Study characteristics.

<p>Study characteristics.</p

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

<p>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 (<i>N</i> = 56), based on the mean of 8000 draws from the posterior.</p

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

<p>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 2.5^th and 97.5^th 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 (<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005255#pcbi.1005255.s008" target="_blank">S1 File</a>).</p

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

<p>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 <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005255#pcbi.1005255.s009" target="_blank">S2 File</a>.</p

Parameter estimates for parasite kinetics in mosquito-based, controlled human malaria infection.

<p>Parameter estimates for parasite kinetics in mosquito-based, controlled human malaria infection.</p

Sensitivity analysis for assumptions about density dependence in transmission and permanent effects of ivermectin on adult worms.

<p>The results presented here are based on a setting where the pre-control community microfilarial load is 30 microfilariae per skin snip.</p><p>* Numbers in parentheses represent differences relative to the strategy of continuing mass treatment annually at 65% coverage.</p><p>** The probability of elimination was less than 99% within the scope of the simulations (maximum 20 future treatment rounds).</p><p>*** Permanent effects of ivermectin on adult worms were assumed to be either a factor 2/3 lower or a factor 3/2 higher (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone-0115886-t002" target="_blank">Table 2</a> for details).</p><p>Sensitivity analysis for assumptions about density dependence in transmission and permanent effects of ivermectin on adult worms.</p

Effects of future control strategy on remaining program duration and treatment rounds until elimination.

<p>All differences are defined compared to the strategy of continuing annual treatment strategy at maintained treatment coverage, and are based on the assumptions of low variation in exposure to fly bites. Estimates are pooled over all combinations of number of past treatment rounds and pre-control community microfilarial load (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone-0115886-g004" target="_blank">Figs. 4</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886.s003" target="_blank">S3</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886.s004" target="_blank">S4</a>, and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886.s005" target="_blank">S5</a> for more detailed estimates of reduction in program duration by pre-control community microfilarial load).</p><p>* Estimates were similar for different assumptions about pre-control levels of infection and number of past treatment rounds.</p><p>** When future mass treatment coverage was assumed to drop, the reduction in program duration tended to be smaller for settings with fewer past treatment rounds and higher pre-control infection levels (and vice versa). Analogously, when future mass treatment coverage was assumed to drop, the increase in remaining number of mass treatment rounds tended to be higher for settings with fewer past treatment rounds and higher pre-control infection levels (and vice versa).</p><p>Effects of future control strategy on remaining program duration and treatment rounds until elimination.</p

Comparison of ONCHOSIM-predicted trends in infection during 15 to 17 years of ivermectin mass treatment to previously published data.

<p>Data are from one hyperendemic village in the River Gambia focus in Senegal where annual and 6-monthly mass treatment took place (closed circles), and three hyperendemic village in the River Bakoye focus in Mali where only annual mass treatment took place (closed diamonds, open squares and triangles) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886-Diawara1" target="_blank">[2]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886-Traore1" target="_blank">[4]</a>. ONCHOSIM predictions (black lines) are the averages of 100 repeated simulations, which were based on either of two assumption sets for ivermectin efficacy (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone-0115886-t002" target="_blank">Table 2</a>). After about ten mass treatment rounds (1994–1995), the model predictions based on ivermectin assumption set 1 are at most somewhat pessimistic compared to the data, though discrepancies may also be due to inaccuracy of data used to populate the model (e.g. information on pre-control infection levels and/or coverage and timing of mass treatment). The seemingly large discrepancies between predictions and data after the year 2005 are due to CMFL values close to zero that had been rounded down to one decimal before logarithmic transformation.</p

Predicted trends in probability of elimination over time for settings with different history of control.

