Progress in Brucella vaccine development

Abstract

Brucella spp. are zoonotic, facultative intracellular pathogens, which cause animal and human disease. Animal disease results in abortion of fetuses; in humans, it manifests flu-like symptoms with an undulant fever, with osteoarthritis as a common complication of infection. Antibiotic regimens for human brucellosis patients may last several months and are not always completely effective. While there are no vaccines for humans, several licensed live Brucella vaccines are available for use in livestock. The performance of these animal vaccines is dependent upon the host species, dose, and route of immunization. Newly engineered live vaccines, lacking well-defined virulence factors, retain low residual virulence, are highly protective, and may someday replace currently used animal vaccines. These also have possible human applications. Moreover, due to their enhanced safety and efficacy in animal models, subunit vaccines for brucellosis show great promise for their application in livestock and humans. This review summarizes the progress of brucellosis vaccine development and presents an overview of candidate vaccines.

Keywords

Brucella / brucellosis / zoonosis / livestock vaccines

References

[1] Abu Shaqra Q M (2000). Epidemiological aspects of brucellosis in Jordan. Eur J Epidemiol, 16(6): 581-584

[2] Adone R, Ciuchini F, Marianelli C, Tarantino M, Pistoia C, Marcon G, Petrucci P, Francia M, Riccardi G, Pasquali P (2005). Protective properties of rifampin-resistant rough mutants of Brucella melitensis. Infect Immun, 73(7): 4198-4204

[3] Al-Mariri A, Tibor A, Mertens P, De Bolle X, Michel P, Godefroid J, Walravens K, Letesson J J (2001). Protection of BALB/c mice against Brucella abortus 544 challenge by vaccination with bacterioferritin or P39 recombinant proteins with CpG oligodeoxynucleotides as adjuvant. Infect Immun, 69(8): 4816-4822

[4] Alcantara R B, Read R D, Valderas M W, Brown T D, Roop R M 2nd (2004). Intact purine biosynthesis pathways are required for wild-type virulence of Brucella abortus 2308 in the BALB/c mouse model. Infect Immun, 72(8): 4911-4917

[5] Almirón M, Martínez M, Sanjuan N, Ugalde R A (2001). Ferrochelatase is present in Brucella abortus and is critical for its intracellular survival and virulence. Infect Immun, 69(10): 6225-6230

[6] Alton G G (1966). Duration of the immunity produced in goats by the Rev. 1 Brucella melitensis vaccine. J Comp Pathol, 76(3): 241-253

[7] Alton G G (1968). Further studies on the duration of the immunity produced in goats by the Rev. 1 Brucella melitensis vaccine. J Comp Pathol, 78(2): 173-178

[8] Arellano-Reynoso B, Lapaque N, Salcedo S, Briones G, Ciocchini A E, Ugalde R, Moreno E, Moriyón I, Gorvel J P (2005). Cyclic β-1,2-glucan is a Brucella virulence factor required for intracellular survival. Nat Immunol, 6(6): 618-625

[9] Arenas-Gamboa A M, Ficht T A, Davis D S, Elzer P H, Kahl-McDonagh M, Wong-Gonzalez A, Rice-Ficht A C (2009a). Oral vaccination with microencapsuled strain 19 vaccine confers enhanced protection against Brucella abortus strain 2308 challenge in red deer (Cervus elaphus elaphus). J Wildl Dis, 45(4): 1021-1029

[10] Arenas-Gamboa A M, Ficht T A, Davis D S, Elzer P H, Wong-Gonzalez A, Rice-Ficht A C (2009b). Enhanced immune response of red deer (Cervus elaphus) to live rb51 vaccine strain using composite microspheres. J Wildl Dis, 45(1): 165-173

[11] Arenas-Gamboa A M, Ficht T A, Kahl-McDonagh M M, Gomez G, Rice-Ficht A C (2009c). The Brucella abortus S19 DeltavjbR live vaccine candidate is safer than S19 and confers protection against wild-type challenge in BALB/c mice when delivered in a sustained-release vehicle. Infect Immun, 77(2): 877-884

[12] Arenas-Gamboa A M, Ficht T A, Kahl-McDonagh M M, Rice-Ficht A C (2008). Immunization with a single dose of a microencapsulated Brucella melitensis mutant enhances protection against wild-type challenge. Infect Immun, 76(6): 2448-2455

[13] Arenas-Gamboa A M, Rice-Ficht A C, Kahl-McDonagh M M, Ficht T A (2011). Protective efficacy and safety of Brucella melitensis 16MΔmucR against intraperitoneal and aerosol challenge in BALB/c mice. Infect Immun, 79(9): 3653-3658

[14] Ascón M A, Ochoa-Repáraz J, Walters N, Pascual D W (2005). Partially assembled K99 fimbriae are required for protection. Infect Immun, 73(11): 7274-7280

[15] Ashford D A, di Pietra J, Lingappa J, Woods C, Noll H, Neville B, Weyant R, Bragg S L, Spiegel R A, Tappero J, Perkins B A (2004). Adverse events in humans associated with accidental exposure to the livestock brucellosis vaccine RB51. Vaccine, 22(25-26): 3435-3439

[16] Atluri V L, Xavier M N, de Jong M F, den Hartigh A B, Tsolis R E (2011). Interactions of the human pathogenic Brucella species with their hosts. Annu Rev Microbiol, 65(1): 523-541

[17] Audic S, Lescot M, Claverie J M, Scholz H C (2009). Brucella microti: the genome sequence of an emerging pathogen. BMC Genomics, 10(1): 352

[18] Bäckhed F, Normark S, Schweda E K, Oscarson S, Richter-Dahlfors A (2003). Structural requirements for TLR4-mediated LPS signalling: a biological role for LPS modifications. Microbes Infect, 5(12): 1057-1063

[19] Baldi, P.C., Wallach, J.C., Ferrero, M.C., Delpino, M.V., and Fossati, C.A. (2008). Occupational infection due to Brucella abortus S19 among workers involved in vaccine production in Argentina. CMI, 14: 805-807

[20] Baloglu S, Boyle S M, Vemulapalli R, Sriranganathan N, Schurig G G, Toth T E (2005). Immune responses of mice to vaccinia virus recombinants expressing either Listeria monocytogenes partial listeriolysin or Brucella abortus ribosomal L7/L12 protein. Vet Microbiol, 109(1-2): 11-17

[21] Banai M (2002). Control of small ruminant brucellosis by use of Brucella melitensis Rev.1 vaccine: laboratory aspects and field observations. Vet Microbiol, 90(1-4): 497-519

[22] Bandara A B, Poff-Reichow S A, Nikolich M, Hoover D L, Sriranganathan N, Schurig G G, Dobrean V, Boyle S M (2009). Simultaneous expression of homologous and heterologous antigens in rough, attenuated Brucella melitensis. Microbes Infect, 11(3): 424-428

