Vaccination with Plasmodium knowlesi AMA1 Formulated in the Novel Adjuvant Co-Vaccine HT™ Protects against Blood-Stage Challenge in Rhesus Macaques

Muzamil Mahdi Abdel Hamid,Bart W Faber,Nicole Van Der Werff,Leonie M Van Duivenvoorde,Alan W Thomas,Edmond J Remarque,Vanessa Walraven,Clemens H M Kocken,Denise L Doolan

doi:10.1371/journal.pone.0020547

Muzamil Mahdi Abdel Hamid, Bart W Faber + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0020547

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Journal: PloS one	Publication Date: May 31, 2011
Citations: 100	License type: CC BY 4.0

Affiliation: Biomedical Primate Research Centre

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 IC50 values correlated with estimated in vivo growth rates.

Highlights

The Plasmodium falciparum parasite is responsible for at least 300 million cases of malaria [1] and about 800,000 deaths every year [2]
P. knowlesi causes a fulminent infection in rhesus monkeys, often resulting in high parasitaemias similar to levels observed in P. falciparum infections in humans, and in death if left untreated [10,11,12]
Table-2-captionThe apparent molecular masses of the two constructs analyzed by 4–12% gradient SDS-PAGE were 50 kDa and 40 kDa for PkAMA1 DI-II-III and PkAMA1 DIII respectively, in accordance with theoretical mass calculated from their respective amino acid sequences

Summary

Introduction

The Plasmodium falciparum parasite is responsible for at least 300 million cases of malaria [1] and about 800,000 deaths every year [2]. The majority of these deaths occur in children under five and nulliparous women in sub-Saharan Africa [3]. P. knowlesi causes a fulminent infection in rhesus monkeys, often resulting in high parasitaemias similar to levels observed in P. falciparum infections in humans, and in death if left untreated [10,11,12]. P. knowlesi has recently been shown to infect humans under natural conditions and was shown to be a contributing cause of death [13,14]

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