Understanding the incidence and timing of rabies cases in domestic animals and wildlife in south-east Tanzania in the presence of widespread domestic dog vaccination campaigns.

The "Zero by 30" strategic plan aims to eliminate human deaths from dog-mediated rabies by 2030 and domestic dog vaccination is a vital component of this strategic plan. In areas where domestic dog vaccination has been implemented, it is important to assess the impact of this intervention. Additionally, understanding temporal and seasonal trends in the incidence of animal rabies cases may assist in optimizing such interventions. Data on the incidence of probable rabies cases in domestic and wild animals were collected between January 2011 and December 2018 in thirteen districts of south-east Tanzania where jackals comprise over 40% of reported rabies cases. Vaccination coverage was estimated over this period, as five domestic dog vaccination campaigns took place in all thirteen districts between 2011 and 2016. Negative binomial generalized linear models were used to explore the impact of domestic dog vaccination on the annual incidence of animal rabies cases, whilst generalized additive models were used to investigate the presence of temporal and/or seasonal trends. Increases in domestic dog vaccination coverage were significantly associated with a decreased incidence of rabies cases in both domestic dogs and jackals. A 35% increase in vaccination coverage was associated with a reduction in the incidence of probable dog rabies cases of between 78.0 and 85.5% (95% confidence intervals ranged from 61.2 to 92.2%) and a reduction in the incidence of probable jackal rabies cases of between 75.3 and 91.2% (95% confidence intervals ranged from 53.0 to 96.1%). A statistically significant common seasonality was identified in the monthly incidence of probable rabies cases in both domestic dogs and jackals with the highest incidence from February to August and lowest incidence from September to January. These results align with evidence supporting the use of domestic dog vaccination as part of control strategies aimed at reducing animal rabies cases in both domestic dogs and jackals in this region. The presence of a common seasonal trend requires further investigation but may have implications for the timing of future vaccination campaigns.

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.

Development of Dog Vaccination Strategies to Maintain Herd Immunity against Rabies.

Human rabies can be prevented through mass dog vaccination campaigns; however, in rabies endemic countries, pulsed central point campaigns do not always achieve the recommended coverage of 70%. This study describes the development of a novel approach to sustain high coverage based on decentralized and continuous vaccination delivery. A rabies vaccination campaign was conducted across 12 wards in the Mara region, Tanzania to test this approach. Household surveys were used to obtain data on vaccination coverage as well as factors influencing dog vaccination. A total 17,571 dogs were vaccinated, 2654 using routine central point delivery and 14,917 dogs using one of three strategies of decentralized continuous vaccination. One month after the first vaccination campaign, coverage in areas receiving decentralized vaccinations was higher (64.1, 95% Confidence Intervals (CIs) 62.1-66%) than in areas receiving pulsed vaccinations (35.9%, 95% CIs 32.6-39.5%). Follow-up surveys 10 months later showed that vaccination coverage in areas receiving decentralized vaccinations remained on average over 60% (60.7%, 95% CIs 58.5-62.8%) and much higher than in villages receiving pulsed vaccinations where coverage was on average 32.1% (95% CIs 28.8-35.6%). We conclude that decentralized continuous dog vaccination strategies have the potential to improve vaccination coverage and maintain herd immunity against rabies.

Participation in mass dog vaccination campaigns in Tanzania: Benefits of community engagement.

Background: Canine rabies causes about 59,000 human deaths each year globally but the disease can be eliminated by sustaining sufficient dog vaccination coverage over several consecutive years. A challenge to achieving high coverage is low participation of dog owners in vaccination campaigns. We explored whether and how previously identified contributory factors to low participation can be addressed through community engagement activities. Methods: We engaged communities in two wards in Tanzania on dog behavior and handling, safe ways of interacting with dogs, and their perceptions of dog vaccination. We shared and elicited information from them through village meetings, video screenings, posters and leaflets and involved the leadership of one of the wards in planning and implementing a dog vaccination exercise to explore the feasibility of their participation. We assessed the impact of engagement activities with household surveys, meeting reports, observations and focus group discussions. We used a generalized linear mixed-effects model to identify predictors of knowledge and perceptions and compared knowledge amongst respondents before and after engagement activities. Qualitative data was analyzed inductively to explore perceptions of dog handling and vaccination and feasibility, opportunities and barriers to community leadership participation in organizing mass dog vaccination. Main findings: Knowledge of dog behavior, dog handling, and safe ways of interacting with dogs was positively associated with age (p < 0.0001), dog ownership (p = 0.0203), training (p = 0.0010) and previous experience of a dog bite (p = 0.0002); and was negatively associated with being afraid of dogs (p = 0.0061) and participation in a recent dog vaccination campaign (p = 0.0077). Knowledge was low before and significantly improved after engagement activities. The majority (92%) of respondents believed dog vaccination has no negative effects on dogs. Respondents perceived lack of bonding with their dog as a limitation to the ability to restrain a dog for vaccination. The community performed most roles assigned to them in the dog vaccination exercise, but barriers such as lack of motivation for volunteering exist. Conclusion: Engaging communities regularly on dog vaccination can improve their knowledge of dog behavior and dog handling techniques, and may help improve owner participation in dog vaccination campaigns.

