Sex-differential non-specific effects of adjuvanted and non-adjuvanted rabies vaccines versus placebo on all-cause mortality in dogs (NERVE-Dog study): a study protocol for a randomized controlled trial with a nested case-control study.

BACKGROUND: It has been proposed that childhood vaccines in high-mortality populations may have substantial impacts on mortality rates that are not explained by the prevention of targeted diseases, nor conversely by typical expected adverse reactions to the vaccines, and that these non-specific effects (NSEs) are generally more pronounced in females. The existence of these effects, and any implications for the development of vaccines and the design of vaccination programs to enhance safety, remain controversial. One area of controversy is the reported association of non-live vaccines with increased female mortality. In a previous randomized controlled trial (RCT), we observed that non-live alum-adjuvanted animal rabies vaccine (ARV) was associated with increased female but not male mortality in young, free-roaming dogs. Conversely, non-live non-adjuvanted human rabies vaccine (NRV) has been associated with beneficial non-specific effects in children. Alum adjuvant has been shown to suppress Th1 responses to pathogens, leading us to hypothesize that alum-adjuvanted rabies vaccine in young dogs has a detrimental effect on female survival by modulating the immune response to infectious and/or parasitic diseases. In this paper, we present the protocol of a 3-arm RCT comparing the effect of alum-adjuvanted rabies vaccine, non-adjuvanted rabies vaccine and placebo on all-cause mortality in an owned, free-roaming dog population, with causal mediation analysis of the RCT and a nested case-control study to test this hypothesis. METHODS: Randomised controlled trial with a nested case-control study. DISCUSSION: We expect that, among the placebo group, males will have higher mortality caused by higher pathogen loads and more severe disease, as determined by haematological parameters and inflammatory biomarkers. Among females, we expect that there will be no difference in mortality between the NRV and placebo groups, but that the ARV group will have higher mortality, again mediated by higher pathogen loads and more severe disease. We anticipate that these changes are preceded by shifts in key serum cytokine concentrations towards an anti-inflammatory immune response in females. If confirmed, these results will provide a rational basis for mitigation of detrimental NSEs of non-live vaccines in high-mortality populations.

Rickettsia felis infection in febrile patients, western Kenya, 2007-2010.

To determine previous exposure and incidence of rickettsial infections in western Kenya during 2007-2010, we conducted hospital-based surveillance. Antibodies against rickettsiae were detected in 57.4% of previously collected serum samples. In a 2008-2010 prospective study, Rickettsia felis DNA was 2.2× more likely to be detected in febrile than in afebrile persons.

Domestic dog demographic structure and dynamics relevant to rabies control planning in urban areas in Africa: the case of Iringa, Tanzania.

BACKGROUND: Mass vaccinations of domestic dogs have been shown to effectively control canine rabies and hence human exposure to rabies. Knowledge of dog population demography is essential for planning effective rabies vaccination programmes; however, such information is still rare for African domestic dog populations, particularly so in urban areas. This study describes the demographic structure and population dynamics of a domestic dog population in an urban sub-Saharan African setting. In July to November 2005, we conducted a full household-level census and a cross-sectional dog demography survey in four urban wards of Iringa Municipality, Tanzania. The achievable vaccination coverage was assessed by a two-stage vaccination campaign, and the proportion of feral dogs was estimated by a mark-recapture transect study. RESULTS: The estimated size of the domestic dog population in Iringa was six times larger than official town records assumed, however, the proportion of feral dogs was estimated to account for less than 1% of the whole population. An average of 13% of all households owned dogs which equalled a dog:human ratio of 1:14, or 0.31 dogs per household or 334 dogs km-2. Dog female:male ratio was 1:1.4. The average age of the population was 2.2 years, 52% of all individuals were less than one year old. But mortality within the first year was high (72%). Females became fertile at the age of 10 months and reportedly remained fertile up to the age of 11 years. The average number of litters whelped per fertile female per year was 0.6 with an average of 5.5 pups born per litter. The population growth was estimated at 10% y-1. CONCLUSIONS: Such high birth and death rates result in a rapid replacement of anti-rabies immunised individuals with susceptible ones. This loss in herd immunity needs to be taken into account in the design of rabies control programmes. The very small proportion of truly feral dogs in the population implies that vaccination campaigns aimed at the owned dog population are sufficient to control rabies in urban Iringa, and the same may be valid in other, comparable urban settings.

