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A safe vaccine (DV-STM-07) against Salmonella infection prevents abortion and confers protective immunity to the pregnant and new born mice.

Negi VD, Nagarajan AG, Chakravortty D - PLoS ONE (2010)

Bottom Line: The altered immune response of the pregnant female leads to increased susceptibility to invading pathogens, resulting in abortion and congenital defects of the fetus and a subnormal response to vaccination.These results suggest that our vaccine DV-STM-07 can be very useful in preventing abortion in the pregnant individuals and confer immunity to the new born.Since there are no such vaccine candidates which can be given to the new born and to the pregnant women, this vaccine holds a very bright future to combat Salmonella induced pregnancy loss.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Cell Biology, Centre for Infectious Disease Research and Biosafety Laboratories, Indian Institute of Science, Bangalore, India.

ABSTRACT
Pregnancy is a transient immuno-compromised condition which has evolved to avoid the immune rejection of the fetus by the maternal immune system. The altered immune response of the pregnant female leads to increased susceptibility to invading pathogens, resulting in abortion and congenital defects of the fetus and a subnormal response to vaccination. Active vaccination during pregnancy may lead to abortion induced by heightened cell mediated immune response. In this study, we have administered the highly attenuated vaccine strain DeltapmrG-HM-D (DV-STM-07) in female mice before the onset of pregnancy and followed the immune reaction against challenge with virulent S. Typhimurium in pregnant mice. Here we demonstrate that DV-STM-07 vaccine gives protection against Salmonella in pregnant mice and also prevents Salmonella induced abortion. This protection is conferred by directing the immune response towards Th2 activation and Th1 suppression. The low Th1 response prevents abortion. The use of live attenuated vaccine just before pregnancy carries the risk of transmission to the fetus. We have shown that this vaccine is safe as the vaccine strain is quickly eliminated from the mother and is not transmitted to the fetus. This vaccine also confers immunity to the new born mice of vaccinated mothers. Since there is no evidence of the vaccine candidate reaching the new born mice, we hypothesize that it may be due to trans-colostral transfer of protective anti-Salmonella antibodies. These results suggest that our vaccine DV-STM-07 can be very useful in preventing abortion in the pregnant individuals and confer immunity to the new born. Since there are no such vaccine candidates which can be given to the new born and to the pregnant women, this vaccine holds a very bright future to combat Salmonella induced pregnancy loss.

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Th1 cytokine levels are lower in the splenocytes of vaccinated mothers.Isolated splenocytes (details in material and methods) were cultured for 48 hrs and 72 hrs. Level of TNFα (A) and INFγ (B) was significantly reduced in primed splenocytes as compared to the control followed by the infection. The level of IFNγ was significantly more in serum of single dose infection with WT Salmonella not in control and primed (C). Data shows the representative of three independent experiments performed. * p<0.05, ** p<0.001 *** p<0.0001 (Student “t” test).
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pone-0009139-g004: Th1 cytokine levels are lower in the splenocytes of vaccinated mothers.Isolated splenocytes (details in material and methods) were cultured for 48 hrs and 72 hrs. Level of TNFα (A) and INFγ (B) was significantly reduced in primed splenocytes as compared to the control followed by the infection. The level of IFNγ was significantly more in serum of single dose infection with WT Salmonella not in control and primed (C). Data shows the representative of three independent experiments performed. * p<0.05, ** p<0.001 *** p<0.0001 (Student “t” test).

Mentions: During pregnancy, cytokine ratios are altered to facilitate allograft survival. Increase in the cytokines regulating cell mediated immunity classified as Th1 cytokine levels can lead to abortion. The levels of Th1 cytokines; IFNγ and TNFα, following WT challenge in pregnant, vaccinated and unvaccinated mice were analyzed. Splenocytes isolated from pregnant mice (13–15 days of gestation) of both the groups were cultured and cytokine levels in the cell supernatants at different time were measured. The levels of Th1 cytokine TNFα (2–3 fold) (Figure 4A) and IFNγ (11-fold) (Figure 4B) in the cell supernatant were significantly higher in the WT infected pregnant mice as compared to the vaccinated and WT challenged mice which received one priming and two booster doses of vaccine. The level of IFNγ in serum increased drastically after giving single infection with 107 CFU of WT Salmonella as compared to the vaccine strain (Figure 4C). The level of TNFα in the amniotic fluid was 1.5 fold more in unvaccinated pregnant infected mice which could be a possible cause of increased incidence of abortion and fetal death in the unvaccinated mice (Figure 5A). IFNγ level were also found to be more in the serum of unvaccinated pregnant mice challenged with WT Salmonella than the vaccinated one (Figure 5B). The serum levels of IL-6, IL-4, TNFα and IFNγ were found to be similar in mice given either PBS or DV-STM-07 (Figure 6). Increased Th1 cytokines in pregnant mice infected with WT Salmonella indicate the loss of immunosuppressive state of the mother and hence could be deleterious to the fetus. The level of IL-12 was 17-fold less in the serum of vaccinated and challenged pregnant mice as compared to the unvaccinated and challenged pregnant mice. IL-12 level in amniotic fluid of those mice was also 3.5-fold less than control pregnant mice (Figure 5C). But in case of non pregnant mice, the level of IL-12 was more after vaccination as compared to the control mice (Figure 6). The cytokine profile observed was pregnancy specific which differs from the normal non pregnancy condition of the mice.


