A Live Attenuated Vaccine Model Confers Cross-Protective Immunity Against Different Species of<i>Leptospira</i>spp.

Wunder, Elsio A.; Adhikarla, Haritha; Hamond, Camila; Owers, Katharine A.; Liang, Li; Rodrigues, Camila B.; Bisht, Vimla; Nally, Jarlath E.; Alt, David P.; Reis, Mitermayer Galvão dos; Diggle, Peter J.; Felgner, Philip L.; Ko, Albert I.

doi:10.1101/2020.04.13.039438

“…Another attenuated Copenhageni mutant, fcpA , is a motility-deficient mutant lacking the expression of a flagellar protein, FcpA [ 48 ]. Both have been used as cross-protective vaccines [ 44 , 49 ]. Single infection with either mutant protected mice and hamsters against homologous and heterologous challenges and reduced renal colonization [ 44 , 49 ].…”

Section: Introductionmentioning

confidence: 99%

“…Both have been used as cross-protective vaccines [ 44 , 49 ]. Single infection with either mutant protected mice and hamsters against homologous and heterologous challenges and reduced renal colonization [ 44 , 49 ]. Interestingly, it has been recently shown that the attenuated fcp1/fcpA mutant conferred cross-protection through anti- Leptospira antibodies directed against proteins, but not through agglutinating antibodies.…”

Section: Introductionmentioning

confidence: 99%

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Anti-Leptospira immunoglobulin profiling in mice reveals strain specific IgG and persistent IgM responses associated with virulence and renal colonization

Vernel-Pauillac

¹

,

Murray

²

,

Adler

³

et al. 2021

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Leptospira interrogans is a pathogenic spirochete responsible for leptospirosis, a neglected, zoonotic reemerging disease. Humans are sensitive hosts and may develop severe disease. Some animal species, such as rats and mice can become asymptomatic renal carriers. More than 350 leptospiral serovars have been identified, classified on the basis of the antibody response directed against the lipopolysaccharide (LPS). Similarly to whole inactivated bacteria used as human vaccines, this response is believed to confer only short-term, serogroup-specific protection. The immune response of hosts against leptospires has not been thoroughly studied, which complicates the testing of vaccine candidates. In this work, we studied the immunoglobulin (Ig) profiles in mice infected with L. interrogans over time to determine whether this humoral response confers long-term protection after homologous challenge six months post-infection. Groups of mice were injected intraperitoneally with 2×107 leptospires of one of three pathogenic serovars (Manilae, Copenhageni or Icterohaemorrhagiae), attenuated mutants or heat-killed bacteria. Leptospira-specific immunoglobulin (IgA, IgM, IgG and 4 subclasses) produced in the first weeks up to 6 months post-infection were measured by ELISA. Strikingly, we found sustained high levels of IgM in mice infected with the pathogenic Manilae and Copenhageni strains, both colonizing the kidney. In contrast, the Icterohaemorrhagiae strain did not lead to kidney colonization, even at high dose, and triggered a classical IgM response that peaked at day 8 post-infection and disappeared. The virulent Manilae and Copenhageni serovars elicited high levels and similar profiles of IgG subclasses in contrast to Icterohaemorrhagiae strains that stimulated weaker antibody responses. Inactivated heat-killed Manilae strains elicited very low responses. However, all mice pre-injected with leptospires challenged with high doses of homologous bacteria did not develop acute leptospirosis, and all antibody responses were boosted after challenge. Furthermore, we showed that 2 months post challenge, mice pre-infected with the attenuated M895 Manilae LPS mutant or heat-killed bacterin were completely protected against renal colonization. In conclusion, we observed a sustained IgM response potentially associated with chronic leptospiral renal infection. We also demonstrated in mice different profiles of protective and cross-reactive antibodies after L. interrogans infection, depending on the serovar and virulence of strains.

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“…Another attenuated Copenhageni mutant, fcpA , is a motility-deficient mutant lacking the expression of a flagellar protein, FcpA (48). Both have been used as cross-protective vaccines (44, 49). Single infection with either mutant protected mice and hamsters against homologous and heterologous challenges and reduced renal colonization (44, 49).…”

Section: Introductionmentioning

confidence: 99%

“…Both have been used as cross-protective vaccines (44, 49). Single infection with either mutant protected mice and hamsters against homologous and heterologous challenges and reduced renal colonization (44, 49). This protection has been shown to be conferred by antibodies, although, this has not been investigated in detail.…”

