Comparison of clinical and parasitological data from controlled human malaria infection trials

Meta Roestenberg, Geraldine A O'Hara, Christopher J A Duncan, Judith E Epstein, Nick J Edwards, Anja Scholzen, André J A M van der Ven, Cornelus C Hermsen, Adrian V S Hill, Robert W Sauerwein, Meta Roestenberg, Geraldine A O'Hara, Christopher J A Duncan, Judith E Epstein, Nick J Edwards, Anja Scholzen, André J A M van der Ven, Cornelus C Hermsen, Adrian V S Hill, Robert W Sauerwein

Abstract

Background: Exposing healthy human volunteers to Plasmodium falciparum-infected mosquitoes is an accepted tool to evaluate preliminary efficacy of malaria vaccines. To accommodate the demand of the malaria vaccine pipeline, controlled infections are carried out in an increasing number of centers worldwide. We assessed their safety and reproducibility.

Methods: We reviewed safety and parasitological data from 128 malaria-naïve subjects participating in controlled malaria infection trials conducted at the University of Oxford, UK, and the Radboud University Nijmegen Medical Center, The Netherlands. Results were compared to a report from the US Military Malaria Vaccine Program.

Results: We show that controlled human malaria infection trials are safe and demonstrate a consistent safety profile with minor differences in the frequencies of arthralgia, fatigue, chills and fever between institutions. But prepatent periods show significant variation. Detailed analysis of Q-PCR data reveals highly synchronous blood stage parasite growth and multiplication rates.

Conclusions: Procedural differences can lead to some variation in safety profile and parasite kinetics between institutions. Further harmonization and standardization of protocols will be useful for wider adoption of these cost-effective small-scale efficacy trials. Nevertheless, parasite growth rates are highly reproducible, illustrating the robustness of controlled infections as a valid tool for malaria vaccine development.

Conflict of interest statement

Competing Interests: This work was supported by Top Institute Pharma. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Time to microscopically detected parasitemia…
Figure 1. Time to microscopically detected parasitemia by cohort.
Survival curve for four cohorts: RUNMC I (orange), RUNMC II (blue), USMMVP (interrupted grey line) and Oxford (green).
Figure 2. Geometric mean parasite density by…
Figure 2. Geometric mean parasite density by Q-PCR per cohort.
Three cohorts are depicted RUNMC I (orange), RUNMC II (blue) and Oxford (green).
Figure 3. Statistics of Q-PCR parasitemia per…
Figure 3. Statistics of Q-PCR parasitemia per cohort.
Peak parasitemia (A, one-way ANOVA p = 0.13), geometric mean parasitemia during the first blood stage parasite multiplication cycle, day 6.5 to 8.5 (B, one-way ANOVA p45 was assigned a parasitemia of 10 parasites/ml.
Figure 4. Correlation of Q-PCR parasitemia with…
Figure 4. Correlation of Q-PCR parasitemia with prepatent period.
Correlation between peak parasitemia (A) or geometric mean parasitemia during the first multiplication cycle from day 6.5 to day 8.5 (B) with prepatent period (R2 = 0.27 and −0.73, p = 0.006 and p = <0.001, respectively). Prepatent period was defined as the time between exposure to infectious mosquito bites until detection of blood stage parasites by microscopy.

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