Integrating contact tracing and whole-genome sequencing to track the elimination of dog-mediated rabies

Abstract

Background: Dog-mediated rabies is endemic across Africa causing thousands of human deaths annually. A One Health approach to rabies is advocated, comprising emergency post-exposure vaccination of bite victims and mass dog vaccination to break the transmission cycle. However, the impacts and cost-effectiveness of these components are difficult to disentangle. Methods: We combined contact tracing with whole-genome sequencing to track rabies transmission in the animal reservoir and spillover risk to humans from 2010-2020, investigating how the components of a One Health approach reduced the disease burden and eliminated rabies from Pemba island, Tanzania. With the resulting high-resolution spatiotemporal and genomic data we inferred transmission chains, estimated case detection and quantified the public health burden to evaluate these interventions. Results: We resolved five transmission chains co-circulating on Pemba from 2010 that were all eliminated by May 2014. During this period, rabid dogs, human rabies exposures and deaths all progressively declined following initiation and improved implementation of annual islandwide dog vaccination. We identified two introductions to Pemba in late 2016 that seeded re-emergence after dog vaccination had lapsed. The ensuing outbreak was eliminated in October 2018 through reinstated islandwide dog vaccination. While post-exposure vaccines were highly cost-effective ($405 per death averted), their accessibility was limited and only dog vaccination interrupted transmission. A combined One Health approach rapidly eliminated rabies, was highly cost-effective ($1865 per death averted) and saved 20-120 families from rabid dog bites annually. Conclusions: A One Health approach underpinned by dog vaccination is an efficient, cost-effective, equitable and feasible approach to rabies elimination, but needs scaling up across connected populations to sustain the benefits of elimination, as seen on Pemba, and for similar progress to be achieved elsewhere.

Examining the molecular clock hypothesis for the contemporary evolution of the rabies virus

“…While the low substitution rate means that comparing the number of SNPs between sequences alone may not be an effective method of determining infector-infectee relationships, it could be used in conjunction with temporal and location data to make more accurate predictions of transmission events by ruling out relationships between more distantly related transmission chains co-circulating in the same area, as in (48). While the Jukes-Cantor model was the most appropriate to use on our synthetic data due to the simplicity of the mutation models, phylogenetic analyses on real RABV genome data usually use a more complex model, such as the GTR + G substitution model used to generate the Tanzanian tree shown in this study (36). This, along with the simplicity of our mutation model as well as sampling biases in the real dataset, may affect how comparable synthetic root-to-tip divergence plots are to the real data.…”

“…In order to compare our synthetic patterns of divergence over time to real rabies data, a root-to-tip divergence plot was also generated for a dataset of real RABV sequences (data from (36); Figure 1A) using TempEst (v1.5.3 (37)), with the best-fit root located (Figure 1B). These rabies cases occurred between 2001 and 2017 and were primarily from the Serengeti district and Pemba Island, with the remaining sequences from elsewhere in Tanzania (Figure 1A inset).…”

“…These rabies cases occurred between 2001 and 2017 and were primarily from the Serengeti district and Pemba Island, with the remaining sequences from elsewhere in Tanzania (Figure 1A inset). Sequence acquisition and tree building methods are detailed in (36).…”

“… (A) The time-scaled tree (36) used to generate the root-to-tip divergence plot and to calculate the per-generation substitution rate. The inset map shows the approximate locations that the samples were collected from, and the lineages present in each location.…”

Genomic epidemiology on the move

“…This has enabled the identification of different rabies virus lineages and some results are suggestive of predominantly enzootic viral transmission cycles in selected study areas 4 . Preliminary results suggest that the combination of these genomic data with traditional epidemiological analysis and contact tracing following the occurrence of an infected bite enables more accurate targeting of control strategies and vaccination programmes 5 . Portable sequencing technology will also enable the timely monitoring of cross-border incursion of the virus, or specific viral lineages, into a country, which is particularly important in light of the current programme to eliminate rabies in dogs globally by 2030.…”