Towards elimination of dog-mediated human rabies: experiences from implementing a large-scale demonstration project in Southern Tanzania

No abstract available

Rapid in-country sequencing of whole virus genomes to inform rabies elimination programmes.

Genomic surveillance is an important aspect of contemporary disease management but has yet to be used routinely to monitor endemic disease transmission and control in low- and middle-income countries. Rabies is an almost invariably fatal viral disease that causes a large public health and economic burden in Asia and Africa, despite being entirely vaccine preventable. With policy efforts now directed towards achieving a global goal of zero dog-mediated human rabies deaths by 2030, establishing effective surveillance tools is critical. Genomic data can provide important and unique insights into rabies spread and persistence that can direct control efforts. However, capacity for genomic research in low- and middle-income countries is held back by limited laboratory infrastructure, cost, supply chains and other logistical challenges. Here we present and validate an end-to-end workflow to facilitate affordable whole genome sequencing for rabies surveillance utilising nanopore technology. We used this workflow in Kenya, Tanzania and the Philippines to generate rabies virus genomes in two to three days, reducing costs to approximately £60 per genome. This is over half the cost of metagenomic sequencing previously conducted for Tanzanian samples, which involved exporting samples to the UK and a three- to six-month lag time. Ongoing optimization of workflows are likely to reduce these costs further. We also present tools to support routine whole genome sequencing and interpretation for genomic surveillance. Moreover, combined with training workshops to empower scientists in-country, we show that local sequencing capacity can be readily established and sustainable, negating the common misperception that cutting-edge genomic research can only be conducted in high resource laboratories. More generally, we argue that the capacity to harness genomic data is a game-changer for endemic disease surveillance and should precipitate a new wave of researchers from low- and middle-income countries

Detection and genetic characterisation of dengue virus among patients in Dar es salaam, Tanzania during the 2013-2014 outbreak

MSc ThesisThe present study was carried out to confirm and genetically characterize dengue virus (DENV) present in sera collected from patients with dengue fever during the 2013 and 2014 dengue outbreaks in Tanzania. Sera were collected from patients who met the clinical case definition for dengue fever. Dengue fever was diagnosed in patients included in this study by detection of IgM and IgG DENV antibodies using a combination of a rapid test and enzyme-linked immunosorbent assay (ELISA). DENV detection in sera samples positive for anti-DENV IgM and IgG was performed using conventional and real-time reverse transcription polymerase chain reaction (RT-PCR). All sera (n = 23) tested positive for anti-DENV IgG and IgM antibodies and for the presence of DENV genomes using RT-PCR. In addition, both conventional and real- time RT-PCR showed the presence of DENV serotype 2 (DENV-2). Nucleotide sequencing of RT-PCR products after amplification of the core-pre-membrane (CprM) region of DENV using conventional RT-PCR produced a 500 bp fragment. BLASTn and phylogenetic analysis of the DENV nucleotide sequence obtained from this study clustered DENV-2 confirming the results obtained during conventional and real-time RT-PCR. The DENV-2 involved during the dengue fever outbreaks in 2013 and 2014 had 100% nucleotide and amino acid identity. This indicated that the same DENV-2 was responsible for the dengue fever outbreaks of 2013 and 2014.The phylogenetic analysis and BLASTn results of the DENV-2 CprM junction region obtained in the present study indicated that it has 98.2% nucleotide identity to SG/D2Y98P-PP1/2009 (Accession number JF327392). The SG/D2Y98P-PP1/2009 is a DENV isolate with a Phe-to-Leu alteration at position 52 in the NS4B protein of the original D2Y98P virus that was isolated in 1998 from a DENV-infected patient in Singapore. This mutation completely abolished the pathogenicity of the D2Y98P virus, as evidenced by a lack of lethality and the absence of histological signs of disease, which correlated with reduced viral titers and intact vascular permeability. Future studies are recommended in order to fully sequence the DENV-2 isolate obtained in the present study in order to determine the presence or absence of this mutation. In addition, it is recommended that the control of Aedes mosquitoes in Dar es Salaam be performed in order to avoid maintenance of DENV in mosquitoes that may lead to future outbreaks.Southern African Centre for Infectious Disease Surveillance (SACIDS

