Development of a deployable tuberculosis vaccine for cattle

Yes, the candidate vaccine is BCG (Bacille Calmette-Guérin) Danish strain trialled in cattle under the name CattleBCG. BCG is the same vaccine used to protect people and badgers from TB.

CattleBCG stimulates a protective immune response in vaccinated cattle. When combined with other disease control measures, we anticipate the added value of cattle vaccination will be in reducing both the prevalence and incidence of bovine TB (bTB). In the Animal and Plant Health Agency (APHA)’s experimental challenge model which attempts to mirror natural infection in the field, vaccinated animals display a range of protection. 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 (presenting with similar clinical signs of bTB as observed in unvaccinated control animals). The extent of disease reduction from CattleBCG depends on many factors including severity of exposure to bTB and herd immunity. A 2014-2018 New Zealand field trial using the same BCG Danish strain vaccine administered subcutaneously but at a much lower dose than any previous trials, gave an overall protective efficacy of over 85%1 (there were 2 cattle confirmed with TB among 520 BCG vaccinated animals compared to 8 among 297 non-vaccinated animals). Establishing the level of protection afforded by CattleBCG to bTB will be critical for any future application for a marketing authorisation in the UK. Both onset and duration of immunity will be demonstrated to support the recommended vaccination schedule for cattle.

Reference 

1. Nugent, G. and others (2018) Low-dose BCG vaccination protects free-ranging cattle against naturally-acquired bovine tuberculosis. Vaccine, Volume 36, Issue 48 https://doi.org/10.1016/j.vaccine.2018.10.025

BCG vaccination sensitises cattle to the tuberculin tests which are the cornerstone of our bTB eradication programme and used for international trade in live cattle. It causes most cattle (approximately 80%) 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. Therefore, OIE makes no provision for vaccination of cattle against bTB and UK legislation prohibits the vaccination of cattle against bTB without Ministerial consent. There is also a need to obtain UK marketing authorisations from the Veterinary Medicines Directorate (VMD) to market CattleBCG in the UK and ensure it meets the required standards of quality, safety and efficacy.

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 breakthrough. If the DIVA skin test (DST-F) is successfully validated and approved for use it will remove the problem of BCG vaccine-related false positives with the current tuberculin test by detecting only those vaccinated animals that are bTB-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 (DST-F) need UK marketing authorisations from VMD in the same way as any other veterinary medicine. We also need to do further work to validate the DIVA skin test. APHA is embarking on field trials to evaluate further the CattleBCG vaccine and DIVA skin test (DST-F). These field trials are funded by Defra, Welsh Government and Scottish Government. It’s hoped that they will provide the additional evidence required for future UK national marketing authorisation applications and for the DIVA skin test (DST-F) 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 specificity/performance of the candidate DIVA skin test (DST-F). Defra, Welsh Government and Scottish Government are also funding two supplementary research projects. One is looking at the duration of immunity of CattleBCG. The other is looking at the sensitivity of the DIVA skin test (DST-F) in cattle naturally infected with bTB (i.e. TB reactors sourced from farms). These two projects are scheduled to run until 2023.

The DIVA skin test (DST-F) specificity* (the probability that a test will correctly identify an animal that is free from infection as negative) will be evaluated in the first phase of the field trial anticipated to be completed by early 2022. Then a decision will be made on continuation to the second phase. The performance of the DIVA skin test (DST-F) 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 (DST-F) 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 bTB restrictions for a very long time, putting business viability at risk

* The higher the specificity, the lower the probability of incorrectly classifying an uninfected animal as infected (a false positive result)

 

Phase 1 of the field trials started in June 2021.

Following an open competition, APHA awarded a contract to Eville & Jones to run veterinary field trials. Eville & Jones have brought together an experienced team for conducting the field trials to the internationally recognised high standards of Good Clinical Practice (GCP) to deliver the project.

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

  • Phase 1: Establishing the DIVA skin test (DST-F) specificity and safety in unvaccinated animals from bTB-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 (DST-F) in vaccinated cattle and further establishing the specificity of the DIVA skin test (DST-F) in different groups of vaccinated animals from herds in England and Wales.

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

  • Phase 1 is taking place on participating farms in the Low Risk Area (England)/Low TB Area (Wales). It started in June 2021 on a bTB-free farm in Hertfordshire.
  • Phase 2 will take place on participating farms in England and 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 1000 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. This would involve over seven separate herds with approximately 1000 cattle vaccinated and approximately 1000 cattle used as a control.

No, Eville & Jones is responsible for recruiting suitable farms and herds to participate on a voluntary basis.

If you are a farmer interested in taking part in this crucial research project, please contact Dr Lindsay Heasman at Eville & Jones by emailing [email protected]

 

Farmers will 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 DIVA skin test (DST-F). 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 bTB in England and Wales.

No. Progress was hampered because of not having a suitable DIVA test but research has now identified a candidate DIVA skin test (DST-F). Like other veterinary medicines, in addition to laboratory studies, both CattleBCG and the DIVA skin test (DST-F) 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 bTB. To enable trade in vaccinated cattle, we need to validate the DIVA skin test (DST-F) 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 bTB. 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 (DST-F) 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 Animal Test Certificates 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 (DST-F) or on milk from cattle vaccinated with CattleBCG.

Until we have an authorised and validated DIVA skin test (DST-F) to certify that vaccinated herds and animals are not infected for trade purposes, any deployment of an authorised CattleBCG would necessarily be limited to herds which are both under TB restrictions and sell cattle only to slaughter (potentially via approved finishing units). Once we have both an authorised CattleBCG and an authorised and validated DIVA skin test (DST-F) government would be looking at piloting large-scale deployment over a defined area in partnership with local farmers ahead of decisions on more extensive roll-out. Successful deployment would require high levels of herd participation within the defined area underpinned by suitable incentives. Voluntary deployment elsewhere may be permitted. Current expectation is that administration of CattleBCG would need to be government-authorised and veterinary-administered to ensure that vaccinated cattle are traceable via official databases. 

APHA’s Science Blog post of September 2020 provided further information on the programme of work to develop a deployable cattle vaccine.