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.

A number of studies conducted in the past 25 years, where vaccinated and unvaccinated animals were exposed to a stringent experimental infection with the bovine TB bacterium (Mycobacterium bovis or ‘M. bovis’), provide significant evidence that CattleBCG can reduce the severity of disease in cattle. As with other vaccines, a range of protection is expected, some animals will be fully or only partially protected after vaccination whilst others will remain susceptible to the disease.

However, these were experimental challenge studies that may not necessarily reflect performance under field conditions. A Recent international field experiment investigated the full extent of the protection BCG could offer in natural conditions. This natural transmission study showed a 74% reduction in onward bTB transmission in vaccinated animals. When this substantial indirect effect of vaccination is considered alongside the direct protection against infection, the total efficacy of BCG increases to 89%

The effectiveness of CattleBCG in reducing disease in British cattle herds under real-life, field conditions will depend on many factors, including the level of exposure to bTB. We plan to establish the protection afforded by CattleBCG to herds by continually monitoring and assessing its performance in the field during routine use over several years, as is usual for both veterinary and human vaccines. When combined with existing disease control measures, we are confident that widespread vaccination will help to further reduce the incidence of bTB and its impact on cattle farms in England and Wales.

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 (WOAH), 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, neither the WOAH’s Manual of Diagnostic Tests and Vaccines nor its Terrestrial Animal Health Code make provision for vaccination of cattle against TB at present. The Tuberculosis in Animals (England) Order 2021 prohibits the vaccination of cattle against TB without the written consent of the Secretary of State.

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 three defined antigens that induce an immune response in M. bovis-infected animals (and therefore a positive skin test result), but not in BCG vaccinates. This was developed as a companion test for use alongside CattleBCG. This development is a major 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 reacting only in those animals that became infected with the bTB bacterium despite having received the vaccine, i.e. true-positives.

The WOAH recognises that significant progress has been made in the development of DIVA tests and supports the field trials under way in the UK. 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. In its meeting of September 2021, the members of the WOAH’s Biological Standards Commission agreed that “the BCG vaccination and DIVA skin test approach looks very promising and could provide an alternative to bTB control that could be used in certain countries in certain situations” (especially in low and middle-income countries where the traditional bTB control approach of testing and slaughtering infected cattle is not affordable or socially acceptable).

Both the candidate CattleBCG vaccine and the DIVA skin test (DST-F) need UK Marketing Authorisations from the VMD in the same way as any other veterinary medicines. We also need to do further work to validate the DST-F to WOAH standards.

APHA has embarked on field trials to evaluate further the CattleBCG vaccine and DST-F. These field trials are funded through the GB bTB Research & Development budget on behalf of Defra, Welsh Government and Scottish Government. It is hoped that they will provide the additional evidence required for future UK national Marketing Authorisation applications and for the 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 DST-F.

Defra, Welsh Government and Scottish Government are also funding two supplementary research projects. One is looking at the minimum duration of immunity afforded by CattleBCG. The other is assessing the sensitivity of the DST-F in cattle naturally infected with TB (i.e. TB test reactors sourced from farms). These two projects  results will feed into the dossier to be submitted to the VMD in support of the CattleBCG and DST-F Marketing Authorisation applications.

A summary of the DST-F data generated to date at APHA demonstrates promising results. The DST-F has been shown to be effective in detecting infected animals while giving negative results in vaccinated uninfected cattle. Separate field trials and experimental studies are currently underway to obtain more precise estimates of both the specificity and sensitivity of the DST-F, respectively, in both vaccinated and unvaccinated cattle.

Phase 1 of the field trials started in June 2021 and Phase 2 in January 2023, the field component for both is now complete. Planning for Phase 3 is underway. In July 2020, Defra announced that VMD had granted permission (Animal Test Certificates) for field trials. This followed detailed assessment of applications submitted by APHA in October 2019. 

During Phase 2 of the cattle TB vaccine field trial in 2023, two vaccinated animals on one of the participating farms displayed skin reactions at or above the proposed ≥2mm positive cut-off point.  There are several potential causes for these reactions and that is why we have made the decision to collect more data on the performance of the test. While no test is perfect, we want to maximise the performance of the DIVA skin test. A further phase (Phase 3) of the trials provides the opportunity to collect field data on a larger cohort of cattle herds and explore options to optimise the performance of the test. 

