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56 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4, 5, 6 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography	Rapid escape of new SARS-CoV-2 Omicron variants from BA.2 directed antibody responses Aiste Dijokaite-Guraliuc , Raksha Das , Daming Zhou , Helen M. Ginn , Chang Liu , Helen M. E. Duyvesteyn , Jiandong Huo , Rungtiwa Nutalai , Piyada Supasa , Muneeswaran Selvaraj , Thushan I. De Silva , Megan Plowright , Thomas A. H. Newman , Hailey Hornsby , Alexander J. Mentzer , Donal Skelly , Thomas G. Ritter , Nigel Temperton , Paul Klenerman , Eleanor Barnes , Susanna J. Dunachie , Cornelius Roemer , Thomas P. Peacock , Neil G. Paterson , Mark A. Williams , David R. Hall , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell Reports DOI: 10.1016/j.celrep.2023.112271 Diamond Proposal Number(s): [27009] Open Access Show Abstract ▼ Abstract: In November 2021 Omicron BA.1, containing a raft of new spike mutations emerged and quickly spread globally. Intense selection pressure to escape the antibody response produced by vaccines or SARS-CoV-2 infection then led to a rapid succession of Omicron sub-lineages with waves of BA.2 then BA.4/5 infection. Recently, many variants have emerged such as BQ.1 and XBB, which carry up to 8 additional RBD amino-acid substitutions compared to BA.2. We describe a panel of 25 potent mAbs generated from vaccinees suffering BA.2 breakthrough infections. Epitope mapping shows potent mAb binding shifting to 3 clusters, 2 corresponding to early-pandemic binding hotspots. The RBD mutations in recent variants map close to these binding sites and knock out or severely knock down neutralization activity of all but 1 potent mAb. This recent mAb escape corresponds with large falls in neutralization titre of vaccine or BA.1, BA.2 or BA.4/5 immune serum.	Mar 2023
I03-Macromolecular Crystallography	A delicate balance between antibody evasion and ACE2 affinity for Omicron BA.2.75 Jiandong Huo , Aiste Dijokaite-Guraliuc , Chang Liu , Raksha Das , Piyada Supasa , Muneeswaran Selvaraj , Rungtiwa Nutalai , Daming Zhou , Alexander J. Mentzer , Donal Skelly , Thomas G. Ritter , Ali Amini , Sagida Bibi , Sandra Adele , Sile Ann Johnson , Neil G. Paterson , Mark A. Williams , David R. Hall , Megan Plowright , Thomas A. H. Newman , Hailey Hornsby , Thushan I. De Silva , Nigel Temperton , Paul Klenerman , Eleanor Barnes , Susanna J. Dunachie , Andrew J. Pollard , Teresa Lambe , Philip Goulder , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell Reports DOI: 10.1016/j.celrep.2022.111903 Diamond Proposal Number(s): [27009] Open Access Show Abstract ▼ Abstract: Variants of SARS CoV-2 have caused successive global waves of infection. These variants, with multiple mutations in the spike protein are thought to facilitate escape from natural and vaccine-induced immunity and often increase in the affinity for ACE2. The latest variant to cause concern is BA.2.75, identified in India where it is now the dominant strain, with evidence of wider dissemination. BA.2.75 is derived from BA.2 and contains four additional mutations in the receptor binding domain (RBD). Here we perform an antigenic and biophysical characterization of BA.2.75, revealing an interesting balance between humoral evasion and ACE2 receptor affinity. ACE2 affinity for BA.2.75 is increased 9-fold compared to BA.2; there is also evidence of escape of BA.2.75 from immune serum, particularly that induced by Delta infection which may explain the rapid spread in India, where BA.2.75 is now the dominant variant. ACE2 affinity appears to be prioritised over greater escape.	Dec 2022
