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73 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4, 5, 6, 7, 8 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I04-1-Macromolecular Crystallography (fixed wavelength)	Emergence of immune escape at dominant SARS-CoV-2 killer T-cell epitope Garry Dolton , Cristina Rius , Md Samiul Hasan , Aaron Wall , Barbara Szomolay , Enas Behiry , Thomas Whalley , Joel Southgate , Anna Fuller , Théo Morin , Katie Topley , Li Rong Tan , Philip J. R. Goulder , Owen B. Spiller , Pierre J. Rizkallah , Lucy C. Jones , Thomas R. Connor , Andrew K. Sewell Cell DOI: 10.1016/j.cell.2022.07.002 Diamond Proposal Number(s): [29502] Open Access Show Abstract ▼ Abstract: We studied the prevalent cytotoxic CD8 T-cell response mounted against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike glycoprotein269-277 epitope (sequence YLQPRTFLL) via the most frequent Human Leukocyte Antigen (HLA) class I worldwide, HLA A∗02. The Spike P272L mutation that has arisen in at least 112 different SARS-CoV-2 lineages to date, including in lineages classified as ‘variants of concern’, was not recognised by the large CD8 T-cell response seen across cohorts of HLA A∗02+ convalescent patients and individuals vaccinated against SARS-CoV-2, despite these responses comprising of over 175 different individual T-cell receptors. Viral escape at prevalent T-cell epitopes restricted by high frequency HLAs may be particularly problematic when vaccine immunity is focussed on a single protein such as SARS-CoV-2 Spike providing a strong argument for inclusion of multiple viral proteins in next generation vaccines and highlighting the need for monitoring T-cell escape in new SARS-CoV-2 variants.	Jul 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
I24-Microfocus Macromolecular Crystallography	A bivalent Epstein-Barr virus vaccine induces neutralizing antibodies that block infection and confer immunity in humanized mice Chih-Jen Wei , Wei Bu , Laura A. Nguyen , Joseph D. Batchelor , Junghyun Kim , Stefania Pittaluga , James R. Fuller , Hanh Nguyen , Te-Hui Chou , Jeffrey I. Cohen , Gary J. Nabel Science Translational Medicine 14 DOI: 10.1126/scitranslmed.abf3685 Diamond Proposal Number(s): [22894] Show Abstract ▼ Abstract: Epstein-Barr virus (EBV) is the major cause of infectious mononucleosis and is associated with several human cancers and, more recently, multiple sclerosis. Despite its prevalence and health impact, there are currently no vaccines or treatments. Four viral glycoproteins (gp), gp350 and gH/gL/gp42, mediate entry into the major sites of viral replication, B cells, and epithelial cells. Here, we designed a nanoparticle vaccine displaying these proteins and showed that it elicits potent neutralizing antibodies that protect against infection in vivo. We designed single-chain gH/gL and gH/gL/gp42 proteins that were each fused to bacterial ferritin to form a self-assembling nanoparticle. Structural analysis revealed that single-chain gH/gL and gH/gL/gp42 adopted a similar conformation to the wild-type proteins, and the protein spikes were observed by electron microscopy. Single-chain gH/gL or gH/gL/gp42 nanoparticle vaccines were constructed to ensure product homogeneity needed for clinical development. These vaccines elicited neutralizing antibodies in mice, ferrets, and nonhuman primates that inhibited EBV entry into both B cells and epithelial cells. When mixed with a previously reported gp350 nanoparticle vaccine, gp350D123, no immune competition was observed. To confirm its efficacy in vivo, humanized mice were challenged with EBV after passive transfer of IgG from mice vaccinated with control, gH/gL/gp42+gp350D123, or gH/gL+gp350D123 nanoparticles. Although all control animals were infected, only one mouse in each vaccine group that received immune IgG had detectable transient viremia. Furthermore, no EBV lymphomas were detected in immune animals. This bivalent EBV nanoparticle vaccine represents a promising candidate to prevent EBV infection and EBV-related malignancies in humans.	May 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
