A DNA Prime- Mycobacterium bovis BCG Boost Vaccination Strategy for Cattle Induces Protection against Bovine Tuberculosis

Abstract

The variable efficacy of bacillus Calmette-Guérin (Mycobacterium bovis BCG) in protecting humans and cattle against tuberculosis has prompted a search for a more effective vaccination regimen. A prime-boost strategy was investigated in cattle naturally sensitized to environmental mycobacteria by using a combination of three DNA vaccines coding for Hsp 65, Hsp 70, and Apa for priming, followed by a boost with BCG prior to experimental challenge with virulent M. bovis. Controls were vaccinated with DNA or BCG alone or were not vaccinated. The immune responses were monitored throughout the study, and protection was assessed based on reductions in the numbers of lesions and viable mycobacteria in lymph node samples. Vaccination with BCG alone or with a DNA prime-BCG boost regimen induced high levels of antigen-specific gamma interferon (IFN-␥) in whole-blood cultures. In the prime-boost group there were fewer animals with severe lung lesions, fewer lymph nodes with lesions per animal, a smaller proportion of animals with lesions, lower mean lung and lymph node lesion scores, and less M. bovis isolated from retropharyngeal and thoracic lymph nodes compared to the results obtained for the nonvaccinated animals. The prime-boost regimen induced significant enhancement of protection in six parameters, compared with significant enhancement of protection in only two parameters for BCG alone. In addition, following challenge, in vitro IFN-␥ responses against ESAT-6 and CFP-10, as well as bovine tuberculin-induced skin test and in vitro IFN-␥ responses, were identified as immunological markers that predicted protection. The use of the prime-boost strategy suggested that a combination of vaccines may be better than a single vaccine for protection against tuberculosis.

A novel live recombinant mycobacterial vaccine against bovine tuberculosis more potent than BCG

“…bovis, or a protein vaccine as a boost [28][29][30]. None of these vaccines were significantly more potent than BCG and some were less potent, including a DNA 13 vaccine that was found to be equivalent to BCG in an inbred mouse model but clearly inferior to BCG in the more stringent guinea pig model [26,27].…”

“…None of these vaccines were significantly more potent than BCG and some were less potent, including a DNA 13 vaccine that was found to be equivalent to BCG in an inbred mouse model but clearly inferior to BCG in the more stringent guinea pig model [26,27]. The most impressive vaccine regimens reported have utilized a DNA prime or a prime comprising M. bovis culture filtrate in a CpG oligodeoxynucleotide-containing adjuvant and a BCG boost; these prime-boost vaccine regimens showed a trend toward improvement over BCG in several parameters studied in cattle [29,31].…”

Immunity and Vaccination against Tuberculosis in Cattle

“…DNA vaccines have induced minimal protection against TB when used alone, although some protection has been observed when mycobacterial DNA was combined with DNA encoding co-stimulatory molecules CD80 and CD86 [67] or combined with an adjuvant [68]. More encouraging results have been reported when DNA vaccines have been used in heterologous prime-boost regimes with BCG, and priming or boosting with mycobacterial DNA vaccines induced greater protection than with BCG vaccine alone [44,69,70]. Similarly, TB protein vaccines have induced little protection in cattle when used alone, whereas when coadministered at adjacent sites with BCG have induced protection that was better than that observed with BCG alone [45,71].…”

“…Antigen-specific post-vaccination T cell central memory (Tcm) immune responses can be measured 12 weeks post-vaccination using a Cultured ELIS POT technique and serve as a positive predictor of vaccine efficacy [46••, 47, 77]. IL-17 responses to mycobacterial antigen have also been used as a positive predictor of vaccine efficacy post-vaccination, while post-challenge, IL-17 expression correlated with disease severity [44,56]. A population of poly-functional T cells that simultaneously release IFN-γ, IL-2, and TNF-α have recently been investigated from cattle naturally infected with M. bovis and revealed that these CD4 + T cells express a CD44 hi CD45RO + CD62L lo T-effector memory (TEM) phenotype which is associated with pathology [78].…”

Cellular immune response of Curraleiro Pé-duro and Nellore calves following Mycobacterium bovis-BCG vaccination

“…The release of IFN-g in infected cattle may be caused by the bacterial burden during later stages of infection, after the immune control of the pathogen has failed, leading to the destructive effects of Th1 response on tissues. Notwithstanding the negative effects that IFN-g release may cause, the specific production of IFN-g is a parameter widely used in vaccine studies (Skinner et al 2003, Waters et al 2009, De Souza et al 2012 because in mice, IFN-g production seems to be substantial for protection. Mice in which the IFN-g gene was disrupted were unable to contain or control a normally sublethal dose of M. tuberculosis.…”