Safety and immunogenicity of multi-antigen AMA1-based vaccines formulated with CoVaccine HT™ and Montanide ISA 51 in rhesus macaques

Kwadwo A Kusi,Vanessa Riasat,Clemens Hm Kocken,Vanessa Walraven,Alan W Thomas,Edmond J Remarque,Bart W Faber

doi:10.1186/1475-2875-10-182

Abstract

BackgroundIncreasing the breadth of the functional antibody response through immunization with Plasmodium falciparum apical membrane antigen 1 (PfAMA1) multi-allele vaccine formulations has been demonstrated in several rodent and rabbit studies. This study assesses the safety and immunogenicity of three PfAMA1 Diversity-Covering (DiCo) vaccine candidates formulated as an equimolar mixture (DiCo mix) in CoVaccine HT™ or Montanide ISA 51, as well as that of a PfAMA1-MSP119 fusion protein formulated in Montanide ISA 51.MethodsVaccine safety in rhesus macaques was monitored by animal behaviour observation and assessment of organ and systemic functions through clinical chemistry and haematology measurements. The immunogenicity of vaccine formulations was assessed by enzyme-linked immunosorbent assays and in vitro parasite growth inhibition assays with three culture-adapted P. falciparum strains.ResultsThese data show that both adjuvants were well tolerated with only transient changes in a few of the chemical and haematological parameters measured. DiCo mix formulated in CoVaccine HT™ proved immunologically and functionally superior to the same candidate formulated in Montanide ISA 51. Immunological data from the fusion protein candidate was however difficult to interpret as four out of six immunized animals were non-responsive for unknown reasons.ConclusionsThe study highlights the safety and immunological benefits of DiCo mix as a potential human vaccine against blood stage malaria, especially when formulated in CoVaccine HT™, and adds to the accumulating data on the specificity broadening effects of DiCo mix.

Highlights

Increasing the breadth of the functional antibody response through immunization with Plasmodium falciparum apical membrane antigen 1 (PfAMA1) multi-allele vaccine formulations has been demonstrated in several rodent and rabbit studies
Essential P. falciparum antigens that are currently being considered as subunit vaccine candidates include apical membrane antigen 1 (AMA1) and merozoite surface protein 1 (MSP1)
The PfAMA1-MSP119 fusion protein consists of amino acids 106 - 442 of the FVO AMA1 ectodomain fused with a mutant form of PfMSP119 of the Wellcome strain of P. falciparum [35]

Summary

Introduction

Increasing the breadth of the functional antibody response through immunization with Plasmodium falciparum apical membrane antigen 1 (PfAMA1) multi-allele vaccine formulations has been demonstrated in several rodent and rabbit studies. Current knowledge of Plasmodium falciparum, the parasite responsible for the most severe form of disease suggests that a potentially effective vaccine would likely include multiple antigens, preferably expressed in different stages of the parasite’s life cycle. Essential P. falciparum antigens that are currently being considered as subunit vaccine candidates include apical membrane antigen 1 (AMA1) and merozoite surface protein 1 (MSP1). AMA1 is highly polymorphic and is found in both merozoite and sporozoite stages of the parasite [1,2,3,4] It is initially expressed as an 83 kDa precursor protein in the micronemes and undergoes an N-terminal prosequence cleavage to form the 66 kDa antigen at the same site [5]. The ectodomain has 16 cysteine residues that form disulphide bonds to divide the antigen’s tertiary structure into three different but interactive domains [11]

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Results

Conclusion