We are continuing to work at pace but will only deploy the vaccine and companion DIVA skin test when we have all the right steps in place to enable the programme to be effectively delivered. We hope to be able to start using an authorised vaccine and companion diagnostic test within the next few years.

Phase 1 and Phase 2 of the Field trials have already been completed. Phase 3 of the Field Trials is due to start in 2025.

• Phase 1: Assessed the DIVA skin test (DST-F) specificity and safety in unvaccinated animals from officially TB-free (OTF) cattle herds in the Low Risk Area of England.
• Phase 2: Assessed the safety of both the CattleBCG vaccine and DST-F, and the specificity of DST-F in vaccinated animals from OTF cattle herds in low bovine TB (bTB) risk areas of England. 
• Phase 3: Gathering additional data on the DST-F reagent specificity in a broader cohort of vaccinated animals in low bTB risk areas of England and Wales to optimise the planning of the future vaccine deployment strategy.

The Animal and Plant Health Agency will lead the delivery of Phase 3 of the field trials. The additionally generated data will be used to inform the future deployment strategy. 

The completed to date phase 1 and phase 2 of the field trials were carried out on participating farms with no history of TB in the Low Risk Area (LRA) of England.  

For the upcoming Phase 3 we plan to recruit farms from the LRA of England and the low TB area of Wales. 

The field trials to date are carried out in three phases:

• Phase 1: 524 cattle from ten herds were included.
• Phase 2: 657 cattle from five herds were included. Approximately the same number of cattle in each participating herd randomly received either the vaccine or a placebo substance (i.e. used as controls).
• Phase 3: Approximately 750 cattle will be included from at least 10 herds. All included cattle will be vaccinated and subsequently tested with the DIVA skin test.

Cattle vaccinated with CattleBCG are always a proportion of the herd as opposed to the whole herd. Vaccinated animals are required to remain in their herds until the end of their productive lives or until moved directly to slaughter (England and Wales) or to an Approved/Licenced Finishing Unit (AFU/LFU) (England only). There is a designed exit strategy for herds that may be required to complete a TB skin test while vaccinated animals still remain.

No, APHA is responsible for recruiting suitable cattle herds, whose owners choose to participate in the trials on a voluntary basis.

If you believe that your herd meets the inclusion criteria and are interested in participating in the next phase of the field trials, please complete the Expression of Interest or email [email protected].

Cattle herds meeting all of the listed eligibility criteria can have a proportion of their herd considered for inclusion in the trial:

Officially TB Free (OTF) herds in the Low-Risk Area (LRA) of England or the Low TB Area (LTBA) of Wales that:

• •  have been in existence for 8 years or more
  • are not in a currently enhanced surveillance testing regime, such as radial or contiguous TB testing
  • are not in an active TB hotspot (as defined by APHA)
  • *have been OTF for a minimum of three continuous years with a herd tuberculin skin test completed within 3 calendar years
  • *have not purchased cattle from a higher TB risk area in the 12 months prior to the enrolment date

* If your herd does not meet one or both of these criteria, please still contact APHA to register your interest.

APHA is offering financial incentives for participating. You will be contributing to this world-leading research effort to bring a cattle TB vaccine and DIVA test into the toolbox of controls to combat bTB.

Financial incentives are provided, and farmers will not be financially disadvantaged through participating in the field trials.

This will depend on the outcome of phase 3. The current timeline anticipates completion of Phase 3 in 2026/7.

Data gathered from the completed field trials is currently being used to support the application to Veterinary Medicine Directorate (VMD) for marketing authorisation for the CattleBCG vaccine. Completion of the field trials will provide additional data to support the separate application for Marketing Authorisations (MA) for the DIVA skin test which is also dependent on the DST-F technology being successfully transferred to a manufacturer operating to Good Manufacturing Process.

Providing VMD considers the Marketing Authorisation applications satisfactory with respect to quality, safety and efficacy, the timeline envisages those authorisations being granted in the next few years. This would pave the way for removing or relaxing the current legal barriers to vaccinating cattle against TB in England and Wales.

No. Progress in the past was hampered because of the lack of a suitable companion DIVA test, but APHA research has now developed the DIVA skin test (DST-F). Like other veterinary medicines, in addition to laboratory studies, both CattleBCG and DST-F must be shown to be effective and safe under field conditions before VMD can authorise their use. The estimated timeframe for having a deployable CattleBCG and companion DST-F in the UK is the next few years, subject to successfully completing the field trials, successfully transferring the DST-F technology to a manufacturer operating to Good Manufacturing Process and gaining the necessary Marketing Authorisations.