[23] Barquero-Calvo E, Chaves-Olarte E, Weiss D S, Guzmán-Verri C, Chacón-Díaz C, Rucavado A, Moriyón I, Moreno E (2007). Brucella abortus uses a stealthy strategy to avoid activation of the innate immune system during the onset of infection. PLoS ONE, 2(7): e631

[24] Barrio M B, Grilló M J, Muñoz P M, Jacques I, González D, de Miguel M J, Marín C M, Barberán M, Letesson J J, Gorvel J P, Moriyón I, Blasco J M, Zygmunt M S (2009). Rough mutants defective in core and O-polysaccharide synthesis and export induce antibodies reacting in an indirect ELISA with smooth lipopolysaccharide and are less effective than Rev 1 vaccine against Brucella melitensis infection of sheep. Vaccine, 27(11): 1741-1749

[25] Barrionuevo P, Delpino M V, Velásquez L N, García Samartino C, Coria L M, Ibañez A E, Rodríguez M E, Cassataro J, Giambartolomei G H (2011). Brucella abortus inhibits IFN-γ-induced FcγRI expression and FcγRI-restricted phagocytosis via toll-like receptor 2 on human monocytes/macrophages. Microbes Infect, 13(3): 239-250

[26] Beckett F W, MacDiarmid S C (1985). The effect of reduced-dose Brucella abortus strain 19 vaccination in accredited dairy herds. Br Vet J, 141(5): 507-514

[27] Bercovich Z (2000). The use of skin delayed-type hypersensitivity as an adjunct test to diagnose brucellosis in cattle: a review. Vet Q, 22(3): 123-130

[28] Bhattacharjee A K, Izadjoo M J, Zollinger W D, Nikolich M P, Hoover D L (2006). Comparison of protective efficacy of subcutaneous versus intranasal immunization of mice with a Brucella melitensis lipopolysaccharide subunit vaccine. Infect Immun, 74(10): 5820-5825

[29] Blasco J M, Díaz R (1993). Brucella melitensis Rev-1 vaccine as a cause of human brucellosis. Lancet, 342(8874): 805

[30] Blasco J M, Marín C, Jiménez de Bagüés M P, Barberán M (1993). Efficacy of Brucella suis strain 2 vaccine against Brucella ovis in rams. Vaccine, 11(13): 1291-1294

[31] Borts I H, McNUTT S H, Jordan C F (1946). Brucella melitensis isolated from swine tissues in Iowa. J Am Med Assoc, 130(14): 966-966

[32] Boschiroli M L, Cravero S L, Arese A I, Campos E, Rossetti O L (1997). Protection against infection in mice vaccinated with a Brucella abortus mutant. Infect Immun, 65(2): 798-800

[33] Bosseray N (1991). Brucella melitensis Rev. 1 living attenuated vaccine: stability of markers, residual virulence and immunogenicity in mice. Biologicals, 19(4): 355-363

[34] Bosseray N, Plommet M (1990). Brucella suis S2, brucella melitensis Rev. 1 and Brucella abortus S19 living vaccines: residual virulence and immunity induced against three Brucella species challenge strains in mice. Vaccine, 8(5): 462-468

[35] Briones G, Iñón de Iannino N, Roset M, Vigliocco A, Paulo P S, Ugalde R A (2001). Brucella abortus cyclic beta-1,2-glucan mutants have reduced virulence in mice and are defective in intracellular replication in HeLa cells. Infect Immun, 69(7): 4528-4535

[36] Burkhardt S, Jiménez de Bagüés M P, Liautard J P, Köhler S (2005). Analysis of the behavior of eryC mutants of Brucella suis attenuated in macrophages. Infect Immun, 73(10): 6782-6790

[37] Buyukcangaz E, Sen A (2007). The first isolation of Brucella melitensis from bovine aborted fetus in Turkey. J Biol Environ Sci, 1: 139-142

[38] Cabrera A, Sáez D, Céspedes S, Andrews E, Oñate A (2009). Vaccination with recombinant Semliki Forest virus particles expressing translation initiation factor 3 of Brucella abortus induces protective immunity in BALB/c mice. Immunobiology, 214(6): 467-474

[39] Caporale V, Bonfini B, Di Giannatale E, Di Provvido A, Forcella S, Giovannini A, Tittarelli M, Scacchia M (2010). Efficacy of Brucella abortus vaccine strain RB51 compared to the reference vaccine Brucella abortus strain 19 in water buffalo. Vet Ital, 46(1): 13-19, 5-11

[40] Cardena A P, Herrera D M, Zamora J L F, Pina F B, Sanchez B M, Ruiz E J G, Williams J J, Alvarez F M, Castro R F (2009). Evaluation of vaccination with Brucella abortus S19 vaccine in cattle naturally infected with brucellosis in productive systems found in the Mexican Tropic. Int J Dairy Sci, 4(4): 142-151

[41] Cassataro J, Estein S M, Pasquevich K A, Velikovsky C A, de la Barrera S, Bowden R, Fossati C A, Giambartolomei G H (2005). Vaccination with the recombinant Brucella outer membrane protein 31 or a derived 27-amino-acid synthetic peptide elicits a CD4+ T helper 1 response that protects against Brucella melitensis infection. Infect Immun, 73(12): 8079-8088

[42] Castaño M J, Solera J (2009). Chronic brucellosis and persistence of Brucella melitensis DNA. J Clin Microbiol, 47(7): 2084-2089

[43] Centers for Disease Control and Prevention (CDC) (1998). Human exposure to Brucella abortus strain RB51—Kansas, 1997. MMWR Morb Mortal Wkly Rep, 47(9): 172-175

[44] Cespedes S, Andrews E, Folch H, Oñate A (2000). Identification and partial characterisation of a new protective antigen of Brucella abortus. J Med Microbiol, 49(2): 165-170

[45] Chacón-Díaz C, Muñoz-Rodríguez M, Barquero-Calvo E, Guzmán-Verri C, Chaves-Olarte E, Grilló M J, Moreno E (2011). The use of green fluorescent protein as a marker for Brucella vaccines. Vaccine, 29(3): 577-582

[46] Chain P S, Comerci D J, Tolmasky M E, Larimer F W, Malfatti S A, Vergez L M, Aguero F, Land M L, Ugalde R A, Garcia E (2005). Whole-genome analyses of speciation events in pathogenic Brucellae. Infect Immun, 73(12): 8353-8361

[47] Cheville N F, McCullough D R, Paulson L R (1998). Brucellosis in the greater Yellowstone area, Vol National Research Council (U.S.). Board on Agriculture. National Research Council (U.S.). Board on Environmental Studies and Toxicology, Washington, D.C., National Academy Press

