Abstract
Pathogenic spirochetes from genus Leptospira are etiologic agents of leptospirosis. Cellular vaccines against Leptospira infection often elicit mainly response against the LPS antigen of the serovars present in the formulation. There is no suitable protein candidate capable of replacing whole-cell vaccines, thus requiring new approaches on vaccine development to improve leptospirosis prevention. Our goal was to develop a whole-cell vaccine sorovar-independent based on LPS removal and conservation of protein antigens exposure, to evaluate the protective capacity of monovalent or bivalent vaccines against homologous and heterologous virulent Leptospira in hamster. Leptospire were subjected to heat inactivation, or to LPS extraction with butanol and in some cases further inactivation with formaldehyde. Hamsters were immunized and challenged with homologous or heterologous virulent serovars, blood and organs were collected from the survivors for bacterial quantification, chemokine evaluation, and analysis of sera antibody reactivity and cross-reactivity by Western blot. Immunization with either heated or low LPS vaccines with serovar Copenhageni or Canicola resulted in 100% protection of the animals challenged with homologous virulent bacteria. Notably, different from the whole-cell vaccine, the low LPS vaccines produced with serovar Canicola provided only partial protection in heterologous challenge with the virulent Copenhageni serovar. Immunization with bivalent formulation results in 100% protection of immunized animals challenged with virulent serovar Canicola. All vaccines produced were able to eliminate bacteria from the kidney of challenged animals. All the vaccines raised antibodies capable to recognize antigens of serovars not present in the vaccine formulation. Transcripts of IFNγ, CXCL16, CCL5, CXCL10, CXCR6, and CCR5, increased in all immunized animals. Conclusion: Our results showed that bivalent vaccines with reduced LPS may be an interesting strategy for protection against heterologous virulent serovars. Besides the desirable multivalent protection, the low LPS vaccines are specially promising due to the expected lower reatogenicity.
Highlights
Pathogenic species of the genus Leptospira are the etiologic agents of leptospirosis, an emerging zoonotic disease affecting humans and animals in a global scale
Cell suspensions were distributed in equal volumes and submitted to the following treatments: a sample was inactivated by heat at 56 ̊C for 30 min (Heat), other sample was treated with Butanol 8% (But), and a third sample was treated with Butanol 8% and inactivated with Formaldehyde 1% (ButForm)
The levels of LPS were evaluated by purpald assay [22], that indicated about 45% LPS reduction in butanol-treated vaccines, when compared to heat-treated and untreated samples
Summary
Pathogenic species of the genus Leptospira are the etiologic agents of leptospirosis, an emerging zoonotic disease affecting humans and animals in a global scale. Humans can be infected with Leptospira resulting from asymptomatic manifestations to severe and life-threatening conditions such as leptospirosisassociated pulmonary hemorrhagic syndrome (LPHS) and Weil’s disease, involving jaundice, renal failure, and hemorrhage [2,3,4]. Human leptospirosis is endemic in tropical regions and outbreaks are often associated with inadequate home and sanitation conditions, besides extensive flood events after rainfalls contributing to bacterial dissemination, exacerbating the risk of exposure to urban and rural communities. The majority of zoonotic diseases are underestimated due to misdiagnosis and occurrence in poor resource regions [5,6,7]
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