Long-term efficacy of BCG vaccination in goat herds with a high prevalence of tuberculosis

Caprine tuberculosis (TB), caused primarily by *Mycobacterium caprae* and *Mycobacterium bovis*, significantly impacts goat health and the economy. Infected goats contribute to the epidemiology of animal TB and pose a zoonotic risk. In high-prevalence settings, eradication programs based solely on testing and culling are often not cost-effective. BCG vaccination, while not offering complete protection, has been proposed as a supplementary control measure. The efficacy of BCG against TB in livestock is variable, and one major challenge is its interference with standard diagnostic tests. Differentiation of infected from vaccinated animals (DIVA) tests have been developed to overcome this. This study aimed to assess the long-term efficacy of BCG vaccination in five goat farms, considering both herd-level effects and factors influencing vaccine success.

Previous research has demonstrated the safety and relatively low cost of BCG vaccination. Studies in cattle, goats, and wildlife have shown variable results, with some suggesting reductions in lesion extent and TB transmission. The interference of BCG with standard TB diagnostic tests like the single intradermal test (SIT) or the single intradermal cervical comparative tuberculin test (SICCT) and IGRA is a key challenge. DIVA tests have emerged to distinguish between infected and vaccinated animals. Studies have identified risk factors for TB persistence in cattle, such as herd size, housing, and feeding practices. While experimental studies showed BCG protection in goats, the influence of herd-level factors on vaccination efficacy remains unclear.

This field trial involved five goat farms in Catalonia, Spain, with confirmed *M. caprae* infections. The trial lasted 36 months. At month 0, all animals underwent SICCT and IGRA tests using *M. bovis* and *M. avium* tuberculins and a DIVA reagent. BCG-vaccinated animals were tested using IGRA with DIVA reagents at months 6, 12, 24, and 36. All replacement goat kids were vaccinated at 2–3 months of age. The BCG Danish 1331 strain was used. SICCT was performed following Spanish bovine TB eradication program recommendations. IGRA was performed and interpreted as recommended by the manufacturer. Data analysis included chi-square tests to compare TB-positive animals at months 0 and 36, and generalized mixed-effect models with Poisson error structures to evaluate TB incidence risk among BCG-vaccinated batches and influencing factors, with farm as a random effect. Model selection was based on AIC.

Vaccine efficacy varied among farms. Four of five farms showed favorable outcomes (prevalence reductions), with an overall attributable fraction (AF) of 18.1% from month 0 to 36. The overall prevalence decreased significantly. In farms with positive outcomes, unvaccinated animals represented 32.8% of TB-positive animals at month 36. Adult goats vaccinated at the beginning showed higher TB positivity than kids. The multilevel model revealed that the number of positive unvaccinated animals remaining in the herd and the number of positive adult vaccinated goats significantly increased the risk of TB infection in vaccinated animals. The initial herd prevalence was not a significant risk factor.

The study's moderate vaccine efficacy was similar to that observed in systematic reviews of BCG vaccination trials in children. The heterogeneity of results among farms mirrors observations in human studies. Differences in herd TB prevalence (ranging from 33-63% in this study compared to under 6% in some cattle studies) and intra-herd transmission rates may explain the varying efficacy. Intensive management, common in four of the five farms, likely increased animal contact and TB transmission. BCG vaccination reduced TB transmission, aligning with previous findings. Removal of positive unvaccinated animals and systematic vaccination of kids reduced TB incidence. Farm 5 showed an initial prevalence increase, possibly due to a census reduction and poor ventilation. Vaccine failure in farm 4 might be due to pre-vaccination infection in some kids. Adult vaccinated goats showed higher TB incidence than kids, potentially due to prior sensitization by environmental mycobacteria or helminth co-infections. The multilevel model confirmed a higher risk of infection in adult vaccinated goats during the first year. Protection waned after one year, indicating a need for further strategies such as BCG revaccination. Initial prevalence did not significantly influence TB risk, although high prevalence might hinder the vaccine's positive effects. The IGRA DIVA test, while highly specific, had limitations in sensitivity.

Systematic BCG vaccination of replacement goat kids reduced *M. caprae* transmission and overall TB prevalence, although individual efficacy decreased after one year. Removing positive unvaccinated goats further reduced TB risk. Additional measures such as test and cull of positive animals are crucial. This study provides valuable data for evaluating the cost-benefit of long-term BCG vaccination strategies for caprine TB control.

The study had variable outcomes across farms, highlighting the influence of herd-specific factors. The sensitivity of the IGRA DIVA test might have affected the detection of infected animals, particularly in vaccinated goats. The sample size, especially in some batches, might affect the generalization of findings. The influence of some herd-level factors was not conclusive.