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Instruments / Technical Area	Publication Details	Published
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
	Mammalian expression of virus-like particles as a proof of principle for next generation polio vaccines Mohammad W. Bahar , Claudine Porta , Helen Fox , Andrew J. Macadam , Elizabeth E. Fry , David I. Stuart Npj Vaccines 6 DOI: 10.1038/s41541-020-00267-3 Open Access Show Abstract ▼ Abstract: Global vaccination programs using live-attenuated oral and inactivated polio vaccine (OPV and IPV) have almost eradicated poliovirus (PV) but these vaccines or their production pose significant risk in a polio-free world. Recombinant PV virus-like particles (VLPs), lacking the viral genome, represent safe next-generation vaccines, however their production requires optimisation. Here we present an efficient mammalian expression strategy producing good yields of wild-type PV VLPs for all three serotypes and a thermostabilised variant for PV3. Whilst the wild-type VLPs were predominantly in the non-native C-antigenic form, the thermostabilised PV3 VLPs adopted the native D-antigenic conformation eliciting neutralising antibody titres equivalent to the current IPV and were indistinguishable from natural empty particles by cryo-electron microscopy with a similar stabilising lipidic pocket-factor in the VP1 β-barrel. This factor may not be available in alternative expression systems, which may require synthetic pocket-binding factors. VLPs equivalent to these mammalian expressed thermostabilized particles, represent safer non-infectious vaccine candidates for the post-eradication era.	Jan 2021
Krios I-Titan Krios I at Diamond	Plant-made polio type 3 stabilized VLPs—a candidate synthetic polio vaccine Johanna Marsian , Helen Fox , Mohammad W. Bahar , Abhay Kotecha , Elizabeth E. Fry , David I. Stuart , Andrew J. Macadam , David J. Rowlands , George P. Lomonossoff Nature Communications 8 DOI: 10.1038/s41467-017-00090-w Open Access Show Abstract ▼ Abstract: Poliovirus (PV) is the causative agent of poliomyelitis, a crippling human disease known since antiquity. PV occurs in two distinct antigenic forms, D and C, of which only the D form elicits a robust neutralizing response. Developing a synthetically produced stabilized virus-like particle (sVLP)-based vaccine with D antigenicity, without the drawbacks of current vaccines, will be a major step towards the final eradication of poliovirus. Such a sVLP would retain the native antigenic conformation and the repetitive structure of the original virus particle, but lack infectious genomic material. In this study, we report the production of synthetically stabilized PV VLPs in plants. Mice carrying the gene for the human PV receptor are protected from wild-type PV when immunized with the plant-made PV sVLPs. Structural analysis of the stabilized mutant at 3.6 Å resolution by cryo-electron microscopy and single-particle reconstruction reveals a structure almost indistinguishable from wild-type PV3.	Aug 2017

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