Abstract

BackgroundTyphoid fever caused by Salmonella enterica serovar Typhi (S. Typhi) remains a serious burden of disease, especially in developing countries of Asia and Africa. It is estimated that it causes 200,000 deaths per year, mainly in children. S. Typhi is an obligate pathogen of humans and although it has a relatively complex life cycle with a long lived carrier state, the absence of non-human hosts suggests that well targeted control methods should have a major impact on disease. Newer control methods including new generations of vaccines offer hope but their implementation would benefit from quantitative models to guide the most cost effective strategies. This paper presents a quantitative model of Typhoid disease, immunity and transmission as a first step in that process.Methodology/Principal FindingsA stochastic agent-based model has been developed that incorporates known features of the biology of typhoid including probability of infection, the consequences of infection, treatment options, acquisition and loss of immunity as a result of infection and vaccination, the development of the carrier state and the impact of environmental or behavioral factors on transmission. The model has been parameterized with values derived where possible from the literature and where this was not possible, feasible parameters space has been determined by sensitivity analyses, fitting the simulations to age distribution of field data. The model is able to adequately predict the age distribution of typhoid in two settings.Conclusions/SignificanceThe modeling highlights the importance of variations in the exposure/resistance of infants and young children to infection in different settings, especially as this impacts on design of control programs; it predicts that naturally induced clinical and sterile immunity to typhoid is long lived and highlights the importance of the carrier state especially in areas of low transmission.

Highlights

  • Salmonella enterica serovar Typhi (Typhi), the causal agent of typhoid, is a bacterial pathogen transmitted between humans, by ingestion of contaminated faces and urine

  • A specific element of the biology is the existence of longterm carrier states involving colonization of the gall bladder and of other sites

  • In particular in endemic areas, the reservoir of carriers, the continuing supply of susceptibles and the impact of immunity may all play a role in determining the incidence of disease and the transition between epidemic and stable endemic typhoid disease

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Summary

Introduction

Salmonella enterica serovar Typhi (Typhi), the causal agent of typhoid, is a bacterial pathogen transmitted between humans, by ingestion of contaminated faces and urine. To encompass different types of infectious people, Rc is defined as the number of new infections (subclinical and clinical) that would result in a completely naive population from a single acute untreated clinical patient of average age infected with a strain 1 Salmonella Typhi where both the infected and susceptible individuals are in a homogeneously mixed population This reproduction number corresponds to the average infectiousness of acute clinical cases, bc, and relates to average levels of exposure and susceptibility (in the case of temporally invariant environments) via: Rc~N. bc ftcIu N where f is the mean over the whole population of f ðai,ri,tÞ, the scale factor measuring contamination of the environment, and tc is the mean duration of infectiousness of the clinical cases. Second order polynomial fit to the log likelihood values as a function of the parameter being estimated

Results
Discussion
N Engl J Med 283

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