[48] Cheville N F, Olsen S C, Jensen A E, Stevens M G, Florance A M, Houng H S, Drazek E S, Warren R L, Hadfield T L, Hoover D L (1996a). Bacterial persistence and immunity in goats vaccinated with a purE deletion mutant or the parental 16M strain of Brucella melitensis. Infect Immun, 64(7): 2431-2439

[49] Cheville N F, Olsen S C, Jensen A E, Stevens M G, Palmer M V, Florance A M (1996b). Effects of age at vaccination on efficacy of Brucella abortus strain RB51 to protect cattle against brucellosis. Am J Vet Res, 57(8): 1153-1156

[50] Cheville N F, Stevens M G, Jensen A E, Tatum F M, Halling S M (1993). Immune responses and protection against infection and abortion in cattle experimentally vaccinated with mutant strains of Brucella abortus. Am J Vet Res, 54(10): 1591-1597

[51] Clapp B, Skyberg J A, Yang X, Thornburg T, Walters N, Pascual D W (2011a). Protective live oral brucellosis vaccines stimulate Th1 and th17 cell responses. Infect Immun, 79(10): 4165-4174

[52] Clapp B, Walters N, Thornburg T, Hoyt T, Yang X, Pascual D W (2011b). DNA vaccination of bison to brucellar antigens elicits elevated antibody and IFN-γ responses. J Wildl Dis, 47(3): 501-510

[53] Cloeckaert A, Debbarh H S, Vizcaíno N, Saman E, Dubray G, Zygmunt M S (1996). Cloning, nucleotide sequence, and expression of the Brucella melitensis bp26 gene coding for a protein immunogenic in infected sheep. FEMS Microbiol Lett, 140(2-3): 139-144

[54] Commander N J, Spencer S A, Wren B W, MacMillan A P (2007). The identification of two protective DNA vaccines from a panel of five plasmid constructs encoding Brucella melitensis 16M genes. Vaccine, 25(1): 43-54

[55] Conde-Alvarez R, Grilló M J, Salcedo S P, de Miguel M J, Fugier E, Gorvel J P, Moriyón I, Iriarte M (2006). Synthesis of phosphatidylcholine, a typical eukaryotic phospholipid, is necessary for full virulence of the intracellular bacterial parasite Brucella abortus. Cell Microbiol, 8(8): 1322-1335

[56] Confer A W, Hall S M, Faulkner C B, Espe B H, Deyoe B L, Morton R J, Smith R A (1985). Effects of challenge dose on the clinical and immune responses of cattle vaccinated with reduced doses of Brucella abortus strain 19. Vet Microbiol, 10(6): 561-575

[57] Contreras-Rodriguez A, Ramirez-Zavala B, Contreras A, Schurig G G, Sriranganathan N, Lopez-Merino A (2003). Purification and characterization of an immunogenic aminopeptidase of Brucella melitensis. Infect Immun, 71(9): 5238-5244

[58] Cook, W.E., Williams, E.S., Thorne, E.T., Kreeger, T.J., Stout, G., Bardsley, K., Edwards, H., Schurig, G., Colby, L.A., Enright, F., et al. (2002). Brucella abortus strain RB51 vaccination in elk. I. Efficacy of reduced dosage. J Wildl Dis, 38: 18-26

[59] Corbel M J (1997). Brucellosis: an overview. Emerg Infect Dis, 3(2): 213-221

[60] Crasta O R, Folkerts O, Fei Z, Mane S P, Evans C, Martino-Catt S, Bricker B, Yu G, Du L, Sobral B W (2008). Genome sequence of Brucella abortus vaccine strain S19 compared to virulent strains yields candidate virulence genes. PLoS ONE, 3(5): e2193

[61] Da Costa Martins R, Irache J M, Blasco J M, Muñoz M P, Marín C M, Jesús Grilló M, Jesús De Miguel M, Barberán M, Gamazo C (2010). Evaluation of particulate acellular vaccines against Brucella ovis infection in rams. Vaccine, 28(17): 3038-3046

[62] Davis D S, Elzer P H (2002). Brucella vaccines in wildlife. Vet Microbiol, 90(1-4): 533-544

[63] Davis D S, Templeton J W, Ficht T A, Huber J D, Angus R D, Adams L G (1991). Brucella abortus in Bison. II. Evaluation of strain 19 vaccination of pregnant cows. J Wildl Dis, 27(2): 258-264

[64] Delpino M V, Estein S M, Fossati C A, Baldi P C, Cassataro J (2007). Vaccination with Brucella recombinant DnaK and SurA proteins induces protection against Brucella abortus infection in BALB/c mice. Vaccine, 25(37-38): 6721-6729

[65] den Hartigh A B, Sun Y H, Sondervan D, Heuvelmans N, Reinders M O, Ficht T A, Tsolis R M (2004). Differential requirements for VirB1 and VirB2 during Brucella abortus infection. Infect Immun, 72(9): 5143-5149

[66] Diju I U (2009). Brucellosis—an under-estimated cause of arthralgia & muscular pains in general population. J Ayub Med Coll Abbottabad, 21(2): 128-131

[67] Diptee M D, Adesiyun A A, Asgarali Z, Campbell M, Adone R (2006). Serologic responses, biosafety and clearance of four dosages of Brucella abortus strain RB51 in 6-10 months old water buffalo (Bubalus bubalis). Vet Immunol Immunopathol, 109(1-2): 43-55

[68] Dornand J, Lafont V, Oliaro J, Terraza A, Castaneda-Roldan E, Liautard J P (2004). Impairment of intramacrophagic Brucella suis multiplication by human natural killer cells through a contact-dependent mechanism. Infect Immun, 72(4): 2303-2311

[69] Dueñas A I, Orduña A, Crespo M S, García-Rodríguez C (2004). Interaction of endotoxins with Toll-like receptor 4 correlates with their endotoxic potential and may explain the proinflammatory effect of Brucella spp. LPS. Int Immunol, 16(10): 1467-1475

[70] Dzata G K, Confer A W, Wyckoff J H 3rd (1991). The effects of adjuvants on immune responses in cattle injected with a Brucella abortus soluble antigen. Vet Microbiol, 29(1): 27-48

[71] Ebel E D, Williams M S, Tomlinson S M (2008). Estimating herd prevalence of bovine brucellosis in 46 USA states using slaughter surveillance. Prev Vet Med, 85(3-4): 295-316

[72] Edmonds M D, Cloeckaert A, Elzer P H (2002a). Brucella species lacking the major outer membrane protein Omp25 are attenuated in mice and protect against Brucella melitensis and Brucella ovis. Vet Microbiol, 88(3): 205-221

[73] Edmonds M D, Cloeckaert A, Hagius S D, Samartino L E, Fulton W T, Walker J V, Enright F M, Booth N J, Elzer P H (2002b). Pathogenicity and protective activity in pregnant goats of a Brucella melitensis Deltaomp25 deletion mutant. Res Vet Sci, 72(3): 235-239

