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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 , Dave 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
	A COVID-19 vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain induces potent neutralising antibody responses Tiong Kit Tan , Pramila Rijal , Rolle Rahikainen , Anthony H. Keeble , Lisa Schimanski , Saira Hussain , Ruth Harvey , Jack W. P. Hayes , Jane C. Edwards , Rebecca K. Mclean , Veronica Martini , Miriam Pedrera , Nazia Thakur , Carina Conceicao , Isabelle Dietrich , Holly Shelton , Anna Ludi , Ginette Wilsden , Clare Browning , Adrian K. 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 A. Hammond , Elma Tchilian , Bryan Charleston , Dalan Bailey , Tobias J. Tuthill , Simon P. Graham , Helen M. E. Duyvesteyn , Tomas Malinauskas , Jiandong Huo , Julia A. Tree , Karen R. Buttigieg , Raymond J. Owens , Miles W. Carroll , Rodney S. Daniels , John W. Mccauley , David I. Stuart , Kuan-ying A. Huang , Mark Howarth , Alain R. Townsend Nature Communications 12 DOI: 10.1038/s41467-020-20654-7 Open Access Show Abstract ▼ Abstract: There is need for effective and affordable vaccines against SARS-CoV-2 to tackle the ongoing pandemic. In this study, we describe a protein nanoparticle vaccine against SARS-CoV-2. The vaccine is based on the display of coronavirus spike glycoprotein receptor-binding domain (RBD) on a synthetic virus-like particle (VLP) platform, SpyCatcher003-mi3, using SpyTag/SpyCatcher technology. Low doses of RBD-SpyVLP in a prime-boost regimen induce a strong neutralising antibody response in mice and pigs that is superior to convalescent human sera. We evaluate 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 show that RBD-SpyVLP induces a polyclonal antibody response that recognises key epitopes on the RBD, reducing the likelihood of selecting neutralisation-escape mutants. Moreover, RBD-SpyVLP is thermostable and can be lyophilised without losing immunogenicity, to facilitate global distribution and reduce cold-chain dependence. The data suggests that RBD-SpyVLP provides strong potential to address clinical and logistic challenges of the COVID-19 pandemic.	Jan 2021
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	Neutralizing nanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2 Jiangdong Huo , Audrey Le Bas , Reinis R. Ruza , Helen M. E. Duyvesteyn , Halina Mikolajek , Tomas Malinauskas , Tiong Kit Tan , Pramila Rijal , Maud Dumoux , Philip N. Ward , Jingshan Ren , Daming Zhou , Peter J. Harrison , Miriam Weckener , Daniel K. Clare , Vinod K. Vogirala , Julika Radecke , Lucile Moynie , Yuguang Zhao , Javier Gilbert-jaramillo , Michael L. Knight , Julia A. Tree , Karen R. Buttigieg , Naomi Coombes , Michael J. Elmore , Miles W. Carroll , Loic Carrique , Pranav N. M. Shah , William James , Alain R. Townsend , David I. Stuart , Raymond J. Owens , James H. Naismith Nature Structural & Molecular Biology 21 DOI: 10.1038/s41594-020-0469-6 Diamond Proposal Number(s): [27031, 27051] Open Access Show Abstract ▼ Abstract: The SARS-CoV-2 virus is more transmissible than previous coronaviruses and causes a more serious illness than influenza. The SARS-CoV-2 receptor binding domain (RBD) of the spike protein binds to the human angiotensin-converting enzyme 2 (ACE2) receptor as a prelude to viral entry into the cell. Using a naive llama single-domain antibody library and PCR-based maturation, we have produced two closely related nanobodies, H11-D4 and H11-H4, that bind RBD (KD of 39 and 12 nM, respectively) and block its interaction with ACE2. Single-particle cryo-EM revealed that both nanobodies bind to all three RBDs in the spike trimer. Crystal structures of each nanobody–RBD complex revealed how both nanobodies recognize the same epitope, which partly overlaps with the ACE2 binding surface, explaining the blocking of the RBD–ACE2 interaction. Nanobody-Fc fusions showed neutralizing activity against SARS-CoV-2 (4–6 nM for H11-H4, 18 nM for H11-D4) and additive neutralization with the SARS-CoV-1/2 antibody CR3022.	Jul 2020

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