Avaliação epidemiológica dos casos de mordedura animal e factores associados a raiva em Moçambique, 2017-2021 / Epidemiological evaluation of animal bite cases, rabies and associated factors in Mozambique, 2017-2021

A mordedura por animal incluindo o cão é a principal forma de transmissão da raiva humana na África subsaariana, inclusive, Moçambique. Nos últimos anos tem-se registado um aumento de ocorrência de mordedura animal. Este estudo objetiva avaliar epidemiologia de mordedura animal e factores associados à raiva em Moçambique no período de 2017 a 2021.Realizou-se um estudo descritivo transversal de abordagem quantitativa. Foram usados dados secundários do sistema de vigilância da raiva em humano e animal. Calculou-se estatística descritiva, regressão logística multivariada, considerando um P ˂0,05 como significativo e um IC95%. O teste de Hosmer-Lemeshow foi usado para avaliar o ajuste do modelo final a um nível de significância de 0,05, através do programa estatístico IBM SPSS, versão 27. Durante o período de estudo, em média, foram registados 87,9 casos de mordedura animal por 100.000 habitantes (IC95%:86,8­89,0) com uma tendência. As províncias de Maputo Cidade 263,3 (IC95%:253,8­272,8), Sofála 222,3 (IC95%:216,3­228,3), Gaza 154,3 casos por 100.000 habitantes (IC95%:147,8­160,7) tiveram incidência acima da média nacional. Dos casos investigados, 42,4% (1831/4321) eram menores de 15 anos, 56,4% (2435/4321) foram masculinos, 77,6% (3454/4321) residiam em área urbana e 91,3% (3943/4321) foram mordidos por cão. Dos cães envolvidos, 85,4% (3368/3943) não estavam vacinados. Entre os casos investigados com critério, 50,0% (1874/3746) não tiveram profilaxia pós-exposição. As pessoas mordidas em Zambézia (ORa=91,3; IC95%:22,06­378,09; P˂0,001); Niassa (ORa=14,2; IC95%:10,13­19,96; P˂0,001) e Cabo Delgado (ORa =13,8; IC95%:8,34­22,69; P˂0,001) tiveram mais chances de não fazer profilaxia pós-exposição do que as pessoas mordidas em Maputo Província. Residir na área rural aumenta 70% vezes mais chance de não fazer profilaxia pós-exposição do que residir na área urbana (ORa=1,80; IC95%:1,50­2,18; P˂0,0001). No período de estudo, foram registados, em média, 187,7 casos de raiva humana por 100.000 pessoas mordidas (IC95%:134,9­240,6). A pessoa mordida em Niassa (ORa=12,1; IC95%:5,8-25,0; P˂0,001), ou Cabo Delgado (ORa=9,5; IC95%:4,0-22,6; P˂0,001), ou Zambézia (ORa=5,3; IC95%:2,6-10,8; P˂0,001) ou Inhambane (ORa=3,7; IC95%:1,5-8,8; P=0,004) tem mais chance para devolver raiva do que a pessoa mordida em Maputo Província. A raiva continua a ser um grave problema de saúde pública em Moçambique. Viver nas províncias de Niassa, Cabo Delgado, Zambézia e Inhambane diminui a chance para fazer a profilaxia pós-exposição em humano e aumenta o risco de desenvolver raiva após uma mordedura animal. Baixa cobertura vacinal dos animais. Recomenda-se melhorar a logística da distribuição das vacinas antirrábicas, priorizando as áreas de maior incidência de mordedura animal e raiva.