	Switching of receptor binding poses between closely related enteroviruses Daming Zhou , Ling Qin , Helen M. E. Duyvesteyn , Yuguang Zhao , Tzou-Yien Lin , Elizabeth E. Fry , Jingshan Ren , Kuan-Ying A. Huang , David I. Stuart Viruses 14 DOI: 10.3390/v14122625 Open Access Show Abstract ▼ Abstract: Echoviruses, for which there are currently no approved vaccines or drugs, are responsible for a range of human diseases, for example echovirus 11 (E11) is a major cause of serious neonatal morbidity and mortality. Decay-accelerating factor (DAF, also known as CD55) is an attachment receptor for E11. Here, we report the structure of the complex of E11 and the full-length ectodomain of DAF (short consensus repeats, SCRs, 1–4) at 3.1 Å determined by cryo-electron microscopy (cryo-EM). SCRs 3 and 4 of DAF interact with E11 at the southern rim of the canyon via the VP2 EF and VP3 BC loops. We also observe an unexpected interaction between the N-linked glycan (residue 95 of DAF) and the VP2 BC loop of E11. DAF is a receptor for at least 20 enteroviruses and we classify its binding patterns from reported DAF/virus complexes into two distinct positions and orientations, named as E6 and E11 poses. Whilst 60 DAF molecules can attach to the virion in the E6 pose, no more than 30 can attach to E11 due to steric restrictions. Analysis of the distinct modes of interaction and structure and sequence-based phylogenies suggests that the two modes evolved independently, with the E6 mode likely found earlier.	Nov 2022
I03-Macromolecular Crystallography	Antigenic characterization of SARS-CoV-2 Omicron subvariant BA.4.6 Aiste Dijokaite-Guraliuc , Raksha Das , Rungtiwa Nutalai , Daming Zhou , Alexander J. Mentzer , Chang Liu , Piyada Supasa , Susanna J. Dunachie , Teresa Lambe , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , Jiandong Huo , David I. Stuart , Gavin R. Screaton Cell Discovery 8 DOI: 10.1038/s41421-022-00493-0 Diamond Proposal Number(s): [27009] Open Access	Nov 2022
I03-Macromolecular Crystallography	Humoral responses against SARS-CoV-2 Omicron BA.2.11, BA.2.12.1 and BA.2.13 from vaccine and BA.1 serum Jiandong Huo , Aiste Dijokaite-Guraliuc , Rungtiwa Nutalai , Raksha Das , Daming Zhou , Alexander J. Mentzer , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton Cell Discovery 8 DOI: 10.1038/s41421-022-00482-3 Diamond Proposal Number(s): [27009] Open Access	Nov 2022
Krios IV-Titan Krios IV at Diamond	A conserved glutathione binding site in poliovirus is a target for antivirals and vaccine stabilisation Mohammad W. Bahar , Veronica Nasta , Helen Fox , Lee Sherry , Keith Grehan , Claudine Porta , Andrew J. Macadam , Nicola J. Stonehouse , David J. Rowlands , Elizabeth E. Fry , David I. Stuart Communications Biology 5 DOI: 10.1038/s42003-022-04252-5 Diamond Proposal Number(s): [20223] Open Access Show Abstract ▼ Abstract: Strategies to prevent the recurrence of poliovirus (PV) after eradication may utilise non-infectious, recombinant virus-like particle (VLP) vaccines. Despite clear advantages over inactivated or attenuated virus vaccines, instability of VLPs can compromise their immunogenicity. Glutathione (GSH), an important cellular reducing agent, is a crucial co-factor for the morphogenesis of enteroviruses, including PV. We report cryo-EM structures of GSH bound to PV serotype 3 VLPs showing that it can enhance particle stability. GSH binds the positively charged pocket at the interprotomer interface shown recently to bind GSH in enterovirus F3 and putative antiviral benzene sulphonamide compounds in other enteroviruses. We show, using high-resolution cryo-EM, the binding of a benzene sulphonamide compound with a PV serotype 2 VLP, consistent with antiviral activity through over-stabilizing the interprotomer pocket, preventing the capsid rearrangements necessary for viral infection. Collectively, these results suggest GSH or an analogous tight-binding antiviral offers the potential for stabilizing VLP vaccines.	Nov 2022
	Production and characterisation of stabilised PV-3 virus-like particles using Pichia pastoris Lee Sherry , Keith Grehan , Jessica J. Swanson , Mohammad W. Bahar , Claudine Porta , Elizabeth E. Fry , David I. Stuart , David J. Rowlands , Nicola J. Stonehouse Viruses 14 DOI: 10.3390/v14102159 Open Access Show Abstract ▼ Abstract: Following the success of global vaccination programmes using the live-attenuated oral and inactivated poliovirus vaccines (OPV and IPV), wild poliovirus (PV) is now only endemic in Afghanistan and Pakistan. However, the continued use of these vaccines poses potential risks to the eradication