Open Access

Leptospirosis vaccines

Microbial Cell Factories20076:39

https://doi.org/10.1186/1475-2859-6-39

Received: 21 September 2007

Accepted: 11 December 2007

Published: 11 December 2007

Abstract

Leptospirosis is a serious infection disease caused by pathogenic strains of the Leptospira spirochetes, which affects not only humans but also animals. It has long been expected to find an effective vaccine to prevent leptospirosis through immunization of high risk humans or animals. Although some leptospirosis vaccines have been obtained, the vaccination is relatively unsuccessful in clinical application despite decades of research and millions of dollars spent. In this review, the recent advancements of recombinant outer membrane protein (OMP) vaccines, lipopolysaccharide (LPS) vaccines, inactivated vaccines, attenuated vaccines and DNA vaccines against leptospirosis are reviewed. A comparison of these vaccines may lead to development of new potential methods to combat leptospirosis and facilitate the leptospirosis vaccine research. Moreover, a vaccine ontology database was built for the scientists working on the leptospirosis vaccines as a starting tool.

1. Background

Leptospirosis is a widespread disease [1], caused by infection with the spirochete bacterium Leptospira, which affects almost all mammals [113]. Leptospirosis was initially described as Weil's syndrome [8, 14]. It is predominantly an occupational disease which affects humans who come into frequently contact with rodents, pets or polluted water [1518] (Fig. 1). Infection is facilitated with penetrating leptospires through mucosa or an open skin [19]. After gaining entry through the skin, the bacterium causes a serious disease [19]. The symptoms of leptospirosis are extremely broad from meningitis [20], pneumonitis [21, 22], hepatitis [23], nephritis [2427], pancreatitis [28] and erythema nodosum [29] and death [30, 31]. Fig. 2 shows the data of human leptospirosis cases reported by Ministry of Health of the People's Republic of China from January 2002 to October 2007 in China mainland. During this time, about 1,500 infected cases and 50 dead were reported. However, many human leptospirosis cases might be misdiagnosed or omitted due to poor medical care and information. Leptospira has over 200 pathogenic serovars, and divides into 25 serogroups, and many different strains with small antigenic differences can be found in some serovars [2, 17].
Figure 1

The infection pathway of Leptospire. A): Leptospires in the nature resource. B): Leptospires in the rodents or wield animals. C): Leptospires in pets. D): Leptospires in water or soil. E): The infected human can develop meningitis, pneumonitis, hepatitis, pancreatitis, nephritis and erythema nodosum. The organisms are excreted in urine. They survive for longer periods in natural waters.

Figure 2

Human leptospirosis cases in People's Republic of China during 2002–2007 in China mainland. The data were reported by the Ministry of Health of the People's Republic of China. The blue bars are the infected cases, and the yellow bars are the dead cases. The data of 2007 are the infected and dead human leptospirosis cases from January to October.

Leptospires have evolved ways to escape the immune defense. Pathogenic leptospires are able to translocate through cell monolayers at a rate significantly greater than that of nonpathogenic leptospires [32]. The rapid translocation of pathogenic leptospires between mammalian cells allows the bacteria to quickly reach the bloodstream and disseminate to multiple organs [32]. Virulent leptospires can rapidly enter kidney fibroblasts and induce a programmed cell death [33]. Thus, it is a challenge for immunologists to develop an effective and safe leptospirosis vaccine [3437]. Currently, molecular and cellular studies on leptospirosis vaccines have been focused on bacterial motility [38, 39], lipopolysaccharides (LPSs) [10, 4047], lipoproteins [4856], outer-membrane proteins (OMPs) [52, 53, 5762] and potential virulence factors [39, 6368]. However, it is still a lack of an extensive knowledge-based annotation of leptospirosis vaccines for the scientists working in the field of leptospirosis vaccines. It has inspired us to investigate the current developments of leptospirosis vaccines and to construct a database of the leptospirosis vaccines for incorporating the leptospirosis vaccine information into bioinformatics by using Microsoft SQL server technology and intelligent algorithms (see section 6 and website [69]).

Here, we classified the leptospirosis vaccines into recombinant protein vaccines, lipopolysaccharide (LPS) vaccines, inactivated and attenuated vaccines, and DNA vaccines for reviewing the current advancements in leptospirosis vaccine research.

2. Recombinant protein vaccines

Recombinant protein vaccines have a great potential against leptospirosis. Several leptospiral recombinant protein vaccines have been constructed with modern biotechnological methods [48, 53, 56, 58, 61, 7075], of which recombinant OMPs, lipoproteins, and virulence factors acquired a considerable interest.

2.1. Recombinant OMP vaccines

The protective characteristics of several recombinant OMP vaccines have been tested, including leptospiral outer membrane protein OmpL1, lipoprotein LipL41 [53], hemolysis-associated protein 1 (Hap1) [76] and immunoglobulin-like (Lig) protein [77]. In 1993, the first leptospiral OMP protein, a 31 kDa surface protein OmpL1 of Leptospira, was reported [78]. 6 years later, studies on the Golden Syrian hamster model of leptospirosis demonstrated immunoprotective effects of the leptospiral outer membrane protein OmpL1 and lipoprotein LipL41 [53]. However, after another 2 years, it was reported that adenovirus-mediated OmpL1 failed to protect gerbils against heterologous Leptospira infection, contrary to adenovirus-mediated Hap1, which induced a significant protection [76]. In 2002, a 130 kDa immunoreactive leptospiral immunoglobulin-like protein A (LigA) from L. interrogans was described [77]. Then, the immune response of LigA proteins was confirmed, as two immunoglobulin-like proteins, LigA and LigB, induced a protection against leptospires [56, 73, 74]. These results indicated that LigA and LigB may play an important role in the host cell attachment, as well as invasion during leptospiral pathogenesis [7981]. Moreover, the lig gene was shown to be useful in the detection of pathogenic Leptospira [82].

Several leptospiral outer membrane proteins, e.g. LAg42, Loa22, Lk73.5, have been recognized as leptospirosis vaccine candidates, but they were not tested in animal models for vaccine development. LAg42 is a 42 kDa inner-membrane protein. It was identified in pathogenic Leptospira as a factor involved in virulence [83]. Loa22 was found among pathogenic leptospires but not in non-pathogenic leptospires. It is located in the outer membrane and exposed on the cell surface. It has been considered as a candidate for a novel vaccine against leptospirosis [49]. Lk73.5 is a host-inducible immunogenicity protein from pathogenic L. interrogans [72]. Although the protective characteristics of LAg42, Loa22 and Lk73.5 are not available, we believe these outer membrane proteins might be suitable as vaccine candidates.

2.2. Recombinant lipoprotein vaccines

Lipoproteins are important proteins in leptospires. These proteins are abundant in the outer membrane, to which they are attached through fatty acids. Because of difficulty in production of lipoproteins in heterologous expression systems, only LipL41 was reported as a potential vaccine. However, many lipoproteins (for example: LipL32, LipL45 and LipL21) could be suitable as vaccine candidates. LipL32 [52] and LipL41 were identified as targets during natural infection by leptospires [37]. They are potentially useful for serodiagnosis and may serve as targets for vaccine design. LipL45 [67] and LipL21 [50] were described as surface membrane lipoproteins that are produced during infection and conserved among pathogenic Leptospira species. LipL45 is produced as a 45-kDa lipoprotein and it is processed to a 31-kDa C-terminal form, P31LipL45 [67]. LipL45 is also called Qlp42 [84].

Moreover, the lipoprotein-like complex glycolipoproteins (GLPs) were suggested as vaccine candidates. A glycolipoprotein (GLP) extracted from either pathogenic L. interrogans or nonpathogenic L. biflexa was shown to induce production of the tumor necrosis factor, interleukin-10 and CD69 [85]. Obviously, the reported lipoproteins (LipL32, LipL45, LipL21 and GLP) are leptospirosis vaccine candidates.

On the other hand, lipoprotein LipL36 was found not suitable as leptospirosis vaccine. LipL36 is a 36 kDa leptospiral outer membrane lipoprotein [54], which is synthesized at 30°C, but not at 37°C in vivo [84, 86]. Production of this protein was downregulated in host-adapted leptospires, suggesting that it is not involved in pathogenesis after entry into the mammalian host [62].

