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Vaccination with Plasmodium knowlesi AMA1 formulated in the novel adjuvant co-vaccine HT™ protects against blood-stage challenge in rhesus macaques.

Mahdi Abdel Hamid M, Remarque EJ, van Duivenvoorde LM, van der Werff N, Walraven V, Faber BW, Kocken CH, Thomas AW - PLoS ONE (2011)

Bottom Line: Combined with the adjuvant CoVaccine HT™, PkAMA1 was found to be highly immunogenic in rabbits and the efficacy of the PkAMA1 was subsequently tested in a rhesus macaque blood-stage challenge model.In the PfAMA1 vaccinated control group, five out of six animals had to be treated with antimalarials 8 days after challenge; one animal did not become patent during the challenge period.This study shows that: i) Yeast-expressed PkAMA1 can protect against blood stage challenge; ii) Functional antibody levels as measured by GIA correlated inversely with the day of onset and iii) GIA IC(50) values correlated with estimated in vivo growth rates.

View Article: PubMed Central - PubMed

Affiliation: Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.

ABSTRACT
Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a leading blood stage vaccine candidate. Plasmodium knowlesi AMA1 (PkAMA1) was produced and purified using similar methodology as for clinical grade PfAMA1 yielding a pure, conformational intact protein. Combined with the adjuvant CoVaccine HT™, PkAMA1 was found to be highly immunogenic in rabbits and the efficacy of the PkAMA1 was subsequently tested in a rhesus macaque blood-stage challenge model. Six rhesus monkeys were vaccinated with PkAMA1 and a control group of 6 were vaccinated with PfAMA1. A total of 50 µg AMA1 was administered intramuscularly three times at 4 week intervals. One of six rhesus monkeys vaccinated with PkAMA1 was able to control parasitaemia, upon blood stage challenge with P. knowlesi H-strain. Four out of the remaining five showed a delay in parasite onset that correlated with functional antibody titres. In the PfAMA1 vaccinated control group, five out of six animals had to be treated with antimalarials 8 days after challenge; one animal did not become patent during the challenge period. Following a rest period, animals were boosted and challenged again. Four of the six rhesus monkeys vaccinated with PkAMA1 were able to control the parasitaemia, one had a delayed onset of parasitaemia and one animal was not protected, while all control animals required treatment. To confirm that the control of parasitaemia was AMA1-related, animals were allowed to recover, boosted and re-challenged with P. knowlesi Nuri strain. All control animals had to be treated with antimalarials by day 8, while five out of six PkAMA1 vaccinated animals were able to control parasitaemia. This study shows that: i) Yeast-expressed PkAMA1 can protect against blood stage challenge; ii) Functional antibody levels as measured by GIA correlated inversely with the day of onset and iii) GIA IC(50) values correlated with estimated in vivo growth rates.

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IFN-γ and IL-13 production following in vitro stimulation with PkAMA1.Blue triangles on the x-axis indicate immunisation time points, red triangles indicate time of parasite challenges. PfAMA1 = PfAMA1-immunised control animals, PkAMA1 = PkAMA1-immunised experimental animals. The point not depicted for PkAMA1 [⋄] is at 2757 pg mL−1 IFN-γ.
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pone-0020547-g006: IFN-γ and IL-13 production following in vitro stimulation with PkAMA1.Blue triangles on the x-axis indicate immunisation time points, red triangles indicate time of parasite challenges. PfAMA1 = PfAMA1-immunised control animals, PkAMA1 = PkAMA1-immunised experimental animals. The point not depicted for PkAMA1 [⋄] is at 2757 pg mL−1 IFN-γ.

Mentions: Antigen-specific lymphocyte stimulation assays showed that IFN-γ levels were generally low with a median values of 25.4 (Quartile range: 17.7 to 36.3 pg mL−1) and 1 (Quartile range 1 to 1 pg mL−1) for the PkAMA1 and PfAMA1 groups, respectively. The difference in IFN-γ levels was statistically significant (p = 0.025, Mann-Whitney test). The protected monkey in the PkAMA1 group produced the highest IFN-γ level upon stimulation with PkAMA1, while all other samples were low to negative in this assay (Figure 6). IL-13 levels were low; the median IL-13 values were 14.5 (Quartile range 2.8 to 84.2 pg mL−1) and 33.8 (Quartile range 8.2 to 91.5) for the PkAMA1 and PfAMA1 groups, respectively (p = 0.68, Mann-Whitney test). The IL-13 level of the protected monkey was not elevated; in the PkAMA1 group only two monkeys (R00066 [○] and Ri9902011 [▪]) had elevated levels of IL-13 following stimulation with PkAMA1 (figure 6). The animal in the control group that did not become patent did not produce detectable IFN-γ nor IL-13 upon stimulation with PkAMA1. Four out of two control monkeys (Ri10177 [▪], Ri9806051 [⧫], Ri397 [⋄] and R01077 [□]) in the control group produced some IL-13, but no detectable IFN-γ.


