The Power of Malaria Vaccine Trials Using Controlled Human Malaria Infection

Abstract

Controlled human malaria infection (CHMI) in healthy human volunteers is an important and powerful tool in clinical malaria vaccine development. However, power calculations are essential to obtain meaningful estimates of protective efficacy, while minimizing the risk of adverse events. To optimize power calculations for CHMI-based malaria vaccine trials, we developed a novel non-linear statistical model for parasite kinetics as measured by qPCR, using data from mosquito-based CHMI experiments in 57 individuals. We robustly account for important sources of variation between and within individuals using a Bayesian framework. Study power is most dependent on the number of individuals in each treatment arm; inter-individual variation in vaccine efficacy and the number of blood samples taken per day matter relatively little. Due to high inter-individual variation in the number of first-generation parasites, hepatic vaccine trials required significantly more study subjects than erythrocytic vaccine trials. We provide power calculations for hypothetical malaria vaccine trials of various designs and conclude that so far, power calculations have been overly optimistic. We further illustrate how upcoming techniques like needle-injected CHMI may reduce required sample sizes.

Trial registration: ClinicalTrials.gov NCT00442377 NCT00757887 NCT00509158 NCT01002833 NCT01236612.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Example model predictions for blood parasite levels in a subset of individuals.

Black bullets represent data points; black triangles are observations below the detection limit (dashed line). The solid black line represents the posterior mean. The shaded band around it represents the 2.5th and 97.5th percentiles of the predicted parasite concentrations, based on 8000 draws from the posterior distribution. Panel headers refer to unique identifiers for CHMI volunteers, which can also be found in the data (S1 File).

Fig 2. Matrix scatter plot of random effects for sources of inter-individual variation.

Random effects (x-axes and y-axes) pertain to the average time of appearance of first generation blood parasites, the number of first cycle parasites, the multiplication rate of blood parasites, and the log-odds ratio of an individual having parasites detected during blood microscopy, adjusted for predicted parasite levels. Within each panel, each bullet represents the point estimate for one CHMI volunteer (N = 56), based on the mean of 8000 draws from the posterior.

Fig 3. Simulated vaccine trial power to detect a statistically significant difference between an intervention and control group (T-test assuming unequal variances, setting α = 0.05).

Simulations were performed for each combination of vaccine type (erythrocytic or hepatic), efficacy (50%, 60%, 70%, 80%, or 90% reduction in first-generation parasite loads or parasite multiplication rate), variation in efficacy between individuals (standard deviation or SD), and the frequency of blood samples taken: one per two days (8am or 4pm), or one (8am), two (8am, 4pm), or three (8am, 4pm, 10pm) per day. Power calculations for a wider range of vaccine efficacy (30%–95%) can be visualized with the graphical user interface in S2 File.