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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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Parasite Growth Inhibition by purified IgG antibodies.GIA titres with P. knowlesi H-strain at 10 and 5 mg mL−1 IgG for PkAMA1 immunised experimental group and PfAMA1 immunised controls. Blue triangles on the x-axis indicate immunisation time points, red triangles indicate time of parasite challenges.
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pone-0020547-g005: Parasite Growth Inhibition by purified IgG antibodies.GIA titres with P. knowlesi H-strain at 10 and 5 mg mL−1 IgG for PkAMA1 immunised experimental group and PfAMA1 immunised controls. Blue triangles on the x-axis indicate immunisation time points, red triangles indicate time of parasite challenges.

Mentions: Figure 5 shows the GIA titres in the two treatment groups. The first two immunisations at days 0 and 28 induced clearly detectable GIA activity in the PkAMA1 vaccinated animals and GIA levels had reached 41.3% at day 42 (95% CI 15.6 to 67.0, paired t-test with day 0, p = 0.0218) between days 0 and 42 (figure 5). By contrast GIA levels in the PfAMA1 group did not change significantly (−2.7%, 95% CI −2.9 to 6.6% at day 42, paired t-test with day 0, p = 0.226) (figure 5). The third immunisation increased GIA levels even further in the PkAMA1 group to 78.4% at day 70 (95% CI 61.8 to 94.9%, paired t-test with day 42, p = 0.003), while GIA levels remained unchanged in the PfAMA1 group 1.9% (, 95% CI −12.6 to 7.2%, paired t-test with day 42, p = 0.437). At the time of challenge (day 70) GIA levels were significantly higher in the PkAMA1 group as compared to the PfAMA1 control group (t-test, p<0.0001) (figure 5). GIA levels in the PkAMA1 group decreased significantly during the challenge phase to 46.7% (95% CI 15.2 to 78.3%, paired t-test with day 70, p = 0.0128) and a small non-significant decrease was observed for animals in the PfAMA1 group; −18.2% at day 91 (−95% CI −35.1 to −1.4%, paired t-test with day 70, p = 0.053).


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)

Parasite Growth Inhibition by purified IgG antibodies.GIA titres with P. knowlesi H-strain at 10 and 5 mg mL−1 IgG for PkAMA1 immunised experimental group and PfAMA1 immunised controls. Blue triangles on the x-axis indicate immunisation time points, red triangles indicate time of parasite challenges.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020547-g005: Parasite Growth Inhibition by purified IgG antibodies.GIA titres with P. knowlesi H-strain at 10 and 5 mg mL−1 IgG for PkAMA1 immunised experimental group and PfAMA1 immunised controls. Blue triangles on the x-axis indicate immunisation time points, red triangles indicate time of parasite challenges.
Mentions: Figure 5 shows the GIA titres in the two treatment groups. The first two immunisations at days 0 and 28 induced clearly detectable GIA activity in the PkAMA1 vaccinated animals and GIA levels had reached 41.3% at day 42 (95% CI 15.6 to 67.0, paired t-test with day 0, p = 0.0218) between days 0 and 42 (figure 5). By contrast GIA levels in the PfAMA1 group did not change significantly (−2.7%, 95% CI −2.9 to 6.6% at day 42, paired t-test with day 0, p = 0.226) (figure 5). The third immunisation increased GIA levels even further in the PkAMA1 group to 78.4% at day 70 (95% CI 61.8 to 94.9%, paired t-test with day 42, p = 0.003), while GIA levels remained unchanged in the PfAMA1 group 1.9% (, 95% CI −12.6 to 7.2%, paired t-test with day 42, p = 0.437). At the time of challenge (day 70) GIA levels were significantly higher in the PkAMA1 group as compared to the PfAMA1 control group (t-test, p<0.0001) (figure 5). GIA levels in the PkAMA1 group decreased significantly during the challenge phase to 46.7% (95% CI 15.2 to 78.3%, paired t-test with day 70, p = 0.0128) and a small non-significant decrease was observed for animals in the PfAMA1 group; −18.2% at day 91 (−95% CI −35.1 to −1.4%, paired t-test with day 70, p = 0.053).

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