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How acute pathogens persist and what curtails their epidemic growth in the absence of acquired immunity remains unknown. Canine rabies is a fatal zoonosis that circulates endemically at low prevalence among domestic dogs in low- and middle-income countries. We traced rabies transmission in a population of 50,000 dogs in Tanzania from 2002 to 2016 and applied individual-based models to these spatially resolved data to investigate the mechanisms modulating transmission and the scale over which they operate. Although rabies prevalence never exceeded 0.15%, the best-fitting models demonstrated appreciable depletion of susceptible animals that occurred at local scales because of clusters of deaths and dogs already incubating infection. Individual variation in rabid dog behavior facilitated virus dispersal and cocirculation of virus lineages, enabling metapopulation persistence. These mechanisms have important implications for prediction and control of pathogens that circulate in spatially structured populations.

Fundamental questions remain about the regulation of acute pathogens in the absence of acquired immunity. This is especially true for canine rabies, a universally fatal zoonosis. From tracing rabies transmission in a population of 50,000 dogs in Tanzania between 2002-2016 we unravel the processes through which rabies is regulated and persists, fitting individual-based models to spatially-resolved data to investigate the mechanisms modulating transmission and the scale over which they operate. We find that while prevalence never exceeds 0.15%, we detect significant susceptible depletion at local scales commensurate with rabid dog movement, reducing transmission through clustering of rabies deaths and individuals incubating infection. Individual variation in rabid dog behaviour facilitates virus dispersal and co-circulation of lineages, enabling metapopulation persistence. These mechanisms likely operate in many pathogens circulating in spatially structured populations, with important implications for prediction and control, yet are unobservable unless the scale of host interactions is identified.One-Sentence SummaryIdentifying the spatial scale of contact reveals the mechanisms that limit the size of rabies outbreaks and that are critical for predicting transmission dynamics.

The Magombera forest is a home of endemic and endangered biological species such as Udzungwa red colobus monkey (Procolobus gordonorum) and the Magombera chameleon (Kinyongia magomberae). However, the forest is facing high threat of disappearing through resources extraction pressure from adjacent local communities. The project aimed at improving conservation of Magombera forest by involving the adjacent communities through provision of conservation education, restoration initiatives and bee keeping as alternative livelihoods. The study revealed that the concept of forest conservation is well supported. Nevertheless, people are extracting resources from the forest for their subsistence. The dependence of the people on the forest is due to lack of alternatives to the forest resources, inability of the people to produce alternatives source of income and little conservation education. The project resulted in a community having a positive attitude change towards conservation. The improved bee keeping was introduced to the community and successfully adopted. About 89% of indigenous trees planted for restoring the degraded area of the forest survived, only 11% of trees planted could not survive. There is a need to expand the scale of the project by involving many participants particularly youths that showed strong interest in the project.

Livestock production in Africa is key to national economies, food security and rural livelihoods, and > 85% of livestock keepers live in extreme poverty. With poverty elimination central to the Sustainable Development Goals, livestock keepers are therefore critically important. Foot-and-mouth disease is a highly contagious livestock disease widespread in Africa that contributes to this poverty. Despite its US$2.3 billion impact, control of the disease is not prioritized: standard vaccination regimens are too costly, its impact on the poorest is underestimated, and its epidemiology is too weakly understood. Our integrated analysis in Tanzania shows that the disease is of high concern, reduces household budgets for human health, and has major impacts on milk production and draft power for crop production. Critically, foot-and-mouth disease outbreaks in cattle are driven by livestock-related factors with a pattern of changing serotype dominance over time. Contrary to findings in southern Africa, we find no evidence of frequent infection from wildlife, with outbreaks in cattle sweeping slowly across the region through a sequence of dominant serotypes. This regularity suggests that timely identification of the epidemic serotype could allow proactive vaccination ahead of the wave of infection, mitigating impacts, and our preliminary matching work has identified potential vaccine candidates. This strategy is more realistic than wildlife-livestock separation or conventional foot-and-mouth disease vaccination approaches. Overall, we provide strong evidence for the feasibility of coordinated foot-and-mouth disease control as part of livestock development policies in eastern Africa, and our integrated socioeconomic, epidemiological, laboratory and modelling approach provides a framework for the study of other disease systems.