Section: Introductionmentioning

confidence: 99%

Anti-Leptospira immunoglobulin profiling in mice reveals strain specific IgG and persistent IgM responses associated with virulence and renal colonization

Vernel-Pauillac

¹

,

Murray

²

,

Adler

³

et al. 2020

Preprint

View full text Add to dashboard Cite

Leptospira interrogans is a pathogenic spirochete responsible for leptospirosis, a neglected, zoonotic reemerging disease. Humans are sensitive hosts and may develop severe disease. Some animal species, such as rats and mice can become asymptomatic renal carriers. More than 350 leptospiral serovars have been identified, classified on the basis of the antibody response directed against the lipopolysaccharide (LPS). Similarly to whole inactivated bacteria used as human vaccines, this response is believed to confer only short-term, serogroup-specific protection. The immune response of hosts against leptospires has not been thoroughly studied and correlates of protection would be required to test vaccine candidates. In this work, we studied the immunoglobulin (Ig) profiles in mice infected with L. interrogans over time to determine whether this humoral response confers long-term protection after homologous challenge six months post-infection.Groups of mice were injected intraperitoneally with 2×107 leptospires of one of three pathogenic serovars (Manilae, Copenhageni or Icterohaemorrhagiae), attenuated mutants or heat-killed bacteria. Leptospira-specific immunoglobulin (IgA, IgM, IgG and 4 subclasses) produced in the first weeks up to 6 months post-infection were measured by ELISA. Strikingly, we found sustained high levels of IgM in mice infected with the pathogenic Manilae and Copenhageni strains, both colonizing the kidney. In contrast, the Icterohaemorrhagiae strain did not lead to kidney colonization, even at high dose, and triggered a classical IgM response that peaked at day 8 post-infection and disappeared. The virulent Manilae and Copenhageni serovars elicited high levels and similar profiles of IgG subclasses in contrast to Icterohaemorrhagiae strains that stimulated weaker antibody responses. Inactivated heat-killed Manilae strains elicited very low responses. However, all mice pre-injected with leptospires challenged with high doses of homologous bacteria did not develop acute leptospirosis, and all antibody responses were boosted after challenge. Furthermore, we showed that 2 months post challenge, mice pre-infected with the M895 Manilae LPS mutant or heat-killed bacterin were completely protected against renal colonization. In conclusion, we observed a sustained IgM response potentially associated with chronic leptospiral renal infection. We also demonstrated in mice different profiles of protective antibody response after L. interrogans infection, depending on the serovar and virulence of strains.Author summaryLeptospira interrogans is a pathogenic spirochete responsible for leptospirosis, a neglected zoonotic reemerging disease. The immune response of hosts against these bacteria has not been thoroughly studied. Here, we studied over 6 months the immunoglobulin (Ig) profiles in mice infected with L. interrogans and determined whether this humoral response confers long-term protection after homologous challenge six months after primary infection. Groups of mice were infected intraperitoneally with 2×107 bacteria of one of three different pathogenic serovars (Manilae, Copenhageni and Icterohaemorrhagiae) and some corresponding attenuated avirulent mutants. We measured by ELISA each type of Leptospira-specific Ig (IgA, IgM, IgG and 4 subclasses) produced in the first weeks up to 6 months post-infection. We showed different profiles of antibody response after L. interrogans challenge in mice, depending on the serovar and virulence of strains. However, all infected mice, including the ones harboring low antibody levels, like mice vaccinated with an inactivated, heat-killed strain, were protected against leptospirosis after challenge. Notably, we also showed an unusual sustained IgM response associated with chronic leptospiral colonization. Altogether, this long-term immune protection is different from what is known in humans and warrants further investigation.

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Protective efficacy of whole-cell inactivated Leptospira vaccines made using virulent or avirulent strains in a hamster model

Oliveira¹,

Jorge²,

Maia³

et al. 2021

Vaccine

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A Live Attenuated Vaccine Model Confers Cross-Protective Immunity Against Different Species ofLeptospiraspp.

Abstract: 26

Cited by 4 publications

References 54 publications

Anti-Leptospira immunoglobulin profiling in mice reveals strain specific IgG and persistent IgM responses associated with virulence and renal colonization

Anti-Leptospira immunoglobulin profiling in mice reveals strain specific IgG and persistent IgM responses associated with virulence and renal colonization

Anti-Leptospira immunoglobulin profiling in mice reveals strain specific IgG and persistent IgM responses associated with virulence and renal colonization

Protective efficacy of whole-cell inactivated Leptospira vaccines made using virulent or avirulent strains in a hamster model

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