Evaluation of a yeast-based BVDV vaccine approach
Lead Research Organisation:
Royal Veterinary College
Department Name: Pathology and Pathogen Biology
Abstract
Bovine Viral Diarrhoea Virus (BVDV) has been implicated as a major
economic disease risk for the cattle industry, resulting in a variety of
associated problems. Control of BVDV infection is economically
important to the cattle industry because the virus causes a variety
of clinical diseases and reproductive disorders, as well as potential
secondary infections such as mastitis that adversely affect
essentially all stages of the production cycle, and depending on the
country, various BVDV eradication programs are in place (Ridpath,
2013). Production losses primarily stem from reproductive failure
and from immunosuppression during acute BVDV infection, which
predisposes calves to respiratory or enteric diseases. Indeed, the
effects of a BVDV infection on the innate and acquired immune
system are unique and result in dramatic immune dysfunction.
Vaccination alone is not sufficient to protect against foetal infection
and losses due to BVDV. This is because no single BVDV vaccine has
been shown to give complete foetal protection. Despite increased
awareness regarding bio-security measurements and PI eradication
programs, vaccination is still the most important control strategy for
controlling BVDV infections in many countries (Ridpath, 2013).
Providing acquired immune protection against infection with BVDV
is challenging due to the heterogeneity that exists among BVDV
strains. Both modified live and killed vaccines have been shown to
be efficacious. Both humoral and cellular immune responses are
protective. Following natural infection or vaccination with a
modified live vaccine, the majority of the serum antibodies are
directed against the viral proteins E2 and NS2/3, with minor
responses against the Erns and E1 proteins. Current BVDV vaccines
require injection and a 'cold chain', and to date all commercially
available vaccines are produced in cell culture.
Here, new oral vaccines may provide a more convenient route of
administration, and thus being of great advantage, if shown to be as
protective as the current injectable ones. Saccharomyces cerevisiae
(S. cerevisiae), a non-invasive, non-pathogenic organism, is generally
considered to be a "generally regarded as safe" (GRAS) species and
for this reason, it is an attractive tool for delivering antigens and
therapeutic molecules (Chen et al., 2005; Garrait et al., 2007).
Indeed, as little as 5 recombinant yeast particles of S. cerevisiae
expressing ovalbumin have been shown to induce dendritic
cell-based T cell proliferation to the same degree as those primed
with saturating amounts of ovalbumin peptide. This was
accompanied by up-regulation of CD80, CD86, CD40, CD54 and MHC
II as well as an increase in IL-12 production by dendritic cells (Stubbs
et al., 2001). Similar to these data generated in mice, work by Lu et
al and by Franzusoff et al in humans has demonstrated that
immunisation with inactivated S. cerevisiae expressing tumour
antigens elicits a far stronger response compared to antigen alone,
and was equal to the anti-tumour response generated by
immunisation using their live counter-parts (Ardiani et al., 2010;
Franzusoff et al., 2005; Lu et al., 2004). Indeed, S. cerevisiae used as
a vaccine vehicle can effectively elicit mucosal and systemic
immunization by administration to mucosal sites, including the oral,
respiratory and genital tracts (Allnutt et al., 2007; Sasagawa et al.,
2005; Shin et al., 2005). In mammals in particular, S. cerevisiae has
been demonstrated to have superior safety and efficacy, where it
has been shown to elicit both innate and adaptative immune
responses due to the presence of TLR ligands in its cell wall (Ogra et
al., 2001) as well as its antigenic feature due to its size.
Thus, we propose to assess the value of using recombinant S.
cerevisiae yeast expressing BVDV E2 and/or NS2/3 proteins on its
surface in a non-secreted form as a vaccine candidate for oral
administration.
economic disease risk for the cattle industry, resulting in a variety of
associated problems. Control of BVDV infection is economically
important to the cattle industry because the virus causes a variety
of clinical diseases and reproductive disorders, as well as potential
secondary infections such as mastitis that adversely affect
essentially all stages of the production cycle, and depending on the
country, various BVDV eradication programs are in place (Ridpath,
2013). Production losses primarily stem from reproductive failure
and from immunosuppression during acute BVDV infection, which
predisposes calves to respiratory or enteric diseases. Indeed, the
effects of a BVDV infection on the innate and acquired immune
system are unique and result in dramatic immune dysfunction.
