Development of a deployable tuberculosis vaccine for cattle

Yes, the candidate vaccine is CattleBCG (Bacille Calmette Guérin).

In the Animal and Plant Health Agency (APHA)’s experimental challenge infection model, which is far more stringent than natural infection in the field, CattleBCG produces a spectrum of protection in cattle. Around one third of animals are fully protected with an absence of lung pathology, one third are partially protected (reduced pathology and bacterial load) and one third are not protected at all (similar clinical signs to unvaccinated control animals). This spectrum at the individual animal level is also seen in BCG vaccination of other animals and humans. The scale of disease reduction from CattleBCG depends on many factors including severity of exposure to bovine TB and herd immunity. A recent New Zealand field trial using the same BCG vaccine and vaccination route as proposed here, suggested an overall efficacy of over 80%. When combined with other disease control measures, we anticipate the added value of cattle vaccination will be in reducing the prevalence and incidence of the disease. Establishing the efficacy of CattleBCG will be part of any future application for marketing authorisation.

 

BCG vaccination sensitises cattle to the tuberculin tests which are the cornerstone of our bovine TB eradication programme and used for international trade in live cattle. It causes a substantial proportion to react to the tuberculin test i.e. to become false positive animals. The World Organisation for Animal Health (OIE) which sets standards for international trade in animals and their products advises that cattle vaccination should not be used in countries which operate control or trade measures based on tuberculin tests. This is why OIE makes no provision for vaccination of cattle against TB and UK legislation prohibits the vaccination of cattle against TB without Ministerial consent.

Yes, APHA has developed a DIVA format of the skin test (DST-F) based on defined antigens, as the most likely useful candidate for use alongside CattleBCG. This development is a major breakthrough. If the DIVA skin test is validated and authorised, it will avoid the problem of false positives by detecting only those vaccinated animals that are TB-infected, i.e. true-positives. OIE recognises that significant progress has been made in the development of DIVA tests. It envisages that vaccination could be applied in combination with such DIVA tests once these have been fully validated and the legal framework amended accordingly.

Both the candidate CattleBCG vaccine and the DIVA skin test need Veterinary Medicines Directorate (VMD) marketing authorisations in the same way as any other veterinary medicine. We also need to do further work to validate the DIVA skin test. APHA has developed field trial designs to evaluate the CattleBCG vaccine and DIVA skin test further. It’s hoped that they will provide the evidence required for future UK national marketing authorisations and for the DIVA skin test to be internationally recognised. The field trials are being conducted to investigate the safety of CattleBCG in cattle in the field and the safety and effectiveness of the candidate DIVA skin test in the field, and to generate evidence/data required to apply for future marketing authorisations.

The DIVA skin test specificity* will be evaluated in the first phase of the field trial anticipated to be completed by December 2021. Then a decision will be made on continuation to the second phase. The performance of the DIVA skin test is crucial in enabling the CattleBCG vaccine to realise disease control benefits. As well as identifying vaccinated cattle that are truly infected (i.e. not protected by vaccination) it is essential that the DIVA skin test has a high specificity i.e. we need to be confident that the number of false positive results is very low. Otherwise we risk vaccinated herds having frequent and/or repeated reactor cattle and thereby remaining under TB restrictions for a very long time, putting business viability at risk.

*Specificity is the probability that a test will correctly identify an animal that is free from infection as negative. The higher the specificity, the lower the probability of incorrectly classifying an uninfected animal as infected (a false positive result).

The aim is to start the field trials in 2021 subject to procuring a Contract Research Organisation (CRO) to run them. In July 2020, VMD granted permission for field trials of both the CattleBCG vaccine and the skin test DIVA. The issuing of Animal Test Certificates (ATCs) followed detailed assessment of applications submitted by APHA in October 2019.

APHA is preparing an open tender for a CRO which will be responsible for engaging with farmers, identifying suitable trial sites and developing detailed trial protocols. Ultimately the CRO will undertake the field trials. In June 2020, APHA issued a Prior Information Notice and Information Pack for CROs.

There will be two phases with Phase 2 dependent on the outcome of Phase 1:

  • Phase 1: Establishing the DIVA skin test specificity and safety in unvaccinated animals from TB-free cattle herds in the Low Risk Area (England)/Low TB Area (Wales).
  • Phase 2: Establishing the safety of both the CattleBCG vaccine and the DIVA skin test in vaccinated cattle and further establishing the specificity of the DIVA skin test in different groups of vaccinated animals from herds in High Risk and Edge Areas (England)/High and Intermediate TB Areas (Wales).

There will be two phases with Phase 2 dependent on the outcome of Phase 1:

  • Phase 1 – The initial number of cattle to be tested in this part of the trial is approximately 300 from five separate herds. This may increase up to 2,500 cattle depending on initial specificity performance and the required level of precision for the specificity estimate.
  • Phase 2 – The number of cattle for this phase will be approximately 2000 (1900 minimum). This would involve over seven separate herds with approximately 1000 cattle vaccinated and approximately 1000 cattle used as a control.

No, the CRO will be responsible for recruiting suitable farms and herds to participate on a voluntary basis.

Farmers should not be financially disadvantaged through participating in the field trials.

The aim is to complete the field trials by 2024.

Following successful completion of field trials, APHA will then be able to apply to VMD for marketing authorisations for both the CattleBCG vaccine and the skin test DIVA. Provided the field trials go as hoped and VMD considers the marketing authorisation applications satisfactory with respect to quality, safety and efficacy, the timeline envisages those authorisations being granted in 2025. This would pave the way for removing or relaxing the current legal barriers to vaccinating cattle against TB in England.

No. Progress was hampered as a result of not having a suitable DIVA test but research has now identified a candidate DIVA skin test (DFT-F). Like other veterinary medicines, in addition to laboratory studies, both CattleBCG and the DIVA skin test must be shown to be effective and safe under field conditions before VMD can authorise their use. The estimated timeframe is five years subject to successfully completing the field trials and then successfully applying for marketing authorisations.

OIE sets animal health standards for international trade in animals as the principal reference for World Trade Organization members. OIE makes no provision for vaccination of cattle against TB. In order to enable trade in vaccinated cattle, we need to validate the DIVA skin test and secure amendments to OIE standards to clarify how they apply to trade in vaccinated cattle and possibly to their products. Defra has considered the risk of commercial cattle buyers discriminating against cattle vaccinated against TB. A limited expert elicitation commissioned to seek the views of key UK meat sector decision makers concluded that there was no significant risk of discrimination of this nature, provided the safety of the products derived from vaccinated cattle could be assured.

Yes. The applications to conduct field trials of CattleBCG and the DIVA skin test underwent careful scientific assessment by VMD to ensure that the necessary requirements to conduct veterinary field trials of unauthorised veterinary medicines in a food producing species were met and to ensure safety for the target, user, consumer and environment. The ATCs permitting the field trials require a 90 day withdrawal period for meat and offal from cattle vaccinated with CattleBCG. There are no restrictions on cattle tested with the DIVA skin test or on milk from cattle vaccinated with CattleBCG.

That is a decision for the future which depends on the outcome of the field trials. In England, Defra’s current view is that CattleBCG vaccine would be best used to reduce bovine TB prevalence in the High Risk Area, targeting high risk herds to maximise the disease control benefits while reducing the costs from deployment and from any false positive results. The future scale of use would be informed by monitoring and analyses of effects following initial rollout after authorisation.