Revealing the Micro-scale Signature of Endemic Zoonotic Disease Transmission in an African Urban Setting

Abstract

The development of novel approaches that combine epidemiological and genomic data provides new opportunities to reveal the spatiotemporal dynamics of infectious diseases and determine the processes responsible for their spread and maintenance. Taking advantage of detailed epidemiological time series and viral sequence data from more than 20 years reported by the National Reference Centre for Rabies of Bangui, the capital city of Central African Republic, we used a combination of mathematical modeling and phylogenetic analysis to determine the spatiotemporal dynamics of rabies in domestic dogs as well as the frequency of extinction and introduction events in an African city. We show that although dog rabies virus (RABV) appears to be endemic in Bangui, its epidemiology is in fact shaped by the regular extinction of local chains of transmission coupled with the introduction of new lineages, generating successive waves of spread. Notably, the effective reproduction number during each wave was rarely above the critical value of 1, such that rabies is not self-sustaining in Bangui. In turn, this suggests that rabies at local geographic scales is driven by human-mediated dispersal of RABV among sparsely connected peri-urban and rural areas as opposed to dispersion in a relatively large homogenous urban dog population. This combined epidemiological and genomic approach enables development of a comprehensive framework for understanding disease persistence and informing control measures, indicating that control measures are probably best targeted towards areas neighbouring the city that appear as the source of frequent incursions seeding outbreaks in Bangui.

Fig 1. Sampling of RABV samples.

Map of the Central African Republic and neighbouring countries (a) showing the location (red points and squares) of the 162 isolates of RABV analyzed in this study. The cities in red indicate the presence of RABV belonging to the Africa 1 clade. Cities in blue represent those where RABV belonging to the Africa 2 clade were found. In Bangui, both clades were identified. Detailed map of Bangui (b), showing the location of the 122 samples analyzed in the context of the landscape. Number of specimens positive for rabies (c) by trimester during sentinel surveillance, January 1993 to March 2012.

Fig 2. MCC tree of 162 sequences from the Central African Republic and other locations in Africa estimated from 5000 nt of dog RABV genome.

Tips representing isolates from Bangui are coloured according to the selected subtypes of RABV; other tips are colored by location. Tip times are scaled to the date of sampling (years) and branches are estimated in time units as indicated by the time bar.

Fig 3. Temporal distribution of RABV subtypes in Bangui as determined by the MCC analysis (number of specimens positive for rabies by months from January 2003 to March 2012 and same color code as in Fig 2).

Black arrows indicates RABV introduction events in the city (first introduction of a new subtype circulating in Bangui). Grey areas indicated periods without any reported cases.

Fig 4. Estimation of the rate of introduction of rabid dogs in Bangui, λ _t (in rabid dogs imported to Bangui per week), the instantaneous effective reproduction number, R _t, and observed number of rabid dogs infected locally (red bar) or from outside the city (blue bar) and simulated number of rabid dogs from the model (black line: posterior median; grey area: 95% credible interval of the posterior distribution).

If R _t, is above 1, a local self-sustaining epidemic in dogs may occur in the city.