<p>The three panels represent predictions for different histories of control in terms of number of past treatment rounds (14 or 8) and mass treatment coverage (65% or 80%). Black lines represent the probability of elimination (y-axis) if mass treatment were to be suspended at a certain point in time (x-axis). Trends until now (time 0) are displayed against a shaded background, while expected future trends are shown against a white background. Different line types pertain to different future mass treatment frequencies (annual, 6-monthly, or 3-monthly). Red lines highlight the predicted minimum remaining program duration required to achieve 99% probability of elimination (based on 1,000 repeated simulations). The three panels are equal with respect to assumed transmission conditions (pre-control community microfilarial load of about 30 mf per skin snip, low variation between individuals in relative exposure to fly bites) and ivermectin efficacy (assumption set 1). Elimination was defined as absence of infection 50 years after suspension of mass treatment.</p

Two sets of assumptions about ivermectin efficacy in ONCHOSIM.

<p>Assumption set 1 was quantified such that ONCHOSIM could reproduce trends in skin mf levels as observed in a community trial that encompassed five consecutive annual ivermectin treatments <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886-Plaisier2" target="_blank">[14]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886-Alley1" target="_blank">[19]</a>. Assumption set 2 was quantified such that ONCHOSIM could reproduce trends in worm survival during three years of 3-monthly and 6-monthly mass treatment, as estimated from nodulectomy data <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886-Cupp3" target="_blank">[23]</a>, and trends in skin mf levels up to two years after a single dose of ivermectin as reported in a published meta-analysis <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886-Basez2" target="_blank">[31]</a>. Parameter values were fitted to the data with maximum likelihood, using the mean output of 100 repeated ONCHOSIM simulations as expected values (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886.s007" target="_blank"><b>S1 Text</b></a> for details).</p>a<p>Excess mortality has been reported for both female <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886-Cupp3" target="_blank">[23]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886-Klger2" target="_blank">[30]</a> and male worms <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886-Duke2" target="_blank">[25]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886-Duke3" target="_blank">[26]</a>. In the current study, excess mortality due to ivermectin was allowed to differ between male and female worms, reflecting the relative absence of male worms from subcutaneous nodules after repeated ivermectin treatment <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886-Cupp2" target="_blank">[22]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886-Klger2" target="_blank">[30]</a>. The macrofilaricidal effects of ivermectin were allowed to vary per treatment; however, this variation could not be estimated due to the aggregated nature of the Guatemalan data <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886-Cupp3" target="_blank">[23]</a>. Instead, we arbitrarily assumed beta distributions with sample size 50 and mean 6% for males (2.5% and 97.5% percentiles 1.3%–14.0%) and 12% (3.9%–19.0%) for females, with the macrofilaricidal effects on male and female worms being perfectly correlated. Macrofilaricidal effects were assumed to be independent of earlier exposure to ivermectin and worm age, and hence reproductive capacity of the worm. In the sensitivity analysis, we set the average macrofilaricidal effects to either 4% and 8% (for males and females), or 9% and 18% (difference of factor 2/3 or 3/2) while keeping the sample size of the beta distribution at 50.</p>b<p>This treatment effect was assumed to vary per worm and treatment; 2.5% and 97.5% percentiles 2–24 months.</p>c<p>This assumption represents the notion that ivermectin causes temporary congestion of female worm uteri with dead mf, effectively preventing insemination and release of microfilariae <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886-Chavasse1" target="_blank">[20]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886-Klger1" target="_blank">[21]</a>. Time until recovery was assumed to vary per worm and treatment, and to follow an exponential distribution with mean 3.5 years (fitted to data <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886-Basez2" target="_blank">[31]</a>). This implies that 5% of adult female worms can be inseminated and release microfilariae within two months after exposure to ivermectin. Likewise, congestion resolves in 25%, 50%, 75%, and 95% of adult female worms within 1, 2.5, 5, and 10.5 years after exposure to ivermectin, respectively.</p>d<p>To account for variation in treatment efficacy between persons and treatments, for every simulated person and treatment, the average reduction was multiplied with a random value drawn from a Weibull distribution with mean 1 and shape 2 (see also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115886#pone.0115886.s007" target="_blank">S1 Text</a>). In the sensitivity analysis, the average reduction was set to 23% or 52% (difference of factor 2/3 or 3/2).</p><p>Two sets of assumptions about ivermectin efficacy in ONCHOSIM.</p