Vaccination of Guinea Pigs with DNA Encoding the Mycobacterial Antigen MPB83 Influences Pulmonary Pathology but Not Hematogenous Spread following Aerogenic Infection withMycobacterium bovis

Abstract

Protection of cattle against bovine tuberculosis by vaccination could be an important control strategy in countries where there is persistent Mycobacterium bovis infection in wildlife and in developing countries where it is not economical to implement a tuberculin test and slaughter control program. The main aim of such a vaccination strategy would be to reduce transmission of infection by reducing the lung pathology caused by infection and preventing seeding of the organism to organs from which M. bovis could be excreted. Recent reports of successful DNA vaccination against Mycobacterium tuberculosis in small-animal models have suggested that DNA vaccines act by reducing lung pathology without sensitizing animals to tuberculin testing. We therefore evaluated the ability of vaccines consisting of DNA encoding the mycobacterial antigens MPB83 and 85A to reduce lung pathology and prevent hematogenous spread in guinea pigs challenged with a low dose of aerosolized M. bovis. Vaccination with MPB83 DNA reduced the severity of pulmonary lesions, as assessed by histopathology, and resembled M. bovis BCG vaccination in this respect. However, unlike BCG vaccination, MPB83 DNA vaccination did not protect challenged guinea pigs from hematogenous spread of organisms to the spleen. In contrast, vaccination with antigen 85A DNA, a promising DNA vaccine for human tuberculosis, had no measurable protective effect against infection with M. bovis.It has been estimated that more than 50 million cattle are infected with Mycobacterium bovis worldwide and that the resulting economic losses are approximately $3 billion (40). In developed countries pasteurization of milk and control of bovine tuberculosis (TB) by test-and slaughter-based control measures have dramatically reduced the transmission of M. bovis infection from cattle to humans. In these countries M. bovis is now predominantly an occupational zoonosis with potential risk for workers on farms, in abattoirs, and in zoos (13,19,37). In contrast, human TB caused by M. bovis is still a major health issue in many developing countries (11,12,14,20). A number of factors maintain the threat of bovine TB to human health, including the increase in the number of immunocompromised individuals (20), the emergence of strains of M. bovis resistant to known drugs (33), and, in some countries, an increasing prevalence of disease in cattle (25).In countries with little or no wildlife reservoir, test and slaughter strategies have proved to be extremely successful in controlling bovine TB. However, this approach has been less successful in countries with significant reservoirs of M. bovis in their wildlife populations, and the cost of such a strategy precludes its use in many low-income countries. In these countries vaccination may be the only available option for the control of bovine TB. In Great Britain, a recent independent scientific review for the government of the recent sharp rise in bovine TB concluded that the best prospect for future control of the disease is to develop a vaccine to ...

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

“…These include a leucine auxotroph of BCG [24], a nutritionally impaired avirulent mutant of M. bovis [25], DNA vaccines [26,27] and primeboost vaccines utilizing DNA vaccines as the prime and BCG, attenuated M.…”

“…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].…”

Animal Models of Tuberculosis: Guinea Pigs

“…Despite the opportunities to study infection caused by Mycobacterium bovis in the natural hosts (e.g., cattle and deer), guinea pigs have proven useful as an experimental tool to develop diagnostic skin test reagents (van Pinxteren et al 2000), screen mutants (Collins 2001), or perform early-stage down-selection of vaccines intended for use in cattle or wildlife (De Lisle et al 1999;Chambers et al 2002;Clark et al 2008).…”

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

“…DNA vaccines expressing mycobacterial proteins that are key targets of mycobacterial protective immunity provide both immunogenic and adjuvant components. Protection against tuberculosis has been conferred by DNA vaccines (8,13,15,17), but it has been difficult to find a vaccine that performs better than BCG by using small animal models.…”