The World Organisation for Animal Health (WOAH) sets animal health standards for international trade in animals and animal products as the principal reference for World Trade Organization members.

Dairy: Under WOAH standards for international trade in milk and milk products, importing countries require certification attesting that these products originate from cattle in TB-free herds or have been subjected to pasteurisation or equivalent control measures.

Meat and meat products: WOAH standards do not require any additional TB controls for international trade in fresh meat and meat products, cured hides, skins and trophies, or gelatine, collagen, tallow and meat-and-bone meal originating from animals that have been subjected to ante- and post-mortem inspections. These are considered safe commodities.

Live cattle: WOAH standards make no provision for vaccination of cattle against TB at present, as BCG vaccination interferes with internationally-accepted tuberculin-based tests which underpin current criteria for certifying herds free of TB.  Enabling international trade in vaccinated live cattle will require WOAH recognition of CattleBCG and the DIVA skin test (DST-F), and amendments to WOAH standards to clarify how they apply to trade in live cattle vaccinated against TB. The same applies to any international trade in genetic products from vaccinated live cattle which relies upon negative results of tuberculin testing.

Trade requirements are agreed on a bilateral basis between trading partners. Defra will continue to engage with WOAH and trading partners to mitigate the likelihood of any trade impacts from potential future deployment of CattleBCG and DST-F. Defra has previously considered the risk of commercial cattle buyers discriminating against cattle vaccinated against TB. A limited expert elicitation project 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. There is no withdrawal period for milk from cattle vaccinated with CattleBCG. The Animal Test Certificate permitting the field trials, requires a 90-day withdrawal period for meat and offal from cattle vaccinated with CattleBCG. Withdrawal periods for CattleBCG will be regulated in the same way as those for other veterinary medicines. Keepers are required to provide Food Chain Information for cattle sent to slaughter, declaring that withdrawal periods have been observed. There are no withdrawal periods for meat, offal or milk from cattle tested with the DST-F.

No. CattleBCG is administered subcutaneously (under the skin) and would therefore never be expected to enter the meat. There has never been any evidence for BCG vaccine lesions in cattle carcases.

Initial data obtained from testing sera collected at seven time-points over 12 months from animals in the ‘BCG duration of immunity’ study (project SE3333) suggests that BCG vaccination does not induce false-positive responses to the IDEXX Paratuberculosis Screening ELISA test.

Soil Association organic standards indicate that use of immunological veterinary medicines (vaccines) is permitted.

3.4.6 Use of vaccines is permitted. You may use immunological veterinary medicines.

Further consultation to develop a CattleBCG deployment policy is planned. Without 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 internationally recognised DST-F, government may consider piloting deployment in partnership with farmers ahead of decisions on more extensive deployment. Current expectation is that CattleBCG will need to be prescribed by a veterinary surgeon, government-authorised and administered under official veterinary control. This would ensure that vaccinated cattle are identifiable and traceable via official databases. 

Further consultation to develop a CattleBCG deployment policy is planned.

Under the Animal Test Certificate specification for the field trials, CattleBCG is indicated for cattle from 21 days of age. Administration is by subcutaneous (under the skin) injection. Current understanding, based on duration of immunity data, is that annual vaccination with CattleBCG would be necessary to maintain a protective effect.

Due to the structure of the ruminant placenta, there is no pre-partum transfer of maternal antibodies to Mycobacterium bovis from the vaccinated dam to the unborn calf.  So, any transfer of TB-specific antibodies induced by the vaccine in pregnant cows or heifers can only happen post-partum via colostrum consumption.  Any maternally-derived antibody titres in new born calves will wane over a relatively short timeframe.

Maternal antibodies transferred to neonate calves before vaccination are understood to not affect the cell-mediated immunity parameters on which both the conventional tuberculin (SICCT) and DIVA skin tests rely.  Those tests, along with the interferon-gamma blood test, do not measure M. bovis-specific antibody responses anyway. Therefore, once the cBCG vaccine is ready for deployment in the UK, for TB testing purposes there will be no need to treat the unvaccinated offspring of vaccinated cows any differently from calves born to unvaccinated dams.  This will be irrespective of whether such calves are retained in a vaccinated herd and subject to DIVA skin testing before receiving their first vaccine dose, or moved (unvaccinated) to an unvaccinated herd routinely screened for TB using the conventional tuberculin skin test.