Cattle TB Vaccine Development in GB Martin Vordermeier Animal Health &Veterinary Laboratories Agency...
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Transcript of Cattle TB Vaccine Development in GB Martin Vordermeier Animal Health &Veterinary Laboratories Agency...
Cattle TB Vaccine Development in GBCattle TB Vaccine Development in GB
Martin VordermeierMartin Vordermeier
Animal Health &Veterinary Laboratories Agency - Weybridge, U.K.Animal Health &Veterinary Laboratories Agency - Weybridge, U.K.
17 August 2012
• Background on cattle TB vaccine development programme in GB
• BCG laboratory and field study results: Which strain, vaccination age, skin test effects, duration of immunity
• BCG plus: Vaccines better than BCG (principles)
• DIVA development (principles)
• Summary
Presentation outline
Control strategy: Tuberculin skin test and cull
Developing TB cattle vaccines
• Developing an effective cattle TB vaccine is a high priority for Defra. We have invested ca. $ 500 million in cattle vaccine and associated diagnostics R&D since 1998/99, and over the next 5 years have budgeted to spend a further $19 million
• To date the most promising approaches in cattle are BCG based - either with BCG on its own or to use a heterologous BCG prime-boost strategy where combinations of BCG-DNA, BCG-protein and BCG-virus-vectored vaccines have induced better protection than BCG vaccine alone
Current state of play with a cattle BCG
• Experimental vaccination-challenge studies now completed to:
– Demonstrate efficacy of BCG in neonates and older cattle– Demonstrate safety of BCG in neonates and cattle in each trimester
(allows for vaccination in all age groups)– Determine duration of immunity (demonstrated out to one year)
• Licensing portfolio for Marketing Authorisation submitted and is being assessed by the Veterinary Medicines Directorate (VMD) for approval
• If satisfied with the dossier, VMD would be able to provide ‘agreement in principle’ to license (but would not be able to grant an MA due to EU prohibition on anti-tuberculosis cattle vaccines)
EU prohibition on cattle TB vaccination
• TB vaccination of cattle specifically prohibited under EU national eradication plans (Directive 78/52/EEC) – This includes field trials!
• OTF (Officially TB Free) testing requirements (tuberculin skin test) for trade in live cattle (Directive 64/432/EEC)
• Trade in cattle products tightly controlled by Reg (EC) 853/2004 and BCG vaccinated cattle would give false positives
• Need these lifted before vaccination could be used in the UK
• Opportunity created by new Animal Health Law which is under consideration but we must not underestimate the difficulties involved in lifting prohibition on vaccines and allowing DIVA use
DIVA test requirement
• BCG vaccination of cattle can result in reactivity to tuberculin diagnostic tests (both to the Single Intradermal Comparative Cervical Tuberculin test (SICCT skin test) and the interferon gamma blood test)
• As many as 80% of BCG vaccinated but uninfected animals can be skin test positive 6 months post vaccination but thereafter proportion drops quickly with about 10% testing positive 9 months post vaccination
• In parallel with our cattle vaccine research we are developing a DIVA test to differentiate infected from vaccinated animals
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M. bovis bacille Calmette-Guérin:BCG/BCG based strategies(e.g. ‘Heterologous prime-boosting’)
• Live, attenuated M. bovis• Attenuated in cattle since 1912• Used in humans since 1927• Safe in a wide range of species• Cheap• Recommended by WHO for humans• Variable efficacy in humans and
cattle (average ca. 50%), and compromises tuberculin based diagnosis
Albert Calmette
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BCG strains:
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Experimental approaches to test TB vaccines in cattle
Model Advantages Disadvantages
Experimental challenge: Low dose intratracheal model
‘Few’ animals required
(n <10-12/group)Still relatively high dose: Immune system may be overwhelmed
Short duration (3-4 months)
‘Field experiment’:In contact transmission
Natural route and infective dose
Many more animals required (60/group)
Long in-contact period (12 months)
Field trial Real-life situation
Very large numbers required (n = 100-1000s)
Long and expensive (years) and illegal in EU
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In our earlier studies we used BCG Pasteur (as this was recommended by WHO for humans).