A safe vaccine (DV-STM-07) against Salmonella infection prevents abortion and confers protective immunity to the pregnant and new born mice.

Negi VD, Nagarajan AG, Chakravortty D - PLoS ONE (2010)

Th1 cytokine levels are lower in the splenocytes of vaccinated mothers.Isolated splenocytes (details in material and methods) were cultured for 48 hrs and 72 hrs. Level of TNFα (A) and INFγ (B) was significantly reduced in primed splenocytes as compared to the control followed by the infection. The level of IFNγ was significantly more in serum of single dose infection with WT Salmonella not in control and primed (C). Data shows the representative of three independent experiments performed. * p<0.05, ** p<0.001 *** p<0.0001 (Student “t” test).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2818715&req=5

pone-0009139-g004: Th1 cytokine levels are lower in the splenocytes of vaccinated mothers.Isolated splenocytes (details in material and methods) were cultured for 48 hrs and 72 hrs. Level of TNFα (A) and INFγ (B) was significantly reduced in primed splenocytes as compared to the control followed by the infection. The level of IFNγ was significantly more in serum of single dose infection with WT Salmonella not in control and primed (C). Data shows the representative of three independent experiments performed. * p<0.05, ** p<0.001 *** p<0.0001 (Student “t” test).
Mentions: During pregnancy, cytokine ratios are altered to facilitate allograft survival. Increase in the cytokines regulating cell mediated immunity classified as Th1 cytokine levels can lead to abortion. The levels of Th1 cytokines; IFNγ and TNFα, following WT challenge in pregnant, vaccinated and unvaccinated mice were analyzed. Splenocytes isolated from pregnant mice (13–15 days of gestation) of both the groups were cultured and cytokine levels in the cell supernatants at different time were measured. The levels of Th1 cytokine TNFα (2–3 fold) (Figure 4A) and IFNγ (11-fold) (Figure 4B) in the cell supernatant were significantly higher in the WT infected pregnant mice as compared to the vaccinated and WT challenged mice which received one priming and two booster doses of vaccine. The level of IFNγ in serum increased drastically after giving single infection with 107 CFU of WT Salmonella as compared to the vaccine strain (Figure 4C). The level of TNFα in the amniotic fluid was 1.5 fold more in unvaccinated pregnant infected mice which could be a possible cause of increased incidence of abortion and fetal death in the unvaccinated mice (Figure 5A). IFNγ level were also found to be more in the serum of unvaccinated pregnant mice challenged with WT Salmonella than the vaccinated one (Figure 5B). The serum levels of IL-6, IL-4, TNFα and IFNγ were found to be similar in mice given either PBS or DV-STM-07 (Figure 6). Increased Th1 cytokines in pregnant mice infected with WT Salmonella indicate the loss of immunosuppressive state of the mother and hence could be deleterious to the fetus. The level of IL-12 was 17-fold less in the serum of vaccinated and challenged pregnant mice as compared to the unvaccinated and challenged pregnant mice. IL-12 level in amniotic fluid of those mice was also 3.5-fold less than control pregnant mice (Figure 5C). But in case of non pregnant mice, the level of IL-12 was more after vaccination as compared to the control mice (Figure 6). The cytokine profile observed was pregnancy specific which differs from the normal non pregnancy condition of the mice.

Bottom Line: The altered immune response of the pregnant female leads to increased susceptibility to invading pathogens, resulting in abortion and congenital defects of the fetus and a subnormal response to vaccination.These results suggest that our vaccine DV-STM-07 can be very useful in preventing abortion in the pregnant individuals and confer immunity to the new born.Since there are no such vaccine candidates which can be given to the new born and to the pregnant women, this vaccine holds a very bright future to combat Salmonella induced pregnancy loss.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Cell Biology, Centre for Infectious Disease Research and Biosafety Laboratories, Indian Institute of Science, Bangalore, India.

ABSTRACT
Pregnancy is a transient immuno-compromised condition which has evolved to avoid the immune rejection of the fetus by the maternal immune system. The altered immune response of the pregnant female leads to increased susceptibility to invading pathogens, resulting in abortion and congenital defects of the fetus and a subnormal response to vaccination. Active vaccination during pregnancy may lead to abortion induced by heightened cell mediated immune response. In this study, we have administered the highly attenuated vaccine strain DeltapmrG-HM-D (DV-STM-07) in female mice before the onset of pregnancy and followed the immune reaction against challenge with virulent S. Typhimurium in pregnant mice. Here we demonstrate that DV-STM-07 vaccine gives protection against Salmonella in pregnant mice and also prevents Salmonella induced abortion. This protection is conferred by directing the immune response towards Th2 activation and Th1 suppression. The low Th1 response prevents abortion. The use of live attenuated vaccine just before pregnancy carries the risk of transmission to the fetus. We have shown that this vaccine is safe as the vaccine strain is quickly eliminated from the mother and is not transmitted to the fetus. This vaccine also confers immunity to the new born mice of vaccinated mothers. Since there is no evidence of the vaccine candidate reaching the new born mice, we hypothesize that it may be due to trans-colostral transfer of protective anti-Salmonella antibodies. These results suggest that our vaccine DV-STM-07 can be very useful in preventing abortion in the pregnant individuals and confer immunity to the new born. Since there are no such vaccine candidates which can be given to the new born and to the pregnant women, this vaccine holds a very bright future to combat Salmonella induced pregnancy loss.

Show MeSH
Related in: MedlinePlus