Experimental infection and protection against ... - TI Pharma

General Discussion 223
troponins can also be found in marathon runners [70], providing evidence for
minimal cardiac damage that may not be clinically relevant. D-dimers and LDH
have also been proposed as markers for ischemia, based on the hypothesis that
endothelial cell activation and increased turnover of coagulation would lead to
thrombotic events. Again, although highly sensitive, these markers lack
specificity for clinically relevant cardiac damage. Highly elevated d-dimers,
particularly after initiation of antimalarial-treatment, have been found in several
CHMI volunteers since the initiation of monitoring without re-occurrence of
cardiac damage. The correlation of d-dimers with peak temperature suggests
that d-dimers are a bystander in inflammation rather than a predictor of cardiac
damage (Chapter 10). In conclusion, the lack of knowledge on the aetiology of
the cardiac event makes the identification of a “risk correlate” for cardiac
damage, and the subsequent identification of volunteers at risk difficult, if not
impossible. The continuous monitoring of volunteers for the occurrence of
cardiac damage, by means of regular measurement of highly-sensitive troponins
thus seems reasonable in order to detect any cardiac event in an early stage.
Moreover, the occurrence of the cardiac event has, once again, stressed the
importance of close and committed monitoring by the study physicians in order
to detect any events in an early stage and prevent escalation. However, the
apparently infrequent occurrence of serious adverse events in the large group of
volunteers exposed to controlled infections so far and the wealth of data on
clinical cases lacking evidence for cardiac damage, may be somewhat reassuring.
In addition to the clinical manifestations, participation in a controlled malaria
infection trial has a major impact on the daily life of volunteers. This is
particularly due to the intense follow-up with blood sampling several times daily.
Volunteers’ perception of their participation in such a trial depends mainly on
whether they have realistic expectations of trial procedures and the severity of
symptoms, indicating the importance of providing accurate and sufficient
information to volunteers before the onset of the trial.
As is true for any type of clinical research, risks must be minimized and scientific
benefits maximized. We believe that the benefits of Phase IIa trials outweigh the
potential risks in well-designed studies and will be essential to the development
of an effective malaria vaccine, provided that all safeguards are in place for the
safety of volunteers [71].
Differences between natural and controlled experimental infections signify the
importance of validating the results of Phase IIa challenge trials with data from