Human rabies: prospects for elimination

Almost half of all countries in the world are effectively free of human deaths from dog-mediated rabies. But the disease still affects people in low- and middle-income countries, especially the rural poor, and children. Successful regional elimination of human rabies is attributable to advances in significant and sustained investment in dog vaccination, post-exposure vaccination and surveillance, illustrated by productive efforts to reduce human rabies in Latin America over the last 35 years. Nonetheless, countries still facing endemic rabies face significant barriers to elimination. Using the 2017 Global Strategic Plan to end human rabies deaths from dog-mediated rabies by 2030 as a reference point and an organizing framework, we assess progress toward global rabies elimination by examining the characteristics of successful regional control efforts and barriers to elimination. Although substantive barriers exist for countries where rabies remains endemic, advances in knowledge, technology, institutions, and economics provide a basis for optimism

Whole genome sequencing for rapid characterization of rabies virus using nanopore technology

No abstract available

On Stirling functions of second kind

SIGLETIB Hannover: RN 5141(373) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Integrating contact tracing and whole-genome sequencing to track the elimination of dog-mediated rabies: An observational and genomic study

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 to 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 and estimated case detection. Using a decision tree model, we quantified the public health burden and evaluated the impact and cost-effectiveness of interventions over a 10-year time horizon. 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 projected to be highly cost-effective ($256 per death averted), only dog vaccination interrupts transmission. A combined One Health approach of routine annual dog vaccination together with free post-exposure vaccines for bite victims, rapidly eliminates rabies, is highly cost-effective ($1657 per death averted) and by maintaining rabies freedom prevents over 30 families from suffering traumatic rabid dog bites annually on Pemba island. 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. Funding: Wellcome [207569/Z/17/Z, 095787/Z/11/Z, 103270/Z/13/Z], the UBS Optimus Foundation, the Department of Health and Human Services of the National Institutes of Health [R01AI141712] and the DELTAS Africa Initiative [Afrique One-ASPIRE/DEL-15-008] comprising a donor consortium of the African Academy of Sciences (AAS), Alliance for Accelerating Excellence in Science in Africa (AESA), the New Partnership for Africa’s Development Planning and Coordinating (NEPAD) Agency, Wellcome [107753/A/15/Z], Royal Society of Tropical Medicine and Hygiene Small Grant 2017 [GR000892] and the UK government. The rabies elimination demonstration project from 2010-2015 was supported by the Bill & Melinda Gates Foundation [OPP49679]. Whole-genome sequencing was partially supported from APHA by funding from the UK Department for Environment, Food and Rural Affairs (Defra), Scottish government and Welsh government under projects SEV3500 and SE0421

Mobile phones as potential tools for surveillance in Tanzania.

<p>(A) Access and use of mobile phones versus computers by surveillance system users and 95% confidence intervals. The effects are shown of user (B) age and (C) self-reported use of text messaging (short message service or SMS), on the standardized time to complete surveillance forms on mobile phones, with boxes shaded in proportion to the sample size in the group (<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002002#pmed.1002002.s002" target="_blank">S2 Data</a>). Time to completion in minutes was standardized by computing z-scores by sector, because forms used by health workers for recording bite patients were longer than forms used by livestock field officers to record mass dog vaccination campaigns (<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002002#pmed.1002002.s005" target="_blank">S3 Table</a>, <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002002#pmed.1002002.s008" target="_blank">S1 Text</a>). (D) Number and percentage of mobile phone form submissions where helpline support was used (<8% overall and <3% for the most commonly used form, that for bite patient records, data in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002002#pmed.1002002.s003" target="_blank">S1 Table</a>). Additional forms submitted by staff involved in system development and therefore familiar with the mobile phone application were excluded.</p

Example of mobile phone surveillance application.

<p>Mobile phone interface showing form being (A) completed for an example bite patient and (B) submitted.</p

The mobile-phone–based surveillance system.

<p>In the map, blue dots represent facilities that provide post-exposure prophylaxis (PEP) and report using the surveillance system (large dots represent hospitals, small dots represent health centres). The map is shaded by population density with wildlife-protected areas in white. The panels illustrate example surveillance data (<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002002#pmed.1002002.s001" target="_blank">S1 Data</a>) from different districts that are annotated on the map by their initials. These data show monthly incidence of bite patients per 100,000 people on Pemba Island (P) and Ulanga (U), PEP use and shortages for Kibaha rural (KR) and Kisarawe (K), progress switching from intramuscular (IM) to intradermal (ID) administration of PEP for Morogoro rural (MR) and Rufiji (R), and numbers of dogs vaccinated each month for Nachingwea (N) and Masasi (M).</p