This study is the first to partially quantify the potential economic benefits that a vaccine, effective at protecting cattle against malignant catarrhal fever (MCF), could accrue to pastoralists living in East Africa. The benefits would result from the removal of household resource and management costs that are traditionally incurred avoiding the disease. MCF, a fatal disease of cattle caused by a virus transmitted from wildebeest calves, has plagued Maasai communities in East Africa for generations. The threat of the disease forces the Maasai to move cattle to less productive grazing areas to avoid wildebeest during calving season when forage quality is critical. To assess the management and resource costs associated with moving, we used household survey data. To estimate the costs associated with changes in livestock body condition that result from being herded away from wildebeest calving grounds, we exploited an ongoing MCF vaccine field trial and we used a hedonic price regression, a statistical model that allows estimation of the marginal contribution of a good's attributes to its market price. We found that 90 percent of households move, on average, 82 percent of all cattle away from home to avoid MCF. In doing so, a herd's productive contributions to the household was reduced, with 64 percent of milk being unavailable for sale or consumption by the family members remaining at the boma (the children, women, and the elderly). In contrast cattle that remained on the wildebeest calving grounds during the calving season (and survived MCF) remained fully productive to the family and gained body condition compared to cattle that moved away. This gain was, however, short-lived. We estimated the market value of these condition gains and losses using hedonic regression. The value of a vaccine for MCF is the removal of the costs incurred in avoiding the disease.

Malignant catarrhal fever (MCF) is a fatal disease of cattle that, in East Africa, follows contact with\ud wildebeest excreting alcelaphine herpesvirus 1 (AlHV-1). Recently an attenuated vaccine (atAlHV-1) was\ud tested under experimental challenge on Friesian-Holstein (FH) cattle and gave a vaccine efficacy (VE) of\ud approximately 90%. However testing under field conditions on an East African breed, the shorthorn zebu\ud cross (SZC), gave a VE of 56% suggesting that FH and SZC cattle may respond differently to the vaccine. To\ud investigate, a challenge trial was carried out using SZC. Additionally three adjuvant combinations were\ud tested: (i) Emulsigen1, (ii) bacterial flagellin (FliC) and (iii) Emulsigen1 + bacterial flagellin. We report\ud 100% seroconversion in all immunized cattle. The group inoculated with atAlHV-1 + Emulsigen1 had\ud significantly higher antibody titres than groups inoculated with FliC, the smallest number of animals that\ud became infected and the fewest fatalities, suggesting this was the most effective combination. A larger\ud study is required to more accurately determine the protective effect of this regime in SZC. There was an\ud apparent inhibition of the antibody response in cattle inoculated with atAlHV-1 + FliC, suggesting FliC\ud might induce an immune suppressive mechanism. The VE in SZC (50–60%) was less than that in FH (80–\ud 90%). We speculate that this might be due to increased risk of disease in vaccinated SZC (suggesting that\ud the vaccine may be less effective at stimulating an appropriate immune response in this breed) and/or\ud increased survival in unvaccinated SZC (suggesting that these cattle may have a degree of prior immunity\ud against infection with AlHV-1).

Thermotolerant vaccines greatly improved the reach and impact of large-scale vaccination programs to eliminate diseases such as smallpox, polio and rinderpest. A recent study demonstrated that the potency of the Nobivac® Canine Rabies vaccine was not impacted following experimental storage at 30 °C for three months. We conducted a study to develop a passive cooling device (PCD) that could store thermotolerant vaccines under fluctuating subambient temperatures. Through a participatory process with local communities in Northern Tanzania, we developed innovative PCD designs for local manufacture. A series of field experiments were then carried out to evaluate the effectiveness of five PCDs for vaccine storage under varying climatic conditions. Following iterative improvement, a final prototype “Zeepot Clay” was developed at the cost of US$11 per unit. During a further field-testing phase over a 12-month period, the internal temperature of the device remained below 26 °C, despite ambient temperatures exceeding 42 °C. Our study thus demonstrated that locally designed PCDs have utility for storing thermotolerant rabies vaccines at subambient temperatures. These results have application for the scaling up of mass dog vaccination programs in low-and-middle income countries, particularly for hard-to-reach populations with limited access to power and cold-chain vaccine storage.

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.