2.3. Recombinant virulence factor vaccines

Only a few papers were reported to identify leptospiral virulence factors, including FlaA, FlaB [87], Hsp58 [88], SphH [89, 90] and ChpK [91]. FlaA and FlaB are important components of leptospiral periplasmic flagella (PF). PF is a complex structure, composed of a core, surrounded by two sheath layers, which are important virulence factors of Leptospira [92]. In most spirochete species, the core of PF consists of at least three proteins: FlaB1, FlaB2 and FlaB3. The FlaA protein forms a sheath around the FlaB core. FlaA, together with FlaB, impact PF helical morphology [87].

Using flaA::cat, flaA::kan, flaB1::kan, flaB2::cat and flaB3::cat mutants, it was shown that these strains were less motile than the wild-type strain [38]. These results indicate that FlaA and FlaB are virulence factors of Leptospira. The gene encoding the FlaB virulence factor, flaB, can be amplified from the genomic DNA of several pathogenic serovars. Cloning and sequence analysis indicated that flaB is suitable in the detection of infection by pathogenic leptospires [93].

The virulence factor Hsp58 is a major target for the vaccine design [88]. The virulence factor hemolysin SphH is a pore-forming protein on several mammalian cells. The immune serum against the full-length hemolysin can effectively neutralize the SphH-mediated hemolytic and cytotoxic activities. SphH is required for pore formation in mammalian cell membranes and cytotoxic activities to mammalian cells [89, 90]. The virulence factor ChpK is encoded by L. interrogans chp locus, which consists of two genes: chpK and chpI. Expression of chpK in Escherichia coli results in inhibition of bacterial growth. Coexpression of chpI neutralizes ChpK toxicity. The chp locus was found in all representative pathogenic strains of L. interrogans [91]. All virulence factors described above (Hsp58, FlaA, FlaB, SphH and ChpK) can be considered as candidates for leptospirosis vaccines.

Only Lig, LipL41 and Hap1 proteins were approved as vaccines against Leptospira in animals. Many recently reported outer membrane proteins (LAg42, Loa22, Lk73.5), lipoproteins (LipL32, LipL45, LipL21 and GLP) and newly discovered virulence factors (Hsp58, FlaA, FlaB, SphH and ChpK) can help us to find more suitable vaccine candidates [14, 8, 9, 1113, 94]. Because the genomes of L. interrogans serovar Icterohaemorrhagiae Lai [63] and L. interrogans serovar Copenhageni [95] were reported, heterologous expression of leptospiral outer membrane proteins (OMPs) became possible and opened new possibilities for vaccine development [10]. The basic rout of large-scale screening of the leptospirosis vaccines is shown in Fig. 3. Before recombinant protein vaccines against leptospirosis can be used for clinical application, extensive testing is required. Recombinant protein vaccines must be free of contaminations, they should be stable and safe, and easy to transport and store.
Figure 3

Large-scale screening of the leptospirosis vaccines. A): The screening experiment is started from the Leptospira genome sequence, B): Putative outer membrane protein genes are cloned into expression vector for recombinant protein production. C): Vaccination experiments are performed in an animal model. D): Selected vaccines are applied to human for clinical application testing.

3. LPS vaccines

Analysis of LPSs should open new avenues for vaccine developments [10, 66]. The synthesis of LPSs in Leptospira is similar to that in other Gram-negative bacteria [42, 9698]. Leptospiral LPSs activate macrophages through CD14 and the Toll-like receptor 2 (TLR2) [40, 99, 100]. It is LPS, not lipoprotein, that stimulates the signaling component for macrophages through the TLR2 pathway [99]. Many reports have been published on leptospiral LPSs as vaccine candidates against leptospirosis [4347, 101103].

It has been found that a LPS vaccine may be serovar-independent. For example, LPS vaccine prepared from L. biflexa serovar Patoc can effectively protect hamsters against L. interrogans serovar Manilae. In this case, the protective effect strongly depended on the dose and administration times of LPS vaccine prepared from L. biflexa serovar Patoc [104]. However, it was also reported that a LPS vaccine can be serovar-dependent; for example, LPS vaccines prepared from several different serovar strains could not induce a protective immune response in gerbils against the strains of different serovars [105]. Obviously, further studies are required to determine whether other LPS vaccines are serovar-dependent or -independent. If LPS vaccines are serovar-independent in different animals or human, it will make LPS vaccines more simple and efficient.

In 1989, a pioneer research on leptospiral LPS vaccines was reported [44]. Immunization characteristics of LPSs and polysaccharide (PS) in hamsters were compared. When hamsters were immunized with leptospiral LPSs or PS fraction from L. interrogans serovar Copenhageni, maximum titers were observed approximately 6 weeks after immunization. The protection was achieved by immunization with as little as 2.5 μg of LPS or PS [44]. The immune characteristics of LPS were compared with PS and immunoconjugate of PS and diphtheria toxoid (DT) in mice vaccinated with these compounds. The maximum agglutinin titers could be achieved at 6–10 weeks after vaccination with LPS or PS-DT conjugate. PS-DT gave antibody titers at least 10 times higher than those produced in response to LPS. Titers obtained in experiments with antigens of serovar Pomona were higher than those of serovar Hardjo [43]. The protective ability of LPS extracts were compared with the protein extracts in experiments in which leptospirosis was induced in gerbils [105]. Total extracts induced complete protection against homologous infections and partial protection against heterologous infections. LPS fractions only protected against homologous but not heterologous infections, whereas protein extracts caused a significant protection against both types of infections [105].

Moreover, an immunogenicity of oligosaccharide fraction from the LPS of L. interrogans serovar Pomona was reported [102]. The oligosaccharide was isolated by endo-glycosidase H digestion and column chromatography purification. When conjugated to diphtheria toxoid, the oligosaccharide caused production of a significant amount of protective antibodies [102].

Several lipopolysaccharide-like substances (LSSs) were reported as Leptospira antigens [47, 106, 107]. LSS was extracted from L. interrogans with a chloroform-methanol-water solution and partially purified by silica gel column chromatography. This antigen exhibited a protective activity in hamsters infected with lethal doses of L. interrogans [106, 107]. Moreover, LLS extracted from L. interrogans by the hot phenol-water method could enhance the immunological response in vivo [47].

Since LPSs are major antigens involved in serological response [45], these molecules can be considered as candidates for serodiagnosis [41]. For example, although L. borgpetersenii subtype Hardjobovis and L. interrogans subtype Hardjoprajitno belong to different species, they are serologically indistinguishable, and thus classified as serovar Hardjo. This is because the LPSs of these subtypes are identical [103]. Hence, LPSs can be used not only as leptospirosis vaccines, but also as antigens for serodiagnostics.

Although LPSs have been tested as leptospirosis vaccines for almost 20 years, and promising results have been obtained, there are still have many problems to be solved. Between others, details of compositions and structures of leptospiral LPSs have to be determined.

4. Inactivated and attenuated vaccines

The inactivated and attenuated vaccines have been reported for more than 50 years. Some inactivated or attenuated leptospirosis vaccines were successfully tested in cattle [108116] and dog [7, 27, 117122]. Inactivated leptospirosis vaccines were also tested in human volunteers [12, 123126]. The sera from persons vaccinated with a bivalent whole cell inactivated vaccine of L. interrogans serovar Hardjo or serovar Pomona contained IgM specific to both serovars [125]. Although the only leptospirosis vaccine licensed for humans is being produced in Cuba since 2006, inactivated and attenuated vaccines still acquire considerable interests. They are especially suitable as veterinary vaccines. When dogs were vaccinated twice with such vaccines and infection with L. interrogans followed the second vaccination, a high rate of protection against L. interrogans was observed and duration of immunity was at least 1-year [127]. The efficiency of inactivated vaccine could be improved by adjuvant and vaccination frequency. A commercial inactivated leptospirosis vaccine (with adjuvant) induced a poor antibody production in cattle during preliminary vaccination. However, after booster vaccination, this vaccine caused a remarkable immune response [128]. Hydrostatic pressure-treated leptospires can be used as inactivated vaccine. After such leptospires were inoculated into rabbits, the vaccine was immunogenic [129]. The inactivated vaccine can induce a strong antigen-specific proliferative response by peripheral blood mononuclear cells (PBMC) of vaccinated cattle 2 months after the first dose of vaccine [130].