[74] Eker A, Uzunca I, Tansel O, Birtane M (2011). A patient with brucellar cervical spondylodiscitis complicated by epidural abscess. J Clin Neurosci, 18(3): 428-430

[75] el Idrissi A H, Benkirane A, el Maadoudi M, Bouslikhane M, Berrada J, Zerouali A (2001). Comparison of the efficacy of Brucella abortus strain RB51 and Brucella melitensis Rev. 1 live vaccines against experimental infection with Brucella melitensis in pregnant ewes. Rev Sci Tech, 20(3): 741-747

[76] Elberg S S, Faunce K J Jr (1957). Immunization against Brucella infection. VI. Immunity conferred on goats by a nondependent mutant from a streptomycin-dependent mutant strain of Brucella melitensis. J Bacteriol, 73(2): 211-217

[77] Elzer P H, Edmonds M D, Hagius S D, Walker J V, Gilsdorf M J, Davis D S (1998). Safety of Brucella abortus strain RB51 in Bison. J Wildl Dis, 34(4): 825-829

[78] Entessar F, Ardalan A, Ebadi A, Jones L M (1967). Effect of living Rev. 1 vaccine in producing long-term immunity against Brucella melitensis infection in sheep in Iran. J Comp Pathol, 77(4): 367-376

[79] Eschenbrenner M, Horn T A, Wagner M A, Mujer C V, Miller-Scandle T L, DelVecchio V G (2006). Comparative proteome analysis of laboratory grown Brucella abortus 2308 and Brucella melitensis 16M. J Proteome Res, 5(7): 1731-1740

[80] Fensterbank R, Pardon P, Marly J (1982). Efficacy of Brucella melitensis Rev. 1 vaccine against Brucella ovis infection in rams. Ann Rech Vet, 13(2): 185-190

[81] Ferguson G P, Datta A, Baumgartner J, Roop R M 2nd, Carlson R W, Walker G C (2004). Similarity to peroxisomal-membrane protein family reveals that Sinorhizobium and Brucella BacA affect lipid-A fatty acids. Proc Natl Acad Sci USA, 101(14): 5012-5017

[82] Ferrero M C, Fossati C A, Baldi P C (2009). Smooth Brucella strains invade and replicate in human lung epithelial cells without inducing cell death. Microbes Infect, 11(4): 476-483

[83] Fiorentino M A, Campos E, Cravero S, Arese A, Paolicchi F, Campero C, Rossetti O (2008). Protection levels in vaccinated heifers with experimental vaccines Brucella abortus M1-luc and INTA 2. Vet Microbiol, 132(3-4): 302-311

[84] Fosgate G T, Adesiyun A A, Hird D W, Johnson W O, Hietala S K, Schurig G G, Ryan J, Diptee M D (2003). Evaluation of brucellosis RB51 vaccine for domestic water buffalo (Bubalus bubalis) in Trinidad. Prev Vet Med, 58(3-4): 211-225

[85] Foulongne V, Walravens K, Bourg G, Boschiroli M L, Godfroid J, Ramuz M, O’Callaghan D (2001). Aromatic compound-dependent Brucella suis is attenuated in both cultured cells and mouse models. Infect Immun, 69(1): 547-550

[86] Franco M P, Mulder M, Gilman R H, Smits H L (2007). Human brucellosis. Lancet Infect Dis, 7(12): 775-786

[87] Galindo R C, Muñoz P M, de Miguel M J, Marin C M, Labairu J, Revilla M, Blasco J M, Gortazar C, de la Fuente J (2010). Gene expression changes in spleens of the wildlife reservoir species, Eurasian wild boar (Sus scrofa), naturally infected with Brucella suis biovar 2. J Genet Genomics, 37(11): 725-736

[88] García-Carrillo C (1980). Comparison of B. melitensis Rev. 1 and B. abortus strain 19 as a vaccine against brucellosis in cattle. Zentralbl Veterinarmed B, 27(2): 131-138

[89] González D, Grilló M J, De Miguel M J, Ali T, Arce-Gorvel V, Delrue R M, Conde-Alvarez R, Muñoz P, López-Goñi I, Iriarte M, Marín C M, Weintraub A, Widmalm G, Zygmunt M, Letesson J J, Gorvel J P, Blasco J M, Moriyón I (2008). Brucellosis vaccines: assessment of Brucella melitensis lipopolysaccharide rough mutants defective in core and O-polysaccharide synthesis and export. PLoS ONE, 3(7): e2760

[90] Graves R R (1943). The story of John M. Buck's and Matilda's contribution to the cattle industry. J Am Vet Med Assoc, 102: 193-195

[91] Gulsun S, Aslan S, Satici O, Gul T (2011). Brucellosis in pregnancy. Trop Doct, 41(2): 82-84

[92] Haag A F, Myka K K, Arnold M F, Caro-Hernández P, Ferguson G P (2010). Importance of lipopolysaccharide and cyclic β-1,2-glucans in Brucella-mammalian infections. Int J Microbiol, 2010: 1-12

[93] Hall W H (1990). Modern chemotherapy for brucellosis in humans. Rev Infect Dis, 12(6): 1060-1099

[94] Halling S M, Peterson-Burch B D, Bricker B J, Zuerner R L, Qing Z, Li L L, Kapur V, Alt D P, Olsen S C (2005). Completion of the genome sequence of Brucella abortus and comparison to the highly similar genomes of Brucella melitensis and Brucella suis. J Bacteriol, 187(8): 2715-2726

[95] Herrera E, Rivera A, Palomares E G, Hernández-Castro R, Díaz-Aparicio E (2011). Isolation of Brucella melitensis from a RB51-vaccinated seronegative goat. Trop Anim Health Prod, 43(6): 1069-1070

[96] Hofer E, Revilla-Fernández S, Al Dahouk S, Riehm J M, Nöckler K, Zygmunt M S, Cloeckaert A, Tomaso H, Scholz H C (2011). A potential novel Brucella species isolated from mandibular lymph nodes of red foxes in Austria. Vet Microbiol, (In press)

[97] Jelastopulu E, Bikas C, Petropoulos C, Leotsinidis M (2008). Incidence of human brucellosis in a rural area in Western Greece after the implementation of a vaccination programme against animal brucellosis. BMC Public Health, 8(1): 241-245

[98] Jiménez de Bagüés M P, Barberán M, Marín C M, Blasco J M (1995). The Brucella abortus RB51 vaccine does not confer protection against Brucella ovis in rams. Vaccine, 13(3): 301-304

[99] Jiménez de Bagués M P, Marín C M, Barberán M, Blasco J M (1989). Responses of ewes to B. melitensis Rev1 vaccine administered by subcutaneous or conjunctival routes at different stages of pregnancy. Ann Rech Vet, 20(2): 205-213

