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
calculated the geometric mean multiplication rate and SD. Samples with a Q-PCR
CT >45 were estimated at half the detection limit (10 or 50 Pf/ml).
Geometric mean parasitemia in the first cycle and parasite multiplication rates
showed a normal distribution, so power calculations were performed using a
two-sample t test power analysis with α=0.05 and β=0.80. We separately
determined the power using all three daily time points if available (8:00am,
4:00pm and 10:00pm, n=33), two daily time points (8:00am and 4:00pm, n=48)
or one daily time point (8:00am, n=48).
Power calculations estimated the group size required to detect significant
differences between vaccinees and controls. Vaccine and control group were
assumed of equal size. Pre-erythrocytic vaccines were assumed to reduce the
geometric mean parasitemia of the first multiplication cycle, but not alter the
parasite multiplication rate. Erythrocytic stage vaccines were assumed to reduce
the parasite blood-stage multiplication rate, reducing parasite load from the first
cycle onwards. Vaccine effects were simulated by beta distribution with an
assumed mean inhibition of 70, 80, 90 and 95% and SD of 5 or 10%. Vaccine
inhibition was simulated 100 times for every individual subject and repeated ten
times based on random sampling from the distribution. We assumed a
continuous infectious dose of merozoites, as opposed to the actual release of
discrete batches of merozoites from infected hepatocytes. Interindividual
variation masked the discrete nature of infection in empirical situations with
high numbers of infected hepatocytes. In simulations with low numbers of
infected hepatocytes, where a discrete variable would give a binary outcome
(i.e. protected or non-protected), the resulting blood-stage parasitemia was
always below the Q-PCR detection limit. In such cases, values were corrected to
a standard value of half the Q-PCR detection limit. The number of subjects with
simulated parasitemia ≤ 1Pf/ml or multiplication rate ≤1 was counted. For some
subjects second cycle data were missing because they had already received
antimalarial treatment for safety reasons: eight volunteers in the group with
samples thrice daily (24%) and nine volunteers in the group with samples twice
daily (19%). The group size for erythrocytic vaccines was corrected for these
missing data by addition of the respective proportion of volunteers. Similarly,
the power for pre-erythrocytic vaccines was corrected for the number of
volunteers with the first cycle data points below the detection limit: two
volunteers in the group with samples once daily (4%).
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