VACCINE - Development of novel picornavirus virus-like particle vaccines
Lead Research Organisation:
University of Leeds
Department Name: Sch of Molecular & Cellular Biology
Abstract
The strategy of the Medical Research Council is to improve the progress of international health research worldwide. Vaccination has had an enormous impact on human and animal health and is therefore one of the most important and effective medical interventions. However, there are still many examples of diseases for which we do not have effective vaccines. Furthermore, much of our current vaccine production involves the production of disease-causing agents (e.g. viruses) which are subsequently inactivated during the production process. In their simplest terms, viruses can be thought of as protein containers that protect the viral genetic material inside. The container is inert - it is the viral genetic material inside which is responsible for causing disease. However, the container (capsid) is of key importance in the process of developing immunity through vaccination. Here, the body's immune system recognises the capsid proteins and generates antibodies to these, which then give the body protection against the disease. Therefore, production of just the capsid as a virus-like particle (VLP) should elicit a protective immune response, yet be totally safe. Furthermore, such production could be undertaken under low containment, which is both easier and cheaper, thus making such virus-like particle vaccines more accessible to developing countries. However, there are problems to be overcome, as many VLPs are unstable. We have a large amount of proof-of-principle data with the production of VLPs for poliovirus and have generated stabilised VLPs that offer better protection than the current polio vaccine (in animal models). We now we wish to apply our strategy to other viruses, focussing on the causative agents of hand, foot and mouth disease. This is a disease of growing concern due to outbreaks particularly in the SE Asia region, associated with hospitalisation and death. According to the World Health Organisation, this affected 1,520,274 people by the end of July in 2012 in China, with 431 reported deaths, and outbreaks are now reported in Europe.
Technical Summary
Virus-like particles (VLPs) are of interest as novel vaccines. They can present antigenic features of a viral pathogen in a safe and highly immunogenic form. The hepatitis B and human papillomavirus vaccines are well-established examples. Some viruses e.g. the picornavirus, poliovirus, produce empty particles as part of the natural lifecycle. Although these empty particles could be VLP vaccine candidates, they are very unstable and readily undergo an antigenic conversion to a non-native state and therefore would not elicit a protective immune response. Over the past 5 years, we have generated VLPs of poliovirus that are now being expressed in recombinant systems as novel vaccine candidates. By selecting viruses at elevated temperatures and by identifying reversion of temperature-sensitive mutants, we have identified a number of residues in the capsid which renders this stable, even when empty. We now propose to extend our studies to other picornaviruses and thus develop a generic approach to VLP vaccine development. The focus of the current application is the causative agents of human hand, foot and mouth disease (HFMD), enterovirus 71 (EV71) and Coxsackie virus A16 (CVA16). HFMD is a disease of growing concern due to outbreaks affecting children in the SE Asia region, associated with hospitalisation and death. Outbreaks have recently been reported in Europe.
Planned Impact
The initial fundamental and exploratory phases of the study will be of interest and value to academic investigators in the fields of protein expression, structure and assembly and to vaccinologists, as outlined in the 'academic beneficiaries' section. Delivery of impact during the grant to non-academic beneficiaries will be pursued in four main areas. Firstly, the UK/global economy will benefit through the development of highly skilled researchers, with high level scientific and transferable skills equipping him/her to continue on the pathway to an independent research career. Secondly, the general public (both adults and children) will benefit through a range of public engagement events, leading to improved understanding of the science of infectious diseases, viruses and their control by vaccination. In addition, the research community beyond academia (for example pharmaceutical companies) will benefit from this research through having access to the exploitation of techniques/approaches with potential for wide application in the area of vaccine development. Finally, government organisations in developing countries may benefit from this research through new approaches for the development of vaccines to counter diseases prevalent or emerging in these regions. In the medium and longer term, there is significant potential for impact to pharmaceutical companies and governments to be realised through further development and uptake of the research carried out in this project. As an example, the development of technology which reduces the cost of production of vaccines through the use of appropriate technology and low containment facilities has the potential to greatly benefit companies in developing countries, and ultimately to benefit healthcare professionals and patients through availability of lower cost vaccines.
Publications
Adeyemi OO
(2019)
Involvement of a Nonstructural Protein in Poliovirus Capsid Assembly.
in Journal of virology
Adeyemi OO
(2017)
Increasing Type 1 Poliovirus Capsid Stability by Thermal Selection.
in Journal of virology
Kejriwal R
(2023)
Development of Enterovirus Antiviral Agents That Target the Viral 2C Protein.
in ChemMedChem
Kingston N
(2022)
Thermal stabilization of enterovirus A 71 and production of antigenically stabilized empty capsids
in Journal of General Virology
Kingston NJ
(2022)
Development of an Enzyme-Linked Immunosorbent Assay for Detection of the Native Conformation of Enterovirus A71.
in mSphere
Kingston NJ
(2023)
Production of antigenically stable enterovirus A71 virus-like particles in Pichia pastoris as a vaccine candidate.
in The Journal of general virology
Kingston NJ
(2023)
VelcroVax: a "Bolt-On" Vaccine Platform for Glycoprotein Display.
