Experimental infection and protection against ... - TI Pharma
Experimental infection and protection against ... - TI Pharma
Experimental infection and protection against ... - TI Pharma
Create successful ePaper yourself
Turn your PDF publications into a flip-book with our unique Google optimized e-Paper software.
206 Chapter 10<br />
temperature (Pearson R=0.83, p=0.02). Platelets decreased slightly below<br />
120x10 9 /l in one volunteer (nadir 108x10 9 /l). Lactate dehydrogenase levels were<br />
never elevated above 1000 U/l. Highly sensitive troponin T was never abnormal<br />
(max 0.011 µg/l). None of the volunteers showed any bleeding or thrombotic<br />
complications. None of the protected volunteers showed an elevation of ddimers<br />
above detection level (250 ng/ml).<br />
Real-time quantitative PCR (Q-PCR) was performed on all collected samples<br />
retrospectively. Control volunteers showed cyclical parasite growth, identical to<br />
control volunteers in previous malaria challenge <strong>infection</strong> trials [9,14]. Asexual<br />
blood-stage parasites were never detected by Q-PCR (detection limit 20<br />
parasites/ml) in any of the four protected volunteers during the entire 21 day<br />
follow-up period. The remaining two immunised volunteers with delayed<br />
patency by microscopy also showed delayed appearance of blood-stage<br />
parasitemia by Q-PCR (Figure 4).<br />
Specific anti-parasite antibody responses were detectable at 28 months postimmunisation<br />
in only one of six immunised volunteers, i.e. <strong>against</strong> the major<br />
circumsporozoite antigen (NANP6 repeats) <strong>and</strong> crude blood-stage antigens (data<br />
not shown). Antibodies with specificity for individual asexual blood stage<br />
antigens (AMA-1 <strong>and</strong> GLURP) were not detectable. Blood stage parasitemia was<br />
accompanied by increased plasma concentrations of systemic inflammatory<br />
markers, including IFNγ (median peak 69 pg/ml, IQR 51-135), IL-6 (median peak<br />
9.2 pg/ml, IQR 6.4-14) <strong>and</strong> C-reactive protein (median peak 52 mg/l, IQR 26.5-<br />
57.5) with no difference between controls <strong>and</strong> volunteers with delayed patency.<br />
None of the protected volunteers showed any increase in plasma concentrations<br />
of IFNγ, IL-6 or CRP (max 5 pg/ml, 7 pg/ml <strong>and</strong> 2.5 mg/l respectively).<br />
In vitro stimulation assays showed a sustained Pf-specific T cell IFNγ re-call<br />
response to both pre-erythrocytic (sporozoite) <strong>and</strong> blood-stage parasites that<br />
persisted over years in all six immunised individuals (Figure 5). These responses<br />
remained significantly higher than those of control volunteers (p
Change language