of PV. The production of recombinant PV virus-like particles (VLPs), which lack the viral genome offer great potential as next-generation vaccines for the post-polio world. We have previously reported production of PV VLPs using Pichia pastoris, however, these VLPs were in the non-native conformation (C Ag), which would not produce effective protection against PV. Here, we build on this work and show that it is possible to produce wt PV-3 and thermally stabilised PV-3 (referred to as PV-3 SC8) VLPs in the native conformation (D Ag) using Pichia pastoris. We show that the PV-3 SC8 VLPs provide a much-improved D:C antigen ratio as compared to wt PV-3, whilst exhibiting greater thermostability than the current IPV vaccine. Finally, we determine the cryo-EM structure of the yeast-derived PV-3 SC8 VLPs and compare this to previously published PV-3 D Ag structures, highlighting the similarities between these recombinantly expressed VLPs and the infectious virus, further emphasising their potential as a next-generation vaccine candidate for PV.	Oct 2022
	Nonlytic cellular release of hepatitis A virus requires dual capsid recruitment of the ESCRT-associated Bro1 domain proteins HD-PTP and ALIX Takayoshi Shirasaki , Hui Feng , Helen M. E. Duyvesteyn , William G. Fusco , Kevin L. Mcknight , Ling Xie , Mark Boyce , Sathish Kumar , Rina Barouch-Bentov , Olga González-López , Ryan Mcnamara , Li Wang , Adriana Hertel-Wulff , Xian Chen , Shirit Einav , Joseph A. Duncan , Maryna Kapustina , Elizabeth E. Fry , David I. Stuart , Stanley M. Lemon Plos Pathogens 18 DOI: 10.1371/journal.ppat.1010543 Open Access Show Abstract ▼ Abstract: Although picornaviruses are conventionally considered ‘nonenveloped’, members of multiple picornaviral genera are released nonlytically from infected cells in extracellular vesicles. The mechanisms underlying this process are poorly understood. Here, we describe interactions of the hepatitis A virus (HAV) capsid with components of host endosomal sorting complexes required for transport (ESCRT) that play an essential role in release. We show release of quasi-enveloped virus (eHAV) in exosome-like vesicles requires a conserved export signal located within the 8 kDa C-terminal VP1 pX extension that functions in a manner analogous to late domains of canonical enveloped viruses. Fusing pX to a self-assembling engineered protein nanocage (EPN-pX) resulted in its ESCRT-dependent release in extracellular vesicles. Mutational analysis identified a 24 amino acid peptide sequence located within the center of pX that was both necessary and sufficient for nanocage release. Deleting a YxxL motif within this sequence ablated eHAV release, resulting in virus accumulating intracellularly. The pX export signal is conserved in non-human hepatoviruses from a wide range of mammalian species, and functional in pX sequences from bat hepatoviruses when fused to the nanocage protein, suggesting these viruses are released as quasi-enveloped virions. Quantitative proteomics identified multiple ESCRT-related proteins associating with EPN-pX, including ALG2-interacting protein X (ALIX), and its paralog, tyrosine-protein phosphatase non-receptor type 23 (HD-PTP), a second Bro1 domain protein linked to sorting of ubiquitylated cargo into multivesicular endosomes. RNAi-mediated depletion of either Bro1 domain protein impeded eHAV release. Super-resolution fluorescence microscopy demonstrated colocalization of viral capsids with endogenous ALIX and HD-PTP. Co-immunoprecipitation assays using biotin-tagged peptides and recombinant proteins revealed pX interacts directly through the export signal with N-terminal Bro1 domains of both HD-PTP and ALIX. Our study identifies an exceptionally potent viral export signal mediating extracellular release of virus-sized protein assemblies and shows release requires non-redundant activities of both HD-PTP and ALIX.	Aug 2022
