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

PLoS Comput Biol. 2018 Oct 1;14(10):e1006333. doi: 10.1371/journal.pcbi.1006333. eCollection 2018 Oct.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier State* / epidemiology
  • Carrier State* / microbiology
  • Carrier State* / prevention & control
  • Computational Biology / methods*
  • Host-Pathogen Interactions / immunology
  • Humans
  • Incidence
  • Models, Immunological*
  • Pneumococcal Infections* / epidemiology
  • Pneumococcal Infections* / microbiology
  • Pneumococcal Infections* / prevention & control
  • Pneumococcal Vaccines*
  • Prevalence
  • Randomized Controlled Trials as Topic
  • Streptococcus pneumoniae / immunology
  • Streptococcus pneumoniae / pathogenicity


  • Pneumococcal Vaccines

Grants and funding

PATH Vaccine Solutions ( provided input on the scientific question that motivated this work as well as funding (award #1773-00460733-COL). They reviewed the manuscript with the option to provide advice only. The funder had no role in data collection and analysis, decision to publish, or the contents of the manuscript.