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92 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
B21-High Throughput SAXS	Biophysical characterization of the structure of a SARS-CoV-2 self-amplifying RNA (saRNA) vaccine Daniel Myatt , Lewis Wharram , Charlotte Graham , John Liddell , Harvey Branton , Claire Pizzey , Nathan P. Cowieson , Robert Rambo , Robin J. Shattock Biology Methods And Protocols 8 DOI: 10.1093/biomethods/bpad001 Open Access Show Abstract ▼ Abstract: The current SARS-Covid-2 (SARS-CoV-2) pandemic has led to an acceleration of messenger ribonucleic acid (mRNA) vaccine technology. The development of production processes for these large mRNA molecules, especially self-amplifying mRNA (saRNA), has required concomitant development of analytical characterization techniques. Characterizing the purity, shape and structure of these biomolecules is key to their successful performance as drug products. This article describes the biophysical characterization of the Imperial College London Self-amplifying viral RNA vaccine (IMP-1) developed for SARS-CoV-2. A variety of analytical techniques have been used to characterize the IMP-1 RNA molecule. In this article, we use ultraviolet spectroscopy, dynamic light scattering, size-exclusion chromatography small-angle X-ray scattering and circular dichroism to determine key biophysical attributes of IMP-1. Each technique provides important information about the concentration, size, shape, structure and purity of the molecule.	Jan 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
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
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
	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
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Structure of the malaria vaccine candidate Pfs48/45 and its recognition by transmission blocking antibodies Kuang-Ting Ko , Frank Lennartz , David Mekhaiel , Bora Guloglu , Arianna Marini , Danielle J. Deuker , Carole A. Long , Matthijs Jore , Kazutoyo Miura , Sumi Biswas , Matthew K. Higgins Nature Communications 13 DOI: 10.1038/s41467-022-33379-6 Diamond Proposal Number(s): [23459] Open Access Show Abstract ▼ Abstract: An effective malaria vaccine remains a global health priority and vaccine immunogens which prevent transmission of the parasite will have important roles in multi-component vaccines. One of the most promising candidates for inclusion in a transmission-blocking malaria vaccine is the gamete surface protein Pfs48/45, which is essential for development of the parasite in the mosquito midgut. Indeed, antibodies which bind Pfs48/45 can prevent transmission if ingested with the parasite as part of the mosquito bloodmeal. Here we present the structure of full-length Pfs48/45, showing its three domains to form a dynamic, planar, triangular arrangement. We reveal where transmission-blocking and non-blocking antibodies bind on Pfs48/45. Finally, we demonstrate that antibodies which bind across this molecule can be transmission-blocking. These studies will guide the development of future Pfs48/45-based vaccine immunogens.	Sep 2022
	East Coast fever, a neglected tropical disease with an outdated vaccine approach? Jeannine Kolakowski , Tim Connelley , Petra Lukacik , Mark Pfuhl , Dirk Werling Trends In Parasitology 67 DOI: 10.1016/j.pt.2022.08.006 Open Access Show Abstract ▼ Abstract: Since its discovery, bovine theileriosis has caused major socioeconomic losses in sub-Saharan Africa. Acaricide resistance of the intermediate host, paucity of therapeutics, and lack of sufficiently cross-protective vaccines increase the risk of parasite spread due to global warming. Here, we highlight three important areas that require investigation to develop next-generation vaccines.	Aug 2022
Krios I-Titan Krios I at Diamond	Structure of trimeric pre-fusion rabies virus glycoprotein in complex with two protective antibodies Weng M. Ng , Sofiya Fedosyuk , Solomon English , Gilles Augusto , Adam Berg , Luke Thorley , Anna-Sophie Haselon , Rameswara R. Segireddy , Thomas A. Bowden , Alexander D. Douglas Cell Host & Microbe 58 DOI: 10.1016/j.chom.2022.07.014 Diamond Proposal Number(s): [20223] Open Access Show Abstract ▼ Abstract: Rabies virus (RABV) causes lethal encephalitis and is responsible for approximately 60,000 deaths per year. As the sole virion-surface protein, the rabies virus glycoprotein (RABV-G) mediates host-cell entry. RABV-G’s pre-fusion trimeric conformation displays epitopes bound by protective neutralizing antibodies that can be induced by vaccination or passively administered for post-exposure prophylaxis. We report a 2.8-Å structure of a RABV-G trimer in the pre-fusion conformation, in complex with two neutralizing and protective monoclonal antibodies, 17C7 and 1112-1, that recognize distinct epitopes. One of these antibodies is a licensed prophylactic (17C7, Rabishield), which we show locks the protein in pre-fusion conformation. Targeted mutations can similarly stabilize RABV-G in the pre-fusion conformation, a key step toward structure-guided vaccine design. These data reveal the higher-order architecture of a key therapeutic target and the structural basis of neutralization by antibodies binding two key antigenic sites, and this will facilitate the development of improved vaccines and prophylactic antibodies.	Aug 2022
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

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