Evaluation of different strategies to promote a protective immune response against leptospirosis using a recombinant LigA and LigB chimera

Cunha, C. E.; Bettin, Everton Burlamarque; Bakry, Aisha Farid Abdel Aziz Yousef; Neto, Amilton Clair Pinto Seixas; Amaral, Marta; Dellagostin, Odir Antônio

doi:10.1016/j.vaccine.2019.02.010

Cited by 25 publications

(35 citation statements)

References 41 publications

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“…Therefore, no predominant IgG isotype or Th immune response was correlated with protective efficacy of each FHBP formulation in either the mono or multisubunit vaccines. In some studies, IgG2 isotype or Th1 response has been observed to confer protection against leptospirosis [34,52,53]. However, Th2 is conventionally believed to be responsible for protection against extracellular pathogens including leptospires in spite of their transient tissue invasion [54].…”

Section: Discussionmentioning

confidence: 99%

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Reduced Renal Colonization and Enhanced Protection by Leptospiral Factor H Binding Proteins as a Multisubunit Vaccine against Leptospirosis in Hamsters

et al. 2019

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Subunit vaccines conferring complete protection against leptospirosis are not currently available. The interactions of factor H binding proteins (FHBPs) on pathogenic leptospires and host factor H are crucial for immune evasion by inhibition of complement-mediated killing. The inhibition of these interactions may be a potential strategy to clear leptospires in the host. This study aimed to evaluate a multisubunit vaccine composed of four known leptospiral FHBPs: LigA domain 7–13 (LigAc), LenA, LcpA, and Lsa23, for its protective efficacy in hamsters. The mono and multisubunit vaccines formulated with LMQ adjuvant, a combination of neutral liposome, monophosphoryl lipid A, and Quillaja saponaria fraction 21, induced high and comparable specific antibody (IgG) production against individual antigens. Hamsters immunized with the multisubunit vaccine showed 60% survival following the challenge by 20 LD50 of Leptospira interrogans serovar Pomona. No significant difference in survival rate and pathological findings of target organs was observed after vaccinations with multisubunit or mono-LigAc vaccines. However, the multisubunit vaccine significantly reduced leptospiral burden in surviving hamsters in comparison with the monosubunit vaccines. Therefore, the multisubunit vaccine conferred partial protection and reduced renal colonization against virulence Leptospira infection in hamsters. Our multisubunit formulation could represent a promising vaccine against leptospirosis.

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Section: Discussionmentioning

confidence: 99%

“…Further investigations using different combinations of these subunit vaccines including all FHBPs, except LigAc, are required to determine the crucial components. Chimeric vaccines containing fusion of protective FHBPs will be a promising strategy to deliver the vaccine antigens as previously reported [49,52,53].…”

Section: Discussionmentioning

confidence: 99%

Reduced Renal Colonization and Enhanced Protection by Leptospiral Factor H Binding Proteins as a Multisubunit Vaccine against Leptospirosis in Hamsters

et al. 2019

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“…Manilae strain L495 wild-type and mutant strains were cultivated in DMCs as previously described [42,43,108]. Briefly, DMCs were prepared with 9-10 mls of EMJH medium Table. Copy numbers were calculated using internal standard curves (10 7-10 1 copies) generated using purified amplicons for perRA, perRB, LIMLP18590 and LIMLP04825 and then normalized against lipL32 [179]. The standard curve for lipL32 was generated using a copy of the lipL32 amplicon cloned into pCR2.1-TOPO plasmid (Invitrogen).…”

Section: Generation Of Host-adapted Leptospiresmentioning

confidence: 99%

The FUR-like regulators PerRA and PerRB integrate a complex regulatory network that promotes mammalian host-adaptation and virulence ofLeptospira interrogans

