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Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography	SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses Wanwisa Dejnirattisai , Jiandong Huo , Daming Zhou , Jiří Zahradník , Piyada Supasa , Chang Liu , Helen M. E. Duyvesteyn , Helen M. Ginn , Alexander J. Mentzer , Aekkachai Tuekprakhon , Rungtiwa Nutalai , Beibei Wang , Aiste Dijokaite , Suman Khan , Ori Avinoam , Mohammad Bahar , Donal Skelly , Sandra Adele , Sile Ann Johnson , Ali Amini , Thomas Ritter , Chris Mason , Christina Dold , Daniel Pan , Sara Assadi , Adam Bellass , Nikki Omo-Dare , David Koeckerling , Amy Flaxman , Daniel Jenkin , Parvinder K. Aley , Merryn Voysey , Sue Ann Costa Clemens , Felipe Gomes Naveca , Valdinete Nascimento , Fernanda Nascimento , Cristiano Fernandes Da Costa , Paola Cristina Resende , Alex Pauvolid-Correa , Marilda M. Siqueira , Vicky Baillie , Natali Serafin , Gaurav Kwatra , Kelly Da Silva , Shabir A. Madhi , Marta C. Nunes , Tariq Malik , Peter J. M. Openshaw , J. Kenneth Baillie , Malcolm G. Semple , Alain R. Townsend , Kuan-Ying A. Huang , Tiong Kit Tan , Miles W. Carroll , Paul Klenerman , Eleanor Barnes , Susanna J. Dunachie , Bede Constantinides , Hermione Webster , Derrick Crook , Andrew J. Pollard , Teresa Lambe , Neil G. Paterson , Mark A. Williams , David R. Hall , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , Gideon Schreiber , David I. Stuart , Gavin R. Screaton Cell DOI: 10.1016/j.cell.2021.12.046 Diamond Proposal Number(s): [27009] Show Abstract ▼ Abstract: On the 24th November 2021 the sequence of a new SARS CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titres of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic as well as Alpha, Beta, Gamma, Delta are substantially reduced or fail to neutralize. Titres against Omicron are boosted by third vaccine doses and are high in cases both vaccinated and infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of a large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses, combining mutations conferring tight binding to ACE2 to unleash evolution driven by immune escape, leading to a large number of mutations in the ACE2 binding site which rebalance receptor affinity to that of early pandemic viruses.	Jan 2022
I24-Microfocus Macromolecular Crystallography	Bacteriophage PRD1 as a nanoscaffold for drug loading Helen M. E. Duyvesteyn , Isaac Santos-Perez , Francesca Peccati , Ane Martinez-Castillo , Thomas S. Walter , David Reguera , Felix M. Goñi , Gonzalo Jiménez-Osés , Hanna M. Oksanen , David I. Stuart , Nicola G. A. Abrescia Nanoscale 156 DOI: 10.1039/D1NR04153C Diamond Proposal Number(s): [14744] Open Access Show Abstract ▼ Abstract: Viruses are very attractive biomaterials owing to their capability as nanocarriers of genetic material. Efforts have been made to functionalize self-assembling viral protein capsids on their exterior or interior to selectively take up different payloads. PRD1 is a double-stranded DNA bacteriophage comprising an icosahedral protein outer capsid and an inner lipidic vesicle. Here, we report the three-dimensional structure of PRD1 in complex with the antipsychotic drug chlorpromazine (CPZ) by cryo-electron microscopy. We show that the jellyrolls of the viral major capsid protein P3, protruding outwards from the capsid shell, serve as scaffolds for loading heterocyclic CPZ molecules. Additional X-ray studies and molecular dynamics simulations show the binding modes and organization of CPZ molecules when complexed with P3 only and onto the virion surface. Collectively, we provide a proof of concept for the possible use of the lattice-like organisation and the quasi-symmetric morphology of virus capsomers for loading heterocyclic drugs with defined properties.	Dec 2021