Introduction: Animal and dog bites are the main forms of human rabies transmission in sub Saharan Africa, including Mozambique. In recent years there has been an increase in the occurrence of animal bites. This study aims to evaluate the epidemiology of animal bites and factors associated with rabies in Mozambique from 2017 to 2021. Methodology: This was a cross-sectional descriptive study with a quantitative approach. Secondary data from the human and animal rabies surveillance system were used. Descriptive statistics, multivariate logistic regression, considering a P ˂0.05 as significant and a 95% CI were calculated. The Hosmer-Lemeshow test was used to assess the fit of the final model at a significance level of 0.05, using the IBM SPSS statistical program, version 27. Results: During the study period, on average 87.9 animal bite cases per 100,000 inhabitants (95%CI:86.8-89.0) were recorded with a trend. The provinces of Maputo City 263.3 (95%CI:253.8-272.8), Sofala 222.3 (95%CI:216.3-228.3), Gaza 154.3 cases per 100,000 inhabitants (95%CI:147.8-160.7) had incidence above the national average. Of the cases investigated, 42.4% (1831/4321) were under 15 years of age, 56.4% (2435/4321) were male, 77.6% (3454/4321) resided in an urban area and 91.3% (3943/4321) were bitten by a dog. Of the dogs involved, 85.4% (3368/3943) were not vaccinated. Among the cases investigated with criteria, 50.0% (1874/3746) did not have post-exposure prophylaxis. Persons bitten in Zambezia (ORa=91.3; 95%CI:22.06-378.09; P˂0.001); Niassa (ORa=14.2; 95%CI:10.13- 19.96; P˂0.001) and Cabo Delgado (ORa=13.8; 95%CI:8.34-22.69; P˂0.001) were more likely not to take post-exposure prophylaxis than persons bitten in Maputo Province. Living in a rural area increased the odds of not taking post-exposure prophylaxis 70% more than living in an urban area (ORa=1.80; 95%CI:1.50-2.18; P˂0.0001). During the study period, an average of 187.7 human rabies cases per 100,000 people bitten were recorded (95%CI:134.9-240.6). A person bitten in Niassa (ORa=12.1; 95%CI:5.8-25.0; P˂0.001), or Cabo Delgado (ORa=9.5; 95%CI:4.0-22.6; P˂0.001), or Zambezia (ORa=5.3; 95%CI: 2.6-10.8; P˂0.001) or Inhambane (ORa=3.7; 95%CI:1.5-8.8; P=0.004) are more likely to return rabies than the person bitten in Maputo Province. Conclusion: Rabies remains a serious public health problem in Mozambique. Living in the provinces of Niassa, Cabo Delgado, Zambézia and Inhambane decreases the chance to take post-exposure prophylaxis in humans and increases the risk of developing rabies after an animal bite. Low vaccination coverage of animals. It is recommended to improve the logistics of rabies vaccine distribution, prioritizing the areas with the highest incidence of animal bites and rabies.

Caracterización y evolución temporal de la mortalidad por zoonosis bajo declaración obligatoria, entre los años 1997 y 2018 / Characterization and temporal evolution of mortality due to zoonoses under mandatory declaration, between the years 1997 and 2018

INTRODUCCIÓN: Las zoonosis son enfermedades transmitidas desde un hospedador animal al ser humano o viceversa. En Chile, las zoonosis de Notificación Obligatoria (NO) son: brucelosis, carbunco, triquinosis, hidatidosis, leptospirosis, dengue, enfermedad de Chagas, hantavirosis y rabia. OBJETIVO: Evaluar la tendencia y caracterizar la mortalidad por zoonosis de NO en Chile entre 1997-2018. METODOLOGÍA: Estudio ecológico de la mortalidad por zoonosis de NO. Se utilizaron bases de mortalidad y población oficiales. Se describió la mortalidad relativa, general y específica, según variables sociodemográficas. Se calcularon tasas de mortalidad anuales brutas (TMb) y ajustadas (TMa, método directo). Se evaluó la tendencia temporal con modelos de regresión de Prais-Winsten. Resultados: Entre 1997 y 2018 la mortalidad por zoonosis de NO correspondió al 0,12% (2.359 muertes) de la mortalidad total, siendo las principales causas la enfermedad de Chagas (59,8%), hidatidosis (23,9%) y hantavirosis (13,8%). La TMa general disminuyó significativamente (B: -0,017; IC95%: -0,024; -0,009) al igual que hidatidosis (B: -0,011; IC95%: -0,013; -0,008), sólo hantavirosis mostró un aumento (no significativo). CONCLUSIÓN: La mortalidad por zoonosis de NO disminuyó durante el período estudiado; solo la hantavirosis mostró un aumento en su tendencia. Se sugiere enfocar estrategias para prevenir la transmisibilidad y mortalidad por hanta, así como mejorar el acceso a tratamiento para las otras zoonosis.

BACKGROUND: Zoonoses are diseases transmitted from an animal host to humans or vice versa. In Chile, the zoonoses of mandatory notification are brucellosis, anthrax, trichinosis, hydatidosis, leptospirosis, dengue, Chagas disease, hantavirosis and rabies. AIM: To assess the trend and characterize the mortality from zoonoses of mandatory notification in Chile between 1997-2018. METHODS: An official mortality and population data were used. Relative, general and specific mortality rates were described according to sociodemographic variables. Crude and adjusted annual mortality rates (direct method) were calculated. Temporal trend was evaluated with the Prais-Winsten regression model. RESULTS: Between 1997 and 2018, the mortality rate due to zoonosis of mandatory notification corresponded to 0.13% (2152 deaths) of the total mortality, being Chagas disease (59.2%), hydatidosis (24.6%) and hantavirosis (13.5%) the main causes. The general adjusted mortality rate decreased significantly (B: -0.017; IC95%: -0.024; -0.009) as did hydatidosis (B: -0.011; IC95%: -0.013; -0.008), and only hantavirosis showed an increase trend (not significant). CONCLUSION: Mortality due to zoonoses decreased during the period; only hantavirosis showed an increasing trend. It is suggested to focus on strategies to prevent contagion and mortality by hantavirosis, as well as to improve access to treatment for the other zoonoses.