Sex-differential non-specific effects of rabies vaccine in dogs: An extended analysis of a randomized controlled trial in a high-mortality population.

Non-live rabies vaccines have been associated with both beneficial and detrimental effects on host population morbidity and mortality rates to unrelated infections in people and animals, and these non-specific effects may differ by sex. Previous animal studies may have been affected by bias, including selection bias due to loss to follow up in randomized controlled trials (RCTs). We previously reported results of an RCT in dogs on the effect of primary rabies vaccine administered at 6 weeks of age on all-cause mortality over a 7-week follow-up period, in a high-mortality population of owned dogs. Here, we report the results from the same trial of a second vaccination at 13 weeks of age, compared to a primary vaccination. Because a relatively high proportion of study subjects (30%) were lost to follow-up in the RCT, we also conducted an analysis to control for possible selection bias over both periods (6 to 13 weeks and 13 to 20 weeks of age). We found that primary rabies vaccination at 6 weeks of age substantially increased the hazard of death from all causes over the next 7 weeks among females (hazard ratio [HR] 2.69, 95% confidence intervals [CI] 1.27-5.69), but not among males (HR 0.91, 95% CI 0.32-2.59). Among survivors, administration of a second dose of rabies vaccine at 13 weeks of age was associated with a decreased hazard of death among males (HR 0.33, 95% CI 0.10-1.02) but not females (HR 1.64, 95% CI 0.59-4.58), when compared to the group receiving their first dose at this age. Based on our causal assumptions, we show that these results were not affected by selection bias. In this high-mortality dog population, receipt of a non-live rabies vaccine substantially affected all-cause mortality rates, with this effect being strongly modified by sex.

Non-specific effects of veterinary vaccines: a systematic review.

The benefits of vaccines have been centred on their specific effects on subsequent infections by target pathogens. Recent studies, however, have opened up new insights into additional effects of vaccines known as non-specific effects (NSEs) or heterologous effects of vaccines. While several articles have reviewed epidemiological and immunological evidence for NSEs of vaccines in humans, similar works on veterinary vaccines are scarce. The objective of this paper was to review the findings of published studies on NSEs of vaccines developed or repurposed for use in animals. In total 8412 titles were retrieved from PubMed and CABI databases on the 30th of April 2021. After the final stage of screening, 45 eligible articles were included in the review. Data from these articles were summarised and presented here. In general, most of the vaccines studied in the reviewed articles have beneficial NSEs against multiple pathogens and disease conditions. There were, however, fewe studies reporting detrimental NSEs from both non-live and live vaccines which is in contrast to the currently existing evidence of beneficial NSEs of live vaccines and detrimental NSEs of non-live vaccines. This review may be used as a complement for future review of RCT studies of NSEs of vaccines in animals and provide a useful addition to the evolving understanding of the NSEs of vaccines.

Non-specific effects of maternal and offspring rabies vaccination on mortality and antibiotic use in a Danish pig herd: A randomized trial.