But the only BCG strain commercially available and licensed for human in Europe: BCG SSI (Staten Serum Institut, Copenhagen, Denmark)
THEREFORE: We changed to BCG SSI
First challenge: Demonstrate protective equivalence of BCG Pasteur and BCG SSI
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BCG Pasteur and BCG SSI give equivalent protection:
Conclusion:
Conclusion:
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BCG vaccination of neonatal or very young calves works at least as good as vaccinating older animals:
Conclusion:
Conclusion:
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10
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30
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* * * * * *
Pat
holo
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core
BCG Danish vaccination experiments in cattle after intra-tracheal infection conducted at AHVLA/IAH over the last 6
years: BCG works!
Duration of immunity?
1-year
DOI
2-years
DOI
N N N N
BCG M. bovis
BCG M. bovis
1 year
2 years
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Waning of tuberculin skin test responses following BCG vaccination
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Maintenance of skin test responses are not required for protection
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Field BCG (BCG SSI) vaccination experiment conducted in Ethiopia (Wellcome Trust funded study)
TBTB
TBTB
TBTB TBTB
TBTBTBTB
TBTB
TBTB
Unvaccinated sentinelUnvaccinated sentinel
Vaccinated sentinelVaccinated sentinel
Reactor (TB)Reactor (TB)
TBTB
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BCG vaccination experiment in Ethiopia (2007-09)
Study site: High-intensity farm, central highlands west of Addis Ababa (Oromiya Province)
Vaccine, dose and route: BCG SSI (freeze-dried), 106 CFU, subcutaneous
Breed of donors and vaccinates: Pure-bred Holsteins
Neonatal vaccination (<3 weeks of age)
Type of challenge: In-contact with reactor animals, standard farming/husbandry conditions
Exposure to reactors: about 3 months post-vaccination
In-contact period: 10 – 22 months
Read-out: Gross pathology/M. bovis culture
Lead scientist: Dr Gobena Ameni (AHRI/IPB Addis Ababa)
Collaborators: Glyn Hewinson/Martin Vordermeier (VLA)
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BCG vaccination induced good level of protection: Pathology and microbiology
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30
40
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BCG-12 mo BCG-24 mo
Pat
holo
gy S
core
Duration of immunity: Comparison of field study results with experimental infections
Longer in real-life exposure situation?
Experimental intra-tracheal infection studies
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Field transmission study: DOI under natural transmission conditions
BCGControls
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Better than BCG: Strategies P
rote
ctiv
e im
mu
nit
y
Time
BCG
Boost Amplify/Boost
Immunity level sufficient for protection
Boost
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Our approaches to (hopefully) better tests:
•Antigen mining to generate defined reagents for DIVA and not affected by infections with NTM (blood test format, Interferon-gamma
release assay)
•Use of these antigens as skin test reagents
•Search for host biomarkers adding additional sensitivity
DIVA Development
Differential Immune-Diagnosis
Vaccine or cross-reactive pathogen
TB
Blood test detectsresponse to componentsonly recognised in TB
Summary
• Protection: BCG Danish/BCG SSI = BCG Pasteur
• Neonatal BCG vaccination at least as good as vaccinating older animals
• BCG protects reproducibly in experimental challenge studies AND equally if not better in field exposure study
• Duration of immunity: at least 1 year, field study suggests longer
• Boosting with virally vectored vaccines can improve on BCG (not shown)
• DIVA based on blood test (IGRA) or skin test (not shown)
What does the science tell us?
• BCG is the most suitable candidate in the short term
• Could be a useful tool, but not perfect - will still need other TB control measures
• Vaccination affects the skin test – but we can now reliably differentiate between vaccinated and infected animals
• Likely to need annual re-vaccination
• New development pathway: Effective vaccine that does not sensitise tuberculin skin reactions (non-sensitising vaccines)
AHVLA Weybridge
Adam Whelan
Bernardo Villarreal-Ramos
Phil Hogarth
Sabine Steinbach
Elihu Cortes
Gilly Dean
Gareth Jones
Rory Cooney
Glyn Hewinson
AgResearch, NZ
Bryce Buddle
Neil Wedlock
McMaster, Toronto, Canada
Zhou Xing
AHRI, Addis Ababa, Ethiopia
Gobena Ameni
Jenner Institute, Oxford
Adrian Hill
Helen McShane
Sarah Gilbert
Jenny Piercy
IAH, Compton
Martin McAulay
Jayne Hope
Lionex Ltd/Helmholtz Centre, Braunschweig
Mahavir Singh
Sabin Bhuju
NADC, USDA, Ames, USA
Ray Waters
Tyler Thacker
Funded by Defra (UK), EU, Wellcome Trust