The urgency of resuming disrupted dog rabies vaccination campaigns: a modeling and cost-effectiveness analysis.

Dog vaccination is a cost-effective approach to preventing human rabies deaths. In Haiti, the last nation-wide dog vaccination campaign occurred in 2018. We estimated the number of human lives that could be saved by resuming dog vaccination in 2021 compared to 2022 and compared the cost-effectiveness of these two scenarios. We modified a previously published rabies transmission and economic model to estimate trends in dog and human rabies cases in Haiti from 2005 to 2025, with varying assumptions about when dog vaccinations resume. We compared model outputs to surveillance data on human rabies deaths from 2005 to 2020 and animal rabies cases from 2018 to 2020. Model predictions and surveillance data both suggest a 5- to 8-fold increase in animal rabies cases occurred in Haiti's capital city between Fall 2019 and Fall 2020. Restarting dog vaccination in Haiti in 2021 compared to 2022 could save 285 human lives and prevent 6541 human rabies exposures over a five-year period. It may also decrease program costs due to reduced need for human post-exposure prophylaxis. These results show that interruptions in dog vaccination campaigns before elimination is achieved can lead to significant human rabies epidemics if not promptly resumed.

Trends and spatial distribution of animal bites and vaccination status among victims and the animal population, Uganda: A veterinary surveillance system analysis, 2013-2017.

Rabies is a vaccine-preventable fatal zoonotic disease. Uganda, through the veterinary surveillance system at National Animal Disease Diagnostics and Epidemiology Centre (NADDEC), captures animal bites (a proxy for rabies) on a monthly basis from districts. We established trends of incidence of animal bites and corresponding post-exposure prophylactic anti-rabies vaccination in humans (PEP), associated mortality rates in humans, spatial distribution of animal bites, and pets vaccinated during 2013-2017. We reviewed rabies surveillance data at NADDEC from 2013-2017. The surveillance system captures persons reporting bites by a suspected rabid dog/cat/wild animal, human deaths due to suspected rabies, humans vaccinated against rabies, and pets vaccinated. Number of total pets was obtained from the Uganda Bureau of Statistics. We computed incidence of animal bites and corresponding PEP in humans, and analyzed overall trends, 2013-2017. We also examined human mortality rates and spatial distribution of animal bites/rabies and pets vaccinated against rabies. We identified 8,240 persons reporting animal bites in Uganda during 2013-2017; overall incidence of 25 bites/ 100,000population. The incidence significantly decreased from 9.2/100,000 in 2013 to 1.3/100,000 in 2017 (OR = 0.62, p = 0.0046). Of the 8,240 persons with animal bites, 6,799 (82.5%) received PEP, decreasing from 94% in 2013 to 71% in 2017 (OR = 0.65, p<0.001). Among 1441 victims, who reportedly never received PEP, 156 (11%) died. Western region had a higher incidence of animal bites (37/100,000) compared to other regions. Only 5.6% (124,555/2,240,000) of all pets in Uganda were vaccinated. There was a decline in the reporting rate (percentage of annual district veterinary surveillance reports submitted monthly to Commissioner Animal Health by districts) of animal bites. While reported animal bites by districts decreased in Uganda, so did PEP among humans. Very few pets received anti-rabies vaccine. Evaluation of barriers to complete reporting may facilitate interventions to enhance surveillance quality. We recommended improved vaccination of pets against rabies, and immediate administration of exposed humans with PEP.

How geographic access to care shapes disease burden: The current impact of post-exposure prophylaxis and potential for expanded access to prevent human rabies deaths in Madagascar.

