Experimental infection and protection against ... - TI Pharma

208 Chapter 10
immune modulating effects of chloroquine might have enhanced the
development of protective immune responses during the immunisation process
[27].
While Pf-specific antibody responses were negligible and declining (data not
shown), we found a sustained Pf-specific T cell IFNγ re-call response that
persisted over years and paralleled the sustained protection in all six immunised
volunteers. The two volunteers with delayed patency did not show a distinctly
different T cell response as compared to the fully protected individuals.
However, a three to six day delay of exponentially growing parasites equals one
to three logs (e.g. >95%) reduction in parasite burden. The variation in the level
of protection between the volunteers might thus be relatively small. A large
body of evidence supports the view that IFNγ responses are protective against Pf
infection, although naturally acquired T-cell responses to individual antigens
wane after several years of non-exposure [28]. The functional importance of
IFNγ–producing cells, however, still needs to be established in larger study
groups.
We detected cellular responses to both sporozoites and blood-stage parasites
with remarkably similar dynamics, although responses to blood-stage parasites
were consistently higher than to sporozoites. Whether such responses are
directed against both pre-erythrocytic and blood-stage antigens or represent
cross-reactivity, will require further detailed immunological analysis. In either
case, the lack of blood-stage parasites in the fully protected volunteers seems to
indicate a primarily pre-erythrocytic immunological effector mechanism.
Experimental malaria infections provide a unique opportunity to study
protection against Pf malaria in a controlled setting [29]. This trial reconfirms a
solid correlation between the appearance of clinical symptoms and the presence
of microscopically detectable blood stage parasites, including in volunteers with
delayed patency. Clinical symptoms and the pattern of parasitemia by Q-PCR are
very consistent between and within study groups illustrating the power of this
experimental infection model (Chapter 6, [9]). Protected volunteers also
reported some adverse events, without objective signs of inflammation. Possibly
these events reflect natural fluctuations of subjective health perception.
The occurrence of a cardiac event following experimental challenge after a
phase I malaria vaccine trial in the past has necessitated an increased vigilance
and surveillance of cardiac and coagulation markers [12]. We found increased
concentrations of d-dimer that paralleled the increases in inflammatory markers,