I03-Macromolecular Crystallography	Structures and therapeutic potential of anti-RBD human monoclonal antibodies against SARS-CoV-2 Kuan-Ying A. Huang , Daming Zhou , Tiong Kit Tan , Charles Chen , Helen M. E. Duyvesteyn , Yuguang Zhao , Helen M. Ginn , Ling Qin , Pramila Rijal , Lisa Schimanski , Robert Donat , Adam Harding , Javier Gilbert-Jaramillo , William James , Julia A. Tree , Karen Buttigieg , Miles Carroll , Sue Charlton , Chia-En Lien , Meei-Yun Lin , Cheng-Pin Chen , Shu-Hsing Cheng , Xiaorui Chen , Tzou-Yien Lin , Elizabeth E. Fry , Jingshan Ren , Che Ma , Alain R. Townsend , David I. Stuart Theranostics DOI: 10.7150/thno.65563 Diamond Proposal Number(s): [27009] Open Access Show Abstract ▼ Abstract: Background: Administration of potent anti-receptor-binding domain (RBD) monoclonal antibodies has been shown to curtail viral shedding and reduce hospitalization in patients with SARS-CoV-2 infection. However, the structure-function analysis of potent human anti-RBD monoclonal antibodies and its links to the formulation of antibody cocktails remains largely elusive. Methods: Previously, we isolated a panel of neutralizing anti-RBD monoclonal antibodies from convalescent patients and showed their neutralization efficacy in vitro. Here, we elucidate the mechanism of action of antibodies and dissect antibodies at the epitope level, which leads to a formation of a potent antibody cocktail. Results: We found that representative antibodies which target non-overlapping epitopes are effective against wild type virus and recently emerging variants of concern, whilst being encoded by antibody genes with few somatic mutations. Neutralization is associated with the inhibition of binding of viral RBD to ACE2 and possibly of the subsequent fusion process. Structural analysis of representative antibodies, by cryo-electron microscopy and crystallography, reveals that they have some unique aspects that are of potential value while sharing some features in common with previously reported neutralizing monoclonal antibodies. For instance, one has a common VH 3-53 public variable region yet is unusually resilient to mutation at residue 501 of the RBD. We evaluate the in vivo efficacy of an antibody cocktail consisting of two potent non-competing anti-RBD antibodies in a Syrian hamster model. We demonstrate that the cocktail prevents weight loss, reduces lung viral load and attenuates pulmonary inflammation in hamsters in both prophylactic and therapeutic settings. Although neutralization of one of these antibodies is abrogated by the mutations of variant B.1.351, it is also possible to produce a bi-valent cocktail of antibodies both of which are resilient to variants B.1.1.7, B.1.351 and B.1.617.2. Conclusions: These findings support the up-to-date and rational design of an anti-RBD antibody cocktail as a therapeutic candidate against COVID-19.	Nov 2021
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
	Site-specific steric control of SARS-COV-2 spike glycosylation Joel D. Allen , Himanshi Chawla , Firdaus Samsudin , Lorena Zuzic , Aishwary Tukaram Shivgan , Yasunori Watanabe , Wan-Ting He , Sean Callaghan , Ge Song , Peter Yong , Philip J. M. Brouwer , Yutong Song , Yongfei Cai , Helen M. E. Duyvesteyn , Tomas Malinauskas , Joeri Kint , Paco Pino , Maria J. Wurm , Martin Frank , Bing Chen , David I. Stuart , Rogier W. Sanders , Raiees Andrabi , Dennis R. Burton , Sai Li , Peter J. Bond , Max Crispin Biochemistry DOI: 10.1021/acs.biochem.1c00279 Open Access Show Abstract ▼ Abstract: A central tenet in the design of vaccines is the display of native-like antigens in the elicitation of protective immunity. The abundance of N-linked glycans across the SARS-CoV-2 spike protein is a potential source of heterogeneity among the many different vaccine candidates under investigation. Here, we investigate the glycosylation of recombinant SARS-CoV-2 spike proteins from five different laboratories and compare them against S protein from infectious virus, cultured in Vero cells. We find patterns that are conserved across all samples, and this can be associated with site-specific stalling of glycan maturation that acts as a highly sensitive reporter of protein structure. Molecular dynamics simulations of a fully glycosylated spike support a model of steric restrictions that shape enzymatic processing of the glycans. These results suggest that recombinant spike-based SARS-CoV-2 immunogen glycosylation reproducibly recapitulates signatures of viral glycosylation.	Jul 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
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
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

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