Experimental infection and protection against ... - TI Pharma

Efficacy of pre-erythrocytic and blood-stage malaria vaccines can be assessed in small
sporozoite challenge trials in human volunteers
Introduction
The development of an effective vaccine against malaria has public health
priority. With an increasing number of candidate Plasmodium falciparum (Pf)
vaccines and only a limited number of field trial sites available, human
sporozoite challenges are used to assess preliminary vaccine efficacy before
proceeding to phase IIb trials [1]. In such phase IIa challenge trials malaria-naïve
volunteers are immunized with a candidate vaccine and subsequently exposed
to the bites of laboratory-reared Pf-infected mosquitoes. Traditionally, a
comparison of the prepatent period (time from challenge until positive bloodslide)
between controls and vaccinees provides an efficacy estimate. The
development of molecular techniques (Q-PCR) allow for a detailed analysis of
blood-stage parasite growth [2].
Sporozoite challenge trials are thought suitable for testing pre-erythrocytic (liver
stage) vaccines, because of the natural route of exposure (mosquito bite) and
the full pre-erythrocytic development of Pf parasites in volunteers. To date, 30
reports of combined phaseI/IIa sporozoite challenge trials are available, of which
three pre-erythrocytic vaccine candidates induced full protection [1]. One of the
three candidates is currently in phase III clinical development [3], whereas
disappointing preliminary efficacy data have halted the clinical development of
others [4, 5]. This illustrates the importance of challenge trials in the clinical
development path of pre-erythrocytic vaccines.
Preliminary efficacy testing of asexual erythrocytic (blood-stage) stage vaccines
is more complex, since vaccine efficacy can only be obtained by evaluating
blood-stage parasite growth over a sufficient lengthy period of time. However,
blood-stage parasitemia is terminated by curative anti-malarial treatment at
0.0001% infected erythrocytes, limiting parasitemia to an interval of one to six
days only (mean 1.7 multiplication cycles) [6]. Immunological effects have to
exert significant parasite inhibition in this short period in order to ensure
detectable vaccine efficacy, making the use of challenge trials for erythrocytic
vaccine candidates controversial. To date, only two erythrocytic malaria vaccine
candidates have been subjected to sporozoite challenge (Apical Membrane
Antigen 1 and Merozoite Surface Protein 1) [7, 8]. Analysis of parasitological
data from two of these trials revealed an apparent pre-erythrocytic inhibiting
effect, but could not show blood-stage inhibition (S.H. Sheehy pers. comm.) [7].
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