Vaccination alone is not sufficient to protect against foetal infection
and losses due to BVDV. This is because no single BVDV vaccine has
been shown to give complete foetal protection. Despite increased
awareness regarding bio-security measurements and PI eradication
programs, vaccination is still the most important control strategy for
controlling BVDV infections in many countries (Ridpath, 2013).
Providing acquired immune protection against infection with BVDV
is challenging due to the heterogeneity that exists among BVDV
strains. Both modified live and killed vaccines have been shown to
be efficacious. Both humoral and cellular immune responses are
protective. Following natural infection or vaccination with a
modified live vaccine, the majority of the serum antibodies are
directed against the viral proteins E2 and NS2/3, with minor
responses against the Erns and E1 proteins. Current BVDV vaccines
require injection and a 'cold chain', and to date all commercially
available vaccines are produced in cell culture.
Here, new oral vaccines may provide a more convenient route of
administration, and thus being of great advantage, if shown to be as
protective as the current injectable ones. Saccharomyces cerevisiae
(S. cerevisiae), a non-invasive, non-pathogenic organism, is generally
considered to be a "generally regarded as safe" (GRAS) species and
for this reason, it is an attractive tool for delivering antigens and
therapeutic molecules (Chen et al., 2005; Garrait et al., 2007).
Indeed, as little as 5 recombinant yeast particles of S. cerevisiae
expressing ovalbumin have been shown to induce dendritic
cell-based T cell proliferation to the same degree as those primed
with saturating amounts of ovalbumin peptide. This was
accompanied by up-regulation of CD80, CD86, CD40, CD54 and MHC
II as well as an increase in IL-12 production by dendritic cells (Stubbs
et al., 2001). Similar to these data generated in mice, work by Lu et
al and by Franzusoff et al in humans has demonstrated that
immunisation with inactivated S. cerevisiae expressing tumour
antigens elicits a far stronger response compared to antigen alone,
and was equal to the anti-tumour response generated by
immunisation using their live counter-parts (Ardiani et al., 2010;
Franzusoff et al., 2005; Lu et al., 2004). Indeed, S. cerevisiae used as
a vaccine vehicle can effectively elicit mucosal and systemic
immunization by administration to mucosal sites, including the oral,
respiratory and genital tracts (Allnutt et al., 2007; Sasagawa et al.,
2005; Shin et al., 2005). In mammals in particular, S. cerevisiae has
been demonstrated to have superior safety and efficacy, where it
has been shown to elicit both innate and adaptative immune
responses due to the presence of TLR ligands in its cell wall (Ogra et
al., 2001) as well as its antigenic feature due to its size.
Thus, we propose to assess the value of using recombinant S.
cerevisiae yeast expressing BVDV E2 and/or NS2/3 proteins on its
surface in a non-secreted form as a vaccine candidate for oral
administration.
Organisations
People |
ORCID iD |
Dirk Werling (Primary Supervisor) |
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
BB/N504154/1 | 30/09/2015 | 29/09/2019 | |||
1651507 | Studentship | BB/N504154/1 | 30/09/2015 | 29/09/2019 |
Description | 1) The process that is predominantly published as the method used for heat-killing whole cell yeast-based vaccines does not 'kill' the yeast so this reporting is inaccurate, this work was able to 'kill' the yeast at a higher temperature for a longer duration and used viability testing to prove that the yeast were no longer viable. This is important for future marketing of the vaccine because, if the yeast are no longer viable, they are no longer considered genetically modified organisms (GMO). Our heat-killed yeast, which had been proven to be non-viable, were also show in vitro to be recognised by memory T and B cells from cows that had seroconverted to bovine viral diarrhoea virus (BVDV) and this indicates that our heat-killing process didn't prevent the antigen presented by the yeast from being recognised by the immune system in a BVDV-specific manner. 2) Heat-killed and freeze-dried yeast expressing BVDV antigen, either on the yeast cell-surface or intracellularlly, were able to stimulate cell-mediated immune responses in a BVDV-specific manner in vitro |
Exploitation Route | The whole cell yeast-based vaccine is showing promise in vitro and is ready to be taken forward for evaluation in vivo and proof-of-concept trials. |
Sectors | Agriculture Food and Drink Pharmaceuticals and Medical Biotechnology |
Description | Science Policy Internship at the Parliamentary Office of Science and Technology |
Geographic Reach | National |
Policy Influence Type | Implementation circular/rapid advice/letter to e.g. Ministry of Health |
URL | https://researchbriefings.parliament.uk/ResearchBriefing/Summary/POST-PN-0595 |
Description | ECR travel bursary |
Amount | £150 (GBP) |
Organisation | Veterinary Vaccinology Network |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 05/2018 |
End | 06/2018 |
Description | Workshop Grant |
