Experimental infection and protection against ... - TI Pharma

140 Chapter 7
parasitemia for NF135.C10 seemed to occur slightly earlier than for NF54 as
measured by thick smear (median of 7.0 days after infection; range 7.0-9.0
versus median of 10.6; range 10.6-11; p=0.05; Mann-Whitney test) and qPCR
(median day 7.0; range 6.3-7.0 versus median day 7.3; range 7.0-7.3; p=0.1
Mann-Whitney test, Figure 2B). Particularly the peak of the first cycle seemed
higher for NF135.C10 (Geometric Mean (GM) 1.2; 95% CI 0.61-2.4 parasites/µL)
than NF54 (GM 0.16; 95% CI 0.055-0.46; p=0.06 Mann-Whitney test). The GM of
peak parasitemia was 11 parasites/µL (95% CI 1.8-73) and 30 parasites/µL (95%
CI 7.7-120) (p=0.4) for the positive volunteers of the NF135.C10 and NF54
infected groups, respectively. PCR identity of both strains was confirmed by
culture of smear-positive samples from several randomly selected infected
volunteers.
Safety
All volunteers, including the smear-negative volunteers, reported solicited
adverse events (AEs) that were considered possibly or probably related to the
trial procedures (Table 2). All volunteers reported headache with a mean
duration of 1.5 (NF135.C10) versus 2.3 (NF54) days and most volunteers
experienced fatigue, myalgia and nausea. One volunteer infected with NF54
reported grade three adverse events (malaise, headache and vomiting).
Duration and frequency of AEs were not different between NF135.C10 and NF54
infected volunteers in this limited number of volunteers. One infected volunteer
of the NF135.C10 group showed a decreased platelet count of 146x10 9 /L at day
3 after treatment (cut-off 150x10 9 /L), which returned to normal values at
routine check-up on day 28. D-dimers did not increase in any of the volunteers
before thick smear positivity. As can be expected, four volunteers had increased
d-dimers (range 632-1100 ng/mL) during treatment, that decreased to normal
levels after treatment. Highly sensitive troponin T values were always below
0.05 µg/L.
Cellular immune responses
We next compared the induction of cellular recall immune responses between
volunteers infected with NF135.C10 or NF54. In 24-hour in vitro stimulation
assays, T-lymphocytes of volunteers successfully infected with either NF135.C10
or NF54 showed similarly increased IFNγ, TNF and IL-2 responses 35 days after
infection (Figure 3A-C).
Furthermore, cellular responses showed the same kinetics for both homologous
(NF135.C10 infected/NF135.C10 stimulated, NF54 infected/NF54 stimulated)