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Complete Protection against Pneumonic and Bubonic Plague after a Single Oral Vaccination.

Derbise A, Hanada Y, Khalifé M, Carniel E, Demeure CE - PLoS Negl Trop Dis (2015)

Bottom Line: This candidate vaccine however failed to confer full protection against bubonic plague and did not produce F1 stably.It involved cells with a Th1-Th17 effector profile, producing IFNγ, IL-17, and IL-10.To our knowledge, VTnF1 is the only plague vaccine ever reported that could provide high and durable protection against the two forms of plague after a single oral administration.

View Article: PubMed Central - PubMed

Affiliation: Unité de recherche Yersinia, Institut Pasteur, Paris, France.

ABSTRACT

Background: No efficient vaccine against plague is currently available. We previously showed that a genetically attenuated Yersinia pseudotuberculosis producing the Yersinia pestis F1 antigen was an efficient live oral vaccine against pneumonic plague. This candidate vaccine however failed to confer full protection against bubonic plague and did not produce F1 stably.

Methodology/principal findings: The caf operon encoding F1 was inserted into the chromosome of a genetically attenuated Y. pseudotuberculosis, yielding the VTnF1 strain, which stably produced the F1 capsule. Given orally to mice, VTnF1 persisted two weeks in the mouse gut and induced a high humoral response targeting both F1 and other Y. pestis antigens. The strong cellular response elicited was directed mostly against targets other than F1, but also against F1. It involved cells with a Th1-Th17 effector profile, producing IFNγ, IL-17, and IL-10. A single oral dose (108 CFU) of VTnF1 conferred 100% protection against pneumonic plague using a high-dose challenge (3,300 LD50) caused by the fully virulent Y. pestis CO92. Moreover, vaccination protected 100% of mice from bubonic plague caused by a challenge with 100 LD50 Y. pestis and 93% against a high-dose infection (10,000 LD50). Protection involved fast-acting mechanisms controlling Y. pestis spread out of the injection site, and the protection provided was long-lasting, with 93% and 50% of mice surviving bubonic and pneumonic plague respectively, six months after vaccination. Vaccinated mice also survived bubonic and pneumonic plague caused by a high-dose of non-encapsulated (F1-) Y. pestis.

Significance: VTnF1 is an easy-to-produce, genetically stable plague vaccine candidate, providing a highly efficient and long-lasting protection against both bubonic and pneumonic plague caused by wild type or un-encapsulated (F1-negative) Y. pestis. To our knowledge, VTnF1 is the only plague vaccine ever reported that could provide high and durable protection against the two forms of plague after a single oral administration.

No MeSH data available.


Related in: MedlinePlus

Cellular immune response of vaccinated mice.Splenocytes isolated from mice vaccinated orally with VTnF1 (108 CFU) 30 days (dark red boxes), or 180 days (black boxes) earlier, or from unvaccinated (naive) mice (blue boxes), were stimulated in vitro with 5 μg/ml of either an antigenic preparation of Y. pestis CO92Δcaf (noted Y.p.F1-) or purified F1 antigen, or the mitogen Concanavalin A (ConA, 1 μg/ml) as positive control. Supernatants taken three days after stimulation were tested for the presence of IFNγ (A), IL-17 (B), and IL-10 (C) by ELISA. Shown are the mean ± s.e.m. of 14 mice per condition (two pooled experiments). The unpaired Mann Whitney test was used for statistical analysis: *: p<0.05, **: p<0.01, ***: p<0.001, ns: not significant. Comparable results were obtained in two other experiments using naive and 30-days vaccinated mice (16 per group).
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pntd.0004162.g004: Cellular immune response of vaccinated mice.Splenocytes isolated from mice vaccinated orally with VTnF1 (108 CFU) 30 days (dark red boxes), or 180 days (black boxes) earlier, or from unvaccinated (naive) mice (blue boxes), were stimulated in vitro with 5 μg/ml of either an antigenic preparation of Y. pestis CO92Δcaf (noted Y.p.F1-) or purified F1 antigen, or the mitogen Concanavalin A (ConA, 1 μg/ml) as positive control. Supernatants taken three days after stimulation were tested for the presence of IFNγ (A), IL-17 (B), and IL-10 (C) by ELISA. Shown are the mean ± s.e.m. of 14 mice per condition (two pooled experiments). The unpaired Mann Whitney test was used for statistical analysis: *: p<0.05, **: p<0.01, ***: p<0.001, ns: not significant. Comparable results were obtained in two other experiments using naive and 30-days vaccinated mice (16 per group).

Mentions: To evaluate the antigen-specific T cell memory elicited by VTnF1, splenocytes taken from vaccinated animals were re-stimulated in vitro with either purified F1 antigen, or with a sonicate of the un-encapsulated Y. pestis CO92Δcaf. Cells from mice vaccinated one month earlier with VTnF1 produced IFNγ, IL-17, and IL-10 in response to F1 (Fig 4). Although these levels were low, they were significantly higher than those of control mice (Fig 4), indicating that vaccination mobilized F1-specific memory T cells producing both pro- (IFNγ, IL-17) and anti-inflammatory (IL-10) cytokines. IL-1β production was also measured, but levels were very low (<0.02 ng/ml) in all conditions.