I23-Long wavelength MX	Structural basis of antibody-mediated immunity against Crimean-Congo hemorrhagic fever virus glycoproteins Akaash K. Mishra Show Abstract ▼ Abstract: Crimean-Congo hemorrhagic fever virus (CCHFV) is the most widespread tick-borne zoonotic virus, with a 30% case fatality rate in humans. CCHFV is shortlisted as a priority pathogen by the World Health Organization. It is a (-)ssRNA virus of the family Nairoviridae in the Bunyavirales order. The CCHFV membrane fusion glycoprotein Gc has been shown to be the main target of the host neutralizing antibody response, whereas a secreted glycoprotein GP38 was demonstrated to be the target of non-neutralizing protective antibodies. However, structural information on the viral glycoproteins as well as antibody-mediated neutralization mechanisms has been lacking for members of the nairovirus family. The first part of this thesis describes the structure of monomeric prefusion CCHFV Gc bound to the antigen binding fragments (Fabs) of two neutralizing antibodies that display synergy when combined, as well as the structure of trimeric, postfusion Gc. The structures show that the two Fabs act in concert to block membrane fusion, with one targeting the fusion loops and the other blocking Gc trimer formation. The above structures also revealed the neutralization mechanism of antibodies targeting 6 different antigenic sites on CCHFV Gc, a few of which were further validated with structural studies. Describing CCHFV neutralization at the mechanistic level, our data guide the design of future therapeutic antibodies and will likewise support the design of protective CCHFV vaccines. The second part of this thesis presents the structure of GP38, which reveals a novel protein fold. This study also describes the structure of a mouse antibody 13G8 bound to GP38; this antibody has been shown to protect against CCHFV. Mapping of the epitopes of several human GP38 antibodies onto the GP38 structure shows competition with the 13G8 epitope and identification of additional antigenic sites. Our data strongly suggest that GP38 should be evaluated as a vaccine antigen and that its structure provides a foundation to investigate functions of this protein in the viral life cycle. Collectively both these studies provide the molecular underpinnings essential for developing CCHFV-specific medical countermeasures for epidemic preparedness.	Apr 2022
I22-Small angle scattering & Diffraction	Coupling lipid nanoparticle structure and automated single particle composition analysis to design phospholipase responsive nanocarriers Hanna M. G. Barriga , Isaac J. Pence , Margaret N. Holme , James J. Doutch , Jelle Penders , Valeria Nele , Michael R. Thomas , Marta Carroni , Molly M. Stevens Advanced Materials DOI: 10.1002/adma.202200839 Diamond Proposal Number(s): [23642, 18658] Open Access Show Abstract ▼ Abstract: Lipid nanoparticles (LNPs) are versatile structures with tunable physicochemical properties that are ideally suited as a platform for vaccine delivery and RNA therapeutics. A key barrier to LNP rational design is the inability to relate composition and structure to intracellular processing and function. Here we combine Single Particle Automated Raman Trapping Analysis (SPARTA®) with small angle scattering (SAXS / SANS) techniques to link LNP composition with internal structure and morphology and to monitor dynamic LNP - phospholipase D (PLD) interactions. Our analysis demonstrates that phospholipase D, a key intracellular trafficking mediator, can access the entire LNP lipid membrane to generate stable, anionic LNPs. PLD activity on vesicles with matched amounts of enzyme substrate was an order of magnitude lower, indicating that the LNP lipid membrane structure can be used to control enzyme interactions. This represents an opportunity to design enzyme-responsive LNP solutions for stimuli-responsive delivery and diseases where PLD is dysregulated.	Mar 2022
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Heterotypic interactions drive antibody synergy against a malaria vaccine candidate Robert J. Ragotte , David Pulido , Amelia M. Lias , Doris Quinkert , Daniel G. W. Alanine , Abhishek Jamwal , Hannah Davies , Adéla Nacer , Edward D. Lowe , Geoffrey W. Grime , Joseph J. Illingworth , Robert F. Donat , Elspeth F. Garman , Paul W. Bowyer , Matthew K. Higgins , Simon J. Draper Nature Communications 13 DOI: 10.1038/s41467-022-28601-4 Diamond Proposal Number(s): [12346, 18069, 23459] Open Access Show Abstract ▼ Abstract: Understanding mechanisms of antibody synergy is important for vaccine design and antibody cocktail development. Examples of synergy between antibodies are well-documented, but the mechanisms underlying these relationships often remain poorly understood. The leading blood-stage malaria vaccine candidate, CyRPA, is essential for invasion of Plasmodium falciparum