Phase 1 safety and immunogenicity trial of the Plasmodium falciparum blood-stage malaria vaccine AMA1-C1/ISA 720 in Australian adults

Abstract

A Phase 1 trial was conducted in malaria-naïve adults to evaluate the recombinant protein vaccine apical membrane antigen 1-Combination 1 (AMA1-C1) formulated in Montanide ISA 720 (SEPPIC, France), a water-in-oil adjuvant. Vaccinations were halted early due to a formulation issue unrelated to stability or potency. Twenty-four subjects (12 in each group) were enrolled and received 5 or 20 microg protein at 0 and 3 months and four subjects were enrolled and received one vaccination of 80 microg protein. After first vaccination, nearly all subjects experienced mild to moderate local reactions and six experienced delayed local reactions occurring at Day 9 or later. After the second vaccination, three subjects experienced transient grade 3 (severe) local reactions; the remainder experienced grade 1 or 2 local reactions. All related systemic reactogenicity was grade 1 or 2, except one instance of grade 3 malaise. Anti-AMA1-C1 antibody responses were dose dependent and seen following each vaccination, with mean antibody levels 2-3 fold higher in the 20 microg group compared to the 5 microg group at most time points. In vitro growth-inhibitory activity was a function of the anti-AMA1 antibody titer. AMA1-C1 formulated in ISA 720 is immunogenic in malaria-naïve Australian adults. It is reasonably tolerated, though some transient, severe, and late local reactions are seen.

Figure 1. Antibody Responses of 5, 20, and 80 μg Dose Groups

Antibody response of volunteers vaccinated with AMA1-C1/ISA 720. Geometric means, with 95% confidence intervals, of anti-AMA1-C1 antibody level are shown for the 5, 20, and 80 μg dose groups (a, b, and c; n=9, 9, and 4 respectively). Arrows indicate the days of immunization; all 3 groups were immunized on Day 0 and the 5 and 20 μg groups were also immunized on Day 84.

Figure 2. In Vitro Growth Inhibition

Biological activity of anti-AMA1 antibodies against P. falciparum 3D7 parasites judged by in vitro growth inhibition assay (GIA). Days 0 and 112 total IgGs from the 5 (n=11) and 20 μg (n=9) cohorts were tested at 10 mg/ml by GIA. The anti-AMA1-3D7 antibody level in the GIA well (x-axis) is plotted against % inhibition (y-axis) to P. falciparum 3D7 parasites. Line is the Hill model fit calculated using only Day 112 data.