The results discussed above show that inactivated or attenuated vaccines are suitable as the leptospirosis vaccines [4, 5, 811, 13]. However, such vaccines cause safety problems [131, 132].

5. DNA vaccines

DNA vaccines have been used against different diseases [133]. These vaccines have several advantages over recombinant protein vaccines. Namely, DNA vaccines have very simple processing routes [134, 135], low prices [136], and easy administration properties [137, 138]. In just a few years, DNA vaccine technology has been developed from an interesting observation to the practical application [139141]. Surprisingly, only two leptospiral DNA vaccine trials have been reported. DNA vaccine encoding hemolysis-associated protein 1 (Hap1) was tested in gerbils, and partial protection against the infection by pathogenic strains of Leptospira was achieved [142]. Another example is the use of a DNA vaccine containing the endoflagellin gene flaB2 in experiments with guinea pigs [143]. Obviously, leptospirosis DNA vaccines need more extensive investigations. It will be very valuable to test the immune characteristics of multiple leptospirosis DNA vaccine complexes in animals.

6. Leptospirosis vaccine ontology database

With the development of leptospirosis vaccines, it is now possible to construct a database for leptospirosis vaccines. We have constructed a leptospirosis vaccine ontology database, which is available at the website [69]. In this database, we have presented information on some important leptospirosis vaccines. Each vaccine in the database has an ontology value, obtained on the basis of the experimental results from particular report and expert evaluation. We believe that this database may be helpful for scientists working in the leptospirosis field, as well as for those working on bioinformatics. The information on vaccines can be transmitted to the bioinformatics field for vaccine classification, processing optimization and predicting of vaccine efficiency from amino acid sequences or compositions without experiments on animals.

7. Future developments in leptospirosis vaccine

Vaccines are administered to a large number of healthy humans and animals to make them resistant to diseases, therefore, vaccines must be of high safety [144, 145]. There are two basic types of leptospirosis vaccines available, attenuated and inactivated leptospirosis vaccines. However, these two types of vaccines reveal significant safety problems.

The attenuated vaccines were achieved by propagation of the microbe under conditions different from those in the infected host and, hopefully, unfavorable to its growth in the host. Obviously, this method could not guarantee enough safety. It requires many tests to ensure the safety, but the safety still remains an issue. A more rational approach to attenuate the microbe would be to inactivate leptospiral components or genes known to code virulence factors. For example, an attenuated leptospiral vaccine could be developed by elimination of the leptospiral O antigen. Analogously, inactivation of the LPS biosynthetic loci (rfb) might result in attenuation a leptospiral strain. Careful analysis of genes coding for the virulence factors of Leptospira should allow us to construct attenuated strains for leptospirosis vaccines.

Inactivated leptospirosis vaccines were extensively investigated during 70–80s' of 20th century. The major problems concerned both their safety and efficacy. It appears that a combination of attenuated and inactivated leptospirosis vaccine may be highly effective. New attenuated vaccines should be designed on the basis of our knowledge about sequences of genomes and virulence determinants of the pathogens to maximize their safety.

A real breakthrough for leptospirosis vaccines was the genetic technology that allows expression of leptospiral genes in heterologous organisms. In fact, many outer membrane proteins have been obtained, which are candidates for vaccines [58]. The advantages of production of recombinant vaccine antigens in a selected heterologous host organism arises from simplicities of cultivation of the host and purification of recombinant proteins. Furthermore, recombinant proteins are useful as antigens in immunoassays to detect leptospires.

It has been reported that leptospirosis vaccines with adjuvant were more immunogenic than those without adjuvant [146]. Thus, it appears that more research is required to develop novel adjuvants for leptospirosis vaccines, like recently described bacterial tRNA adjuvant [147] and cdiGMP adjuvant [140].

Increasing attention is being devoted to the fact that infections of leptospires are naturally acquired through mucosa. Administering the vaccines by the mucosal route [148152], oral route [153156], nasal spray [157], or through topical application on the skin would be welcome [138]. The optimal formulations, adjuvants, doses and schedules are crucial for vaccine efficacy [127, 158]. The idea to produce leptospiral antigens as protein components of edible plants is indeed feasible, and the idea of the combination of leptospirosis vaccines and drugs to cure leptospirosis is very interesting [6, 8, 9, 158]. An improvement of quality of DNA vaccines and recombinant protein vaccines appears to be important for the practical application [135, 159161]. Moreover, we believe that construction of a web service, like the leptospirosis vaccine ontology database, would be important for scientists working on leptospirosis vaccines.

Declarations

Acknowledgements

We thank Professor Grzegorz Wegrzyn for discussions. This work was supported by National Natural Science Foundation of China (Grant Number: 30400077) and by Institute of Biochemistry and Biophysics of the Polish Academy of Sciences (task grant 32.1).

Authors’ Affiliations

(1)
CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
(2)
Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University
(3)
MOE Key Laboratory of Contemporary Anthropology and Center for Evolutionary Biology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University
(4)
Laboratory of Molecular Biology (affiliated with the University of Gdańsk), Institute of Biochemistry and Biophysics, Polish Academy of Sciences

