Experimental infection and protection against ... - TI Pharma

Efficacy of pre-erythrocytic and blood-stage malaria vaccines can be assessed in small
sporozoite challenge trials in human volunteers
Assumed
mean
Assumed
inhibition
Corresponding Corresponding Group size (N)
subjects with
1st cycle mean
subjects with
multiplication
Pre-erythrocytic
vaccine
Asexual erythrocytic
vaccine
inhibition (%) s.d. (%) ≤ 1 Pf/ml (%) rate ≤ 1 (%) Once Twice Thrice Once Twice Thrice
70 5 2 9 24 21 20 12 12 11
80 5 5 20 13 12 12 7 7 6
90 5 16 47 6 6 6 4 4 4
95 5 40 77 4 3 3 3 3 3
70 10 3 11 22 20 19 12 11 11
80 10 7 24 12 11 11 7 7 7
90 10 29 59 6 5 5 4 4 4
95 10 65 82 3 3 3 3 3 3
Table 1. Sporozoite challenge group size required for determining parasite inhibition
induced by pre-erythrocytic and asexual erythrocytic malaria candidate vaccines when
measuring parasitemia by PCR once, twice or three times a day. For pre-eythrocytic
vaccines a threshold of 1Pf/ml was set somewhat arbitrarily to estimate the percentage
of subjects considered protected. For erythrocytic vaccines, the percentage of subjects
with multiplication rate ≤ 1 is provided. Power calculations were based on data from 48
volunteers participating in seven sporozoite challenge trials at the Radboud University
Medical Centre Nijmegen.
loped microscopically detectable parasitemia (range day 7-12.3). No individuals
were lost to follow-up.
Parasite densities in the first cycle varied from 23 to 5273 Pf/ml (1.37 to 3.17
log), with a geometric mean of 500 Pf/ml (2.70 log, SD 0.60, n=48, Figure 1B).
Group geometric mean parasite density in the first cycle was not significantly
different between the seven trials (ANOVA p=0.5), so data were pooled for
analysis. In the second and third cycle, geometric mean parasite density
increased to 4485 Pf/ml (3.65 log, SD 0.62, n=40) and 11369 Pf/ml (4.06 log, SD
0.48, n=9) respectively. Only limited data were available for the third
multiplication cycle, because the majority had crossed the blood-slide threshold
for antimalarial treatment. Volunteers for whom data were available in the third
cycle started with a lower parasite load in the first cycle (geometric mean
density first cycle: 126 Pf/ml, t-test p=0.001). Generally, multiplication rates
between volunteers were similar, as is clear from the parallel growth in Figure
1B.
Blood-stage multiplication rate was calculated by dividing the mean parasitemia
in the second cycle by the first cycle (subtraction of log-transformed values) for
every individual volunteer. The group geometric mean multiplication rate was
10.9 (1.04 log, SD 0.33, n=40). Similarly, the ratio of the third with the second
123