13 years in 20 minutes: Badger vaccine development and efficacy Dr Mark A. Chambers TB Science Lead...

13 years in 20 minutes:

Badger vaccine development and efficacy

Dr Mark A. Chambers

TB Science Lead

Animal Health and Veterinary Laboratories Agency, U.K.

Badger vaccination: ‘another tool in the box’

Badger vaccination could help reduce the prevalence and severity of bovine TB in a badger population and thereby reduce the rate of transmission to cattle

From Defra infographic - http://www.flickr.com/photos/defragovuk

Why BCG?

• Safety, cost, efficacy, known effect on preventing disseminated disease

• Freeze-dried vaccine obtained from SSI, Denmark

• Intramuscular route (IM) chosen for use Can be administered in the field without

anaesthesia

1. Provide safety data for BCG using captive badgers2. Determine efficacy of BCG in badgers using

experimental challenge3. Provide safety and preliminary efficacy data in wild

badgers4. Compile registration dossier and deal with

questions arising

Animal Test

Certificate

Randomised Badger Culling Trial

Development of immunological

assays

Preparation for field study

Safety in captive badgers

– GLP Study

INJECTABLE BCG

Safety/efficacy in wild badgers – GCP field

study

Efficacy in captive badgers

M.A.Prepare licence

application dossier

First injection site - LHS

0 28 56 84 112 140 168 196 224 2520

5

10

15

20

25

30A8

A13

A14B2B3

B4B5

B6

Day 44 -first BCG

Day 149 -second BCG

Day

Dia

met

er (

mm

)

First injection site - RHS

0 28 56 84 112 140 168 196 224 2520

10

20

30A8

A13

A14B2B3

B4B5

B6

Day 44 -first BCG

Day 149 -second BCG

Day

Dia

met

er (

mm

)

Second injection site

0 28 56 84 112 140 168 196 224 2520

5

10

15A8

A13

A14B2B3

B4B5

B6

Day 44 -first BCG

Day 149 -second BCG

Day

Dia

met

er (

mm

)

• No fever following vaccination• No influence on weight/feeding behaviour• Modest swelling at site of vaccination in some badgers• Data used to obtain Animal Test Certificate for field

evaluation

GLP safety study with captive badgers

10x overdose – 2-8x108 live bacteriaTarget dose –

2-8x107 live bacteria




questions arising

Animal Test

Certificate



assays



– GLP Study

INJECTABLE BCG


study


M.A.Prepare licence

application dossier

Vaccine efficacy studies with captive badgers

• Two studies completed, in total:– 6 unvaccinated– 8 vaccinated with 2-8x106 live

bacteria– 9 vaccinated with 2-8x107 live

bacteria

• 17 weeks between vaccination and experimental infection

• All badgers infected with M. bovis by endobronchial installation using a flexible fibrescope

• Samples taken for immunology & culture at regular intervals throughout

• Detailed post mortem examination 12 weeks after infection

Assessment of vaccine efficacy

• Size, appearance, and distribution of gross TB-confirmed lesions at PM used to derive score

• Statistically significant reduction in disease burden when higher dose of vaccine used (also more immunogenic)

• 10-fold lower dose gave variable levels of protection

• Even with an effective dose some animals are not protected for reasons not understood

Total Visible Lesion Score

0

5

10

15

20 Controls Vaccinated

D313

Badger treatment group

Sco

re (

wit

h m

edia

n)

Proportion of animals excreting M. bovis per treatment group and reduction in % of excreting animals

Total Positive % positiveControls 6 6 100

Low dose (LD) 8 7 88High dose (HD) 9 3 33

Reduction excretion LD (%) 13Reduction excretion HD (%) 67

0 1 2 3 4 5 6 7 8 9 10 11 120.00.10.20.30.40.50.60.70.80.91.0

ControlHD BCGLD BCG

Weeks post-challenge

Pro

po

rtio

n o

f g

rou

p




questions arising

Animal Test

Certificate



assays



– GLP Study

INJECTABLE BCG


study


M.A.Prepare licence

application dossier

GCP field study with wild badgers• Objective: collect data on safety of IM BCG to wild badgers and

maximise the chances of observing protective effect of vaccination

• Study site: ~55km2 area of high badger density in England– Approx. 92 social groups defined by bait marking

• Two trapping sessions per year (2006-2009)– Vaccinated annually but only once per year

1787 trappings, 844 badgers, 519 vaccinates, 325 controls >80 staff involved in total