Vaccination with Plasmodium knowlesi AMA1 formulated in the novel adjuvant co-vaccine HT™ protects against blood-stage challenge in rhesus macaques.

Mahdi Abdel Hamid M, Remarque EJ, van Duivenvoorde LM, van der Werff N, Walraven V, Faber BW, Kocken CH, Thomas AW - PLoS ONE (2011)

IFN-γ and IL-13 production following in vitro stimulation with PkAMA1.Blue triangles on the x-axis indicate immunisation time points, red triangles indicate time of parasite challenges. PfAMA1 = PfAMA1-immunised control animals, PkAMA1 = PkAMA1-immunised experimental animals. The point not depicted for PkAMA1 [⋄] is at 2757 pg mL−1 IFN-γ.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105089&req=5

pone-0020547-g006: IFN-γ and IL-13 production following in vitro stimulation with PkAMA1.Blue triangles on the x-axis indicate immunisation time points, red triangles indicate time of parasite challenges. PfAMA1 = PfAMA1-immunised control animals, PkAMA1 = PkAMA1-immunised experimental animals. The point not depicted for PkAMA1 [⋄] is at 2757 pg mL−1 IFN-γ.
Mentions: Antigen-specific lymphocyte stimulation assays showed that IFN-γ levels were generally low with a median values of 25.4 (Quartile range: 17.7 to 36.3 pg mL−1) and 1 (Quartile range 1 to 1 pg mL−1) for the PkAMA1 and PfAMA1 groups, respectively. The difference in IFN-γ levels was statistically significant (p = 0.025, Mann-Whitney test). The protected monkey in the PkAMA1 group produced the highest IFN-γ level upon stimulation with PkAMA1, while all other samples were low to negative in this assay (Figure 6). IL-13 levels were low; the median IL-13 values were 14.5 (Quartile range 2.8 to 84.2 pg mL−1) and 33.8 (Quartile range 8.2 to 91.5) for the PkAMA1 and PfAMA1 groups, respectively (p = 0.68, Mann-Whitney test). The IL-13 level of the protected monkey was not elevated; in the PkAMA1 group only two monkeys (R00066 [○] and Ri9902011 [▪]) had elevated levels of IL-13 following stimulation with PkAMA1 (figure 6). The animal in the control group that did not become patent did not produce detectable IFN-γ nor IL-13 upon stimulation with PkAMA1. Four out of two control monkeys (Ri10177 [▪], Ri9806051 [⧫], Ri397 [⋄] and R01077 [□]) in the control group produced some IL-13, but no detectable IFN-γ.

Bottom Line: Combined with the adjuvant CoVaccine HT™, PkAMA1 was found to be highly immunogenic in rabbits and the efficacy of the PkAMA1 was subsequently tested in a rhesus macaque blood-stage challenge model.In the PfAMA1 vaccinated control group, five out of six animals had to be treated with antimalarials 8 days after challenge; one animal did not become patent during the challenge period.This study shows that: i) Yeast-expressed PkAMA1 can protect against blood stage challenge; ii) Functional antibody levels as measured by GIA correlated inversely with the day of onset and iii) GIA IC(50) values correlated with estimated in vivo growth rates.

View Article: PubMed Central - PubMed

Affiliation: Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.

ABSTRACT
Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a leading blood stage vaccine candidate. Plasmodium knowlesi AMA1 (PkAMA1) was produced and purified using similar methodology as for clinical grade PfAMA1 yielding a pure, conformational intact protein. Combined with the adjuvant CoVaccine HT™, PkAMA1 was found to be highly immunogenic in rabbits and the efficacy of the PkAMA1 was subsequently tested in a rhesus macaque blood-stage challenge model. Six rhesus monkeys were vaccinated with PkAMA1 and a control group of 6 were vaccinated with PfAMA1. A total of 50 µg AMA1 was administered intramuscularly three times at 4 week intervals. One of six rhesus monkeys vaccinated with PkAMA1 was able to control parasitaemia, upon blood stage challenge with P. knowlesi H-strain. Four out of the remaining five showed a delay in parasite onset that correlated with functional antibody titres. In the PfAMA1 vaccinated control group, five out of six animals had to be treated with antimalarials 8 days after challenge; one animal did not become patent during the challenge period. Following a rest period, animals were boosted and challenged again. Four of the six rhesus monkeys vaccinated with PkAMA1 were able to control the parasitaemia, one had a delayed onset of parasitaemia and one animal was not protected, while all control animals required treatment. To confirm that the control of parasitaemia was AMA1-related, animals were allowed to recover, boosted and re-challenged with P. knowlesi Nuri strain. All control animals had to be treated with antimalarials by day 8, while five out of six PkAMA1 vaccinated animals were able to control parasitaemia. This study shows that: i) Yeast-expressed PkAMA1 can protect against blood stage challenge; ii) Functional antibody levels as measured by GIA correlated inversely with the day of onset and iii) GIA IC(50) values correlated with estimated in vivo growth rates.

Show MeSH
Related in: MedlinePlus