References

  1. Vinetz JM: Leptospirosis. Curr Opin Infect Dis. 2001, 14: 527-538.Google Scholar
  2. Bharti AR, Nally JE, Ricaldi JN, Matthias MA, Diaz MM, Lovett MA, Levett PN, Gilman RH, Willig MR, Gotuzzo E, Vinetz JM, Peru-United States Leptospirosis Consortium: Leptospirosis: a zoonotic disease of global importance. Lancet Infect Dis. 2003, 3: 757-771. 10.1016/S1473-3099(03)00830-2.Google Scholar
  3. Yanagihara Y, Villanueva SY, Yoshida SI, Okamoto Y, Masuzawa T: Current status of leptospirosis in Japan and Philippines. Comp Immunol Microbiol Infect Dis. 2007, 30: 399-413. 10.1016/j.cimid.2007.05.003.Google Scholar
  4. Palaniappan RU, Ramanujam S, Chang YF: Leptospirosis: pathogenesis, immunity, and diagnosis. Curr Opin Infect Dis. 2007, 20: 284-292. 10.1097/QCO.0b013e32814a5729.Google Scholar
  5. Srivastava SK: Prospects of developing leptospiral vaccines for animals. Indian J Med Microbiol. 2006, 24: 331-336.Google Scholar
  6. Pappas G, Cascio A: Optimal treatment of leptospirosis: queries and projections. Int J Antimicrob Agents. 2006, 28: 491-496. 10.1016/j.ijantimicag.2006.08.021.Google Scholar
  7. Andre-Fontaine G: Canine leptospirosis – do we have a problem?. Vet Microbiol. 2006, 117: 19-24. 10.1016/j.vetmic.2006.04.005.Google Scholar
  8. McBride AJ, Athanazio DA, Reis MG, Ko AI: Leptospirosis. Curr Opin Infect Dis. 2005, 18: 376-386. 10.1097/01.qco.0000178824.05715.2c.Google Scholar
  9. Koizumi N, Watanabe H: Leptospirosis vaccines: past, present, and future. J Postgrad Med. 2005, 51: 210-214.Google Scholar
  10. Zuerner R, Haake D, Adler B, Segers R: Technological advances in the molecular biology of Leptospira. J Mol Microbiol Biotechnol. 2000, 2: 455-462.Google Scholar
  11. Plank R, Dean D: Overview of the epidemiology, microbiology, and pathogenesis of Leptospira spp. in humans. Microbes Infect. 2000, 2: 1265-1276. 10.1016/S1286-4579(00)01280-6.Google Scholar
  12. Chandrasekaran S: Review on human leptospirosis. Indian J Med Sci. 1999, 53: 291-298.Google Scholar
  13. Bey RF, Johnson RC: Current status of leptospiral vaccines. Prog Vet Microbiol Immunol. 1986, 2: 175-197.Google Scholar
  14. Looke DF: Weil's syndrome in a zoologist. Med J Aust. 1986, 144: 600-601.Google Scholar
  15. Trueba G, Zapata S, Madrid K, Cullen P, Haake D: Cell aggregation: a mechanism of pathogenic Leptospira to survive in fresh water. Int Microbiol. 2004, 7: 35-40.Google Scholar
  16. Levett PN: Leptospirosis. Clin Microbiol Rev. 2001, 14: 296-326. 10.1128/CMR.14.2.296-326.2001.Google Scholar
  17. Kuriakose M, Eapen CK, Paul R: Leptospirosis in Kolenchery, Kerala, India: epidemiology, prevalent local serogroups and serovars and a new serovar. Eur J Epidemiol. 1997, 13: 691-697. 10.1023/A:1007300729615.Google Scholar
  18. Waitkins SA: Leptospirosis as an occupational disease. Br J Ind Med. 1986, 43: 721-725.Google Scholar
  19. Schmid GP, Steere AC, Kornblatt AN, Kaufmann AF, Moss CW, Johnson RC, Hovind-Hougen K, Brenner DJ: Newly recognized Leptospira species ("Leptospira inadai" serovar lyme) isolated from human skin. J Clin Microbiol. 1986, 24: 484-486.Google Scholar
  20. Souza AL de, Sztajnbok J, Marques SR, Seguro AC: Leptospirosis-induced meningitis and acute renal failure in a 19-month-old male child. J Med Microbiol. 2006, 55: 795-797. 10.1099/jmm.0.46486-0.Google Scholar
  21. Dolhnikoff M, Mauad T, Bethlem EP, Carvalho CR: Leptospiral pneumonias. Curr Opin Pulm Med. 2007, 13: 230-235. 10.1097/MCP.0b013e3280f9df74.Google Scholar
  22. Bethlem EP, Carvalho CR: Pulmonary leptospirosis. Curr Opin Pulm Med. 2000, 6: 436-441. 10.1097/00063198-200009000-00009.Google Scholar
  23. Adamus C, Buggin-Daubie M, Izembart A, Sonrier-Pierre C, Guigand L, Masson MT, Andre-Fontaine G, Wyers M: Chronic hepatitis associated with leptospiral infection in vaccinated beagles. J Comp Pathol. 1997, 117: 311-328. 10.1016/S0021-9975(97)80079-5.Google Scholar
  24. Daher E, Zanetta DM, Cavalcante MB, Abdulkader RC: Risk factors for death and changing patterns in leptospirosis acute renal failure. Am J Trop Med Hyg. 1999, 61: 630-634.Google Scholar
  25. Morsi HM, Shibley GP, Strother HL: Renal leptospirosis: challenge exposure to vaccinated and nonvaccinated cattle to Leptospira icterohaemorrhagiae and Leptospira canicola. Am J Vet Res. 1973, 34: 175-179.Google Scholar
  26. Schreiber P, Martin V, Najbar W, Sanquer A, Gueguen S, Lebreux B: Prevention of renal infection and urinary shedding in dogs by a Leptospira vaccination. Vet Microbiol. 2005, 108: 113-118. 10.1016/j.vetmic.2005.03.007.Google Scholar
  27. Broughton ES, Scarnell J: Prevention of renal carriage of leptospirosis in dogs by vaccination. Vet Rec. 1985, 117: 307-311.Google Scholar
  28. Spichler A, Spichler E, Moock M, Vinetz JM, Leake JA: Acute pancreatitis in fatal anicteric leptospirosis. Am J Trop Med Hyg. 2007, 76: 886-887.Google Scholar
  29. Derham RL, Owens GG, Wooldridge MA: Leptospirosis as a cause of erythema nodosum. Br Med J. 1976, 2: 403-404.Google Scholar
  30. Katz AR, Ansdell VE, Effler PV, Middleton CR, Sasaki DM: Assessment of the clinical presentation and treatment of 353 cases of laboratory-confirmed leptospirosis in Hawaii, 1974–1998. Clin Infect Dis. 2001, 33: 1834-1841. 10.1086/324084.Google Scholar
  31. Christova I, Tasseva E, Manev H: Human leptospirosis in Bulgaria, 1989–2001: epidemiological, clinical, and serological features. Scand J Infect Dis. 2003, 35: 869-872. 10.1080/00365540310016709.Google Scholar
  32. Barocchi MA, Ko AI, Reis MG, McDonald KL, Riley LW: Rapid translocation of polarized MDCK cell monolayers by Leptospira interrogans, an invasive but nonintracellular pathogen. Infect Immun. 2002, 70: 6926-6932. 10.1128/IAI.70.12.6926-6932.2002.Google Scholar
  33. Merien F, Baranton G, Perolat P: Invasion of Vero cells and induction of apoptosis in macrophages by pathogenic Leptospira interrogans are correlated with virulence. Infect Immun. 1997, 65: 729-738.Google Scholar
  34. Gordon PJ: Control of leptospirosis by vaccination. Vet Rec. 2002, 150: 420-Google Scholar
  35. Little TW, Hathaway SC, Boughton ES, Seawright D: Development of a control strategy for Leptospira hardjo infection in a closed beef herd. Vet Rec. 1992, 131: 383-386.Google Scholar
  36. Little TW, Hathaway SC, Broughton ES, Seawright D: Control of Leptospira hardjo infection in beef cattle by whole-herd vaccination. Vet Rec. 1992, 131: 90-92.Google Scholar
  37. Guerreiro H, Croda J, Flannery B, Mazel M, Matsunaga J, Galvao Reis M, Levett PN, Ko AI, Haake DA: Leptospiral proteins recognized during the humoral immune response to leptospirosis in humans. Infect Immun. 2001, 69: 4958-4968. 10.1128/IAI.69.8.4958-4968.2001.Google Scholar
  38. Li C, Motaleb A, Sal M, Goldstein SF, Charon NW: Spirochete periplasmic flagella and motility. J Mol Microbiol Biotechnol. 2000, 2: 345-354.Google Scholar
