A randomized controlled phase 2 trial of the blood stage AMA1-C1/Alhydrogel malaria vaccine in children in Mali

Abstract

A double blind, randomized, controlled Phase 2 clinical trial was conducted to assess the safety, immunogenicity, and biologic impact of the vaccine candidate Apical Membrane Antigen 1-Combination 1 (AMA1-C1), adjuvanted with Alhydrogel. Participants were healthy children 2-3 years old living in or near the village of Bancoumana, Mali. A total of 300 children received either the study vaccine or the comparator. No impact of vaccination was seen on the primary endpoint, the frequency of parasitemia measured as episodes >3000/microL/day at risk. There was a negative impact of vaccination on the hemoglobin level during clinical malaria, and mean incidence of hemoglobin <8.5 g/dL, in the direction of lower hemoglobin in the children who received AMA1-C1, although these differences were not significant after correction for multiple tests. These differences were not seen in the second year of transmission.

Figure 1

Study Flow Chart

Figure 2. Kaplan-Meier curve of time to first parasite density > 3000/μL

Kaplan-Meier curves for time from Day 42 until first observed parasitemia > 3000/uL for AMA1-C1 (solid line, n=139) or Hiberix (dashed line, n=140) groups. Subjects that were included in the biologic impact analysis are shown.

Figure 3

Figure 3a: Cohort 1: Geometric mean of (arithmetic) average of anti-FVO and anti-3D7 AMA1 antibody. Red is the 80 ug AMA1-C1/Alhydrogel group (n=26) and blue is the Hiberix group (n=28). The horizontal axis is Study Day up to Day 154. Day 0 occurred between May 28 and June 2 2006. After day 154, responses shown are as follows: the values at Day 324 are the responses in May/June 2007, the values at Day 503 are from November/December 2007, and responses at Day 545 are from January 2008. Dashed lines are pointwise 95 percent confidence intervals for each group using t-statistics on the log transformed ELISA values. Figure 3b: Cohort 2: Geometric mean of (arithmetic) average of anti-FVO and anti-3D7 AMA1 antibody Red is the 80 ug AMA1-C1/Alhydrogel group (n= 92) and blue is the Hiberix group (n=95). The horizontal axis is Study Day up to Day 154. Day 0 occurred between July 23 and August 14 2006. After Day 154, responses shown are as follows: the values at Day 324 are the responses in May/June 2007, the values at Day 503 are from November/December 2007, and responses at Day 545 are from January 2008. Dashed lines are pointwise 95 percent confidence intervals for each group using t-statistics on the log transformed ELISA values.

Figure 3

Figure 3a: Cohort 1: Geometric mean of (arithmetic) average of anti-FVO and anti-3D7 AMA1 antibody. Red is the 80 ug AMA1-C1/Alhydrogel group (n=26) and blue is the Hiberix group (n=28). The horizontal axis is Study Day up to Day 154. Day 0 occurred between May 28 and June 2 2006. After day 154, responses shown are as follows: the values at Day 324 are the responses in May/June 2007, the values at Day 503 are from November/December 2007, and responses at Day 545 are from January 2008. Dashed lines are pointwise 95 percent confidence intervals for each group using t-statistics on the log transformed ELISA values. Figure 3b: Cohort 2: Geometric mean of (arithmetic) average of anti-FVO and anti-3D7 AMA1 antibody Red is the 80 ug AMA1-C1/Alhydrogel group (n= 92) and blue is the Hiberix group (n=95). The horizontal axis is Study Day up to Day 154. Day 0 occurred between July 23 and August 14 2006. After Day 154, responses shown are as follows: the values at Day 324 are the responses in May/June 2007, the values at Day 503 are from November/December 2007, and responses at Day 545 are from January 2008. Dashed lines are pointwise 95 percent confidence intervals for each group using t-statistics on the log transformed ELISA values.