Cattle TB Vaccine Development in GB
Martin Vordermeier
Animal Health &Veterinary Laboratories Agency - Weybridge, U.K.
17 August 2012
Presentation outline
• 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
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
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
8
BCG strains:
9
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
10
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
11
BCG Pasteur and BCG SSI give equivalent protection:
Conclusion:
Conclusion:
12
BCG vaccination of neonatal or very young calves works at least as
good as vaccinating older animals:
Conclusion:
Conclusion:
13
BCG Danish vaccination experiments in cattle after intratracheal infection conducted at AHVLA/IAH over the last 6
years:
BCG works!
Duration of immunity?
40
Pathology Score
N
N
N
N
30
20
10
*
*
*
0
1-year
DOI
2-years
DOI
1 year
BCG
M. bovis
2 years
BCG
M. bovis
*
*
*
Waning of tuberculin skin test responses following
BCG vaccination
16
Maintenance of skin test responses are not required
for protection
17
Field BCG (BCG SSI) vaccination experiment conducted in
Ethiopia (Wellcome Trust funded study)
18
TB
Unvaccinated sentinel
TB
TB
TB
Vaccinated sentinel
TB
TB
TB
TB
TB
Reactor (TB)
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), 10
6
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)
20
BCG vaccination induced good level of protection: Pathology and
microbiology
Gross pathology
(VL) % (n)
M. bovis
culture +ve
% (n)
Spread
outside head
and lung
regions
Condemned at
meat inspection
% (n)
Naïve (n=14)
86 % (12)
79 % (11)
21 % (3)
71 % (10)
BCG (n=13)
38 % (5)
31 % (4)
0 % (0)
23 % (3)
P-values (Fisher’s
0.018
0.021
NS
0.021
exact test)
21
Duration of immunity: Comparison of field study results with
experimental infections
Longer in real-life exposure situation?
Experimental intra-tracheal infection studies
Pathology Score
40
30
20
10
*
0
BCG-12 mo BCG-24 mo
Field transmission study: DOI under natural
transmission conditions
BCG
Controls
23
Better than BCG: Strategies
Protective immunity
Amplify/Boost
Boost
Boost
Immunity level sufficient for protection
BCG
Time
24
DIVA Development
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
25
Differential Immune-Diagnosis
Vaccine or cross-reactive pathogen
Blood test detects
response to components
only recognised in TB
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
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
AHRI, Addis Ababa, Ethiopia
Gobena Ameni
Funded by Defra (UK), EU, Wellcome Trust