  39. Charon NW, Goldstein SF: Genetics of motility and chemotaxis of a fascinating group of bacteria: the spirochetes. Annu Rev Genet. 2002, 36: 47-73. 10.1146/annurev.genet.36.041602.134359.Google Scholar
  40. Erridge C, Pridmore A, Eley A, Stewart J, Poxton IR: Lipopolysaccharides of Bacteroides fragilis, Chlamydia trachomatis and Pseudomonas aeruginosa signal via toll-like receptor 2. J Med Microbiol. 2004, 53: 735-740. 10.1099/jmm.0.45598-0.Google Scholar
  41. Priya CG, Bhavani K, Rathinam SR, Muthukkaruppan VR: Identification and evaluation of LPS antigen for serodiagnosis of uveitis associated with leptospirosis. J Med Microbiol. 2003, 52: 667-673. 10.1099/jmm.0.05120-0.Google Scholar
  42. Bulach DM, Kalambaheti T, de la Pena-Moctezuma A, Adler B: Lipopolysaccharide biosynthesis in Leptospira. J Mol Microbiol Biotechnol. 2000, 2: 375-380.Google Scholar
  43. Midwinter A, Faine S, Adler B: Vaccination of mice with lipopolysaccharide (LPS) and LPS-derived immuno-conjugates from Leptospira interrogans. J Med Microbiol. 1990, 33: 199-204.Google Scholar
  44. Jost BH, Adler B, Faine S: Experimental immunisation of hamsters with lipopolysaccharide antigens of Leptospira interrogans. J Med Microbiol. 1989, 29: 115-120.Google Scholar
  45. Vinh TU, Shi MH, Adler B, Faine S: Characterization and taxonomic significance of lipopolysaccharides of Leptospira interrogans serovar hardjo. J Gen Microbiol. 1989, 135: 2663-2673.Google Scholar
  46. Shimizu T, Matsusaka E, Nagakura N, Takayanagi K, Masuzawa T, Iwamoto Y, Morita T, Mifuchi I, Yanagihara Y: Chemical properties of lipopolysaccharide-like substance (LLS) extracted from Leptospira interrogans serovar canicola strain Moulton. Microbiol Immunol. 1987, 31: 717-725.Google Scholar
  47. Shimizu T, Matsusaka E, Takayanagi K, Masuzawa T, Iwamoto Y, Morita T, Mifuchi I, Yanagihara Y: Biological activities of lipopolysaccharide-like substance (LLS) extracted from Leptospira interrogans serovar canicola strain Moulton. Microbiol Immunol. 1987, 31: 727-735.Google Scholar
  48. Seixas FK, Fernandes CH, Hartwig DD, Conceicao FR, Aleixo JA, Dellagostin OA: Evaluation of different ways of presenting LipL32 to the immune system with the aim of developing a recombinant vaccine against leptospirosis. Can J Microbiol. 2007, 53: 472-479.Google Scholar
  49. Koizumi N, Watanabe H: Molecular cloning and characterization of a novel leptospiral lipoprotein with OmpA domain. FEMS Microbiol Lett. 2003, 226: 215-219. 10.1016/S0378-1097(03)00619-0.Google Scholar
  50. Cullen PA, Haake DA, Bulach DM, Zuerner RL, Adler B: LipL21 is a novel surface-exposed lipoprotein of pathogenic Leptospira species. Infect Immun. 2003, 71: 2414-2421. 10.1128/IAI.71.5.2414-2421.2003.Google Scholar
  51. Yang CW, Wu MS, Pan MJ, Hsieh WJ, Vandewalle A, Huang CC: The Leptospira outer membrane protein LipL32 induces tubulointerstitial nephritis-mediated gene expression in mouse proximal tubule cells. J Am Soc Nephrol. 2002, 13: 2037-2045. 10.1097/01.ASN.0000022007.91733.62.Google Scholar
  52. Haake DA, Chao G, Zuerner RL, Barnett JK, Barnett D, Mazel M, Matsunaga J, Levett PN, Bolin CA: The leptospiral major outer membrane protein LipL32 is a lipoprotein expressed during mammalian infection. Infect Immun. 2000, 68: 2276-2285. 10.1128/IAI.68.4.2276-2285.2000.Google Scholar
  53. Haake DA, Mazel MK, McCoy AM, Milward F, Chao G, Matsunaga J, Wagar EA: Leptospiral outer membrane proteins OmpL1 and LipL41 exhibit synergistic immunoprotection. Infect Immun. 1999, 67: 6572-6582.Google Scholar
  54. Haake DA, Martinich C, Summers TA, Shang ES, Pruetz JD, McCoy AM, Mazel MK, Bolin CA: Characterization of leptospiral outer membrane lipoprotein LipL36: downregulation associated with late-log-phase growth and mammalian infection. Infect Immun. 1998, 66: 1579-1587.Google Scholar
  55. Shang ES, Summers TA, Haake DA: Molecular cloning and sequence analysis of the gene encoding LipL41, a surface-exposed lipoprotein of pathogenic Leptospira species. Infect Immun. 1996, 64: 2322-2330.Google Scholar
  56. Koizumi N, Watanabe H: Leptospiral immunoglobulin-like proteins elicit protective immunity. Vaccine. 2004, 22: 1545-1552. 10.1016/j.vaccine.2003.10.007.Google Scholar
  57. Gebriel AM, Subramaniam G, Sekaran SD: The detection and characterization of pathogenic Leptospira and the use of OMPs as potential antigens and immunogens. Trop Biomed. 2006, 23: 194-207.Google Scholar
  58. Gamberini M, Gomez RM, Atzingen MV, Martins EA, Vasconcellos SA, Romero EC, Leite LC, Ho PL, Nascimento AL: Whole-genome analysis of Leptospira interrogans to identify potential vaccine candidates against leptospirosis. FEMS Microbiol Lett. 2005, 244: 305-313. 10.1016/j.femsle.2005.02.004.Google Scholar
  59. Yan Y, Chen Y, Liou W, Ding J, Chen J, Zhang J, Zhang A, Zhou W, Gao Z, Ye X, Xiao Y: An evaluation of the serological and epidemiological effects of the outer envelope vaccine to leptospira. J Chin Med Assoc. 2003, 66: 224-230.Google Scholar
  60. Haake DA, Matsunaga J: Characterization of the leptospiral outer membrane and description of three novel leptospiral membrane proteins. Infect Immun. 2002, 70: 4936-4945. 10.1128/IAI.70.9.4936-4945.2002.Google Scholar
  61. Cullen PA, Cordwell SJ, Bulach DM, Haake DA, Adler B: Global analysis of outer membrane proteins from Leptospira interrogans serovar Lai. Infect Immun. 2002, 70: 2311-2318. 10.1128/IAI.70.5.2311-2318.2002.Google Scholar
  62. Barnett JK, Barnett D, Bolin CA, Summers TA, Wagar EA, Cheville NF, Hartskeerl RA, Haake DA: Expression and distribution of leptospiral outer membrane components during renal infection of hamsters. Infect Immun. 1999, 67: 853-861.Google Scholar
  63. Ren SX, Fu G, Jiang XG, Zeng R, Miao YG, Xu H, Zhang YX, Xiong H, Lu G, Lu LF, Jiang HQ, Jia J, Tu YF, Jiang JX, Gu WY, Zhang YQ, Cai Z, Sheng HH, Yin HF, Zhang Y, Zhu GF, Wan M, Huang HL, Qian Z, Wang SY, Ma W, Yao ZJ, Shen Y, Qiang BQ, Xia QC, Guo XK, Danchin A, Saint Girons I, Somerville RL, Wen YM, Shi MH, Chen Z, Xu JG, Zhao GP: Unique physiological and pathogenic features of Leptospira interrogans revealed by whole-genome sequencing. Nature. 2003, 422: 888-893. 10.1038/nature01597.Google Scholar
  64. Gitton X, Daubie MB, Andre F, Ganiere JP, Andre-Fontaine G: Recognition of Leptospira interrogans antigens by vaccinated or infected dogs. Vet Microbiol. 1994, 41: 87-97. 10.1016/0378-1135(94)90138-4.Google Scholar
  65. Nervig RM, Ellinghausen HC, Cardella MA: Growth, virulence, and immunogenicity of Leptospira interrogans serotype szwajizak. Am J Vet Res. 1977, 38: 1421-1424.Google Scholar
  66. Ellinghausen HC, Painter GM: Growth, survival, antigenic stability, and virulence of Leptospira interrogans serotype canicola. J Med Microbiol. 1976, 9: 29-37.Google Scholar