Complete Protection against Pneumonic and Bubonic Plague after a Single Oral Vaccination.

Derbise A, Hanada Y, Khalifé M, Carniel E, Demeure CE - PLoS Negl Trop Dis (2015)

Cellular immune response of vaccinated mice.Splenocytes isolated from mice vaccinated orally with VTnF1 (108 CFU) 30 days (dark red boxes), or 180 days (black boxes) earlier, or from unvaccinated (naive) mice (blue boxes), were stimulated in vitro with 5 μg/ml of either an antigenic preparation of Y. pestis CO92Δcaf (noted Y.p.F1-) or purified F1 antigen, or the mitogen Concanavalin A (ConA, 1 μg/ml) as positive control. Supernatants taken three days after stimulation were tested for the presence of IFNγ (A), IL-17 (B), and IL-10 (C) by ELISA. Shown are the mean ± s.e.m. of 14 mice per condition (two pooled experiments). The unpaired Mann Whitney test was used for statistical analysis: *: p<0.05, **: p<0.01, ***: p<0.001, ns: not significant. Comparable results were obtained in two other experiments using naive and 30-days vaccinated mice (16 per group).
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getmorefigures.php?uid=PMC4608741&req=5

pntd.0004162.g004: Cellular immune response of vaccinated mice.Splenocytes isolated from mice vaccinated orally with VTnF1 (108 CFU) 30 days (dark red boxes), or 180 days (black boxes) earlier, or from unvaccinated (naive) mice (blue boxes), were stimulated in vitro with 5 μg/ml of either an antigenic preparation of Y. pestis CO92Δcaf (noted Y.p.F1-) or purified F1 antigen, or the mitogen Concanavalin A (ConA, 1 μg/ml) as positive control. Supernatants taken three days after stimulation were tested for the presence of IFNγ (A), IL-17 (B), and IL-10 (C) by ELISA. Shown are the mean ± s.e.m. of 14 mice per condition (two pooled experiments). The unpaired Mann Whitney test was used for statistical analysis: *: p<0.05, **: p<0.01, ***: p<0.001, ns: not significant. Comparable results were obtained in two other experiments using naive and 30-days vaccinated mice (16 per group).
Mentions: To evaluate the antigen-specific T cell memory elicited by VTnF1, splenocytes taken from vaccinated animals were re-stimulated in vitro with either purified F1 antigen, or with a sonicate of the un-encapsulated Y. pestis CO92Δcaf. Cells from mice vaccinated one month earlier with VTnF1 produced IFNγ, IL-17, and IL-10 in response to F1 (Fig 4). Although these levels were low, they were significantly higher than those of control mice (Fig 4), indicating that vaccination mobilized F1-specific memory T cells producing both pro- (IFNγ, IL-17) and anti-inflammatory (IL-10) cytokines. IL-1β production was also measured, but levels were very low (<0.02 ng/ml) in all conditions.

Bottom Line: This candidate vaccine however failed to confer full protection against bubonic plague and did not produce F1 stably.It involved cells with a Th1-Th17 effector profile, producing IFNγ, IL-17, and IL-10.To our knowledge, VTnF1 is the only plague vaccine ever reported that could provide high and durable protection against the two forms of plague after a single oral administration.

View Article: PubMed Central - PubMed

Affiliation: Unité de recherche Yersinia, Institut Pasteur, Paris, France.

ABSTRACT

Background: No efficient vaccine against plague is currently available. We previously showed that a genetically attenuated Yersinia pseudotuberculosis producing the Yersinia pestis F1 antigen was an efficient live oral vaccine against pneumonic plague. This candidate vaccine however failed to confer full protection against bubonic plague and did not produce F1 stably.

Methodology/principal findings: The caf operon encoding F1 was inserted into the chromosome of a genetically attenuated Y. pseudotuberculosis, yielding the VTnF1 strain, which stably produced the F1 capsule. Given orally to mice, VTnF1 persisted two weeks in the mouse gut and induced a high humoral response targeting both F1 and other Y. pestis antigens. The strong cellular response elicited was directed mostly against targets other than F1, but also against F1. It involved cells with a Th1-Th17 effector profile, producing IFNγ, IL-17, and IL-10. A single oral dose (108 CFU) of VTnF1 conferred 100% protection against pneumonic plague using a high-dose challenge (3,300 LD50) caused by the fully virulent Y. pestis CO92. Moreover, vaccination protected 100% of mice from bubonic plague caused by a challenge with 100 LD50 Y. pestis and 93% against a high-dose infection (10,000 LD50). Protection involved fast-acting mechanisms controlling Y. pestis spread out of the injection site, and the protection provided was long-lasting, with 93% and 50% of mice surviving bubonic and pneumonic plague respectively, six months after vaccination. Vaccinated mice also survived bubonic and pneumonic plague caused by a high-dose of non-encapsulated (F1-) Y. pestis.

Significance: VTnF1 is an easy-to-produce, genetically stable plague vaccine candidate, providing a highly efficient and long-lasting protection against both bubonic and pneumonic plague caused by wild type or un-encapsulated (F1-negative) Y. pestis. To our knowledge, VTnF1 is the only plague vaccine ever reported that could provide high and durable protection against the two forms of plague after a single oral administration.

No MeSH data available.


Related in: MedlinePlus