Zavala-Alvarado

Bettin

et al. 2020

Preprint

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Leptospira interrogans , the causative agent of most cases of human leptospirosis, must respond to myriad environmental signals during its free-living and pathogenic lifestyles. Previously, we compared L. interrogans cultivated in vitro and in vivo using a dialysis membrane chamber (DMC) peritoneal implant model. From these studies emerged 160 genes that were differentially regulated in response to host signals, including perRA , one of two Peroxide stress response (PerR)-like regulators encoded by L. interrogans . Zavala-Alvarado et al . recently demonstrated that leptospires lacking both PerRA and PerRB are avirulent in hamsters. Herein, we establish that PerRA and PerRB also are required for renal colonization in C3H/HeJ mice. The finding that loss of virulence was observed only with the perRA/B double mutant suggests that these regulators serve redundant or overlapping functions in vivo . Our finding that the perRA / B double mutant survives at wild-type levels in DMCs is noteworthy as it demonstrates that the loss of virulence is not due to a metabolic lesion ( i.e. , metal starvation) but instead reflects dysregulation of virulence-related gene products. Comparative RNA-seq analyses of perRA , perRB and perRA/B mutants cultivated within DMCs identified 106 genes that are dysregulated only in the double mutant, including ligA, ligB and lvrA/B sensory histidine kinases. Decreased expression of LigA and LigB in the perRA / B mutant was not due to loss of LvrAB signal transduction. The majority of genes in the PerRA and PerRB DMC regulons was differentially expressed only in vivo , highlighting the importance of host-specific signals for regulating gene expression in L. interrogans . Importantly, the PerRA, PerRB and PerRA/B DMC regulons each contain multiple genes related to environmental sensing and/or transcriptional regulation. Collectively, our data suggest that PerRA and PerRB are part of a complex signaling network required by L. interrogans for adaptation to and survival within the host.

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“…The variable carboxy-terminal domain 7-13 of leptospiral immunoglobulin-like protein A (LigAc) is currently the most promising antigen for leptospirosis vaccines [5][6][7]. Different types and formulations of LigAc-based vaccines, including DNA [8,9], recombinant single subunit [5][6][7], multisubunit [10,11], chimeric [12][13][14] vaccines, delivery systems [15], and adjuvants [16,17], have been tested for their efficacy in animal models. However, all these strategies were unable to completely prevent Leptospira renal colonization and pathological changes.…”

Section: Introductionmentioning

confidence: 99%

A Comparison of Intramuscular and Subcutaneous Administration of LigA Subunit Vaccine Adjuvanted with Neutral Liposomal Formulation Containing Monophosphoryl Lipid A and QS21

et al. 2020

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Leptospirosis vaccines with higher potency and reduced adverse effects are needed for human use. The carboxyl terminal domain of leptospiral immunoglobulin like protein A (LigAc) is currently the most promising candidate antigen for leptospirosis subunit vaccine. However, LigAc-based vaccines were unable to confer sterilizing immunity against Leptospira infection in animal models. Several factors including antigen properties, adjuvant, delivery system, and administration route need optimization to maximize vaccine efficacy. Our previous report demonstrated protective effects of the recombinant LigAc (rLigAc) formulated with liposome-based adjuvant, called LMQ (neutral liposome combined with monophosphoryl lipid A and Quillaja saponaria fraction 21) in hamsters. This study aimed to evaluate the impact of two commonly used administration routes, intramuscular (IM) and subcutaneous (SC), on immunogenicity and protective efficacy of rLigAc-LMQ administrated three times at 2-week interval. Two IM vaccinations triggered significantly higher levels of total anti-rLigAc IgG than two SC injections. However, comparable IgG titers and IgG2/IgG1 ratio was observed for both routes after the third immunization. The route of vaccine administration did not influence the survival rate (60%) and renal colonization against lethal Leptospira challenge. Importantly, the kidneys of IM group showed no pathological lesions while the SC group showed mild damage. In conclusion, IM vaccination with rLigAc-LMQ not only elicited faster antibody production but also protected from kidney damage following leptospiral infection better than SC immunization. However, both tested routes did not influence protective efficacy in terms of survival rate and the level of renal colonization.

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Evaluation of different strategies to promote a protective immune response against leptospirosis using a recombinant LigA and LigB chimera

Cited by 25 publications

References 41 publications

Reduced Renal Colonization and Enhanced Protection by Leptospiral Factor H Binding Proteins as a Multisubunit Vaccine against Leptospirosis in Hamsters

Reduced Renal Colonization and Enhanced Protection by Leptospiral Factor H Binding Proteins as a Multisubunit Vaccine against Leptospirosis in Hamsters

The FUR-like regulators PerRA and PerRB integrate a complex regulatory network that promotes mammalian host-adaptation and virulence ofLeptospira interrogans

A Comparison of Intramuscular and Subcutaneous Administration of LigA Subunit Vaccine Adjuvanted with Neutral Liposomal Formulation Containing Monophosphoryl Lipid A and QS21

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