INTRODUCTION: Human non-live vaccines have been associated with detrimental non-specific effects (NSE), particularly in females. A large trial found 2-fold increased overall mortality in girls receiving a new malaria vaccine compared to the rabies vaccine used as a coontrol; a beneficial NSE of the rabies vaccine was proposed. Conversely, in dogs increased mortality was seen in females but not males following rabies vaccination of puppies born to immunized mothers. We investigated NSE of non-live rabies vaccine in piglets and the potential modifying effect of maternal priming with rabies vaccine. METHODS: In a Danish herd of commercial rabies virus-free pigs, 575 pregnant sows (2-3 weeks before scheduled farrowing) and 5747 of their offspring (median 6-day-old) were allocated (1:1) to non-live rabies vaccine (Versiguard rabies vet) or no rabies vaccine. Outcomes were overall mortality and antibiotic treatment until departure from the nursery (approximately age 12 weeks/30 kgs). RESULTS: Until weaning, overall offspring mortality was 2.2% (127 piglets died, rabies vaccine: n = 69; control: n = 58), the proportion ratio (PR) being 1.19 (95% confidence interval: 0.84-1.68). Until end of follow-up, mortality was 4.1% (233, rabies vaccine: n = 115; control = 118, PR: 0.97 (0.76-1.25)). Prior sow rabies vaccination did not affect piglet mortality. For mortality as well as risk of antibiotic treatment before weaning, there was indication of a beneficial effect of rabies vaccine in female piglets, but a negative effect in (castrated) male piglets from rabies-naïve sows. Prior sow vaccination significantly modified the vaccine effect estimate in female piglets toward a detrimental effect of rabies vaccine on treatment risk. These effects had waned by 12 weeks of age. CONCLUSION: The study did not support the hypothesized beneficial NSE of rabies vaccine. Although under-powered for subgroup analyses, the study indicated effect modification by sex and maternal vaccination. Results could be different in a herd with higher mortality and infectious burden.

Non-specific effects of rabies vaccine on the incidence of self-reported common infectious disease episodes: A randomized controlled trial.

Vaccines may affect recipients' immune systems in ways that change morbidity or mortality rates to unrelated infections in vaccinated populations. It has been proposed that these non-specific effects differ by type of vaccine and by sex, with non-live vaccines enhancing susceptibility of females to unrelated infections, and live vaccines enhancing resistance in both sexes. Rabies vaccine-a non-live vaccine-has been associated with protection against unrelated central nervous system infections. Data from randomized controlled trials are needed to assess this effect against other illnesses. This phase IV, single-site, participant-blinded, randomized, placebo-controlled trial in a population of veterinary students on the rabies-free island of St. Kitts assessed the effect of a primary course of rabies vaccine on the incidence rate of weekly self-reported new episodes of common infectious disease (CID) syndromes, defined as a new episode of any one of the following syndromes in a particular week: upper respiratory illness (URI), influenza-like illness (ILI), diarrheal illness (DIA) or undifferentiated febrile illness (UFI). As a secondary objective, we tested for modification of the effect of rabies vaccine on study outcomes by sex. 546 participants were randomized (274 to rabies vaccine and 272 to placebo). No statistically significant differences between groups were observed for any study outcomes: CID incidence rate ratio (IRR) 0.95 (95% CI 0.77-1.18); URI IRR 1.15 (95% CI 0.86-1.54); ILI IRR 0.83 (95% CI 0.54-1.27); DIA IRR 0.93 (95% CI 0.70-1.24) and UFI IRR 1.09 (95% CI 0.48-2.44). In a secondary analysis, there was little evidence that sex modified the effect of vaccination on any of the evaluated outcomes, although the power to detect this was low. In conclusion, rabies vaccine did not provide protection against mild self-reported illness among a young and healthy group of adults attending veterinary school. Clinical trial registration. ClinicalTrials.gov: NCT03656198.

A One Medicine Mission for an Effective Rabies Therapy.

