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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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IgG antibody levels to the PkAMA1 vaccine antigen.Blue triangles on the x-axis indicate immunisations and red triangles indicate time of parasite challenge. PkAMA1 = PkAMA1-immunised experimental animals, PfAMA1 = PfAMA1-immunised control animals.
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pone-0020547-g004: IgG antibody levels to the PkAMA1 vaccine antigen.Blue triangles on the x-axis indicate immunisations and red triangles indicate time of parasite challenge. PkAMA1 = PkAMA1-immunised experimental animals, PfAMA1 = PfAMA1-immunised control animals.

Mentions: Figure 4 shows that all animals had low anti-PkAMA1-IgG levels before vaccination (14 95% CI 6 to 34 and 32 95% CI 17 to 61 AU mL−1, for PkAMA1 and PfAMA1 groups respectively). Following vaccination, animals in the PkAMA1 group had detectable levels of antibodies to PkAMA1 two weeks after the first immunisation (939, 95% CI 358 to 2460 AU mL−1, paired t-test with day 0, p = 0.0006). Anti PkAMA1-IgG also increased in the PfAMA1 group, but at a much lower rate (118, 95% CI 51 to 271, paired t-test with day 0, p = 0.0005). The second immunisation at day 28 boosted responses at day 56 to high levels in the PkAMA1 group (22.3, 95% CI 11.7 to 42.6 kAU mL−1, paired t-test with day 28, p = 0.0002). PkAMA1-IgG levels in the PfAMA1 group were also boosted significantly after the second immunisation (3.2, 95% CI 1.6 to 6.5 kAU mL−1, paired t-test with day 28, p = 0.0006). At day 56 anti-PkAMA1-IgG levels were significantly higher in the PkAMA1 group (7.0 fold, 95% CI 3.0 to 16.0 fold, t-test p- value = 0.0004). The third vaccination at day 56 boosted anti PkAMA1-IgG levels at day 70 even further; animals in the PkAMA1 group had 70.5 kAU mL−1 (95% CI 43.2 to 115.1, paired t-test with day 56, p = 0.0002) and animals in the PfAMA1 had 45.5 kAU mL−1 (95% CI 21.5 to 96.5, paired t-test with day 56, p<0.0001). This was in part due to one animal (Ri397 [⋄]) in the PfAMA1 group that had an unexpectedly high anti PkAMA1 titre (164.0 kAU mL−1) at day 70 and this value was confirmed in repeat ELISA's. In parallel, the IgG titre to the PfAMA1 vaccine antigen was also high in this animal (266.6 kAU mL−1). Day 70 IgG levels to PkAMA1 were not significantly higher in the PkAMA1 group [70.5 (95% CI 43.2 to 115.1) versus 45.5 (95% CI 21.5 to 96.5) kAU mL−1 (p = 0.24)] as compared to the PfAMA1 group. IgG levels to PkAMA1 decreased during the challenge phase in both groups (PkAMA1 group: paired t-test with day 70, p = 0.0122 to 45.9 kAU mL−1 95% CI 27.5 to 76.5 and PfAMA1 group: paired t-test with day 70, p = 0.0052 to 18.1 kAU mL−1 95% CI 10.5 to 31.3).


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)

IgG antibody levels to the PkAMA1 vaccine antigen.Blue triangles on the x-axis indicate immunisations and red triangles indicate time of parasite challenge. PkAMA1 = PkAMA1-immunised experimental animals, PfAMA1 = PfAMA1-immunised control animals.
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Related In: Results  -  Collection

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pone-0020547-g004: IgG antibody levels to the PkAMA1 vaccine antigen.Blue triangles on the x-axis indicate immunisations and red triangles indicate time of parasite challenge. PkAMA1 = PkAMA1-immunised experimental animals, PfAMA1 = PfAMA1-immunised control animals.
Mentions: Figure 4 shows that all animals had low anti-PkAMA1-IgG levels before vaccination (14 95% CI 6 to 34 and 32 95% CI 17 to 61 AU mL−1, for PkAMA1 and PfAMA1 groups respectively). Following vaccination, animals in the PkAMA1 group had detectable levels of antibodies to PkAMA1 two weeks after the first immunisation (939, 95% CI 358 to 2460 AU mL−1, paired t-test with day 0, p = 0.0006). Anti PkAMA1-IgG also increased in the PfAMA1 group, but at a much lower rate (118, 95% CI 51 to 271, paired t-test with day 0, p = 0.0005). The second immunisation at day 28 boosted responses at day 56 to high levels in the PkAMA1 group (22.3, 95% CI 11.7 to 42.6 kAU mL−1, paired t-test with day 28, p = 0.0002). PkAMA1-IgG levels in the PfAMA1 group were also boosted significantly after the second immunisation (3.2, 95% CI 1.6 to 6.5 kAU mL−1, paired t-test with day 28, p = 0.0006). At day 56 anti-PkAMA1-IgG levels were significantly higher in the PkAMA1 group (7.0 fold, 95% CI 3.0 to 16.0 fold, t-test p- value = 0.0004). The third vaccination at day 56 boosted anti PkAMA1-IgG levels at day 70 even further; animals in the PkAMA1 group had 70.5 kAU mL−1 (95% CI 43.2 to 115.1, paired t-test with day 56, p = 0.0002) and animals in the PfAMA1 had 45.5 kAU mL−1 (95% CI 21.5 to 96.5, paired t-test with day 56, p<0.0001). This was in part due to one animal (Ri397 [⋄]) in the PfAMA1 group that had an unexpectedly high anti PkAMA1 titre (164.0 kAU mL−1) at day 70 and this value was confirmed in repeat ELISA's. In parallel, the IgG titre to the PfAMA1 vaccine antigen was also high in this animal (266.6 kAU mL−1). Day 70 IgG levels to PkAMA1 were not significantly higher in the PkAMA1 group [70.5 (95% CI 43.2 to 115.1) versus 45.5 (95% CI 21.5 to 96.5) kAU mL−1 (p = 0.24)] as compared to the PfAMA1 group. IgG levels to PkAMA1 decreased during the challenge phase in both groups (PkAMA1 group: paired t-test with day 70, p = 0.0122 to 45.9 kAU mL−1 95% CI 27.5 to 76.5 and PfAMA1 group: paired t-test with day 70, p = 0.0052 to 18.1 kAU mL−1 95% CI 10.5 to 31.3).

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