Experimental infection and protection against ... - TI Pharma

222 Chapter 11
growth in the blood, albeit for a short time window of 2–3 days between liverstage
infection and microscopic detection [52]. We have now formally shown
that these molecular techniques enhance the power of controlled human
infection trials to detect modest vaccine efficacy (which may not necessarily
correspond with clinical protection) with only small numbers of volunteers
(seven per group) (Chapter 6). Statistical models can be applied to further
improve the discriminative power between control and test groups as well as to
provide biological information about the parasite life cycle (including the
duration of liver-stage maturation, number of infected hepatocytes, duration of
blood-stage trophozoite maturation and multiplication rates [54-56]).
Immediate treatment of volunteers at the earliest phase of microscopically
detectable blood-stage infection ensures that the potential risks of
complications associated with severe malaria are minimized to the greatest
extent possible. Indeed, controlled human malaria infections have shown to be
safe in the 1,343 volunteers challenged so far [57-59]. Recently, safety concerns
were raised because of a cardiac event in a young volunteer shortly after
treatment for diagnosed malaria following a controlled infection, although a
definite relationship between the cardiac event and the controlled malaria
infection was not established [60]. The chronology of the event with the malaria
infection has raised discussion on a possible pathophysiological link between
cardiac events and malaria. An ischemic cardiac event has previously been
described after CHMI, however, this volunteer was never parasitemic [59]. There
have been no other reports of ischemic cardiac events in the context of malaria,
but events of myocarditis, although rare, have been found in several malaria
patients [61-65]. Myocarditis has also been recognised as an immunological
complication following all types of vaccinations, although particularly smallpox
vaccines are renown [66-68]. Notwithstanding the aetiology, the identification of
volunteers that may possibly develop cardiac complications before start of the
CHMI and during the infection is important to safeguard volunteers. Therefore,
it has been agreed that volunteers with an increased risk of cardiac disease
should be excluded from such trials. Currently, the SCORE risk assessment [69] is
used to identify those high risk volunteers, although risk factors for malaria
induced ischemia may not resemble those for atherosclerotic processes. In
addition, regular measurements of highly sensitive troponin are performed in
order to detect cardiac damage in an early stage. However, the increased
sensitivity of t-troponin detection parallels decreased clinical relevance with
detection of minimal cardiac damage. For example, increased highly-sensitive