Landscape heterogeneity plays an important role in disease spread and persistence, but quantifying landscape influences and their scale dependence is challenging. Studies have focused on how environmental features or global transport networks influence pathogen invasion and spread, but their influence on local transmission dynamics that underpin the persistence of endemic diseases remains unexplored. Bayesian phylogeographic frameworks that incorporate spatial heterogeneities are promising tools for analysing linked epidemiological, environmental and genetic data. Here, we extend these methodological approaches to decipher the relative contribution and scale‐dependent effects of landscape influences on the transmission of endemic rabies virus in Serengeti district, Tanzania (area ~4,900 km2). Utilizing detailed epidemiological data and 152 complete viral genomes collected between 2004 and 2013, we show that the localized presence of dogs but not their density is the most important determinant of diffusion, implying that culling will be ineffective for rabies control. Rivers and roads acted as barriers and facilitators to viral spread, respectively, and vaccination impeded diffusion despite variable annual coverage. Notably, we found that landscape effects were scale‐dependent: rivers were barriers and roads facilitators on larger scales, whereas the distribution of dogs was important for rabies dispersal across multiple scales. This nuanced understanding of the spatial processes that underpin rabies transmission can be exploited for targeted control at the scale where it will have the greatest impact. Moreover, this research demonstrates how current phylogeographic frameworks can be adapted to improve our understanding of endemic disease dynamics at different spatial scales.

This research was supported by the UK Biotechnology and Biological Sciences Research Council (BB/J010367/1) and the UK Zoonoses and Emerging Livestock Systems Initiative (BB/L017679/1, BB/L018926/1 and BB/L018845/1) (S.C., J.E.B.H., J.S., J.B., A.D., J.A.C., W.A.d.G., R.R.K., T.K., D.T.H., B.T.M., E.S.S., L.W.). The Wellcome Trust provided supported for K.H. and A.L. (095787/Z/11/Z) and K.J.A. (096400/Z/11/Z). The US National Institutes of Health provided support for J.A.C. (R01AI121378) and M.P.R. (R01AI121378, K23AI116869). Emerging zoonoses with pandemic potential are a stated priority for the global health security agenda, but endemic zoonoses also have a major societal impact in low-resource settings. Although many endemic zoonoses can be treated, timely diagnosis and appropriate clinical management of human cases is often challenging. Preventive ‘One Health’ interventions, e.g. interventions in animal populations that generate human health benefits, may provide a useful approach to overcoming some of these challenges. Effective strategies, such as animal vaccination, already exist for the prevention, control and elimination of many endemic zoonoses, including rabies, and several livestock zoonoses (e.g. brucellosis, leptospirosis, Q fever) that are important causes of human febrile illness and livestock productivity losses in low- and middle-income countries. We make the case that, for these diseases, One Health interventions have the potential to be more effective and generate more equitable benefits for human health and livelihoods, particularly in rural areas, than approaches that rely exclusively on treatment of human cases. We hypothesize that applying One Health interventions to tackle these health challenges will help to build trust, community engagement and cross-sectoral collaboration, which will in turn strengthen the capacity of fragile health systems to respond to the threat of emerging zoonoses and other future health challenges. One Health interventions thus have the potential to align the ongoing needs of disadvantaged communities with the concerns of the broader global community, providing a pragmatic and equitable approach to meeting the global goals for sustainable development and supporting the global health security agenda. Publisher PDF

BackgroundWith a global target set for zero human deaths from dog-mediated rabies by 2030 and some regional programmes close to eliminating canine rabies, there is an urgent need for enhanced surveillance strategies suitable for declaring freedom from disease and elimination of transmission with known confidence.MethodsUsing exhaustive contact tracing across settings in Tanzania we generated detailed data on rabies incidence, rabid dog biting behaviour and health-seeking behaviour of bite victims. Using these data we compared case detection of sampling-based and enhanced surveillance methodologies and investigated elimination verification procedures.FindingsWe demonstrate that patients presenting to clinics with bite injuries are sensitive sentinels for identifying dog rabies cases. Triage of patients based on bite history criteria and investigation of suspicious incidents can confirm >10% of dog rabies cases and is an affordable approach that will enable validation of disease freedom following two years without case detection. Approaches based on sampling the dog population without using bite-injury follow-up were found to be neither sensitive nor cost-effective.InterpretationThe low prevalence of rabies, and short window in which disease can be detected, preclude sampling-based surveillance. Instead, active case finding guided by bite-patient triage is needed as elimination is approached. Our proposed methodology is affordable, practical and supports the goal of eliminating human rabies deaths by improving administration of lifesaving post-exposure prophylaxis for genuinely exposed but untreated contacts. Moreover, joint investigations by public health and veterinary workers will strengthen intersectoral partnerships and capacity for control of emerging zoonoses.