in mSphere
Lulla V
(2019)
A novel enterovirus protein modulates infection in gut epithelial cells
in Access Microbiology
Lulla V
(2019)
An upstream protein-coding region in enteroviruses modulates virus infection in gut epithelial cells.
in Nature microbiology
Title | Polio light |
Description | A partnership with an artist (Alison Smith) to build a model of poliovirus from recycled plastic. It is illuminated. |
Type Of Art | Artefact (including digital) |
Year Produced | 2018 |
Impact | 2500 hits on Twitter and 35 retweets |
URL | https://twitter.com/Stonehouse_Lab/status/1075399270713516032 |
Description | Vaccine candidates for hand, foot and mouth disease. |
Exploitation Route | via publications and podcasts etc |
Sectors | Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
Description | Public understanding of vaccines See other sections of the submission for more information. |
First Year Of Impact | 2018 |
Sector | Education,Manufacturing, including Industrial Biotechology |
Impact Types | Cultural Societal Economic |
Description | Barchester - policy on staff vaccination |
Geographic Reach | National |
Policy Influence Type | Citation in other policy documents |
Impact | Increased vaccine uptake amongst staff at Barchester Healthcare by undertaking 8 webinars and 5 written report documents |
URL | https://www.barchester.com/help-and-advice/news/barchester-healthcare-and-uk-coronavirus-outbreak |
Description | Women and Equalities Committee: Vaccine uptake in young women briefing |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | AMBR fermentation experiment - FVRMH |
Amount | £35 (GBP) |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 05/2019 |
End | 06/2020 |
Description | Generation of virus free polio vaccine: v) to support the industrial production of recombinant poliovirus sVLPs |
Amount | $917,120 (USD) |
Organisation | World Health Organization (WHO) |
Sector | Public |
Country | Global |
Start | 02/2022 |
End | 01/2023 |
Description | Outreach Grant |
Amount | £5,000 (GBP) |
Organisation | Microbiology Society |
Sector | Learned Society |
Country | United Kingdom |
Start | 08/2017 |
End | 01/2018 |
Description | Research England - postgraduate training |
Amount | £40,000 (GBP) |
Funding ID | x |
Organisation | Higher Education Funding Council for England |
Sector | Public |
Country | United Kingdom |
Start | 03/2019 |
End | 10/2019 |
Description | Understanding the fundamental enterovirus capsid assembly and maturation pathway. |
Amount | $247,897,300 (USD) |
Funding ID | R01AI169457-01 |
Organisation | National Institutes of Health (NIH) |
Sector | Public |
Country | United States |
Start | 03/2022 |
End | 02/2027 |
Description | VLP vacines for polio |
Amount | $1,600,000 (USD) |
Organisation | World Health Organization (WHO) |
Sector | Public |
Country | Global |
Start | 02/2019 |
End | 01/2022 |
Description | VaxHub E. coli cell free expression |
Amount | £10,000 (GBP) |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 12/2020 |
End | 04/2021 |
Description | VaxHub EPSRC- fermentation |
Amount | £40,000 (GBP) |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 12/2020 |
End | 06/2021 |
Description | nanopatch vaccine delivery |
Amount | $209 (USD) |
Organisation | World Health Organization (WHO) |
Sector | Public |
Country | Global |
Start | 06/2020 |
End | 06/2021 |
Description | Centre for process innovation, Darlington |
Organisation | Centre for Process Innovation (CPI) |
Country | United Kingdom |
Sector | Private |
PI Contribution | Joint research on fermentation |
Collaborator Contribution | Joint research on fermentation |
Impact | Funding from FVMRH |
Start Year | 2018 |
Description | Grant partners |
Organisation | National Institute for Biological Standards and Control (NIBSC) |
Country | United Kingdom |
PI Contribution | A joint grant with Javier Martin and Andy Macadam at NIBSC - NJS is PI |
Collaborator Contribution | A joint grant with Javier Martin and Andy Macadam at NIBSC - NJS is PI |
Impact | this grant |
Start Year | 2017 |
Description | Advice on vaccination - Barchester |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | I have undertaken 8 webinars with staff from Barchester, a leading provider of Healthcare in the UK. They contacted me as a result of my Press Interviews. I have advised staff on vaccination to COVID-19 and this influenced their decisions on vaccination policy |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.barchester.com/help-and-advice/news/barchester-healthcare-and-uk-coronavirus-outbreak |
Description | Aurora |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | Invited as a role model for Aurora in 2016 and 2017 |
Year(s) Of Engagement Activity | 2016,2017 |
Description | Cafe Scientifique invited speaker |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Invited talk at Café Scientifique, Otley. |
Year(s) Of Engagement Activity | 2017 |
Description | Departmental Seminar |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Seminar at Pirbright institute |
Year(s) Of Engagement Activity | 2017 |
Description | Departmental Seminar - UCC |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | A seminar at UCC |
Year(s) Of Engagement Activity | 2019 |
Description | Featured in a book |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Featured in Love of Leeds book |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.loveofleeds.co.uk/ |
Description | Future Vaccines Manufacturing Research Hub |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Future Vaccines Manufacturing Research Hub April 2020 |
Year(s) Of Engagement Activity | 2020 |
Description | Hepworth lecture - National Women's day |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | A talk in Wakefield on National Women's day 2017 |
Year(s) Of Engagement Activity | 2017 |
