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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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Parasitaemia development following i.v. challenge with P. knowlesi blood stage parasites.Parasitaemia development versus time during the 3 challenges. Top panels are PkAMA1-immunised experimental animals and bottom panels PfAMA1-immunised control animals. Day 8 post challenge is indicated by a vertical red line. The symbols within each treatment group refer to the same animals throughout all figures.
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pone-0020547-g003: Parasitaemia development following i.v. challenge with P. knowlesi blood stage parasites.Parasitaemia development versus time during the 3 challenges. Top panels are PkAMA1-immunised experimental animals and bottom panels PfAMA1-immunised control animals. Day 8 post challenge is indicated by a vertical red line. The symbols within each treatment group refer to the same animals throughout all figures.

Mentions: At day 70, all animals were blood stage challenged by in vivo passage of 10,000 P. knowlesi H strain late trophozoites. The left hand panels in figure 3 show the parasitaemia in the blood of individual animals during the course of infection, both in the immunised (top panel) and control (bottom panel) group. Table 2 shows the parasitological and immunological data at the day of challenge. Five animals from the control group had to be cured within 8 days, the sixth animal, however (R01041 [•]) did not become patent during the challenge phase (Figure 3, Table 2). One monkey from the PkAMA1 group, (Ri9980203 [⋄]) was patent at days 10 and 14 post infection, but was obviously able to control the parasitaemia (Table 2). The other 5 animals had to be cured, but there was an average delay of about 2 days in the day of onset of the parasitaemia between the PkAMA1 group and the PfAMA1 control group, albeit not statistically significant (log-rank test, p = 0.453). The time to drug cure was also delayed for 4 out of 6 animals, but again not statistically significant (log-rank test, p = 0.28). When these analyses were repeated excluding the control monkey that did not become patent (R01041 [•]), both time to patency and time to drug cure were significantly longer in the PkAMA1 vaccinated group (log-rank test, p = 0.006 and 0.002, respectively).


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)

Parasitaemia development following i.v. challenge with P. knowlesi blood stage parasites.Parasitaemia development versus time during the 3 challenges. Top panels are PkAMA1-immunised experimental animals and bottom panels PfAMA1-immunised control animals. Day 8 post challenge is indicated by a vertical red line. The symbols within each treatment group refer to the same animals throughout all figures.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020547-g003: Parasitaemia development following i.v. challenge with P. knowlesi blood stage parasites.Parasitaemia development versus time during the 3 challenges. Top panels are PkAMA1-immunised experimental animals and bottom panels PfAMA1-immunised control animals. Day 8 post challenge is indicated by a vertical red line. The symbols within each treatment group refer to the same animals throughout all figures.
Mentions: At day 70, all animals were blood stage challenged by in vivo passage of 10,000 P. knowlesi H strain late trophozoites. The left hand panels in figure 3 show the parasitaemia in the blood of individual animals during the course of infection, both in the immunised (top panel) and control (bottom panel) group. Table 2 shows the parasitological and immunological data at the day of challenge. Five animals from the control group had to be cured within 8 days, the sixth animal, however (R01041 [•]) did not become patent during the challenge phase (Figure 3, Table 2). One monkey from the PkAMA1 group, (Ri9980203 [⋄]) was patent at days 10 and 14 post infection, but was obviously able to control the parasitaemia (Table 2). The other 5 animals had to be cured, but there was an average delay of about 2 days in the day of onset of the parasitaemia between the PkAMA1 group and the PfAMA1 control group, albeit not statistically significant (log-rank test, p = 0.453). The time to drug cure was also delayed for 4 out of 6 animals, but again not statistically significant (log-rank test, p = 0.28). When these analyses were repeated excluding the control monkey that did not become patent (R01041 [•]), both time to patency and time to drug cure were significantly longer in the PkAMA1 vaccinated group (log-rank test, p = 0.006 and 0.002, respectively).

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