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Instruments / Technical Area	Publication Details	Published
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
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
I03-Macromolecular Crystallography Krios I-Titan Krios I at Diamond	Neutralisation of SARS-CoV-2 by destruction of the prefusion Spike Jiandong Huo , Yuguang Zhao , Jingshan Ren , Daming Zhou , Helen M. E. Duyvesteyn , Helen M. Ginn , Loic Carrique , Tomas Malinauskas , Reinis R. Ruza , Pranav N. M. Shah , Tiong Kit Tan , Pramila Rijal , Naomi Coombes , Kevin R. Bewley , Julia A. Tree , Julika Radecke , Neil Paterson , Piyasa Supasa , Juthathip Mongkolsapaya , Gavin R. Screaton , Miles Carroll , Alain Townsend , Elizabeth E. Fry , Raymond J. Owens , David I. Stuart Cell Host & Microbe DOI: 10.1016/j.chom.2020.06.010 Diamond Proposal Number(s): [19946, 26983] Open Access Show Abstract ▼ Abstract: There are as yet no licenced therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric Spike whose receptor binding domain (RBD) recognises angiotensin-converting enzyme 2 (ACE2), initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralising SARS-CoV-2 and report the crystal structure at 2.4 Å of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilising, CR3022 epitope is inaccessible in the prefusion Spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. Cryo-EM analysis confirms that incubation of Spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope may be useful therapeutically, possibly in synergy with an antibody blocking receptor attachment.	Jun 2020
I02-Macromolecular Crystallography	Characterization of a potent and highly unusual minimally enhancing antibody directed against dengue virus Max Renner , Aleksandra Flanagan , Wanwisa Dejnirattisai , Chunya Puttikhunt , Watchara Kasinrerk , Piyada Supasa , Wiyada Wongwiwat , Kriangkrai Chawansuntati , Thaneeya Duangchinda , Alison Cowper , Claire M. Midgley , Prida Malasit , Juha T. Huiskonen , Juthathip Mongkolsapaya , Gavin R. Screaton , Jonathan M. Grimes Nature Immunology 496 DOI: 10.1038/s41590-018-0227-7 Diamond Proposal Number(s): [8423] Show Abstract ▼ Abstract: Dengue virus is a major pathogen, and severe infections can lead to life-threatening dengue hemorrhagic fever. Dengue virus exists as four serotypes, and dengue hemorrhagic fever is often associated with secondary heterologous infections. Antibody-dependent enhancement (ADE) may drive higher viral loads in these secondary infections and is purported to result from antibodies that recognize dengue virus but fail to fully neutralize it. Here we characterize two antibodies, 2C8 and 3H5, that bind to the envelope protein. Antibody 3H5 is highly unusual as it not only is potently neutralizing but also promotes little if any ADE, whereas antibody 2C8 has strong capacity to promote ADE. We show that 3H5 shows resilient binding in endosomal pH conditions and neutralizes at low occupancy. Immunocomplexes of 3H5 and dengue virus do not efficiently interact with Fcγ receptors, which we propose is due to the binding mode of 3H5 and constitutes the primary mechanism of how ADE is avoided.	Oct 2018
	A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus Wanwisa Dejnirattisai , Wiyada Wongwiwat , Sunpetchuda Supasa , Xiaokang Zhang , Xinghong Dai , Alexander Rouvinsky , Amonrat Jumnainsong , Carolyn Edwards , Nguyen Than Ha Quyen , Thaneeya Duangchinda , Jonathan Grimes , Wen-Yang Tsai , Chih-Yun Lai , Wei-Kung Wang , Prida Malasit , Jeremy Farrar , Cameron P Simmons , Z Hong Zhou , Felix A Rey , Juthathip Mongkolsapaya , Gavin. R. Screaton Nature Immunology 16, 170 - 177 DOI: 10.1038/ni.3058 PMID: 25501631 Show Abstract ▼ Abstract: Dengue is a rapidly emerging, mosquito-borne viral infection, with an estimated 400 million infections occurring annually. To gain insight into dengue immunity, we characterized 145 human monoclonal antibodies (mAbs) and identified a previously unknown epitope, the envelope dimer epitope (EDE), that bridges two envelope protein subunits that make up the 90 repeating dimers on the mature virion. The mAbs to EDE were broadly reactive across the dengue serocomplex and fully neutralized virus produced in either insect cells or primary human cells, with 50% neutralization in the low picomolar range. Our results provide a path to a subunit vaccine against dengue virus and have implications for the design and monitoring of future vaccine trials in which the induction of antibody to the EDE should be prioritized.	Dec 2014
I04-Macromolecular Crystallography	Structural Analysis of a Dengue Cross-Reactive Antibody Complexed with Envelope Domain III Reveals the Molecular Basis of Cross-Reactivity C. M. Midgley , A. Flanagan , H. B. Tran , W. Dejnirattisai , K. Chawansuntati , A. Jumnainsong , W. Wongwiwat , T. Duangchinda , J. Mongkolsapaya , J. M. Grimes , G. R. Screaton The Journal Of Immunology 188 (10), 4971 - 4979 DOI: 10.4049/jimmunol.1200227 PMID: 22491255 Diamond Proposal Number(s): [6387] Show Abstract ▼ Abstract: Dengue virus infections are still increasing at an alarming rate in tropical and subtropical countries, underlying the need for a dengue vaccine. Although it is relatively easy to generate Ab responses to dengue virus, low avidity or low concentrations of Ab may enhance infection of FcR-bearing cells with clinical impact, posing a challenge to vaccine production. In this article, we report the characterization of a mAb, 2H12, which is cross-reactive to all four serotypes in the dengue virus group. Crystal structures of 2H12-Fab in complex with domain III of the envelope protein from three dengue serotypes have been determined. 2H12 binds to the highly conserved AB loop of domain III of the envelope protein that is poorly accessible in the mature virion. 2H12 neutralization varied between dengue serotypes and strains; in particular, dengue serotype 2 was not neutralized. Because the 2H12-binding epitope was conserved, this variation in neutralization highlights differences between dengue serotypes and suggests that significant conformational changes in the virus must take place for Ab binding. Surprisingly, 2H12 facilitated little or no enhancement of infection. These data provide a structural basis for understanding Ab neutralization and enhancement of infection, which is crucial for the development of future dengue vaccines.	May 2012

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