogg , Tao Dong Nature Immunology 7 DOI: 10.1038/s41590-020-0782-6 Open Access Show Abstract ▼ Abstract: The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4+ and/or CD8+ epitopes, including six immunodominant regions. Six optimized CD8+ epitopes were defined, with peptide–MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8+ T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design.	Sep 2020
I03-Macromolecular Crystallography Krios I-Titan Krios I at Diamond	Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient 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 Shah , Tiong Kit Tan , Pramila Rijal , Robert F. Donat , Kerry Godwin , Karen R. Buttigieg , Julia A. Tree , Julika Radecke , Neil Paterson , Piyada Supasa , Juthathip Mongkolsapaya , Gavin R. Screaton , Miles W. Carroll , Javier Gilbert-Jaramillo , Michael L. Knight , William James , Raymond J. Owens , James H. Naismith , Alain R. Townsend , Elizabeth E. Fry , Yuguang Zhao , Jingshan Ren , David I. Stuart , Kuan-Ying A. Huang Nature Structural & Molecular Biology 20 DOI: 10.1038/s41594-020-0480-y Diamond Proposal Number(s): [19946, 26983] Show Abstract ▼ Abstract: The COVID-19 pandemic has had an unprecedented health and economic impact and there are currently no approved therapies. We have isolated an antibody, EY6A, from an individual convalescing from COVID-19 and have shown that it neutralizes SARS-CoV-2 and cross-reacts with SARS-CoV-1. EY6A Fab binds the receptor binding domain (RBD) of the viral spike glycoprotein tightly (KD of 2 nM), and a 2.6-Å-resolution crystal structure of an RBD–EY6A Fab complex identifies the highly conserved epitope, away from the ACE2 receptor binding site. Residues within this footprint are key to stabilizing the pre-fusion spike. Cryo-EM analyses of the pre-fusion spike incubated with EY6A Fab reveal a complex of the intact spike trimer with three Fabs bound and two further multimeric forms comprising the destabilized spike attached to Fab. EY6A binds what is probably a major neutralizing epitope, making it a candidate therapeutic for COVID-19.	Jul 2020

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