VACCINE - Development of novel picornavirus virus-like particle vaccines

Virus-like particles (VLPs) are are the holy grail of vaccinology, presenting antigenic features of a viral pathogen in a safe, highly-immunogenic form. The focus of MR/P022626/1 is the development of VLP vaccine candidates for enterovirus 71 (EV71) and Coxsackie virus A16 (CVA16).If repurposed to address COVID-19, the EV71 work Leeds will be continued by a PhD student (Mona Shegdar, MS) alongside work continuing at NIBSC. Amended objectives (in italics) are below: 1. Selection of EV71 and CAV16 viruses and native empty capsids with enhanced stability.Already achieved for EVA71 but will not be undertaken for CAV16. 2. Acquisition/production of antibody reagents to distinguish 'native' (H) and 'expanded' (H) particles; assay development.Ongoing and will be completed by MS and at NIBSC. 3. Development of expression constructs; VLP production and characterisation.Work will be completed by MS. 4. Immunogenicity of natural and recombinant VLPs vs wt virions and VLPs and inactivated vaccines.Work will be completed by NIBSC. 5. Initiate comparable studies with other enteroviruses. Work will be undertaken by MS if time permits. We have developed a VLP scaffold system that allows the presentation platform and the glycoprotein antigen to be made separately and then combined in vitro. This scaffold system therefore allows optimal production protocols to be used for the separate components and means that a number of different antigens can be used individually or in combination on the same scaffold. They are therefore ideal as a rapid and flexible intervention strategy. Furthermore, such multimeric display of antigens has been shown to offer superior antigen presentation. The use of multiple antigens also offers the possibility of vaccines with broad cross-protective potential. In addition, the ability to 'add on' additional new antigens via a common linkage system allows for a rapid response to outbreaks by novel emerging viruses. Here, we will use our novel scaffold system to capture the SARS-CoV-2 glycoprotein receptor binding domain (RBD) and evaluate the antigenicity, immunogenicity and stability of the VLP vaccine candidates. Our VLPs are based on the hepatitis B core protein that expresses an affimer - this binds SUMO with high affinity and hence can capture SUMO-tagged proteins (journal.pone.0120751)A number of vaccine candidates are in development, but many of these rely on clinically unproven technology. However, there are commercially-available VLP vaccines made in yeast (against hepatitis B virus and human papillomavirus). Furthermore, a scaffold system allows the flexibility to respond both to the current SARS-CoV-2 pandemic but also to future disease outbreaks.We have the expertise and collaborators in place. The applicants and the PDRA (Natalie Kingston) have expertise in VLP vaccines and in production of VLPs in yeast (10.1128/mSphere.00838-19). Our collaborators Dave Stuart, Liz Fry and Tom Bowden (Oxford) have produced the RBD in mammalian cells. Mark Page, Nicola Rose at NIBSC have a wealth of expertise in evaluation of vaccine material and in immunogenicity assays and we have the support of Incepta vaccines in Bangladesh.