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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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Survival against pRBC and Sporozoite Challenge(A–C) BALB/c mice were immunized as indicated. Fourteen days after the final immunization, these mice or naive controls were challenged i.v. with 104 pRBCs (A) or 50 sporozoites (B), and Kaplan-Meier plots show survival over time. Data were pooled from multiple experiments, and the number of mice challenged in total (n) is indicated for each group. As shown in (C), mice immunized with AdM33 or naive controls were challenged with 104 pRBCs or 50 sporozoites. Parasitemia in the blood was measured postchallenge by microscopy. Plots show the mean parasitemia ± SEM (n = six mice per group) for the first 4 days following patency. ∗ p ≤ 0.05, ∗∗ p ≤ 0.01, and ∗∗∗ p ≤ 0.001 (independent Student's t test comparing percent parasitemia at each time point between the immunized and naive control mice).
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fig2: Survival against pRBC and Sporozoite Challenge(A–C) BALB/c mice were immunized as indicated. Fourteen days after the final immunization, these mice or naive controls were challenged i.v. with 104 pRBCs (A) or 50 sporozoites (B), and Kaplan-Meier plots show survival over time. Data were pooled from multiple experiments, and the number of mice challenged in total (n) is indicated for each group. As shown in (C), mice immunized with AdM33 or naive controls were challenged with 104 pRBCs or 50 sporozoites. Parasitemia in the blood was measured postchallenge by microscopy. Plots show the mean parasitemia ± SEM (n = six mice per group) for the first 4 days following patency. ∗ p ≤ 0.05, ∗∗ p ≤ 0.01, and ∗∗∗ p ≤ 0.001 (independent Student's t test comparing percent parasitemia at each time point between the immunized and naive control mice).

Mentions: We have reported that AdM42 immunization can protect 76% of BALB/c mice (13 of 17) against a lethal challenge with 104P. yoelii pRBCs (Draper et al., 2008). That study did not confirm whether antibodies against MSP-133 played a role in blood-stage immunity. Here, we assessed the protective efficacy of AdM33 and AdM19 immunization against a blood-stage challenge (Figure 2A). None of the mice immunized with AdM33 survived challenge, despite higher total IgG responses and similar T cell responses against MSP-133 as compared to mice immunized with AdM42 (Figure 1). This confirms that no protection is mediated in this pRBC challenge model by MSP-133-specific immune responses alone. Survival was seen in four of six mice (67%) immunized with Ad42M19, and notably, these mice possessed only high-titer IgG responses to MSP-119 (Figure 1D). In contrast, none of the mice immunized with AdM19 was protected, which was unsurprising, given the absence of detectable immune responses induced by this vaccine regime (Figure 1). In agreement with our previous report, protection in this pRBC challenge model is dependent on MSP-119-specific IgG.


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)

Survival against pRBC and Sporozoite Challenge(A–C) BALB/c mice were immunized as indicated. Fourteen days after the final immunization, these mice or naive controls were challenged i.v. with 104 pRBCs (A) or 50 sporozoites (B), and Kaplan-Meier plots show survival over time. Data were pooled from multiple experiments, and the number of mice challenged in total (n) is indicated for each group. As shown in (C), mice immunized with AdM33 or naive controls were challenged with 104 pRBCs or 50 sporozoites. Parasitemia in the blood was measured postchallenge by microscopy. Plots show the mean parasitemia ± SEM (n = six mice per group) for the first 4 days following patency. ∗ p ≤ 0.05, ∗∗ p ≤ 0.01, and ∗∗∗ p ≤ 0.001 (independent Student's t test comparing percent parasitemia at each time point between the immunized and naive control mice).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2663714&req=5

fig2: Survival against pRBC and Sporozoite Challenge(A–C) BALB/c mice were immunized as indicated. Fourteen days after the final immunization, these mice or naive controls were challenged i.v. with 104 pRBCs (A) or 50 sporozoites (B), and Kaplan-Meier plots show survival over time. Data were pooled from multiple experiments, and the number of mice challenged in total (n) is indicated for each group. As shown in (C), mice immunized with AdM33 or naive controls were challenged with 104 pRBCs or 50 sporozoites. Parasitemia in the blood was measured postchallenge by microscopy. Plots show the mean parasitemia ± SEM (n = six mice per group) for the first 4 days following patency. ∗ p ≤ 0.05, ∗∗ p ≤ 0.01, and ∗∗∗ p ≤ 0.001 (independent Student's t test comparing percent parasitemia at each time point between the immunized and naive control mice).
Mentions: We have reported that AdM42 immunization can protect 76% of BALB/c mice (13 of 17) against a lethal challenge with 104P. yoelii pRBCs (Draper et al., 2008). That study did not confirm whether antibodies against MSP-133 played a role in blood-stage immunity. Here, we assessed the protective efficacy of AdM33 and AdM19 immunization against a blood-stage challenge (Figure 2A). None of the mice immunized with AdM33 survived challenge, despite higher total IgG responses and similar T cell responses against MSP-133 as compared to mice immunized with AdM42 (Figure 1). This confirms that no protection is mediated in this pRBC challenge model by MSP-133-specific immune responses alone. Survival was seen in four of six mice (67%) immunized with Ad42M19, and notably, these mice possessed only high-titer IgG responses to MSP-119 (Figure 1D). In contrast, none of the mice immunized with AdM19 was protected, which was unsurprising, given the absence of detectable immune responses induced by this vaccine regime (Figure 1). In agreement with our previous report, protection in this pRBC challenge model is dependent on MSP-119-specific IgG.

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