Description | Interviews for Yahoo news on vaccines |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Two interviews And this was followed by many other requests including for Sky news, ITV, Channel 4 |
Year(s) Of Engagement Activity | 2020 |
Description | Invited oral presentation |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Invited talk as part of meeting at Centre for Process Engineering, Darlington. |
Year(s) Of Engagement Activity | 2017 |
Description | Keynote presentations at Jahangirnagar and Khulna Universities, Bangladesh |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Keynote talks at two Universities in Bangladesh |
Year(s) Of Engagement Activity | 2017 |
Description | Keynote talk |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Keynote lecture at Jahangirnagar University, Bangladesh - December 2015 |
Year(s) Of Engagement Activity | 2015 |
Description | Media interview - vaccines. BBC news 24 |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Media interview - vaccines. BBC |
Year(s) Of Engagement Activity | 2020 |
Description | Media interview - vaccines. for Wired |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Media interview - vaccines. |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.wired.co.uk/article/coronavirus-vaccine-china |
Description | Neesie - pro-vaccination groups |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Helping a local group of vaccine communicators with accurate information |
Year(s) Of Engagement Activity | 2021 |
URL | https://neesie.org/ |
Description | Outreach in Bangladesh |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Two members of my research group (Dr Lee Sherry and Dr Keith Grehan) and I developed teaching materials to run practical classes and workshops at Jahangirnagar University, Bangladesh. Lee and Keith spent two weeks delivering theses and evaluated students' understanding with questionnaires. Equipment/reagents were left at the University for use in the future. |
Year(s) Of Engagement Activity | 2017 |
Description | Outreach in Bangladesh - follow up |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Two members of my research group (Dr Lee Sherry and Dr Keith Grehan) and I developed teaching materials to run practical classes and workshops at Jahangirnagar University, Bangladesh in 2017. Lee and Keith spent two weeks delivering theses and evaluated students' understanding with questionnaires. Equipment/reagents were left at the University for use in the future. A PG student (Kaniz Featema) visited Banladesh in 2019 to run further classes. |
Year(s) Of Engagement Activity | 2019 |
Description | Over 100 interviews on COVID-19 |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I have given over 100 interviews on the COVID-19 pandemic over the past year. These include testing, virus biology and vaccines. These include ITV news at 10, BBC news 24, Radio 4, Sky news Local radio (BBC and commercial stations and TV (BBC Look North and ITV Calendar). The Guardian, Daily Mail. Some are captured as video clips on youtube. |
Year(s) Of Engagement Activity | 2020,2021 |
Description | Podcast on vaccines |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | A podcast on vaccines - by Microbiology Society |
Year(s) Of Engagement Activity | 2021 |
Description | Poliovirus capsid sculpture |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Together with an artist, we made an illuminated model of poliovirus from recyled plastic. This reached over 2500 people via Twitter and had 35 re-tweets. Follow up activities included display at Microbiology Society meeting in Belfast in 2019 and at University Open Days. |
Year(s) Of Engagement Activity | 2018 |
Description | School activity as part of 'Inspiring the future' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | A school activity (6 classes of primary school children) in Bradford |
Year(s) Of Engagement Activity | 2019 |
Description | School engagement as part of Inspiring the Future |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | I have given three presentations to Schools as part of Inspiring the Future - two secondary and one Primary School. These included a discussion about viruses and also my career path. |
Year(s) Of Engagement Activity | 2016,2017 |
Description | School visit (Bradford) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Inspiring the Future event - primary school |
Year(s) Of Engagement Activity | 2019 |
Description | School visit (Chapel Allerton, Leeds) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Inspiring the Future event - primary school |
Year(s) Of Engagement Activity | 2019 |
Description | Shaping the Future Virtual Seminar on Vaccine Development |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Shaping the Future Virtual Seminar on Vaccine Development August 2020 Bangladesh organised |
Year(s) Of Engagement Activity | 2020 |
Description | Talk and podcast |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Lecture at University of Glasgow followed by an interview (podcast) |
Year(s) Of Engagement Activity | 2020 |
Description | Talk at COVID-19 workshop |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Microbiology Society COVID-19 research event |
Year(s) Of Engagement Activity | 2021 |
Description | Wikipedia page |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | A wikipedia page was set up listing my achievements |
Year(s) Of Engagement Activity | 2020 |
URL | https://en.wikipedia.org/wiki/Nicola_Stonehouse |
Description | Women and Equalities panel in Parliament |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | Women and Equalitles Panel in Parliament - expert witness on vaccine uptake |
Year(s) Of Engagement Activity | 2021 |
URL | https://parliamentlive.tv/event/index/3e29842d-53df-4c63-96fb-f915dd703686 |