  67. Matsunaga J, Young TA, Barnett JK, Barnett D, Bolin CA, Haake DA: Novel 45-kilodalton leptospiral protein that is processed to a 31-kilodalton growth-phase-regulated peripheral membrane protein. Infect Immun. 2002, 70: 323-334. 10.1128/IAI.70.1.323-334.2002.Google Scholar
  68. Yang HL, Zhu YZ, Qin JH, He P, Jiang XC, Zhao GP, Guo XK: In silico and microarray-based genomic approaches to identifying potential vaccine candidates against Leptospira interrogans. BMC Genomics. 2006, 7: 293-10.1186/1471-2164-7-293.Google Scholar
  69. Leptospirosis vaccine ontology database. [http://www.computationalmedicalbiology.org]
  70. Shang ES, Exner MM, Summers TA, Martinich C, Champion CI, Hancock RE, Haake DA: The rare outer membrane protein, OmpL1, of pathogenic Leptospira species is a heat-modifiable porin. Infect Immun. 1995, 63: 3174-3181.Google Scholar
  71. Dai B, Chen Z, Yan H, Zhao H, Li S: PCR amplification, molecular cloning, DNA sequence analysis and immuno/protection in BALB/C mice of the 33 kDa endoflagellar protein of L. interrorgans serovar lai. Chin Med Sci J. 1997, 12: 15-21.Google Scholar
  72. Artiushin S, Timoney JF, Nally J, Verma A: Host-inducible immunogenic sphingomyelinase-like protein, Lk73.5, of Leptospira interrogans. Infect Immun. 2004, 72: 742-749. 10.1128/IAI.72.2.742-749.2004.Google Scholar
  73. Palaniappan RU, McDonough SP, Divers TJ, Chen CS, Pan MJ, Matsumoto M, Chang YF: Immunoprotection of recombinant leptospiral immunoglobulin-like protein A against Leptospira interrogans serovar Pomona infection. Infect Immun. 2006, 74: 1745-1750. 10.1128/IAI.74.3.1745-1750.2006.Google Scholar
  74. Silva EF, Medeiros MA, McBride AJ, Matsunaga J, Esteves GS, Ramos JG, Santos CS, Croda J, Homma A, Dellagostin OA, Haake DA, Reis MG, Ko AI: The terminal portion of leptospiral immunoglobulin-like protein LigA confers protective immunity against lethal infection in the hamster model of leptospirosis. Vaccine. 2007, 25: 6277-6286. 10.1016/j.vaccine.2007.05.053.Google Scholar
  75. Brown JA, LeFebvre RB, Pan MJ: Protein and antigen profiles of prevalent serovars of Leptospira interrogans. Infect Immun. 1991, 59: 1772-1777.Google Scholar
  76. Branger C, Sonrier C, Chatrenet B, Klonjkowski B, Ruvoen-Clouet N, Aubert A, Andre-Fontaine G, Eloit M: Identification of the hemolysis-associated protein 1 as a cross-protective immunogen of Leptospira interrogans by adenovirus-mediated vaccination. Infect Immun. 2001, 69: 6831-6838. 10.1128/IAI.69.11.6831-6838.2001.Google Scholar
  77. Palaniappan RU, Chang YF, Jusuf SS, Artiushin S, Timoney JF, McDonough SP, Barr SC, Divers TJ, Simpson KW, McDonough PL, Mohammed HO: Cloning and molecular characterization of an immunogenic LigA protein of Leptospira interrogans. Infect Immun. 2002, 70: 5924-5930. 10.1128/IAI.70.11.5924-5930.2002.Google Scholar
  78. Haake DA, Champion CI, Martinich C, Shang ES, Blanco DR, Miller JN, Lovett MA: Molecular cloning and sequence analysis of the gene encoding OmpL1, a transmembrane outer membrane protein of pathogenic Leptospira spp. J Bacteriol. 1993, 175: 4225-4234.Google Scholar
  79. Lin YP, Chang YF: A domain of the Leptospira LigB contributes to high affinity binding of fibronectin. Biochem Biophys Res Commun. 2007, 362: 443-448. 10.1016/j.bbrc.2007.07.196.Google Scholar
  80. Wiwanitkit V: Predicted epitopes of Lig A of Leptospira interrogans by bioinformatics method: a clue for further vaccine development. Vaccine. 2007, 25: 2768-2770. 10.1016/j.vaccine.2006.12.023.Google Scholar
  81. Choy HA, Kelley MM, Chen TL, Møller AK, Matsunaga J, Haake DA: Physiological osmotic induction of Leptospira interrogans adhesion: LigA and LigB bind extracellular matrix proteins and fibrinogen. Infect Immun. 2007, 75: 2441-2450. 10.1128/IAI.01635-06.Google Scholar
  82. Palaniappan RU, Chang YF, Chang CF, Pan MJ, Yang CW, Harpending P, McDonough SP, Dubovi E, Divers T, Qu J, Roe B: Evaluation of lig-based conventional and real time PCR for the detection of pathogenic leptospires. Mol Cell Probes. 2005, 19: 111-117. 10.1016/j.mcp.2004.10.002.Google Scholar
  83. Koizumi N, Watanabe H: Identification of a novel antigen of pathogenic Leptospira spp. that reacted with convalescent mice sera. J Med Microbiol. 2003, 52: 585-589. 10.1099/jmm.0.05148-0.Google Scholar
  84. Nally JE, Artiushin S, Timoney JF: Molecular characterization of thermoinduced immunogenic proteins Q1p42 and Hsp15 of Leptospira interrogans. Infect Immun. 2001, 69: 7616-7624. 10.1128/IAI.69.12.7616-7624.2001.Google Scholar
  85. Diament D, Brunialti MK, Romero EC, Kallas EG, Salomao R: Peripheral blood mononuclear cell activation induced by Leptospira interrogans glycolipoprotein. Infect Immun. 2002, 70: 1677-1683. 10.1128/IAI.70.4.1677-1683.2002.Google Scholar
  86. Nally JE, Timoney JF, Stevenson B: Temperature-regulated protein synthesis by Leptospira interrogans. Infect Immun. 2001, 69: 400-404. 10.1128/IAI.69.1.400-404.2001.Google Scholar
  87. Picardeau M, Brenot A, Saint Girons I: First evidence for gene replacement in Leptospira spp. Inactivation of L. biflexa flaB results in non-motile mutants deficient in endoflagella. Mol Microbiol. 2001, 40: 189-199. 10.1046/j.1365-2958.2001.02374.x.Google Scholar
  88. Park SH, Ahn BY, Kim MJ: Expression and immunologic characterization of recombinant heat shock protein 58 of Leptospira species: a major target antigen of the humoral immune response. DNA Cell Biol. 1999, 18: 903-910. 10.1089/104454999314764.Google Scholar
  89. Lee SH, Kim S, Park SC, Kim MJ: Cytotoxic activities of Leptospira interrogans hemolysin SphH as a pore-forming protein on mammalian cells. Infect Immun. 2002, 70: 315-322. 10.1128/IAI.70.1.315-322.2002.Google Scholar
  90. Lee SH, Kim KA, Park YG, Seong IW, Kim MJ, Lee YJ: Identification and partial characterization of a novel hemolysin from Leptospira interrogans serovar lai. Gene. 2000, 254: 19-28. 10.1016/S0378-1119(00)00293-6.Google Scholar
  91. Picardeau M, Le Dantec C, Richard GF, Saint Girons I: The spirochetal chpK-chromosomal toxin-antitoxin locus induces growth inhibition of yeast and mycobacteria. FEMS Microbiol Lett. 2003, 229: 277-281. 10.1016/S0378-1097(03)00848-6.Google Scholar
  92. Trueba GA, Bolin CA, Zuerner RL: Characterization of the periplasmic flagellum proteins of Leptospira interrogans. J Bacteriol. 1992, 174: 4761-4768.Google Scholar
  93. Lin M, Surujballi O, Nielsen K, Nadin-Davis S, Randall G: Identification of a 35-kilodalton serovar-cross-reactive flagellar protein, FlaB, from Leptospira interrogans by N-terminal sequencing, gene cloning, and sequence analysis. Infect Immun. 1997, 65: 4355-4359.Google Scholar
  94. Boutilier P, Carr A, Schulman RL: Leptospirosis in dogs: a serologic survey and case series 1996 to 2001. Vet Ther. 2003, 4: 387-396.Google Scholar