into human erythrocytes. Here we present a panel of anti-CyRPA monoclonal antibodies that strongly inhibit parasite growth in in vitro assays. Structural studies show that growth-inhibitory antibodies bind epitopes on a single face of CyRPA. We also show that pairs of non-competing inhibitory antibodies have strongly synergistic growth-inhibitory activity. These antibodies bind to neighbouring epitopes on CyRPA and form lateral, heterotypic interactions which slow antibody dissociation. We predict that such heterotypic interactions will be a feature of many immune responses. Immunogens which elicit such synergistic antibody mixtures could increase the potency of vaccine-elicited responses to provide robust and long-lived immunity against challenging disease targets.	Feb 2022
I04-1-Macromolecular Crystallography (fixed wavelength)	Maintenance of the Shigella sonnei virulence plasmid is dependent on its repertoire and amino acid sequence of toxin:antitoxin systems Jessica E. Martyn , Giulia Pilla , Sarah Hollingshead , Kristoffer S. Winther , Susan Lea , Gareth Mcvicker , Christoph M. Tang Journal Of Bacteriology DOI: 10.1128/JB.00519-21 Diamond Proposal Number(s): [12346] Open Access Show Abstract ▼ Abstract: Shigella sonnei is a major cause of bacillary dysentery, and of increasing concern due to the spread of multi-drug resistance.S. sonneiharbours pINV, a ∼ 210 kb plasmid that encodes a Type III secretion system (T3SS), which is essential for virulence. During growth in the laboratory, avirulence arises spontaneously inS. sonneiat high frequency, hampering studies on and vaccine development against this important pathogen. Here we investigated the molecular basis for the emergence of avirulence inS. sonnei, and show that avirulence mainly results from pINV loss, consistent with previous findings. Ancestral deletions have led to the loss fromS. sonneipINV of two toxin:antitoxin (TA) systems involved in plasmid maintenance, CcdAB and GmvAT, which are found on pINV inShigella flexneri. We show that introduction of these TA systems intoS. sonneipINV reduced but did not eliminate pINV loss, while single amino acid polymorphisms found in theS. sonneiVapBC TA system compared withS. flexneriVapBC also contribute to pINV loss. Avirulence also results from deletions of T3SS-associated genes on pINV through recombination between insertion sequences (ISs) on the plasmid; these events differ from those observed inS. flexneridue to the different distribution and repertoire of ISs. Our findings demonstrate that TA systems and ISs influence plasmid dynamics and loss inS. sonnei, and could be exploited for the design and evaluation of vaccines.	Jan 2022
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
Krios IV-Titan Krios IV at Diamond	Helical ordering of envelope‐associated proteins and glycoproteins in respiratory syncytial virus Michaela J Conley , Judith M. Short , Andrew Burns , James Streetley , Joshua Hutchings , Saskia E. Bakker , B. Joanne Power , Hussain Jaffery , Joanne Haney , Giulia Zanetti , Pablo R. Murcia , Murray Stewart , Rachel Fearns , Swetha Vijayakrishnan , David Bhella The Embo Journal 12 DOI: 10.15252/embj.2021109728 Diamond Proposal Number(s): [16637] Open Access Show Abstract ▼ Abstract: Human respiratory syncytial virus (RSV) causes severe respiratory illness in children and the elderly. Here, using cryogenic electron microscopy and tomography combined with computational image analysis and three-dimensional reconstruction, we show that there is extensive helical ordering of the envelope-associated proteins and glycoproteins of RSV filamentous virions. We calculated a 16 Å resolution sub-tomogram average of the matrix protein (M) layer that forms an endoskeleton below the viral envelope. These data define a helical lattice of M-dimers, showing how M is oriented relative to the viral envelope. Glycoproteins that stud the viral envelope were also found to be helically ordered, a property that was coordinated by the M-layer. Furthermore, envelope glycoproteins clustered in pairs, a feature that may have implications for the conformation of fusion (F) glycoprotein epitopes that are the principal target for vaccine and monoclonal antibody development. We also report the presence, in authentic virus infections, of N-RNA rings packaged within RSV virions. These data provide molecular insight into the organisation of the virion and the mechanism of its assembly.	Dec 2021

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