Despite the disease's long history, little progress has been made toward a treatment for rabies. The prognosis for patient recovery remains dire. For any prospect of survival, patients require aggressive critical care, which physicians in rabies endemic areas may be reluctant or unable to provide given the cost, clinical expertise required, and uncertain outcome. Systematic clinical research into combination therapies is further hampered by sporadic occurrence of cases. In this Perspective, we examine the case for a One Medicine approach to accelerate development of an effective therapy for rabies through the veterinary care and investigational treatment of naturally infected dogs in appropriate circumstances. We review the pathogenesis of rabies virus in humans and dogs, including recent advances in our understanding of the molecular basis for the severe neurological dysfunction. We propose that four categories of disease process need to be managed in patients: viral propagation, neuronal degeneration, inflammation and systemic compromise. Compassionate critical care and investigational treatment of naturally infected dogs receiving supportive therapy that mimics the human clinical scenario could increase opportunities to study combination therapies that address these processes, and to identify biomarkers for prognosis and therapeutic response. We discuss the safety and ethics of this approach, and introduce the Canine Rabies Treatment Initiative, a non-profit organization with the mission to apply a One Medicine approach to the investigation of diagnostic, prognostic, and therapeutic options for rabies in naturally infected dogs, to accelerate transformation of rabies into a treatable disease for all patients.

Sero-Epidemiological Study of Selected Zoonotic and Abortifacient Pathogens in Cattle at a Wildlife-Livestock Interface in South Africa.

A cross sectional sero-epidemiological study was conducted on cattle in a communal farming area adjacent to Kruger National Park at a wildlife-livestock interface in South Africa. A total of 184 cattle were screened for exposure to 5 abortifacient or zoonotic pathogens, namely Coxiella burnetii, Toxoplasma gondii, Chlamydophila abortus, Neospora caninum, and Rift Valley fever virus (RVFV) using enzyme-linked immunosorbent assays. In addition, the virus neutralization test was used to confirm the presence of antibodies to RVFV. The seroprevalence of C. burnetii, T. gondii, C. abortus, N. caninum, and RVFV antibodies was 38.0%, 32.6%, 20.7%, 1.6%, and 0.5%, respectively, and varied between locations (p < 0.001). Seroprevalence of C. burnetii and T. gondii was highly clustered by location (intraclass correlation coefficient [ICC] = 0.57), and that of C. abortus moderately so (ICC = 0.11). Seroprevalence was not associated with sex or age for any pathogen, except for C. abortus, for which seroprevalence was positively associated with age (p = 0.01). The predominant mixed infections were C. burnetii and T. gondii (15.2%) and C. burnetii, T. gondii, and C. abortus (13.0%). The serological detection of the five abortifacient pathogens in cattle indicates the potential for economic losses to livestock farmers, health impacts to domestic animals, transmission across the livestock-wildlife interface, and the risk of zoonotic transmission. This is the first documentation of T. gondii infection in cattle in South Africa, while exposure to C. burnetii, C. abortus, and N. caninum infections is being reported for the first time in cattle in a wildlife-livestock interface in the country.

Rabies Vaccination of 6-Week-Old Puppies Born to Immunized Mothers: A Randomized Controlled Trial in a High-Mortality Population of Owned, Free-Roaming Dogs.

To achieve global elimination of human rabies from dogs by 2030, evidence-based strategies for effective dog vaccination are needed. Current guidelines recommend inclusion of dogs younger than 3 months in mass rabies vaccination campaigns, although available vaccines are only recommended for use by manufacturers in older dogs, ostensibly due to concerns over interference of maternally-acquired immunity with immune response to the vaccine. Adverse effects of vaccination in this age group of dogs have also not been adequately assessed under field conditions. In a single-site, owner-blinded, randomized, placebo-controlled trial in puppies born to mothers vaccinated within the previous 18 months in a high-mortality population of owned, free-roaming dogs in South Africa, we assessed immunogenicity and effect on survival to all causes of mortality of a single dose of rabies vaccine administered at 6 weeks of age. We found that puppies did not have appreciable levels of maternally-derived antibodies at 6 weeks of age (geometric mean titer 0.065 IU/mL, 95% CI 0.061-0.069; n = 346), and that 88% (95% CI 80.7-93.3) of puppies vaccinated at 6 weeks had titers ≥0.5 IU/mL 21 days later (n = 117). Although the average effect of vaccination on survival was not statistically significant (hazard ratio [HR] 1.35, 95% CI 0.83-2.18), this effect was modified by sex (p = 0.02), with the HR in females 3.09 (95% CI 1.24-7.69) and the HR in males 0.79 (95% CI 0.41-1.53). We speculate that this effect is related to the observed survival advantage that females had over males in the unvaccinated group (HR 0.27; 95% CI 0.11-0.70), with vaccination eroding this advantage through as-yet-unknown mechanisms.

