Despite the significant progress achieved through bovine tuberculosis eradication programs based on slaughterhouse surveillance and the application in herds of the official in vivo diagnostic test (intradermal tuberculin test), with the consequent culling of animals that react to it, animal tuberculosis still remains a major problem. Whenever it is safe, effective, and compatible with diagnosis, vaccination represents a cost-effective and promising tool that can help reduce the impact and spread of this infection. It is particularly relevant in regions where the eradication strategy mentioned is socioeconomically unfeasible or has proved unsuccessful due to reasons such as the recurrence of residual infections derived from the limitations of diagnostic tests, or the existence of domestic and wild species that act as reservoirs of infection.
The live attenuated Mycobacterium bovis BCG vaccine, currently the only one authorized for humans, is also the most extensively studied in animals, showing efficacy in cattle and goats. However, its use under field conditions has not been implemented because the protection it provides is partial, due to the possible persistence of BCG bacilli in livestock products or the environment, and because vaccinated individuals may test positive in the intradermal tuberculin test without being infected (false positives). To make BCG compatible with accurate diagnosis, defined reagents capable of differentiating between infected and vaccinated animals (DIVA) have been developed. Our research groups have also pursued the use of inactivated vaccines prepared with killed bacteria, thereby avoiding issues of shelf life and persistence associated with BCG, among other concerns. Protection and interference results comparable to those of BCG have been obtained in multiple studies. Moreover, since heat inactivation can uncontrollably denature bacterial antigens that may be important for eliciting an adequate stimulation of the immune response, we explored the possibility of inactivating mycobacteria for vaccine development through bacteriophages. Mycobacteriophages infect and kill mycobacteria via specific enzymes targeting their complex cell envelope, thus preserving their antigenic repertoire more effectively than heat treatment.
Thanks to the collaborative work between members of the INNOTUB II network—NEIKER, IRTA-CReSA, and ANSES—with the support of the Universidad Autónoma de Madrid and the UK government’s Animal and Plant Health Agency, we have just published an article in the scientific journal Frontiers in Veterinary Science. It presents the preliminary developments of three vaccines based on M. bovis, M. caprae, and M. microti inactivated by phages, compared with three others based on the same mycobacteria inactivated by heat and one live attenuated M. microti vaccine, as well as the results obtained in assessing their efficacy and their interference with diagnostic techniques. In summary, it is worth highlighting that although all vaccines induced positive reactions in the official intradermal tuberculin test, all of them were nonetheless compatible with the intradermal test when DIVA reagents were used. In the experiment with infected animals, the mean bacterial load was lower in all vaccinated groups compared to the unvaccinated control group, especially in those vaccinated with M. microti and M. caprae inactivated by heat, and M. caprae inactivated by phages. These promising results warrant further studies to evaluate these vaccines and improve phage-directed inactivation.
This work was funded by the Ministry of Science and Innovation and the State Research Agency through projects PID2019-105155RB-C33 and PID2022-142939OR-C21, and by the European Union with FEDER co-funding through project EFA115/01 INNOTUB II of the INTERREG POCTEFA 2021-2027 Program. The article is freely available at the following link: https://doi.org/10.3389/fvets.2025.1620497