[100] Kaushik P, Singh D K, Kumar S V, Tiwari A K, Shukla G, Dayal S, Chaudhuri P (2010). Protection of mice against Brucella abortus 544 challenge by vaccination with recombinant OMP28 adjuvanted with CpG oligonucleotides. Vet Res Commun, 34(2): 119-132

[101] Keller R, Hilton T D, Rios H, Boedeker E C, Kaper J B (2010). Development of a live oral attaching and effacing Escherichia coli vaccine candidate using Vibrio cholerae CVD 103-HgR as antigen vector. Microb Pathog, 48(1): 1-8

[102] Kim S, Lee D S, Watanabe K, Furuoka H, Suzuki H, Watarai M (2005). Interferon-γ promotes abortion due to Brucella infection in pregnant mice. BMC Microbiol, 5(1): 1-11

[103] Kojouri G A, Gholami M (2009). Post vaccination follow-up of Brucella melitensis in blood stream of sheep by PCR assay. Comp Clin Pathol, 18(4): 439-442

[104] Kolar J (1977). Brucella vaccines production in Mongolia. World Health Organization, Assignment Report on WHO Project MOG BLG 001, SEA/Vaccine/89, 40

[105] Kreeger T J, Cook W E, Edwards W H, Elzer P H, Olsen S C (2002). Brucella abortus strain RB51 vaccination in elk. II. Failure of high dosage to prevent abortion. J Wildl Dis, 38(1): 27-31

[106] Kreeger T J, Miller M W, Wild M A, Elzer P H, Olsen S C (2000). Safety and efficacy of Brucella abortus strain RB51 vaccine in captive pregnant elk. J Wildl Dis, 36(3): 477-483

[107] Kurar E, Splitter G A (1997). Nucleic acid vaccination of Brucella abortus ribosomal L7/L12 gene elicits immune response. Vaccine, 15(17-18): 1851-1857

[108] Lavigne J P, Patey G, Sangari F J, Bourg G, Ramuz M, O’Callaghan D, Michaux-Charachon S (2005). Identification of a new virulence factor, BvfA, in Brucella suis. Infect Immun, 73(9): 5524-5529

[109] Levine M M, Ferreccio C, Abrego P, Martin O S, Ortiz E, Cryz S (1999). Duration of efficacy of Ty21a, attenuated Salmonella typhi live oral vaccine. Vaccine, 17(Suppl 2): S22-S27

[110] Li Y K (1988). [A study on one strain of Brucella canis isolated from a cow at the first time]. Zhonghua Liu Xing Bing Xue Za Zhi, 9(6): 342-344

[111] Loisel-Meyer S, Jiménez de Bagüés M P, Bassères E, Dornand J, Köhler S, Liautard J P, Jubier-Maurin V (2006). Requirement of norD for Brucella suis virulence in a murine model of in vitro and in vivo infection. Infect Immun, 74(3): 1973-1976

[112] Lord V R, Schurig G G, Cherwonogrodzky J W, Marcano M J, Melendez G E (1998). Field study of vaccination of cattle with Brucella abortus strains RB51 and 19 under high and low disease prevalence. Am J Vet Res, 59(8): 1016-1020

[113] Manthei C A (1959). Summary of controlled research with strain 19. Proc Annu Meet US Livest Sanit Assoc, 63: 91-97

[114] Marín C M, Moreno E, Moriyón I, Díaz R, Blasco J M (1999). Performance of competitive and indirect enzyme-linked immunosorbent assays, gel immunoprecipitation with native hapten polysaccharide, and standard serological tests in diagnosis of sheep brucellosis. Clin Diagn Lab Immunol, 6(2): 269-272

[115] Martínez de Tejada G, Pizarro-Cerdá J, Moreno E, Moriyón I (1995). The outer membranes of Brucella spp. are resistant to bactericidal cationic peptides. Infect Immun, 63(8): 3054-3061

[116] Memish Z, Mah M W, Al Mahmoud S, Al Shaalan M, Khan M Y (2000). Brucella bacteraemia: clinical and laboratory observations in 160 patients. J Infect, 40(1): 59-63

[117] Minas A, Minas M, Stournara A, Tselepidis S (2004). The “effects” of Rev-1 vaccination of sheep and goats on human brucellosis in Greece. Prev Vet Med, 64(1): 41-47

[118] Mingle C K, Manthei C A, Jasmin A M (1941). The stability of reduced virulence exhibited by Brucella abortus strain 19. J Am Vet Med Assoc, 99: 203-204

[119] Moreno E, Moriyón I (2001). Genus Brucella. In Dworkin (ed.), The procaryotes: an evolving microbiological resource for the microbiological community. Springer, New York, NY

[120] Moriyón I, Grilló M J, Monreal D, González D, Marín C, López-Goñi I, Mainar-Jaime R C, Moreno E, Blasco J M (2004). Rough vaccines in animal brucellosis: structural and genetic basis and present status. Vet Res, 35(1): 1-38

[121] Mukherjee F, Jain J, Grilló M J, Blasco J M, Nair M (2005). Evaluation of Brucella abortus S19 vaccine strains by bacteriological tests, molecular analysis of ery loci and virulence in BALB/c mice. Biologicals, 33(3): 153-160

[122] Muñoz P M, de Miguel M J, Grilló M J, Marín C M, Barberán M, Blasco J M (2008). Immunopathological responses and kinetics of Brucella melitensis Rev 1 infection after subcutaneous or conjunctival vaccination in rams. Vaccine, 26(21): 2562-2569

[123] Muñoz-Montesino C, Andrews E, Rivers R, González-Smith A, Moraga-Cid G, Folch H, Céspedes S, Oñate A A (2004). Intraspleen delivery of a DNA vaccine coding for superoxide dismutase (SOD) of Brucella abortus induces SOD-specific CD4+ and CD8+ T cells. Infect Immun, 72(4): 2081-2087

[124] O’Callaghan D, Maskell D, Liew F Y, Easmon C S, Dougan G (1988). Characterization of aromatic- and purine-dependent Salmonella typhimurium: attention, persistence, and ability to induce protective immunity in BALB/c mice. Infect Immun, 56(2): 419-423

[125] Olsen S C (2010). Brucellosis in the United States: role and significance of wildlife reservoirs. Vaccine, 28(Suppl 5): F73-F76

[126] Olsen S C, Boyle S M, Schurig G G, Sriranganathan N N (2009). Immune responses and protection against experimental challenge after vaccination of bison with Brucella abortus strain RB51 or RB51 overexpressing superoxide dismutase and glycosyltransferase genes. Clin Vaccine Immunol, 16(4): 535-540

