Use of an individual-based model of pneumococcal carriage for planning a randomized trial of a whole-cell vaccine.

For encapsulated bacteria such as Streptococcus pneumoniae, asymptomatic carriage is more common and longer in duration than disease, and hence is often a more convenient endpoint for clinical trials of vaccines against these bacteria. However, using a carriage endpoint entails specific challenges. Carriage is almost always measured as prevalence, whereas the vaccine may act by reducing incidence or duration. Thus, to determine sample size requirements, its impact on prevalence must first be estimated. The relationship between incidence and prevalence (or duration and prevalence) is convex, saturating at 100% prevalence. For this reason, the proportional effect of a vaccine on prevalence is typically less than its proportional effect on incidence or duration. This relationship is further complicated in the presence of multiple pathogen strains. In addition, host immunity to carriage accumulates rapidly with frequent exposures in early years of life, creating potentially complex interactions with the vaccine's effect. We conducted a simulation study to predict the impact of an inactivated whole cell pneumococcal vaccine-believed to reduce carriage duration-on carriage prevalence in different age groups and trial settings. We used an individual-based model of pneumococcal carriage that incorporates relevant immunological processes, both vaccine-induced and naturally acquired. Our simulations showed that for a wide range of vaccine efficacies, sampling time and age at vaccination are important determinants of sample size. There is a window of favorable sampling times during which the required sample size is relatively low, and this window is prolonged with a younger age at vaccination, and in a trial setting with lower transmission intensity. These results illustrate the ability of simulation studies to inform the planning of vaccine trials with carriage endpoints, and the methods we present here can be applied to trials evaluating other pneumococcal vaccine candidates or comparing alternative dosing schedules for the existing conjugate vaccines.

Can the Heterosexual HIV Epidemic be Eliminated in South Africa Using Combination Prevention? A Modeling Analysis.

Little is known about how combining efficacious interventions for human immunodeficiency virus (HIV) prevention could lead to HIV elimination. We used an agent-based simulation model, the HIV calibrated dynamic model, to assess the potential for HIV elimination in South Africa. We examined several scenarios (from continuation of the current status quo to perfect achievement of targets) with differing combinations of male condom use, adult male circumcision, HIV testing, and early antiretroviral therapy (ART). We varied numerous parameters, including the proportion of adult males circumcised, the frequency of condom use during sex acts, acceptance of HIV testing, linkage to health care, criteria for ART initiation, ART viral suppression rates, and loss to follow-up. Maintaining current levels of combination prevention would lead to increasing HIV incidence and prevalence in South Africa, while the perfect combination scenario was projected to eliminate HIV on a 50-year time scale from 2013 to 2063. Perfecting testing and treatment, without changing condom use or circumcision rates, resulted in an 89% reduction in HIV incidence but not elimination. Universal adult male circumcision alone resulted in a 21% incidence reduction within 20 years. Substantial decreases in HIV incidence are possible from sufficient uptake of both primary prevention and ART, but with continuation of the status quo, HIV elimination in South Africa is unlikely within a 50-year time scale.

Displacement of sexual partnerships in trials of sexual behavior interventions: A model-based assessment of consequences.

We investigated the impact of the displacement of sexual activity from adherent recipients of an intervention to others within or outside a trial population on the results from hypothetical trials of different sexual behavior interventions. A short-term model of HIV-prevention interventions that lead to female rejection of male partnership requests showed the impact of displacement expected at the start of a trial. An agent-based model, with sexual mixing and other South African specific demographics, evaluated consequences of displacement for sexual behavior interventions targeting young females in South Africa. This model measured the cumulative incidence among adherent, non-adherent, control and non-enrolled females in a hypothetical trial of HIV prevention. When males made more than one attempt to seek a partnership, interventions reduced short-term HIV infection risk among adherent females, but increased it among non-adherent females as well as controls, non-enrolled (females eligible for the trial but not chosen to participate) and ineligible females (females that did not qualify for the trial due to age). The impact of displacement depends on the intervention and the adherence. In both models, the risk to individuals who are not members of the adherent intervention group will increase with displacement leading to a biased calculation for the effect estimates for the trial. Likewise, intent-to-treat effect estimates become nonlinear functions of the proportion adherent.