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
The decreasing malaria incidence in several endemic areas [12] has increased
the size and costs of Phase IIb malaria vaccine field trials. Sporozoite challenges
can be used for preliminary efficacy selection of candidates. Efficacy goals set by
the Malaria Vaccine Roadmap and the target product profile of RTS,S, the only
candidate currently in phase III clinical development, dictate a protective
efficacy of more than 80% against clinical disease [13] and a 50% reduction of
clinical attacks due to Pf respectively [14]. So called all-or-nothing vaccines or
very effective “leaky” vaccines will induce full protection and can thus easily be
tested by controlled infection. However, in addition to these promising vaccines,
vaccine developers may be interested in less efficacious vaccines when
combining antigens. Such approach is currently followed, for example, for the
malaria vaccine ME-TRAP [15]. We show that in these vaccines, Q-PCR may be
useful to improve the power of sporozoite challenge trials to detect 80-90%
parasite inhibition. These biological effects correspond with clinical protection in
a smaller proportion of subjects.
We show that the sensitivity of sporozoite challenge trials is limited by variation
in vaccine effect, inter-individual variation in parasite development and the
limited time window during which blood-stage parasitemia can be assessed.
Inter-individual variation is the most important determinant. Three factors may
account for this variation: the parasite inoculum size, parasite fitness and human
(innate) immune factors. Standardizations of these points would likely decrease
variance. For this purpose, clinical trials testing the needle administration of a
predefined number of viable sporozoites are currently planned (NCT01086917).
As an alternative, challenge trials using low numbers of erythrocytic stage
parasites are conducted, allowing for a longer time window of follow-up [16].
Careful analyses of Q-PCR data from several of such trials are needed to quantify
their benefit.
We performed calculations using simplified methodology based on crude
empirical data, taking into account a limited number of variables. The power of
sporozoite challenge trials may be higher if inhibiting effects transcend parasite
developmental stage when antigens are shared or combined between stages, or
when inter-individual variation is limited. More complicated statistical models,
such as previously described by Hermsen et al. [6] and Bejon et al. [17], take into
account more variables and may subsequently generate data with higher
precision and power, but also require more assumptions and may be less
reliable.
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