• Badgers trapped and brought to central sampling facility– Micro-chipped and tattooed

– Blood and clinical samples taken for immunology and culture

– Vaccine injected into ~61% of badgers

Safety

• Excretion of BCG• None seen from 3657 clinical samples

• Temperature monitoring 24 hours after vaccination• Temperature fluctuations not attributed to vaccination

• Swelling at site of vaccination• Seen in (22/265) ~8% of badgers but no skin lesions

• Trial badgers found dead within study area (n = 33)• Subjected to detailed post-mortem examination• Examination of vaccination site• Culture for M. bovis and BCG

• BCG cultured from LNs of one vaccinated badger only

Vaccine effect

• Badgers were not killed for post-mortem confirmation of TB; relied on three ‘live’ tests

• 2010: Highly significant reduction (of 74%) in incidence of positive Stat-Pak results at social group level as a result of vaccination

– Consistent with protective effect of vaccination, as antibody production positively correlated with extent & severity of TB in humans & badgers

Vaccine effect (cont.)

• 2012: Further analysis of data identifies an indirect protective effect in unvaccinated cubs (‘herd effect’)

– Risk of unvaccinated badger cubs testing positive to TB decreased significantly as the proportion of vaccinated individuals in their social group increased (Odds ratio = 0.08)

– When more than a third of their social group had been vaccinated, the risk to unvaccinated cubs was reduced by 79% (Odds ratio = 0.21)

Cubs that we have been unable to vaccinate because they are underground might still be protected

Beneficial effect not seen in adults so still need to vaccinate cubs as they emerge and are subject to potentially greater infection challenge

• Blood tests are not an absolute indicator of protection from disease so the results cannot tell us the degree of vaccine efficacy




questions arising

Animal Test

Certificate



assays



– GLP Study

INJECTABLE BCG


study


M.A.Prepare licence

application dossier

Compilation of licensing dossier

• Bound by European Legislation• Takes substantial time and expertise

– Government employed an external consultant– 4 months to compile and write– 82 questions dealt with in total– 13 months from start to finish

Conclusions

• Results from wild badgers are encouraging as indirect benefits of vaccination apparent

• Starting with an existing commercial source of BCG saved time, money, and effort

• As with BCG in other species, it is not 100% effective in preventing TB in badgers

• As far as we know BCG does not benefit already infected animals

• Not all badgers in an area will be trapped and vaccinated – based on experience expect 70% to be trapped

• Submission of dossier is time-consuming

• Takes time - 10 years from start to finish

• But it can be done!

An oral badger TB vaccine

• A vaccine that can be delivered orally is a potentially cheaper and more practical way of vaccinating large numbers of badgers in the wild than an injectable vaccine

• Steps to licensing an oral vaccine the same as for injectable vaccine

• But, R&D phase more demanding and no guarantee of success

Oral badger vaccine – issues to consider

• The science– Efficacy

• Need to produce an oral vaccine formulation that gives consistent protection in badger challenge experiments equivalent to that seen with injectable– Oral vaccines are inherently more variable

than injected

– Progress• Have candidate oral vaccines that can give

significant protection to badgers against experimental infection

• Further work required to show consistency in the levels of protection achieved


• The science– Deployment

• Identifying a palatable bait, compatible with live vaccine and the best way and time to deploy it through field studies– Uptake vs cost vs effort

– Progress• Palatable bait identified• Evaluated in the field without vaccine

– Aiming for coverage at least as good as with injectable vaccine (est. 70%)

– >70% uptake by cubs when deployed down holes but need to improve uptake by adults

– Further field work to be undertaken next year


• Regulatory– Even when we have identified an efficacious

licensable vaccine candidate we still have 4-5 years of further work to do to complete regulatory studies, transfer technology to manufacturer and scale up, and get the product licensed• Manufacturing process• Environmental/operator safety issues

– Need labelling, type of packaging

• Access to non-target species– Safety, implications for cattle exposure

• Field safety study (GCP)– Expensive, when to initiate?

– Progress• GLP safety study completed

Acknowledgements

• Funding:– Defra

• FERA:– Woodchester Park Field Team (now AHVLA)– Stats Team

• AHVLA– Badger Research Team– TB Diagnostic Laboratory– Pathology Department– Animal Services Unit

13 years in 20 minutes: Badger vaccine development and efficacy Dr Mark A. Chambers TB Science Lead...

Documents

Transcript of 13 years in 20 minutes: Badger vaccine development and efficacy Dr Mark A. Chambers TB Science Lead...