  95. Nascimento AL, Verjovski-Almeida S, Van Sluys MA, Monteiro-Vitorello CB, Camargo LE, Digiampietri LA, Harstkeerl RA, Ho PL, Marques MV, Oliveira MC, Setubal JC, Haake DA, Martins EA: Genome features of Leptospira interrogans serovar Copenhageni. Braz J Med Biol Res. 2004, 37: 459-477. 10.1590/S0100-879X2004000400003.Google Scholar
  96. de la Pena-Moctezuma A, Bulach DM, Adler B: Genetic differences among the LPS biosynthetic loci of serovars of Leptospira interrogans and Leptospira borgpetersenii. FEMS Immunol Med Microbiol. 2001, 31: 73-81.Google Scholar
  97. Bulach DM, Kalambaheti T, de la Pena-Moctezuma A, Adler B: Functional analysis of genes in the rfb locus of Leptospira borgpetersenii serovar Hardjo subtype Hardjobovis. Infect Immun. 2000, 68: 3793-3798. 10.1128/IAI.68.7.3793-3798.2000.Google Scholar
  98. Kalambaheti T, Bulach DM, Rajakumar K, Adler B: Genetic organization of the lipopolysaccharide O-antigen biosynthetic locus of Leptospira borgpetersenii serovar Hardjobovis. Microb Pathog. 1999, 27: 105-117. 10.1006/mpat.1999.0285.Google Scholar
  99. Werts C, Tapping RI, Mathison JC, Chuang TH, Kravchenko V, Saint Girons I, Haake DA, Godowski PJ, Hayashi F, Ozinsky A, Underhill DM, Kirschning CJ, Wagner H, Aderem A, Tobias PS, Ulevitch RJ: Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism. Nat Immunol. 2001, 2: 346-352. 10.1038/86354.Google Scholar
  100. Que-Gewirth NL, Ribeiro AA, Kalb SR, Cotter RJ, Bulach DM, Adler B, Girons IS, Werts C, Raetz CR: A methylated phosphate group and four amide-linked acyl chains in leptospira interrogans lipid A. The membrane anchor of an unusual lipopolysaccharide that activates TLR2. J Biol Chem. 2004, 279: 25420-25429. 10.1074/jbc.M400598200.Google Scholar
  101. de Queiroz-Leite LT, Resende M, Ramos-Vieira MdN, Cota-Koury M: Experimental immunization of hamsters with an EDTA extract of Leptospira interrogans, serovar icterohaemorrhagiae. Rev Latinoam Microbiol. 1996, 38: 39-43.Google Scholar
  102. Midwinter A, Vinh T, Faine S, Adler B: Characterization of an antigenic oligosaccharide from Leptospira interrogans serovar pomona and its role in immunity. Infect Immun. 1994, 62: 5477-5482.Google Scholar
  103. de la Pena-Moctezuma A, Bulach DM, Kalambaheti T, Adler B: Comparative analysis of the LPS biosynthetic loci of the genetic subtypes of serovar Hardjo: Leptospira interrogans subtype Hardjoprajitno and Leptospira borgpetersenii subtype Hardjobovis. FEMS Microbiol Lett. 1999, 177: 319-326.Google Scholar
  104. Matsuo K, Isogai E, Araki Y: Control of immunologically crossreactive leptospiral infection by administration of lipopolysaccharides from a nonpathogenic strain of Leptospira biflexa. Microbiol Immunol. 2000, 44: 887-890.Google Scholar
  105. Sonrier C, Branger C, Michel V, Ruvoen-Clouet N, Ganiere JP, Andre-Fontaine G: Evidence of cross-protection within Leptospira interrogans in an experimental model. Vaccine. 2000, 19: 86-94. 10.1016/S0264-410X(00)00129-8.Google Scholar
  106. Masuzawa T, Nakamura R, Shimizu T, Iwamoto Y, Morita T, Yanagihara Y: Immunological characteristics of the glycolipid antigen of Leptospira interrogans serovar lai. Infect Immun. 1989, 57: 2502-2506.Google Scholar
  107. Masuzawa T, Suzuki R, Yanagihara Y: Comparison of protective effects with tetra-valent glycolipid antigens and whole cell-inactivated vaccine in experimental infection of Leptospira. Microbiol Immunol. 1991, 35: 199-208.Google Scholar
  108. Teigland MB: An experience with a Leptospira pomona bacterin in dairy cattle. J Am Vet Med Assoc. 1956, 129: 259-260.Google Scholar
  109. Bramel RG, Scheidy SF: The effect of revaccination of horses and cattle with Leptospira pomona bacterin. J Am Vet Med Assoc. 1956, 128: 399-400.Google Scholar
  110. Hoag WG, Bell WB: An immunogenic agent for the protection of cattle against Leptospira pomona. Am J Vet Res. 1955, 16: 381-385.Google Scholar
  111. Kenzy SG, Gillespie RW, Lee JH: Comparison of Leptospira pomona bacterin and attenuated live culture vaccine for control of abortion in cattle. J Am Vet Med Assoc. 1961, 139: 452-454.Google Scholar
  112. Hanson LE, Tripathy DN, Killinger AH: Current status of leptospirosis immunization in swine and cattle. J Am Vet Med Assoc. 1972, 161: 1235-1243.Google Scholar
  113. Zemjanis R: Vaccination for reproductive efficiency in cattle. J Am Vet Med Assoc. 1974, 165: 689-692.Google Scholar
  114. Huhn RG, Hanson LE, Killinger AH, Cardella MA: Immunity to leptospirosis: Leptospira interrogans serotype pomona bacterins in cattle. Am J Vet Res. 1975, 36: 59-65.Google Scholar
  115. Tripathy DN, Hanson LE, Nervig RM, Cardella MA, Mansfield ME: Evaluation of the immune response of cattle to single and multiple vaccination with a polyvalent leptospiral bacterin. Proc Annu Meet U S Anim Health Assoc. 1976, 173-181.Google Scholar
  116. Morter RL: Serology in cattle vaccinated with leptospirosis bacterins. Mod Vet Pract. 1980, 61: 611, 614-Google Scholar
  117. Marshall V, Kerr DD: Early protection of dogs by a leptospira bacterin. Mod Vet Pract. 1974, 55: 430-432.Google Scholar
  118. Huhn RG, Baldwin CD, Cardella MA: Immunity to leptospirosis: bacterins in dogs and hamsters. Am J Vet Res. 1975, 36: 71-74.Google Scholar
  119. Wilson JH, Hermann-Dekkers WM, Leemans-Dessy S, Meijer JW: Experiements with an inactivated hepatitis leptospirosis vaccine in vaccination programmes for dogs. Vet Rec. 1977, 100: 552-554.Google Scholar
  120. Wilson JH, Hermann-Dekkers WM: Experiments with a homologous, inactivated canine parvovirus vaccine in vaccination programmers for dogs. Vet Q. 1982, 4: 108-116.Google Scholar
  121. York CJ: Combined viral and bacterial antigens for canine vaccines. J Am Vet Med Assoc. 1966, 149: 681-685.Google Scholar
  122. Geisen V, Stengel C, Brem S, Muller W, Greene C, Hartmann K: Canine leptospirosis infections – clinical signs and outcome with different suspected Leptospira serogroups (42 cases). J Small Anim Pract. 2007, 48: 324-328. 10.1111/j.1748-5827.2007.00324.x.Google Scholar
  123. Shenberg E, Torten M: A new leptospiral vaccine for use in man. I. Development of a vaccine from Leptospira grown on a chemically defined medium. J Infect Dis. 1973, 128: 642-646.Google Scholar
  124. Torten M, Shenberg E, Gerichter CB, Neuman P, Klingberg MA: A new leptospiral vaccine for use in man. II. Clinical and serologic evaluation of a field trial with volunteers. J Infect Dis. 1973, 128: 647-651.Google Scholar
  125. Chapman AJ, Faine S, Adler B: Antigens recognized by the human immune response to vaccination with a bivalent hardjo/pomona leptospiral vaccine. FEMS Microbiol Immunol. 1990, 2: 111-118. 10.1111/j.1574-6968.1990.tb03508.x.Google Scholar
  126. Adler B, Faine S: Immunogenicity of boiled compared with formalized leptospiral vaccines in rabbits, hamsters and humans. J Hyg (Lond). 1980, 84 (1): 1-10.Google Scholar
  127. Klaasen HL, Molkenboer MJ, Vrijenhoek MP, Kaashoek MJ: Duration of immunity in dogs vaccinated against leptospirosis with a bivalent inactivated vaccine. Vet Microbiol. 2003, 95: 121-132. 10.1016/S0378-1135(03)00152-4.Google Scholar
