Subcutaneous Administration of a 10-Fold-Lower Dose of a Commercial Human Tuberculosis Vaccine, Mycobacterium bovis Bacillus Calmette-Guérin Danish, Induced Levels of Protection against Bovine Tuberculosis and Responses in the Tuberculin Intradermal Test Similar to Those Induced by a Standard Cattle Dose

Abstract

T he human tuberculosis (TB) vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), has been shown to induce a significant level of protection in cattle against bovine TB, caused by M. bovis, in experimental challenge and field trials (1). However, the vaccine has not been used in national bovine TB control programs because cattle, at least in the first year after vaccination, may react positively to the tuberculin intradermal test, and protection may not be complete (2). Recent research showed that the problem of BCG vaccination compromising the conventional bovine TB diagnostic tests can be overcome by using tests differentiating infected from vaccinated animals (DIVA). For these tests, antigens from the Mycobacterium tuberculosis complex which are not expressed by BCG are used instead of purified protein derivative (PPD) prepared from M. bovis (bovine PPD) in the intradermal test (3) or in the whole-blood gamma interferon (IFN-␥) assay (4, 5). Furthermore, complete protection against TB by vaccination may not be essential for reducing the prevalence of TB in cattle. BCG vaccination of humans against TB is considered a valuable control strategy even though BCG vaccination of newborns and infants significantly reduces the risk of tuberculosis by only 50%, on average (per a meta-analysis of studies [6]). Renewed interest in the use of TB vaccines for cattle has arisen from the realization of the financial impact of bovine TB on animal health and trade and the fact that "test and slaughter" bovine TB control programs have been less effective in countries with wildlife reservoirs of M. bovis infection and those where these programs are not affordable or acceptable.Commercially produced lyophilized BCG Danish vaccine (Statens Serum Institute, Denmark) at a dose equivalent to 5 human doses (1 ϫ 10 6 to 4 ϫ 10 6 CFU) administered subcutaneously to cattle has been shown to induce protection against TB equivalent to that with freshly prepared cultures of BCG Pasteur and Danish strains of BCG (7). This provides a potential licensed product for use in cattle. A series of recent studies confirmed that this dose of the commercial BCG vaccine induced a significant level of protection in cattle against experimental challenge and natural exposure to Mycobacterium bovis (8,9,10). Information on the effectiveness of a lower dose of this vaccine would be valuable to determine whether small variations within the normal range in the dose of different batches of the commercially prepared vaccine affected efficacy and to provide assurance that the specified target dose is well above the minimal effective titer. In addition, the cost of the vaccine can potentially be reduced if a lower dose is efficacious. The aim of the current study was to determine whether a 10-fold-lower dose of the commercial BCG Danish vaccine administered subcutaneously induces protection against bovine TB and responses in the standard tuberculin intradermal tests equivalent to those of cattle vaccinated at the higher dose.

Effect of a low dose of BCG-Phipps vaccine on the development of reactivity to tuberculin skin test in neonatal calves and adult cows

“…This difference in reactivity percentages with our results could be related to the dose and strain used. Similar percentages of TST conversion have been reported in other studies using high vaccine doses between 10 6 -10 8 CFU in humans, wildlife animals, and mouse model (Buddle et al, 2013;Tree et al, 2004). In addition, the protective efficacy reported in those studies was lower in vaccinated animals that showed a strong DTH response to bovine PPD than those animals that did not develop it (Skinner et al, 2001;Ritz et al, 2008).…”

“…Thus, it is relevant to improve the knowledge of factors determining the development of a delayed type hypersensitivity (DTH) response, if it really develops when vaccine is given under a number of different modalities and stages (Cockle et al, 2002;Logan et al, 2005). Few studies talk about the development of a DTH response or conversion of tuberculin skin test (TST); as a result of the vaccine application, one of this studies demonstrated that DTH reaction is developed in the first months and lost in 90% of the vaccinated animals at nine months post-vaccination (Whelan et al, 2011;Buddle et al, 2013).…”

The Effect of Oral Vaccination with Mycobacterium bovis BCG on the Development of Tuberculosis in Captive European Badgers (Meles meles)

“…From the perspective of reducing both the cost of an oral vaccine and the potential for environmental contamination with BCG, we need to define the minimal efficacious dose for badgers. Given that the effective dose of injected BCG appears to bear no relationship to the size of the target animal—10 equivalent human doses of BCG Danish for badgers (Lesellier et al, 2011) compared to 0.5 equivalent human doses for cattle (Buddle et al, 2013)—these data have to be generated empirically using badgers. The objectives of the two vaccine efficacy studies (VES) reported here were to compare the efficacy of BCG Danish strain in a lipid matrix with unformulated BCG given orally (VES3) at a dose of 10 8 CFU, and to evaluate the efficacy of BCG Danish in a lipid matrix at a 10-fold lower dose than previously evaluated in badgers (VES4).…”

Increased TNF-α/IFN-γ/IL-2 and Decreased TNF-α/IFN-γ Production by Central Memory T Cells Are Associated with Protective Responses against Bovine Tuberculosis Following BCG Vaccination

“…BCG Danish is a widely used human pediatric vaccine to reduce human TB. Likewise, BCG Danish has been shown to reduce bovine TB disease burden in both experimental and field studies and has a well-established safety profile in cattle ( 1 , 46 , 47 ). The BCG Danish deletion derivatives used in this study are more attenuated and safer than the parental BCG strain in immunocompromised mice [( 48 , 49 ) and Berney-Meyer et al, unpublished data].…”