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

10 25 50
 
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 Production of virus-like particles in Pichia
Exploitation Route Use in VLP-based vaccines
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 AMBR fermentation experiment - FVRMH
Amount £35 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 06/2019 
End 06/2020
 
Description Outreach Grant
Amount £5,000 (GBP)
Organisation Microbiology Society 
Sector Learned Society
Country United Kingdom
Start 09/2017 
End 01/2018
 
Description Research England - postgraduate training
Amount £40,000 (GBP)
Funding ID
Organisation Higher Education Funding Council for England 
Sector Public
Country United Kingdom
Start 04/2019 
End 10/2019
 
Description VLP vacines for polio
Amount $1,600,000 (USD)
Organisation World Health Organization (WHO) 
Sector Public
Country Global
Start 02/2019 
End 01/2021
 
Description nanopatch vaccine delivery
Amount $209 (USD)
Organisation World Health Organization (WHO) 
Sector Public
Country Global
Start 07/2020 
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 
Sector Public 
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 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 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 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 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 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