  128. Samina I, Brenner J, Moalem U, Berenstein M, Cohen A, Peleg BA: Enhanced antibody response in cattle against Leptospira hardjo by intradermal vaccination. Vaccine. 1997, 15: 1434-1436. 10.1016/S0264-410X(97)00046-7.Google Scholar
  129. Silva CC, Giongo V, Simpson AJ, Camargos ER, Silva JL, Koury MC: Effects of hydrostatic pressure on the Leptospira interrogans: high immunogenicity of the pressure-inactivated serovar hardjo. Vaccine. 2001, 19: 1511-1514. 10.1016/S0264-410X(00)00361-3.Google Scholar
  130. Naiman BM, Alt D, Bolin CA, Zuerner R, Baldwin CL: Protective killed Leptospira borgpetersenii vaccine induces potent Th1 immunity comprising responses by CD4 and gammadelta T lymphocytes. Infect Immun. 2001, 69: 7550-7558. 10.1128/IAI.69.12.7550-7558.2001.Google Scholar
  131. Ada G: Overview of vaccines. Methods Mol Med. 2003, 87: 1-17.Google Scholar
  132. Fletcher MA, Saliou P: Vaccines and infectious disease. Exs. 2000, 89: 69-88.Google Scholar
  133. Cui Z: DNA vaccine. Adv Genet. 2005, 54: 257-289.Google Scholar
  134. Ulmer JB, Wahren B, Liu MA: Gene-based vaccines: recent technical and clinical advances. Trends Mol Med. 2006, 12: 216-222. 10.1016/j.molmed.2006.03.007.Google Scholar
  135. Wang Z, Yuan Z, Hengge UR: Processing of plasmid DNA with ColE1-like replication origin. Plasmid. 2004, 51: 149-161. 10.1016/j.plasmid.2003.12.002.Google Scholar
  136. Babiuk LA, Babiuk SL, Loehr BI, van Drunnen Littel-van den H: Nucleic acid vaccines: research tool or commercial reality. Vet Immunol Immunopathol. 2000, 76: 1-23. 10.1016/S0165-2427(00)00198-7.Google Scholar
  137. Liu MA, Ulmer JB: Human clinical trials of plasmid DNA vaccines. Adv Genet. 2005, 55: 25-40.Google Scholar
  138. Meykadeh N, Mirmohammadsadegh A, Wang Z, Basner-Tschakarjan E, Hengge UR: Topical application of plasmid DNA to mouse and human skin. J Mol Med. 2005, 83: 897-903. 10.1007/s00109-005-0669-x.Google Scholar
  139. Wang Z, Yuan Z, Matsumoto M, Hengge UR, Chang YF: Immune responses with DNA vaccines encoded different gene fragments of severe acute respiratory syndrome coronavirus in BALB/c mice. Biochem Biophys Res Commun. 2005, 327: 130-135. 10.1016/j.bbrc.2004.11.147.Google Scholar
  140. Ebensen T, Schulze K, Riese P, Morr M, Guzman CA: The bacterial second messenger cdiGMP exhibits promising activity as a mucosal adjuvant. Clin Vaccine Immunol. 2007, 14: 952-958. 10.1128/CVI.00119-07.Google Scholar
  141. Lowe DB, Shearer MH, Kennedy RC: DNA vaccines: successes and limitations in cancer and infectious disease. J Cell Biochem. 2006, 98: 235-242. 10.1002/jcb.20775.Google Scholar
  142. Branger C, Chatrenet B, Gauvrit A, Aviat F, Aubert A, Bach JM, Andre-Fontaine G: Protection against Leptospira interrogans sensu lato challenge by DNA immunization with the gene encoding hemolysin-associated protein 1. Infect Immun. 2005, 73: 4062-4069. 10.1128/IAI.73.7.4062-4069.2005.Google Scholar
  143. Dai B, You Z, Chen Z, Yan H, Fang Z: Protection against leptospirosis by immunization with plasmid DNA encoding 33 kDa endoflagellin of L. interrogans serovar lai. Chin Med Sci J. 2000, 15: 14-19.Google Scholar
  144. Francois G, Duclos P, Margolis H, Lavanchy D, Siegrist CA, Meheus A, Lambert PH, Emiroglu N, Badur S, Van Damme P: Vaccine safety controversies and the future of vaccination programs. Pediatr Infect Dis J. 2005, 24: 953-961. 10.1097/01.inf.0000183853.16113.a6.Google Scholar
  145. Day MJ: Vaccine side effects: fact and fiction. Vet Microbiol. 2006, 117: 51-58. 10.1016/j.vetmic.2006.04.017.Google Scholar
  146. Fraser CK, Diener KR, Brown MP, Hayball JD: Improving vaccines by incorporating immunological coadjuvants. Expert Rev Vaccines. 2007, 6: 559-578. 10.1586/14760584.6.4.559.Google Scholar
  147. Wang Z, Xiang L, Shao J, Yuan Z: The 3' CCACCA sequence of tRNAAla(UGC) is the motif that is important in inducing Th1-like immune response, and this motif can be recognized by Toll-like receptor 3. Clin Vaccine Immunol. 2006, 13: 733-739. 10.1128/CVI.00019-06.Google Scholar
  148. Vyas SP, Gupta PN: Implication of nanoparticles/microparticles in mucosal vaccine delivery. Expert Rev Vaccines. 2007, 6: 401-418. 10.1586/14760584.6.3.401.Google Scholar
  149. Fujihashi K, Staats HF, Kozaki S, Pascual DW: Mucosal vaccine development for botulinum intoxication. Expert Rev Vaccines. 2007, 6: 35-45. 10.1586/14760584.6.1.35.Google Scholar
  150. De Magistris MT: Mucosal delivery of vaccine antigens and its advantages in pediatrics. Adv Drug Deliv Rev. 2006, 58: 52-67. 10.1016/j.addr.2006.01.002.Google Scholar
  151. Lee CJ, Lee LH, Gu XX: Mucosal immunity induced by pneumococcal glycoconjugate. Crit Rev Microbiol. 2005, 31: 137-144. 10.1080/10408410591005093.Google Scholar
  152. Foss DL, Murtaugh MP: Mechanisms of vaccine adjuvanticity at mucosal surfaces. Anim Health Res Rev. 2000, 1: 3-24.Google Scholar
  153. Poonam P: The biology of oral tolerance and issues related to oral vaccine design. Curr Pharm Des. 2007, 13: 2001-2007. 10.2174/138161207781039814.Google Scholar
  154. Takaiwa F: A rice-based edible vaccine expressing multiple T-cell epitopes to induce oral tolerance and inhibit allergy. Immunol Allergy Clin North Am. 2007, 27: 129-139. 10.1016/j.iac.2006.11.001.Google Scholar
  155. Mutwiri G, Bowersock TL, Babiuk LA: Microparticles for oral delivery of vaccines. Expert Opin Drug Deliv. 2005, 2: 791-806. 10.1517/17425247.2.5.791.Google Scholar
  156. Fujihashi K, Kato H, van Ginkel FW, Koga T, Boyaka PN, Jackson RJ, Kato R, Hagiwara Y, Etani Y, Goma I, Fujihashi K, Kiyono H, McGhee JR: A revisit of mucosal IgA immunity and oral tolerance. Acta Odontol Scand. 2001, 59: 301-308. 10.1080/000163501750541174.Google Scholar
  157. Alpar HO, Somavarapu S, Atuah KN, Bramwell VW: Biodegradable mucoadhesive particulates for nasal and pulmonary antigen and DNA delivery. Adv Drug Deliv Rev. 2005, 57: 411-430. 10.1016/j.addr.2004.09.004.Google Scholar
  158. Stevens H: Thoughts on leptospirosis vaccines. J Am Vet Med Assoc. 2004, 224: 1245-1246. 10.2460/javma.2004.224.1245.Google Scholar
  159. Wang Z, Xiang L, Shao J, Wegrzyn A, Wegrzyn G: Effects of the presence of ColE1 plasmid DNA in Escherichia coli on the host cell metabolism. Microb Cell Fact. 2006, 5: 34-10.1186/1475-2859-5-34.Google Scholar
  160. Villaverde A, Mattanovich D: Recombinant protein production in the new Millennium. Microbial Cell Fact. 2007, 6: 33-10.1186/1475-2859-6-33.Google Scholar
  161. Sørensen HP, Mortensen KK: Soluble expression of recombinant proteins in the cytoplasm of Escherichia coli. Microbial Cell Fact. 2005, 4: 1-10.1186/1475-2859-4-1.Google Scholar

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© Wang et al; licensee BioMed Central Ltd. 2007

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