Rabies shows how scale of transmission can enable acute infections to persist at low prevalence.

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.

Modelling how face masks and symptoms-based quarantine synergistically and cost-effectively reduce SARS-CoV-2 transmission in Bangladesh.

BACKGROUND: Non-pharmaceutical interventions (NPIs) used to limit SARS-CoV-2 transmission vary in their feasibility, appropriateness and effectiveness in different contexts. In Bangladesh a national lockdown implemented in March 2020 exacerbated poverty and was untenable long-term. A resurgence in 2021 warranted renewed NPIs. We sought to identify NPIs that were feasible in this context and explore potential synergies between interventions. METHODS: We developed an SEIR model for Dhaka District, parameterised from literature values and calibrated to data from Bangladesh. We discussed scenarios and parameterisations with policymakers with the aid of an interactive app. These discussions guided modelling of lockdown and two post-lockdown measures considered feasible to deliver; symptoms-based household quarantining and compulsory mask-wearing. We compared NPI scenarios on deaths, hospitalisations relative to capacity, working days lost, and cost-effectiveness. RESULTS: Lockdowns alone were predicted to delay the first epidemic peak but could not prevent overwhelming of the health service and were costly in lost working days. Impacts of post-lockdown interventions depended heavily on compliance. Assuming 80% compliance, symptoms-based household quarantining alone could not prevent hospitalisations exceeding capacity, whilst mask-wearing prevented overwhelming health services and was cost-effective given masks of high filtration efficiency. Combining masks with quarantine increased their impact. Recalibration to surging cases in 2021 suggested potential for a further wave in 2021, dependent on uncertainties in case reporting and immunity. CONCLUSIONS: Masks and symptoms-based household quarantining synergistically prevent transmission, and are cost-effective in Bangladesh. Our interactive app was valuable in supporting decision-making, with mask-wearing being mandated early, and community teams being deployed to support quarantining across Dhaka. These measures likely contributed to averting the worst public health impacts, but delivering an effective response with consistent compliance across the population has been challenging. In the event of a further resurgence, concurrent messaging to increase compliance with both mask-wearing and quarantine is recommended.

Scaling-up the delivery of dog vaccination campaigns against rabies in Tanzania.

An increasing number of countries are committing to meet the global target to eliminate human deaths from dog-mediated rabies by 2030. Mass dog vaccination is central to this strategy. To interrupt rabies transmission from dogs to humans, the World Health Organization recommends that vaccination campaigns should be carried out every year in all dog-owning communities vaccinating 70% of their susceptible dogs. Monitoring and evaluation of dog vaccination campaigns are needed to measure progress towards elimination. In this study, we measured the delivery performance of large-scale vaccination campaigns implemented in 25 districts in south-east Tanzania from 2010 until 2017. We used regression modelling to infer the factors associated with, and potentially influencing the successful delivery of vaccination campaigns. During 2010-2017, five rounds of vaccination campaigns were carried out, vaccinating in total 349,513 dogs in 2,066 administrative vaccination units (rural villages or urban wards). Progressively more dogs were vaccinated over the successive campaigns. The campaigns did not reach all vaccination units each year, with only 16-28% of districts achieving 100% campaign completeness (where all units were vaccinated). During 2013-2017 when vaccination coverage was monitored, approximately 20% of vaccination units achieved the recommended 70% coverage, with average coverage around 50%. Campaigns were also not completed at annual intervals, with the longest interval between campaigns being 27 months. Our analysis revealed that districts with higher budgets generally achieved higher completeness, with a twofold difference in district budget increasing the odds of a vaccination unit being reached by a campaign by slightly more than twofold (OR: 2.29; 95% CI: 1.69-3.09). However, higher budgets did not necessarily result in higher coverage within vaccination units that were reached. We recommend national programs regularly monitor and evaluate the performance of their vaccination campaigns, so as to identify factors hindering their effective delivery and to guide remedial action.