[127] Olsen S C, Fach S J, Palmer M V, Sacco R E, Stoffregen W C, Waters W R (2006). Immune responses of elk to initial and booster vaccinations with Brucella abortus strain RB51 or 19. Clin Vaccine Immunol, 13(10): 1098-1103

[128] Olsen S C, Hennager S G (2010). Immune responses and protection against experimental Brucella suis biovar 1 challenge in nonvaccinated or B. abortus strain RB51-vaccinated cattle. Clin Vaccine Immunol, 17(12): 1891-1895

[129] Olsen S C, Holland S D (2003). Safety of revaccination of pregnant bison with Brucella abortus strain RB51. J Wildl Dis, 39(4): 824-829

[130] Olsen S C, Jensen A E, Stoffregen W C, Palmer M V (2003). Efficacy of calfhood vaccination with Brucella abortus strain RB51 in protecting bison against brucellosis. Res Vet Sci, 74(1): 17-22

[131] Oñate A A, Donoso G, Moraga-Cid G, Folch H, Céspedes S, Andrews E (2005). An RNA vaccine based on recombinant Semliki Forest virus particles expressing the Cu,Zn superoxide dismutase protein of Brucella abortus induces protective immunity in BALB/c mice. Infect Immun, 73(6): 3294-3300

[132] Osorio M, Wu Y, Singh S, Merkel T J, Bhattacharyya S, Blake M S, Kopecko D J (2009). Anthrax protective antigen delivered by Salmonella enterica serovar Typhi Ty21a protects mice from a lethal anthrax spore challenge. Infect Immun, 77(4): 1475-1482

[133] Palmer M V, Cheville N F, Jensen A E (1996a). Experimental infection of pregnant cattle with the vaccine candidate Brucella abortus strain RB51: pathologic, bacteriologic, and serologic findings. Vet Pathol, 33(6): 682-691

[134] Palmer M V, Olsen S C, Gilsdorf M J, Philo L M, Clarke P R, Cheville N F (1996b). Abortion and placentitis in pregnant bison (Bison bison) induced by the vaccine candidate, Brucella abortus strain RB51. Am J Vet Res, 57(11): 1604-1607

[135] Pappas G, Akritidis N, Bosilkovski M, Tsianos E (2005). Brucellosis. N Engl J Med, 352(22): 2325-2336

[136] Pappas G, Panagopoulou P, Christou L, Akritidis N (2006a). Brucella as a biological weapon. Cell Mol Life Sci, 63(19-20): 2229-2236

[137] Pappas G, Papadimitriou P, Akritidis N, Christou L, Tsianos E V (2006b). The new global map of human brucellosis. Lancet Infect Dis, 6(2): 91-99

[138] Pasquevich K A, Estein S M, García Samartino C, Zwerdling A, Coria L M, Barrionuevo P, Fossati C A, Giambartolomei G H, Cassataro J (2009). Immunization with recombinant Brucella species outer membrane protein Omp16 or Omp19 in adjuvant induces specific CD4+ and CD8+ T cells as well as systemic and oral protection against Brucella abortus infection. Infect Immun, 77(1): 436-445

[139] Petrovska L, Hewinson R G, Dougan G, Maskell D J, Woodward M J (1999). Brucella melitensis 16M: characterisation of the galE gene and mouse immunisation studies with a galE deficient mutant. Vet Microbiol, 65(1): 21-36

[140] Phillips R W, Elzer P H, Robertson G T, Hagius S D, Walker J V, Fatemi M B, Enright F M, Roop R M 2nd (1997). A Brucella melitensis high-temperature-requirement A (htrA) deletion mutant is attenuated in goats and protects against abortion. Res Vet Sci, 63(2): 165-167

[141] Pishva E, Salehi M (2008). First report of isolation of Brucella melitensis, vaccine strain Rev.1 as a source of cattle infection in Iran. J Sci Islam Repub Iran, 19: 19-23

[142] Poester, F.P., Goncalves, V.S., Paixao, T.A., Santos, R.L., Olsen, S.C., Schurig, G.G., and Lage, A.P. (2006). Efficacy of strain RB51 vaccine in heifers against experimental brucellosis. Vaccine, 24: 5327-5334

[143] Pontes D S, Dorella F A, Ribeiro L A, Miyoshi A, Le Loir Y, Gruss A, Oliveira S C, Langella P, Azevedo V (2003). Induction of partial protection in mice after oral administration of Lactococcus lactis producing Brucella abortus L7/L12 antigen. J Drug Target, 11(8-10): 489-493

[144] Pourbagher M A, Pourbagher A, Savas L, Turunc T, Demiroglu Y Z, Erol I, Yalcintas D (2006). Clinical pattern and abdominal sonographic findings in 251 cases of brucellosis in southern Turkey. AJR Am J Roentgenol, 187(2): W191-4

[145] Pugh G W J Jr, Tabatabai L B, Bricker B J, Mayfield J E, Phillips M, Zehr E S, Belzer C A (1990). Immunogenicity of Brucella-extracted and recombinant protein vaccines in CD-1 and BALB/c mice. Am J Vet Res, 51(9): 1413-1420

[146] Radwan A I, Bekairi S I, Mukayel A A, al-Bokmy A M, Prasad P V, Azar F N, Coloyan E R (1995). Control of Brucella melitensis infection in a large camel herd in Saudi Arabia using antibiotherapy and vaccination with Rev. 1 vaccine. Rev Sci Tech, 14(3): 719-732

[147] Rafiei A, Ardestani S K, Kariminia A, Keyhani A, Mohraz M, Amirkhani A (2006). Dominant Th1 cytokine production in early onset of human brucellosis followed by switching towards Th2 along prolongation of disease. J Infect, 53(5): 315-324

[148] Rajasekaran P, Surendran N, Seleem M N, Sriranganathan N, Schurig G G, Boyle S M (2011). Over-expression of homologous antigens in a leucine auxotroph of Brucella abortus strain RB51 protects mice against a virulent B. suis challenge. Vaccine, 29(17): 3106-3110

[149] Rajashekara G, Krepps M, Eskra L, Mathison A, Montgomery A, Ishii Y, Splitter G (2005). Unraveling Brucella genomics and pathogenesis in immunocompromised IRF-1^-/- mice. Am J Reprod Immunol, 54(6): 358-368

[150] Robertson G T, Elzer P H, Roop R M 2nd (1996). In vitro and in vivo phenotypes resulting from deletion of the high temperature requirement A (htrA) gene from the bovine vaccine strain Brucella abortus S19. Vet Microbiol, 49(3-4): 197-207

[151] Roop R M 2nd, Jeffers G, Bagchi T, Walker J, Enright F M, Schurig G G (1991). Experimental infection of goat fetuses in utero with a stable, rough mutant of Brucella abortus. Res Vet Sci, 51(2): 123-127