Rabies can be eliminated by achieving comprehensive coverage of 70% of domestic dogs during annual mass vaccination campaigns. Estimates of vaccination coverage are, therefore, required to evaluate and manage mass dog vaccination programs; however, there is no specific guidance for the most accurate and efficient methods for estimating coverage in different settings. Here, we compare post-vaccination transects, school-based surveys, and household surveys across 28 districts in southeast Tanzania and Pemba island covering rural, urban, coastal and inland settings, and a range of different livelihoods and religious backgrounds. These approaches were explored in detail in a single district in northwest Tanzania (Serengeti), where their performance was compared with a complete dog population census that also recorded dog vaccination status. Post-vaccination transects involved counting marked (vaccinated) and unmarked (unvaccinated) dogs immediately after campaigns in 2,155 villages (24,721 dogs counted). School-based surveys were administered to 8,587 primary school pupils each representing a unique household, in 119 randomly selected schools approximately 2 months after campaigns. Household surveys were conducted in 160 randomly selected villages (4,488 households) in July/August 2011. Costs to implement these coverage assessments were $12.01, $66.12, and $155.70 per village for post-vaccination transects, school-based, and household surveys, respectively. Simulations were performed to assess the effect of sampling on the precision of coverage estimation. The sampling effort required to obtain reasonably precise estimates of coverage from household surveys is generally very high and probably prohibitively expensive for routine monitoring across large areas, particularly in communities with high human to dog ratios. School-based surveys partially overcame sampling constraints, however, were also costly to obtain reasonably precise estimates of coverage. Post-vaccination transects provided precise and timely estimates of community-level coverage that could be used to troubleshoot the performance of campaigns across large areas. However, transects typically overestimated coverage by around 10%, which therefore needs consideration when evaluating the impacts of campaigns. We discuss the advantages and disadvantages of these different methods and make recommendations for how vaccination campaigns can be better monitored and managed at different stages of rabies control and elimination programs.

Highlights • Vaccination induces a pharyngeal antibody response in shorthorn zebu cross (SZC). • Direct challenge with the AlHV-1 virus is effective at inducing MCF in SZC. • Attenuated AlHV–1 + Emulsigen® vaccine efficacy in SZC calculated to be 50%. • Bacterial flagellin is not a good adjuvant as inclusion reduced antibody response. • We provide evidence that non-fatal AlHV-1 infections occur in SZC., Malignant catarrhal fever (MCF) is a fatal disease of cattle that, in East Africa, follows contact with wildebeest excreting alcelaphine herpesvirus 1 (AlHV-1). Recently an attenuated vaccine (atAlHV-1) was tested under experimental challenge on Friesian-Holstein (FH) cattle and gave a vaccine efficacy (VE) of approximately 90%. However testing under field conditions on an East African breed, the shorthorn zebu cross (SZC), gave a VE of 56% suggesting that FH and SZC cattle may respond differently to the vaccine. To investigate, a challenge trial was carried out using SZC. Additionally three adjuvant combinations were tested: (i) Emulsigen®, (ii) bacterial flagellin (FliC) and (iii) Emulsigen® + bacterial flagellin. We report 100% seroconversion in all immunized cattle. The group inoculated with atAlHV-1 + Emulsigen® had significantly higher antibody titres than groups inoculated with FliC, the smallest number of animals that became infected and the fewest fatalities, suggesting this was the most effective combination. A larger study is required to more accurately determine the protective effect of this regime in SZC. There was an apparent inhibition of the antibody response in cattle inoculated with atAlHV-1 + FliC, suggesting FliC might induce an immune suppressive mechanism. The VE in SZC (50–60%) was less than that in FH (80–90%). We speculate that this might be due to increased risk of disease in vaccinated SZC (suggesting that the vaccine may be less effective at stimulating an appropriate immune response in this breed) and/or increased survival in unvaccinated SZC (suggesting that these cattle may have a degree of prior immunity against infection with AlHV-1).