I03-Macromolecular Crystallography	Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum Aekkachai Tuekprakhon , Jiandong Huo , Rungtiwa Nutalai , Aiste Dijokaite-Guraliuc , Daming Zhou , Helen M. Ginn , Muneeswaran Selvaraj , Chang Liu , Alexander J. Mentzer , Piyada Supasa , Helen M. E. Duyvesteyn , Raksha Das , Donal Skelly , Thomas G. Ritter , Ali Amini , Sagida Bibi , Sandra Adele , Sile Ann Johnson , Bede Constantinides , Hermione Webster , Nigel Temperton , Paul Klenerman , Eleanor Barnes , Susanna J. Dunachie , Derrick Crook , Andrew J. Pollard , Teresa Lambe , Philip Goulder , Neil G. Paterson , Mark A. Williams , David R. Hall , Elizabeth E. Fry , Juthathip Mongkolsapaya , Jingshan Ren , David I. Stuart , Gavin R. Screaton , Christopher Conlon , Alexandra Deeks , John Frater , Lisa Frending , Siobhan Gardiner , Anni Jämsén , Katie Jeffery , Tom Malone , Eloise Phillips , Lucy Rothwell , Lizzie Stafford Cell DOI: 10.1016/j.cell.2022.06.005 Diamond Proposal Number(s): [27009] Open Access Show Abstract ▼ Abstract: The Omicron lineage of SARS-CoV-2, first described in November 2021, spread rapidly to become globally dominant and has split into a number of sub-lineages. BA.1 dominated the initial wave but has been replaced by BA.2 in many countries. Recent sequencing from South Africa’s Gauteng region uncovered two new sub-lineages, BA.4 and BA.5 which are taking over locally, driving a new wave. BA.4 and BA.5 contain identical spike sequences and, although closely related to BA.2, contain further mutations in the receptor binding domain of spike. Here, we study the neutralization of BA.4/5 using a range of vaccine and naturally immune serum and panels of monoclonal antibodies. BA.4/5 shows reduced neutralization by serum from triple AstraZeneca or Pfizer vaccinated individuals compared to BA.1 and BA.2. Furthermore, using serum from BA.1 vaccine breakthrough infections there are likewise, significant reductions in the neutralization of BA.4/5, raising the possibility of repeat Omicron infections.	Jun 2022
I03-Macromolecular Crystallography I04-Macromolecular Crystallography Krios I-Titan Krios I at Diamond	Potent cross-reactive antibodies following Omicron breakthrough in vaccinees Rungtiwa Nutalai , Daming Zhou , Aekkachai Tuekprakhon , Helen M. Ginn , Piyada Supasa , Chang Liu , Jiandong Huo , Alexander J. Mentzer , Helen M. E. Duyvesteyn , Aiste Dijokaite-Guraliuc , Donal Skelly , Thomas G. Ritter , Ali Amini , Sagida Bibi , Sandra Adele , Sile Ann Johnson , Bede Constantinides , Hermione Webster , Nigel Temperton , Paul Klenerman , Eleanor Barnes , Susanna J. Dunachie , Derrick Crook , Andrew J. Pollard , Teresa Lambe , Philip Goulder , Neil G. Paterson , Mark A. Williams , David R. Hall , Juthathip Mongkolsapaya , Elizabeth E. Fry , Wanwisa Dejnirattisai , Jingshan Ren , David I. Stuart , Gavin R. Screaton , Christopher Conlon , Alexandra Deeks , John Frater , Lisa Frending , Siobhan Gardiner , Anni Jämsén , Katie Jeffery , Tom Malone , Eloise Phillips , Lucy Rothwell , Lizzie Stafford Cell DOI: 10.1016/j.cell.2022.05.014 Diamond Proposal Number(s): [27009, 26983] Open Access Show Abstract ▼ Abstract: Highly transmissible Omicron variants of SARS-CoV-2 currently dominate globally. Here, we compare neutralization of Omicron BA.1, BA.1.1 and BA.2. BA.2 RBD has slightly higher ACE2 affinity than BA.1 and slightly reduced neutralization by vaccine serum, possibly associated with its increased transmissibility. Neutralization differences between sub-lineages for mAbs (including therapeutics) mostly arise from variation in residues bordering the ACE2 binding site, however, more distant mutations S371F (BA.2) and R346K (BA.1.1) markedly reduce neutralization by therapeutic antibody Vir-S309. In-depth structure-and-function analyses of 27 potent RBD-binding mAbs isolated from vaccinated volunteers following breakthrough Omicron-BA.1 infection reveals that they are focussed in two main clusters within the RBD, with potent right-shoulder antibodies showing increased prevalence. Selection and somatic maturation have optimized antibody potency in less-mutated epitopes and recovered potency in highly mutated epitopes. All 27 mAbs potently neutralize early pandemic strains and many show broad reactivity with variants of concern.	May 2022

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