[152] Roop R M 2nd, Phillips R W, Hagius S, Walker J V, Booth N J, Fulton W T, Edmonds M D, Elzer P H (2001). Re-examination of the role of the Brucella melitensis HtrA stress response protease in virulence in pregnant goats. Vet Microbiol, 82(1): 91-95

[153] Roth F, Zinsstag J, Orkhon D, Chimed-Ochir G, Hutton G, Cosivi O, Carrin G, Otte J (2003). Human health benefits from livestock vaccination for brucellosis: case study. Bull World Health Organ, 81(12): 867-876

[154] Sangari F J, Agüero J (1994). Identification of Brucella abortus B19 vaccine strain by the detection of DNA polymorphism at the ery locus. Vaccine, 12(5): 435-438

[155] Sangari F J, García-Lobo J M, Agüero J (1994). The Brucella abortus vaccine strain B19 carries a deletion in the erythritol catabolic genes. FEMS Microbiol Lett, 121(3): 337-342

[156] Schlabritz-Loutsevitch N E, Whatmore A M, Quance C R, Koylass M S, Cummins L B, Dick E J Jr, Snider C L, Cappelli D, Ebersole J L, Nathanielsz P W, Hubbard G B (2009). A novel Brucella isolate in association with two cases of stillbirth in non-human primates- first report. J Med Primatol, 38(1): 70-73

[157] Schurig G G, Roop R M 2nd, Bagchi T, Boyle S, Buhrman D, Sriranganathan N (1991). Biological properties of RB51; a stable rough strain of Brucella abortus. Vet Microbiol, 28(2): 171-188

[158] SCOFCAH (2011). Portugal: Results of the implementation of the sheep and goat brucellosis eradication programme 2010 Standing Committee on the Food Chain and Animal Health (SCOFCAH), Brusselshttp://ec.europa.eu/food/committees/regulatory/scfcah/animal_health/presentations/0708092011_brucellosis_portugal.pdf

[159] Scurlock B M, Edwards W H (2010). Status of brucellosis in free-ranging elk and bison in Wyoming. J Wildl Dis, 46(2): 442-449

[160] Shi D, Song Y, Li Y J (2006). [Progress on lactococcus lactis expressing heterologous antigens as live mucosal vaccines]. Wei Sheng Wu Xue Bao, 46(4): 680-683

[161] Silva T M, Costa E A, Paixão T A, Tsolis R M, Santos R L (2011a). Laboratory animal models for brucellosis research. J Biomed Biotechnol, 2011: 518323

[162] Silva T M, Paixão T A, Costa E A, Xavier M N, Sá J C, Moustacas V S, den Hartigh A B, Carvalho Neta A V, Oliveira S C, Tsolis R, Santos R L (2011b). Putative ATP-binding cassette transporter is essential for Brucella ovis pathogenesis in mice. Infect Immun, 79(4): 1706-1717

[163] Smith L D, Ficht T A (1990). Pathogenesis of Brucella. Crit Rev Microbiol, 17(3): 209-230

[164] Smither S J, Perkins S D, Davies C, Stagg A J, Nelson M, Atkins H S (2009). Development and characterization of mouse models of infection with aerosolized Brucella melitensis and Brucella suis. Clin Vaccine Immunol, 16(5): 779-783

[165] Spink W W, Hall J W 3rd, Finstad J, Mallet E (1962). Immunization with viable Brucella organisms. Results of a safety test in humans. Bull World Health Organ, 26: 409-419

[166] Stabel T J, Mayfield J E, Morfitt D C, Wannemuehler M J (1993). Oral immunization of mice and swine with an attenuated Salmonella choleraesuis [delta cya-12 delta(crp-cdt)19] mutant containing a recombinant plasmid. Infect Immun, 61(2): 610-618

[167] Stabel T J, Mayfield J E, Tabatabai L B, Wannemuehler M J (1990). Oral immunization of mice with attenuated Salmonella typhimurium containing a recombinant plasmid which codes for production of a 31-kilodalton protein of Brucella abortus. Infect Immun, 58(7): 2048-2055

[168] Stabel T J, Mayfield J E, Tabatabai L B, Wannemuehler M J (1991). Swine immunity to an attenuated Salmonella typhimurium mutant containing a recombinant plasmid which codes for production of a 31-kilodalton protein of Brucella abortus. Infect Immun, 59(9): 2941-2947

[169] Stevens M G, Hennager S G, Olsen S C, Cheville N F (1994). Serologic responses in diagnostic tests for brucellosis in cattle vaccinated with Brucella abortus 19 or RB51. J Clin Microbiol, 32(4): 1065-1066

[170] Stevens M G, Olsen S C (1996). Antibody responses to Brucella abortus 2308 in cattle vaccinated with B. abortus RB51. Infect Immun, 64(3): 1030-1034

[171] Stevens M G, Olsen S C, Cheville N F (1995a). Comparative analysis of immune responses in cattle vaccinated with Brucella abortus strain 19 or strain RB51. Vet Immunol Immunopathol, 44(3-4): 223-235

[172] Stevens M G, Olsen S C, Pugh G W Jr, Brees D (1995b). Comparison of immune responses and resistance to brucellosis in mice vaccinated with Brucella abortus 19 or RB51. Infect Immun, 63(1): 264-270

[173] Taylor A W, McDiarmid A (1949). The stability of the avirulent characters of Brucella abortus, strain 19 and strain 45/20 in lactating and pregnant cows. Vet Rec, 61: 317-318

[174] Teske S S, Huang Y, Tamrakar S B, Bartrand T A, Weir M H, Haas C N (2011). Animal and human dose-response models for Brucella species. Risk Anal, 31(10): 1576-1596

[175] Thorne E T (1997). Brucellosis, bison, elk, and cattle in the Greater Yellowstone area: defining the problem, exploring solutions. Cheyenne, Wyoming Game and Fish Dept. for Greater Yellowstone Interagency Brucellosis Committee

[176] Tibor A, Jacques I, Guilloteau L, Verger J M, Grayon M, Wansard V, Letesson J J (1998). Effect of P39 gene deletion in live Brucella vaccine strains on residual virulence and protective activity in mice. Infect Immun, 66(11): 5561-5564

[177] Trant C G, Lacerda T L, Carvalho N B, Azevedo V, Rosinha G M, Salcedo S P, Gorvel J P, Oliveira S C (2010). The Brucella abortus phosphoglycerate kinase mutant is highly attenuated and induces protection superior to that of vaccine strain 19 in immunocompromised and immunocompetent mice. Infect Immun, 78(5): 2283-2291

[178] Treanor J J, Johnson J S, Wallen R L, Cilles S, Crowley P H, Cox J J, Maehr D S, White P J, Plumb G E (2010). Vaccination strategies for managing brucellosis in Yellowstone bison. Vaccine, 28(Suppl 5): F64-F72