Amount | £6,000 (GBP) |
Organisation | Veterinary Vaccinology Network |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 02/2020 |
End | 02/2020 |
Title | Oral vaccination of neonatal calves against BVDV |
Description | Vaccination of calves from day 1 of life with an oral vaccine based on inactivated yeast |
IP Reference | |
Protection | Patent application published |
Year Protection Granted | |
Licensed | No |
Impact | Ability to vaccinate calves orally |
Description | Brilliant Club Scholars Programme |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Developed and delivered 7 tutorials on 'Novel Vaccination Strategies' to two groups of six year 9 pupils at The Beacon School, Banstead. The Brilliant Club exists to increase the number of pupils from under-represented backgrounds progressing to highly selective universities. They do this by mobilising the PhD community to share its academic expertise with state schools. |
Year(s) Of Engagement Activity | 2018 |
Description | Departmental Research Afternoon |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Other audiences |
Results and Impact | A research afternoon that was organised to bring together all the researchers of the department of Pathobiology and Population Sciences (PPS) to present their research. This was to foster greater understanding within the department about what research was currently ongoing and encourage collaboration. |
Year(s) Of Engagement Activity | 2017 |
Description | Postgraduate Research Day |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | It is an opportunity for all PhD and M(Res) students to present their work to fellow students and staff, to practise vital skills of presentation and public speaking, and to receive constructive criticism of their work. There are even prizes for the best oral and poster presentations. The great interest of the Postgraduate Research Day, however, is in its significance to the body of scientific knowledge more generally. This year, for example, postgraduate study at the RVC has made an important contribution to our collective understanding of how all health disciplines are interrelated. The 'One Health Principle' which recognises that human health, animal health and ecosystem health are inextricably linked, is at the heart of a global initiative dedicated to improving the lives of all species - human and animal - through enhanced cooperation and collaboration between human medicine, veterinary medicine and environmental and social sciences. |
Year(s) Of Engagement Activity | 2016 |
URL | https://www.rvc.ac.uk/research/news/general/postgraduate-research-day |
Description | RVC Research Highlights Day |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | The day was made up of three parts: a public lecture stream (30mins each), a short talk stream (15 mins each) and an interactive collection of stands from 12 research groups across RVC. It was an informal and interesting afternoon, understandable by staff with no scientific training or background, and people were encouraged to freely move between the activities and experience as much of the afternoon had to offer as possible. Prizes for the Best Presentation (kindly provided by Royal Society of Biology, the key sponsor) and Best Interactive Stand were voted for by attendees and awarded at the end of the day. |
Year(s) Of Engagement Activity | 2015 |
URL | https://www.eventbrite.co.uk/e/research-highlights-2015-tickets-19598655105 |
Description | UK Parliament Antimicrobial Resistance (AMR) Reception |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | One year on from the publication of the UK government's 5-year action plan and 20-year vision for antimicrobial resistance (AMR), the Parliamentary Office of Science and Technology (POST) hosted the UK Parliament AMR Reception in partnership with the UK Veterinary Vaccinology Network. This event showcased UK research relevant to AMR and as a centrepiece to the event the Chief Medical Officer (CMO) for England, Professor Chris Whitty, gave a keynote speech on UK progress towards meeting AMR targets. Over 40 AMR experts came to exhibit their work and they represented institutions from across the UK including the University of Edinburgh, University of Exeter, University of Stirling, University of Southampton, University of London, Imperial College London, and UK Centre for Ecology and Hydrology. The event was open to members of the public and had been advertised across the parliamentary estate, to encourage engagement from parliamentarians. As well as exhibiting their work to attendees, the exhibitors also interacted and conversed extensively between each other. Although all the exhibitors work on AMR, the event brought together experts working in the human, animal and environmental spheres and they wouldn't necessarily cross paths. This sparked interesting discussions and hopefully future collaborations with greater capacity for a One Health approach that spans the clinical, veterinary and environmental challenges of AMR. |
Year(s) Of Engagement Activity | 2020 |
URL | https://twitter.com/POST_UK/status/1232714572236283905 |