Experimental infection and protection against ... - TI Pharma

Introduction 19
candidates. Initially developed as a therapy for neurosyphilis in the 1920’s [67],
controlled malaria infections were established in their present form in the
1980s, when techniques to culture parasites and obtain laboratory-reared
infectious mosquitoes were available [68-70]. In controlled infection trials,
human (malaria-naïve) volunteers are deliberately exposed to bites of a predefined
number of infectious mosquitoes. Subjects are subsequently followed,
mostly on an out-patient basis, for clinical and parasitological endpoints. As soon
as parasites are detected in the circulation by microscopy, volunteers are
treated with anti-malarials for obvious safety reasons. As such, parasitemia is
generally kept below 0.0004% (~10-20 Pf/µl) and severe malaria does not occur
[71-73]. By comparing the proportion of infected subjects between vaccine and
control groups, preliminary efficacy data can be obtained. If clinical protection is
not achieved, the pre-patent period may be used as a surrogate marker
preceding clinical protection. The recent development of molecular techniques
for the detection and quantification of parasites [74] has further refined the
parasitological endpoints to include a detailed analysis of kinetics of blood stage
parasite growth. In addition, statistical models have become available to analyse
these data [75, 76]. Such analysis may be helpful to identify the mechanism of
immunity induced by the vaccine candidate [77, 78].
Controlled malaria infection studies have halted the development of candidate
vaccines LSA1 and PfCS102 [31, 79], whereas a ~30-50% protection induced by
the vaccine candidate RTS,S in an initial controlled infection study was translated
into a similar protectivity against clinical malaria in the field [27, 80-83].
Controlled malaria infection trials are thought particularly suitable for evaluation
of pre-erythrocytic malaria vaccine candidates, since they employ the natural
route of infection (mosquito bite) and allow full pre-erythrocytic stage
development. For asexual erythrocytic stage vaccines, the use of controlled
malaria infections is controversial, because only low levels of blood stage
parasitemia are induced until the trial is interrupted by treatment [12]. Vaccines
would thus have to exert significant inhibition in a very small time window.
Because controlled human malaria infection trials require the combined
technical ability to rear Pf infected mosquitoes and the clinical facility to closely
monitor healthy human volunteers, such trials are currently routinely carried out
in only five institutions worldwide: the US Military Malaria Vaccine Program; the
University of Maryland, USA; the Radboud University Nijmegen Medical Centre,