Reservoir dynamics of rabies in south-east Tanzania and the roles of cross-species transmission and domestic dog vaccination.

Understanding the role of different species in the transmission of multi-host pathogens, such as rabies virus, is vital for effective control strategies. Across most of sub-Saharan Africa domestic dogs Canis familiaris are considered the reservoir for rabies, but the role of wildlife has been long debated. Here we explore the multi-host transmission dynamics of rabies across south-east Tanzania.Between January 2011 and July 2019, data on probable rabies cases were collected in the regions of Lindi and Mtwara. Hospital records of animal-bite patients presenting to healthcare facilities were used as sentinels for animal contact tracing. The timing, location and species of probable rabid animals were used to reconstruct transmission trees to infer who infected whom and the relative frequencies of within- and between-species transmission.During the study, 688 probable human rabies exposures were identified, resulting in 47 deaths. Of these exposures, 389 were from domestic dogs (56.5%) and 262 from jackals (38.1%). Over the same period, 549 probable animal rabies cases were traced: 303 in domestic dogs (55.2%) and 221 in jackals (40.3%), with the remainder in domestic cats and other wildlife species.Although dog-to-dog transmission was most commonly inferred (40.5% of transmission events), a third of inferred events involved wildlife-to-wildlife transmission (32.6%), and evidence suggested some sustained transmission chains within jackal populations.A steady decline in probable rabies cases in both humans and animals coincided with the implementation of widespread domestic dog vaccination during the first 6 years of the study. Following the lapse of this program, dog rabies cases began to increase in one of the northernmost districts. Synthesis and applications. In south-east Tanzania, despite a relatively high incidence of rabies in wildlife and evidence of wildlife-to-wildlife transmission, domestic dogs remain essential to the reservoir of infection. Continued dog vaccination alongside improved surveillance would allow a fuller understanding of the role of wildlife in maintaining transmission in this area. Nonetheless, dog vaccination clearly suppressed rabies in both domestic dog and wildlife populations, reducing both public health and conservation risks and, if sustained, has potential to eliminate rabies from this region.

Inference of the drivers of collective movement in two cell types: Dictyostelium and melanoma.

Collective cell movement is a key component of many important biological processes, including wound healing, the immune response and the spread of cancers. To understand and influence these movements, we need to be able to identify and quantify the contribution of their different underlying mechanisms. Here, we define a set of six candidate models-formulated as advection-diffusion-reaction partial differential equations-that incorporate a range of cell movement drivers. We fitted these models to movement assay data from two different cell types: Dictyostelium discoideum and human melanoma. Model comparison using widely applicable information criterion suggested that movement in both of our study systems was driven primarily by a self-generated gradient in the concentration of a depletable chemical in the cells' environment. For melanoma, there was also evidence that overcrowding influenced movement. These applications of model inference to determine the most likely drivers of cell movement indicate that such statistical techniques have potential to support targeted experimental work in increasing our understanding of collective cell movement in a range of systems.

Heterogeneity in the spread and control of infectious disease: consequences for the elimination of canine rabies.

Understanding the factors influencing vaccination campaign effectiveness is vital in designing efficient disease elimination programmes. We investigated the importance of spatial heterogeneity in vaccination coverage and human-mediated dog movements for the elimination of endemic canine rabies by mass dog vaccination in Region VI of the Philippines (Western Visayas). Household survey data was used to parameterise a spatially-explicit rabies transmission model with realistic dog movement and vaccination coverage scenarios, assuming a basic reproduction number for rabies drawn from the literature. This showed that heterogeneous vaccination reduces elimination prospects relative to homogeneous vaccination at the same overall level. Had the three vaccination campaigns completed in Region VI in 2010-2012 been homogeneous, they would have eliminated rabies with high probability. However, given the observed heterogeneity, three further campaigns may be required to achieve elimination with probability 0.95. We recommend that heterogeneity be reduced in future campaigns through targeted efforts in low coverage areas, even at the expense of reduced coverage in previously high coverage areas. Reported human-mediated dog movements did not reduce elimination probability, so expending limited resources on restricting dog movements is unnecessary in this endemic setting. Enhanced surveillance will be necessary post-elimination, however, given the reintroduction risk from long-distance dog movements.