Experimental infection and protection against ... - TI Pharma

124 Chapter 6
cycle gave a multiplication rate of 10.8 (1.03 log, SD 0.21, n=9) and the square
root of third with the first cycle ratio gave an estimate of 8.9 (0.94 log, SD 0.25,
n=9), Figure 1C. Multiplication rates were not significantly different between
trials (ANOVA p=0.1) nor between multiplication cycles (ANOVA p=0.6).
Results for power calculations are shown in Table 1. The vaccine effect SD hardly
affected group size. The power of small sporozoite challenge trials to detect
vaccine inhibition was slightly higher for erythrocytic vaccines as compared to
pre-erythrocytic vaccines, due to smaller inter-individual variation in blood-stage
multiplication rate. Sporozoite challenge trials with a group size of 6-7 subjects
could be powered to detect 80% inhibiting erythrocytic and pre-erythrocytic
vaccines. Drawing additional blood samples up to thrice daily enhanced the
sensitivity of sporozoite challenge trials, allowing a reduced group size
particularly in less efficacious vaccines.
In order to translate biological effects into clinical efficacy, we estimated the
threshold of inhibition necessary to give clinical protection. Clinical protection
was defined as volunteers that do not develop microscopic blood-stage
parasitemia. For erythrocytic vaccines, we estimate that 90% inhibition results in
a multiplication rate of ≤1 [6]. Depending on variation in vaccine effect, 20-25%
of volunteers will cross this threshold in a trial with seven volunteers per group.
Similarly, we hypothesize that parasitemia will have to be reduced to a
somewhat arbitrary value 1 Pf/ml in pre-erythrocytic vaccines for clinical
protection; the remaining low blood-stage parasite loads may possibly induce
erythrocytic immunity [11]. Depending on the variation of vaccine effect, 16-30%
of volunteers will cross this threshold in trials with seven volunteers per group
(Table 1).
Discussion
The current data show that small sporozoite challenge trials, typically including
seven subjects per group, are powered to detect biological effects induced by
both pre-erythrocytic and erythrocytic candidate vaccines that may herald
clinical protection. We thus show that sporozoite challenge trials are a very
sensitive tool to evaluate preliminary efficacy of any pre-erythrocytic or
erythrocytic candidate malaria vaccine.