Experimental infection and protection against ... - TI Pharma

144 Chapter 7
with either the NF54 strain or its clone 3D7 (~1300 volunteers [4, 27]) as
opposed to only 42 volunteers challenged with strain 7G8 of South American
origin [7, 8, 27]. 3D7 is derived from NF54 and cannot be distinguished from
NF54 by drug sensitivity testing, simple genetic markers, or microsatellite
mapping (Sim et al., unpublished). Thus, clinical trials with more genetically
distinct parasite strains including 7G8 or NF135.C10 will be important to
complement current knowledge on heterologous Pf strains. Parasitological and
clinical findings after CHMI with NF54 or 3D7 were recently compared in two
meta-analyses (Roestenberg et al. PLoS One, in press)[28]. Here we show that
clinical signs and symptoms induced by NF135.C10 or NF54 do not show any
differences in successfully infected volunteers. We found slight differences in
infectivity of the parasites; in these small groups of volunteers, NF135.C10
showed a marginally shorter prepatent period, but parasite kinetics of both
NF135.C10 and NF54 were both within the limits of historical NF54 controls.
Notably, not all volunteers exposed to NF54 infected mosquitoes became
parasitemic, as assessed by both microscopy and qPCR in contrast to 22 previous
CHMI trials infecting 128 naive volunteers with NF54 parasites (Roestenberg et
al. PLoS One, in press). Unsuccessful infection after bites of five mosquitoes has
been described previously for 3D7 [29, 30]. Although the exact reason is unclear,
this might due to the unusual low NF135.C10 and NF54 oocyst and sporozoite
counts per mosquito obtained for this trial compared to our routinely obtained
counts (table 1). A technical disturbance in our cultures, leading to suboptimal
culture circumstances prior to this study was most likely the reason for this
relatively low mosquito infection with both strains. However, a formal
relationship between sporozoite counts and mosquito infectivity has never been
established [31] and only small percentages of sporozoites in salivary glands are
injected during a blood meal of a mosquito [32-34]. Surprisingly, all three
unsuccessfully infected volunteers reported AEs that were considered possibly,
probably, or definitely related to the trial procedures. Symptoms reported by
these volunteers might have been the result of over-reporting in an intense
follow-up schedule, concurring with our findings from a previous study, in which
volunteers reported malaria-related symptoms after exposure to bites of only
uninfected mosquitoes [35].
Previously, we reported sustained IFNγ re-call responses in vitro in both αβ-T
cells and γδ-T cells upon homologous PfRBC re-stimulation with NF54 asexual
stage parasites after a single CHMI, suggestive of cross talk between innate and
adaptive compartments with induction of memory [36, 37]. Here we show
similar kinetics and composition of IFNγ responses upon homologous Pf54 and