A cross-sectional study of factors associated with dog ownership in Tanzania.

BACKGROUND: Mass vaccination of owned domestic dogs is crucial for the control of rabies in sub-Saharan Africa. Knowledge of the proportion of households which own dogs, and of the factors associated with dog ownership, is important for the planning and implementation of rabies awareness and dog vaccination programmes, and for the promotion of responsible dog ownership. This paper reports the results of a cross-sectional study of dog ownership by households in urban and rural communities in the United Republic of Tanzania. RESULTS: Fourteen percent (202) of 1,471 households surveyed were identified as dog-owning, with an average of 2.4 dogs per dog-owning household. The percentage of dog-owning households was highest in inland rural areas (24%) and lowest in coastal urban communities (7%). The overall human:dog ratio was 14:1. Multivariable logistic regression revealed that households which owned cattle, sheep or goats were much more likely to own dogs than households with no livestock. Muslim households were less likely to own dogs than Christian households, although this effect of religion was not seen among livestock-owning households. Households were more likely to own a dog if the head of the household was male; if they owned a cat; or if they owned poultry. Dog ownership was also broadly associated with larger, wealthier households. CONCLUSION: The human:dog ratios in Tanzania are similar to those reported elsewhere in sub-Saharan Africa, although cultural and geographic variation is evident. Estimation of the number of owned dogs, and identification of household predictors of dog ownership, will enable targeted planning of rabies control efforts.

Molecular detection and phylogenetic analysis of Anaplasma marginale and Anaplasma centrale amongst transhumant cattle in north-eastern Uganda.

There is little molecular data from Anaplasma marginale and Anaplasma centrale isolates from cattle in Uganda. Between November 2013 and January 2014, blood was collected from 240 cattle in 20 randomly-selected herds in two districts of the Karamoja Region in north-eastern Uganda. A duplex quantitative real-time polymerase chain reaction (qPCR) assay was used to detect and determine the prevalence of A. marginale (targeting the msp1ß gene) and A. centrale (targeting the groEL gene). The qPCR assay revealed that most cattle (82.9%; 95% confidence interval [CI] 78.2-87.7%) were positive for A. marginale DNA, while fewer cattle (12.1%; 95% CI 7.9-16.2%) were positive for A. centrale DNA. A mixed effects logistic regression model showed that the age of cattle was significantly associated with A. centrale infection, while the prevalence of A. marginale varied significantly according to locality. The near full-length 16S ribosomal RNA (16S rRNA) gene and the heat shock protein gene, groEL, for both Anaplasma species were amplified from a selection of samples. The amplicons were cloned and the resulting recombinants sequenced. We found three novel A. marginale 16S rRNA variants, seven A. marginale groEL gene sequence variants and two A. centrale groEL gene sequence variants. Phylogenetic trees were inferred from sequence alignments of the 16S rRNA gene and GroEL amino acid sequences determined here and published sequences using maximum likelihood, Bayesian inference and parsimony methods Phylogenetic analyses classified the 16S rRNA gene and GroEL amino acid sequences into one clade for A. marginale and a separate clade for A. centrale. This study reveals a high prevalence and sequence variability of A. marginale and A. centrale, and is the first report on the phylogenetic characterisation of A. marginale and A. centrale from cattle in Uganda using molecular markers. Sequence variation can be attributed to mobile pastoralism, communal grazing and grazing with wildlife. These data support future epidemiological investigations for bovine anaplasmosis in Uganda.

Spatiotemporal epidemiology of rabies at an interface between domestic dogs and wildlife in South Africa.