[179] Ugalde J E, Comerci D J, Leguizamón M S, Ugalde R A (2003). Evaluation of Brucella abortus phosphoglucomutase (pgm) mutant as a new live rough-phenotype vaccine. Infect Immun, 71(11): 6264-6269

[180] Valderas M W, Barrow W W (2008). Establishment of a method for evaluating intracellular antibiotic efficacy in Brucella abortus-infected Mono Mac 6 monocytes. J Antimicrob Chemother, 61(1): 128-134

[181] Van Campen H, Rhyan J (2010). The role of wildlife in diseases of cattle. Vet Clin North Am Food Anim Pract, 26(1): 147-161

[182] Velikovsky C A, Cassataro J, Giambartolomei G H, Goldbaum F A, Estein S, Bowden R A, Bruno L, Fossati C A, Spitz M (2002). A DNA vaccine encoding lumazine synthase from Brucella abortus induces protective immunity in BALB/c mice. Infect Immun, 70(5): 2507-2511

[183] Vemulapalli R, Contreras A, Sanakkayala N, Sriranganathan N, Boyle S M, Schurig G G (2004). Enhanced efficacy of recombinant Brucella abortus RB51 vaccines against B. melitensis infection in mice. Vet Microbiol, 102(3-4): 237-245

[184] Verger J M, Grayon M, Zundel E, Lechopier P, Olivier-Bernardin V (1995). Comparison of the efficacy of Brucella suis strain 2 and Brucella melitensis Rev. 1 live vaccines against a Brucella melitensis experimental infection in pregnant ewes. Vaccine, 13(2): 191-196

[185] Walker, G.C., LeVier, K., Phillips, R.W., Grippe, V.K., and Roop, R.M., 2nd. (2000). Similar requirements of a plant symbiont and a mammalian pathogen for prolonged intracellular survival. Science, 287: 2492-2493

[186] Wang Y, Bai Y, Qu Q, Xu J, Chen Y, Zhong Z, Qiu Y, Wang T, Du X, Wang Z, Yu S, Fu S, Yuan J, Zhen Q, Yu Y, Chen Z, Huang L (2011). The 16MΔvjbR as an ideal live attenuated vaccine candidate for differentiation between Brucella vaccination and infection. Vet Microbiol, 151(3-4): 354-362

[187] Ward D, Jackson, R., Karomatullo H, Khakimov T, Kurbonov K, Amirbekov M, Stack J, El-Idrissi A, Heuer C (2011). Brucellosis control in Tajikistan using Rev 1 vaccine: change in seroprevalence in small ruminants from 2004 to 2009. Vet Rec

[188] Whatmore A M (2009). Current understanding of the genetic diversity of Brucella, an expanding genus of zoonotic pathogens. Infect Genet Evol, 9(6): 1168-1184

[189] Winter A J, Rowe G E, Duncan J R, Eis M J, Widom J, Ganem B, Morein B (1988). Effectiveness of natural and synthetic complexes of porin and O polysaccharide as vaccines against Brucella abortus in mice. Infect Immun, 56(11): 2808-2817

[190] Wise R I (1980). Brucellosis in the United States. Past, present, and future. JAMA, 244(20): 2318-2322

[191] Wyckoff J H 3rd, Howland J L, Scott C M, Smith R A, Confer A W (2005). Recombinant bovine interleukin 2 enhances immunity and protection induced by Brucella abortus vaccines in cattle. Vet Microbiol, 111(1-2): 77-87

[192] Xavier M N, Paixão T A, Poester F P, Lage A P, Santos R L (2009). Pathological, immunohistochemical and bacteriological study of tissues and milk of cows and fetuses experimentally infected with Brucella abortus. J Comp Pathol, 140(2-3): 149-157

[193] Xin X (1986). Orally administrable brucellosis vaccine: Brucella suis strain 2 vaccine. Vaccine, 4(4): 212-216

[194] Yang X, Becker T, Walters N, Pascual D W (2006). Deletion of znuA virulence factor attenuates Brucella abortus and confers protection against wild-type challenge. Infect Immun, 74(7): 3874-3879

[195] Yang X, Hinnebusch B J, Trunkle T, Bosio C M, Suo Z, Tighe M, Harmsen A, Becker T, Crist K, Walters N, Avci R, Pascual D W (2007). Oral vaccination with salmonella simultaneously expressing Yersinia pestis F1 and V antigens protects against bubonic and pneumonic plague. J Immunol, 178(2): 1059-1067

[196] Yang X, Hudson M, Walters N, Bargatze R F, Pascual D W (2005). Selection of protective epitopes for Brucella melitensis by DNA vaccination. Infect Immun, 73(11): 7297-7303

[197] Yang X, Thornburg T, Walters N, Pascual D W (2010). DeltaznuADeltapurE Brucella abortus 2308 mutant as a live vaccine candidate. Vaccine, 28(4): 1069-1074

[198] Yang Y, Yin J, Guo D, Lang X, Wang X (2011). Immunization of mice with recombinant S-adenosyl-L-homocysteine hydrolase protein confers protection against Brucella melitensis infection. FEMS Immunol Med Microbiol, 61(2): 159-167

[199] Young E J (1989). Clinical manifestations of human brucellosis, p. 97-126. In E. J. Young and M. J. Corbel (ed.), Brucellosis: clinical and laboratory aspects. CRC Press, Inc, Boca Raton, Fla

[200] Yu D H, Hu X D, Cai H, Li M (2007). A combined DNA vaccine encoding BCSP31, SOD, and L7/L12 confers high protection against Brucella abortus 2308 by inducing specific CTL responses. DNA Cell Biol, 26(6): 435-443

[201] Zhan Y, Cheers C (1993). Endogenous gamma interferon mediates resistance to Brucella abortus infection. Infect Immun, 61(11): 4899-4901

[202] Zhao Z, Li M, Luo D, Xing L, Wu S, Duan Y, Yang P, Wang X (2009). Protection of mice from Brucella infection by immunization with attenuated Salmonella enterica serovar typhimurium expressing A L7/L12 and BLS fusion antigen of Brucella. Vaccine, 27(38): 5214-5219

[203] Zinsstag J, Roth F, Orkhon D, Chimed-Ochir G, Nansalmaa M, Kolar J, Vounatsou P (2005). A model of animal-human brucellosis transmission in Mongolia. Prev Vet Med, 69(1-2): 77-95

[204] Zowghi E, Ebadi A (1985). Naturally occurring Brucella melitensis infection in cattle in Iran. Rev Sci Tech Off Int Epiz, 4: 811-814

Acknowledgments

This work was supported by grants from National Institutes of Health Grant R21 AI-080960, 1R01 AI-093372, P20 RR020185, USDA-NIFA grant 2010-34397-21391, US Department of Agriculture Formula Funds, and Montana Agricultural Experiment Station.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg