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Recombinant viral vaccines expressing merozoite surface protein-1 induce antibody- and T cell-mediated multistage protection against malaria.

Draper SJ, Goodman AL, Biswas S, Forbes EK, Moore AC, Gilbert SC, Hill AV - Cell Host Microbe (2009)

Bottom Line: Here, we show that vaccine-induced MSP-1-specific CD4(+) T cells provide essential help for protective B cell responses, and CD8(+) T cells mediate significant antiparasitic activity against liver-stage parasites.This effect is evident both in the presence and absence of protective antibodies and is associated with decreased parasite burden in the liver followed by enhanced induction of the cytokine IFN-gamma in the serum.Multistage immunity against malaria can thus be achieved by using viral vectors recombinant for MSP-1.

View Article: PubMed Central - PubMed

Affiliation: The Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK. simon.draper@ndm.ox.ac.uk

ABSTRACT
Protecting against both liver and blood stages of infection is a long-sought goal of malaria vaccine design. Recently, we described the use of replication-defective viral vaccine vectors expressing the malaria antigen merozoite surface protein-1 (MSP-1) as an antimalarial vaccine strategy that elicits potent and protective antibody responses against blood-stage parasites. Here, we show that vaccine-induced MSP-1-specific CD4(+) T cells provide essential help for protective B cell responses, and CD8(+) T cells mediate significant antiparasitic activity against liver-stage parasites. Enhanced survival is subsequently seen in immunized mice following challenge with sporozoites, which mimics the natural route of infection more closely than when using infected red blood cells. This effect is evident both in the presence and absence of protective antibodies and is associated with decreased parasite burden in the liver followed by enhanced induction of the cytokine IFN-gamma in the serum. Multistage immunity against malaria can thus be achieved by using viral vectors recombinant for MSP-1.

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Blood-Stage Parasitemias in Naive and Immunized Mice 48 hr after Blood-Stage Infection(A) BALB/c mice immunized with AdM33 were challenged with 50 sporozoites (n = 18), or naive controls were challenged with 104 pRBCs (n = 29), 50 sporozoites (n = 44), or 250 sporozoites (n = 8). Blood-stage parasitemia ∼48 hr post blood-stage infection was assessed by microscopy (day 5 post spz challenge and day 2 post pRBC challenge). Data were pooled from multiple experiments. Plots show median values, 25th–75th percentiles, and range. One mouse in the AdM33 group had 0% parasitemia on day 5.(B) BALB/c mice were immunized with AdM33 or 1 × 108 vp AdHu5-PyCSP and challenged with 50 sporozoites 14 days later. The mean parasitemia ± SEM is shown (n = five or six mice per group). ∗p ≤ 0.05 and ∗∗∗ p ≤ 0.001, comparing between all groups by one-way ANOVA.
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fig4: Blood-Stage Parasitemias in Naive and Immunized Mice 48 hr after Blood-Stage Infection(A) BALB/c mice immunized with AdM33 were challenged with 50 sporozoites (n = 18), or naive controls were challenged with 104 pRBCs (n = 29), 50 sporozoites (n = 44), or 250 sporozoites (n = 8). Blood-stage parasitemia ∼48 hr post blood-stage infection was assessed by microscopy (day 5 post spz challenge and day 2 post pRBC challenge). Data were pooled from multiple experiments. Plots show median values, 25th–75th percentiles, and range. One mouse in the AdM33 group had 0% parasitemia on day 5.(B) BALB/c mice were immunized with AdM33 or 1 × 108 vp AdHu5-PyCSP and challenged with 50 sporozoites 14 days later. The mean parasitemia ± SEM is shown (n = five or six mice per group). ∗p ≤ 0.05 and ∗∗∗ p ≤ 0.001, comparing between all groups by one-way ANOVA.

Mentions: Having established that AdM42 and AdM33 immunization can mediate an antiparasitic effect at the liver stage, we sought to assess whether the increased survival outcome against spz challenge was due to a reduction in the blood-stage inoculum from the liver. A single hepatic schizont of P. yoelii malaria will produce approximately 7500–8000 merozoites (Killick-Kendrick and Peters, 1978). Consequently, just two infected hepatocytes should release a larger blood-stage inoculum than the 104 pRBCs used in the blood-stage challenge model. Levels of blood-stage parasitemia were compared 2 days post blood-stage infection in naive BALB/c mice challenged with 104 pRBCs, 50 sporozoites (low dose), or 250 sporozoites (high dose) (Figure 4A). These data showed that spz challenge in naive mice leads to a significantly higher blood-stage parasitemia after 48 hr of blood-stage infection when compared to pRBC challenge. Mice immunized with AdM33 have a reduced liver-stage parasite burden (Figure 3C) but do not possess protective IgG. The same assessment of blood-stage parasitemia in mice immunized with AdM33 and challenged with 50 sporozoites showed, interestingly, that the mean parasitemia level was significantly reduced to one comparable with pRBC challenge (Figure 4A). These data indicate that if the amount of blood-stage inoculum from the liver was the sole determinant of survival outcome, then mice immunized with AdM33 and challenged with 104 pRBCs or 50 sporozoites should show the same percent survival outcome, which was not the case (Figures 2A and 2B).


Recombinant viral vaccines expressing merozoite surface protein-1 induce antibody- and T cell-mediated multistage protection against malaria.

Draper SJ, Goodman AL, Biswas S, Forbes EK, Moore AC, Gilbert SC, Hill AV - Cell Host Microbe (2009)

Blood-Stage Parasitemias in Naive and Immunized Mice 48 hr after Blood-Stage Infection(A) BALB/c mice immunized with AdM33 were challenged with 50 sporozoites (n = 18), or naive controls were challenged with 104 pRBCs (n = 29), 50 sporozoites (n = 44), or 250 sporozoites (n = 8). Blood-stage parasitemia ∼48 hr post blood-stage infection was assessed by microscopy (day 5 post spz challenge and day 2 post pRBC challenge). Data were pooled from multiple experiments. Plots show median values, 25th–75th percentiles, and range. One mouse in the AdM33 group had 0% parasitemia on day 5.(B) BALB/c mice were immunized with AdM33 or 1 × 108 vp AdHu5-PyCSP and challenged with 50 sporozoites 14 days later. The mean parasitemia ± SEM is shown (n = five or six mice per group). ∗p ≤ 0.05 and ∗∗∗ p ≤ 0.001, comparing between all groups by one-way ANOVA.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2663714&req=5

fig4: Blood-Stage Parasitemias in Naive and Immunized Mice 48 hr after Blood-Stage Infection(A) BALB/c mice immunized with AdM33 were challenged with 50 sporozoites (n = 18), or naive controls were challenged with 104 pRBCs (n = 29), 50 sporozoites (n = 44), or 250 sporozoites (n = 8). Blood-stage parasitemia ∼48 hr post blood-stage infection was assessed by microscopy (day 5 post spz challenge and day 2 post pRBC challenge). Data were pooled from multiple experiments. Plots show median values, 25th–75th percentiles, and range. One mouse in the AdM33 group had 0% parasitemia on day 5.(B) BALB/c mice were immunized with AdM33 or 1 × 108 vp AdHu5-PyCSP and challenged with 50 sporozoites 14 days later. The mean parasitemia ± SEM is shown (n = five or six mice per group). ∗p ≤ 0.05 and ∗∗∗ p ≤ 0.001, comparing between all groups by one-way ANOVA.
Mentions: Having established that AdM42 and AdM33 immunization can mediate an antiparasitic effect at the liver stage, we sought to assess whether the increased survival outcome against spz challenge was due to a reduction in the blood-stage inoculum from the liver. A single hepatic schizont of P. yoelii malaria will produce approximately 7500–8000 merozoites (Killick-Kendrick and Peters, 1978). Consequently, just two infected hepatocytes should release a larger blood-stage inoculum than the 104 pRBCs used in the blood-stage challenge model. Levels of blood-stage parasitemia were compared 2 days post blood-stage infection in naive BALB/c mice challenged with 104 pRBCs, 50 sporozoites (low dose), or 250 sporozoites (high dose) (Figure 4A). These data showed that spz challenge in naive mice leads to a significantly higher blood-stage parasitemia after 48 hr of blood-stage infection when compared to pRBC challenge. Mice immunized with AdM33 have a reduced liver-stage parasite burden (Figure 3C) but do not possess protective IgG. The same assessment of blood-stage parasitemia in mice immunized with AdM33 and challenged with 50 sporozoites showed, interestingly, that the mean parasitemia level was significantly reduced to one comparable with pRBC challenge (Figure 4A). These data indicate that if the amount of blood-stage inoculum from the liver was the sole determinant of survival outcome, then mice immunized with AdM33 and challenged with 104 pRBCs or 50 sporozoites should show the same percent survival outcome, which was not the case (Figures 2A and 2B).

Bottom Line: Here, we show that vaccine-induced MSP-1-specific CD4(+) T cells provide essential help for protective B cell responses, and CD8(+) T cells mediate significant antiparasitic activity against liver-stage parasites.This effect is evident both in the presence and absence of protective antibodies and is associated with decreased parasite burden in the liver followed by enhanced induction of the cytokine IFN-gamma in the serum.Multistage immunity against malaria can thus be achieved by using viral vectors recombinant for MSP-1.

View Article: PubMed Central - PubMed

Affiliation: The Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK. simon.draper@ndm.ox.ac.uk

ABSTRACT
Protecting against both liver and blood stages of infection is a long-sought goal of malaria vaccine design. Recently, we described the use of replication-defective viral vaccine vectors expressing the malaria antigen merozoite surface protein-1 (MSP-1) as an antimalarial vaccine strategy that elicits potent and protective antibody responses against blood-stage parasites. Here, we show that vaccine-induced MSP-1-specific CD4(+) T cells provide essential help for protective B cell responses, and CD8(+) T cells mediate significant antiparasitic activity against liver-stage parasites. Enhanced survival is subsequently seen in immunized mice following challenge with sporozoites, which mimics the natural route of infection more closely than when using infected red blood cells. This effect is evident both in the presence and absence of protective antibodies and is associated with decreased parasite burden in the liver followed by enhanced induction of the cytokine IFN-gamma in the serum. Multistage immunity against malaria can thus be achieved by using viral vectors recombinant for MSP-1.

Show MeSH
Related in: MedlinePlus