We characterized the spatiotemporal epidemiology of rabies from January 2009 through March 2014 across the interface between a wildlife reserve and communal livestock farming area in South Africa. Brain tissue from 344 animals of 28 different species were tested for lyssavirus antigen. Of these, 146 (42.4%) samples tested positive, of which 141 (96.6%) came from dogs. Brain samples of dogs were more likely to test positive for lyssavirus antigen if they were found and destroyed in the reserve, compared to samples originating from dogs outside the reserve (65.3% vs. 45.5%; odds ratio (OR) = 2.26, 95% confidence interval (CI) = 1.27-4.03), despite rabies surveillance outside the reserve being targeted to dogs that have a higher index of suspicion due to clinical or epidemiological evidence of infection. In the reserve, dogs were more likely to test positive for rabies if they were shot further from villages (OR = 1.42, 95% CI 1.18-1.71) and closer to water points (OR = 0.41, 95% CI 0.21-0.81). Our results provide a basis for refinement of existing surveillance and control programs to mitigate the threat of spillover of rabies to wildlife populations.

Prevalence of Selected Zoonotic Diseases and Risk Factors at a Human-Wildlife-Livestock Interface in Mpumalanga Province, South Africa.

A lack of surveillance and diagnostics for zoonotic diseases in rural human clinics limits clinical awareness of these diseases. We assessed the prevalence of nine zoonotic pathogens in a pastoral, low-income, HIV-endemic community bordering wildlife reserves in South Africa. Two groups of participants were included: malaria-negative acute febrile illness (AFI) patients, called febrilers, at three clinics (n = 74) and second, farmers, herders, and veterinary staff found at five government cattle dip-tanks, called dip-tanksters (n = 64). Blood samples were tested using one PCR (Bartonella spp.) and eight antibody-ELISAs, and questionnaires were conducted to assess risk factors. Seventy-seven percent of febrilers and 98% of dip-tanksters had at least one positive test. Bartonella spp. (PCR 9.5%), spotted fever group (SFG) Rickettsia spp. (IgM 24.1%), Coxiella burnetii. (IgM 2.3%), and Leptospira spp. (IgM 6.8%) were present in febrilers and could have been the cause of their fever. Dip-tanksters and febrilers had evidence of past infection to Rickettsia spp. (IgG 92.2% and 63.4%, respectively) and C. burnetii (IgG 60.9% and 37.8%, respectively). No Brucella infection or current Bartonella infection was found in the dip-tanksters, although they had higher levels of recent exposure to Leptospira spp. (IgM 21.9%) compared to the febrilers. Low levels of West Nile and Sindbis, and no Rift Valley fever virus exposure were found in either groups. The only risk factor found to be significant was attending dip-tanks in febrilers for Q fever (p = 0.007). Amoxicillin is the local standard treatment for AFI, but would not be effective for Bartonella spp. infections, SFG rickettsiosis, Q fever infections, or the viral infections. There is a need to revise AFI treatment algorithms, educate medical and veterinary staff about these pathogens, especially SFG rickettsiosis and Q fever, support disease surveillance systems, and inform the population about reducing tick and surface water contact.

A framework for evaluating animals as sentinels for infectious disease surveillance.

The dynamics of infectious diseases are highly variable. Host ranges, host responses to pathogens and the relationships between hosts are heterogeneous. Here, we argue that the use of animal sentinels has the potential to use this variation and enable the exploitation of a wide range of pathogen hosts for surveillance purposes. Animal sentinels may be used to address many surveillance questions, but they may currently be underused as a surveillance tool and there is a need for improved interdisciplinary collaboration and communication in order to fully explore the potential of animal sentinels. In different contexts, different animal hosts will themselves vary in their capacity to provide useful information. We describe a conceptual framework within which the characteristics of different host populations and their potential value as sentinels can be evaluated in a broad range of settings.

Could the RTS,S/AS01 meningitis safety signal really be a protective effect of rabies vaccine?

The RTS,S/AS01 malaria vaccine has been associated with meningitis and cerebral malaria safety signals. Key characteristics of the meningitis signal include presence, in the 5-17month but not the 6-12week age group, of delayed and variable meningitis onset after vaccination, and multiple etiologies. For both meningitis and cerebral malaria, the 5-17month old age group control arm had abnormally low incidences while other arms in both age groups had meningitis and cerebral malaria incidences similar to background rates. No single hypothesis postulating an adverse effect from RTS,S/AS01 unites these observations. Unlike the 6-12week group, the control population in the 5-17month old age group received rabies vaccine. This raises the possibility that non-specific rabies vaccine effects had a protective effect against central nervous system infection, a hypothesis consistent with the epidemiologic data. The lack of a confirmed biologic mechanism for such an effect emphasizes the need for additional studies.

Heterogeneous distribution of Dirofilaria immitis in dogs in St. Kitts, West Indies, 2014-2015.

In the Caribbean region, Dirofilaria immitis (heartworm) has been detected on almost all of the islands. While it is assumed to be endemic throughout the region, there is a lack of baseline data from the Leeward Islands (north-east of the Caribbean region). The objective of this study was to estimate the prevalence and the spatial distribution of heartworm disease in dogs on St. Kitts, a small 174km2 island which is part of the Leeward Islands. A cross-sectional study was conducted in 2014 with 100 dogs tested using a commercial antigen test. Dogs were from all regions of the island except the southeastern region, which differs socio-economically from the rest of the island. Heartworm was not detected in these 100 dogs. To complete the survey, in 2015, fifteen dogs from the southeast region were tested, eight of which were positive for heartworm. Prevalence was estimated at 7.0% (95% confidence interval: 4.6-11.6). Data from two other sources were added to complete the report: data from dogs enrolled in a free spay and neuter program and tested against heartworm (164 dogs with 3 positive for heartworm), and the data from positive dogs diagnosed at the Ross University Veterinary Clinic in 2014 and 2015 (3 dogs). Most of the heartworm positive dogs (10/14) lived in a delimited area in the southeast of the island. These results indicate an overall low prevalence of Dirofilaria immitis in St. Kitts, lower than that observed in the other Caribbean islands. Heterogeneity in the spatial distribution of the parasite was observed, with the majority of cases residing in the southeast of the island. Previous spatial models focused on the spread of the parasite over large geographical areas and long distances, but not within a restricted area. Our results indicate the presence of local factors which may have limited spread of the disease over short distances. Further studies are needed to understand this markedly heterogeneous distribution.

Rabies vaccine is associated with decreased all-cause mortality in dogs.

Evidence suggests that rabies vaccine may have non-specific protective effects in animals and children. We analyzed four years of data (2012-2015) from an observational study of the health and demographics of a population of owned, free-roaming dogs in a low-income community in South Africa. The objective of this analysis was to assess the association between rabies vaccine and all-cause mortality in dogs, stratified by age group (0-3months, 4-11months, and 12months and older), and controlling for the effects of sex and number of dogs in the residence. Rabies vaccination reduced the risk of death from any cause by 56% (95% CI=16-77%) in dogs aged 0-3months, by 44% (95% CI=21-60%) in dogs aged 4-11months and by 16% (95% CI=0-29%) in dogs aged 12months and older. We hypothesize that the protective association between rabies vaccination status and all-cause mortality is due to a protective effect of rabies vaccine against diseases other than rabies. Existence of a strong non-specific protective effect of rabies vaccine on mortality in dogs would have implications for the design of dog rabies control programs that aim to eliminate dog-mediated human rabies cases. Further, we propose that owned domestic dogs in high mortality settings provide a useful animal model to better understand any non-specific protective effect of rabies vaccine in children, due to dogs' high numbers, high morbidity and mortality rates, relatively short lifespan, exposure to a variety of infectious and parasitic diseases, and shared environment with people.