BACKGROUND: Post-exposure prophylaxis (PEP) is highly effective at preventing human rabies deaths, however access to PEP is limited in many rabies endemic countries. The 2018 decision by Gavi to add human rabies vaccine to its investment portfolio should expand PEP availability and reduce rabies deaths. We explore how geographic access to PEP impacts the rabies burden in Madagascar and the potential benefits of improved provisioning. METHODOLOGY & PRINCIPAL FINDINGS: We use spatially resolved data on numbers of bite patients seeking PEP across Madagascar and estimates of travel times to the closest clinic providing PEP (N = 31) in a Bayesian regression framework to estimate how geographic access predicts reported bite incidence. We find that travel times strongly predict reported bite incidence across the country. Using resulting estimates in an adapted decision tree, we extrapolate rabies deaths and reporting and find that geographic access to PEP shapes burden sub-nationally. We estimate 960 human rabies deaths annually (95% Prediction Intervals (PI): 790-1120), with PEP averting an additional 800 deaths (95% PI: 640-970) each year. Under these assumptions, we find that expanding PEP to one clinic per district (83 additional clinics) could reduce deaths by 19%, but even with all major primary clinics provisioning PEP (1733 additional clinics), we still expect substantial rabies mortality. Our quantitative estimates are most sensitive to assumptions of underlying rabies exposure incidence, but qualitative patterns of the impacts of travel times and expanded PEP access are robust. CONCLUSIONS & SIGNIFICANCE: PEP is effective at preventing rabies deaths, and in the absence of strong surveillance, targeting underserved populations may be the most equitable way to provision PEP. Given the potential for countries to use Gavi funding to expand access to PEP in the coming years, this framework could be used as a first step to guide expansion and improve targeting of interventions in similar endemic settings where PEP access is geographically restricted and baseline data on rabies risk is lacking. While better PEP access should save many lives, improved outreach, surveillance, and dog vaccination will be necessary, and if rolled out with Gavi investment, could catalyze progress towards achieving zero rabies deaths.

Causes of death in beef cattle in southern Brazil.

We determined the prevalence of diseases and pathogens associated with mortality in beef cattle in the State of Rio Grande do Sul, Brazil, based on pathology laboratory submissions. Postmortem examinations were conducted on 1,277 beef cattle that died between 2008 and 2018. Information regarding age, time of the year, breed, and regional location were analyzed statistically. Most cattle were from the surrounding region of Porto Alegre, and 78.7% of the analyzed cases had diagnostic value. The diagnostic category with most cases was infectious and/or parasitic diseases (60%), followed by toxic and toxicoinfectious (25%). Most cases occurred in the fall. Major disease conditions identified included hemoprotozoal infection (18.2%), rabies (8.2%), and plant intoxications by Senecio spp. (8.5%) and Pteridium arachnoideum (4.6%). Hemoprotozoal infection occurred at a higher frequency in young cattle, mainly in animals up to 1 y old. Intoxication by Senecio spp. was more frequent in cattle 2-3 y old.

An assessment of risk factors for contracting rabies among dog bite cases recorded in Ward 30, Murewa district, Zimbabwe.

BACKGROUND: Zoonoses are a major threat to human health. Worldwide, rabies is responsible for approximately 59 000 deaths annually. In Zimbabwe, rabies is one of the top 5 priority diseases and it is notifiable. It is estimated that rabies causes 410 human deaths per year in the country. Murewa district recorded 938 dog bite cases and 4suspected rabies deaths between January 2017 and July 2018, overshooting the threshold of zero rabies cases. Of the 938dog bite cases reported in the district, 263 were reported in Ward 30 and these included all the 4suspected rabies deaths reported in the district. This necessitated a study to assess risk factors for contracting rabies in Ward 30, Murewa. METHODOLOGY/ PRINCIPAL FINDINGS: A descriptive cross sectional survey was used for a retrospective analysis of a group of dog bite cases reported at Murewa Hospital, in Ward 30. Purposive sampling was used to select dog bite cases and snowball sampling was used to locate unvaccinated dogs and areas with jackal presence. The dog bite cases and relatives of rabies cases were interviewed using a piloted interviewer-administered questionnaire. Geographical Positioning System (GPS) coordinates of dog bite cases, vaccinated and unvaccinated dogs and jackal presence were collected using handheld GPS device. QGIS software was used to spatially analyse and map them. Dog owners were 10 times more likely to contract rabies compared to non-dog owners (RR = 10, 95% CI 1.06-93.7). Owners of unvaccinated dogs were 5 times more likely to contract rabies compared to owners of vaccinated dogs (RR = 5.01, 95% CI 0.53-47.31). Residents of the high density cluster (area with low cost houses and stand size of 300 square meters and below) were 64 times more likely to contract rabies compared to non-high density cluster residents (RR = 64.87, 95% CI 3.6039-1167.82). Participants who were not knowledgeable were 0.07 times more likely to contract rabies, compared to those who had knowledge about rabies. (RR = 0.07, 95% CI 0.004-1.25). Our study shows that the risk factors for contacting rabies included; low knowledge levels regarding rabies, dog ownership residing in the high density cluster, owning unvaccinated dogs and spatial overlap of jackal presence with unvaccinated dogs.

Awareness and knowledge of canine rabies: A state-wide cross-sectional study in Nigeria.

Rabies is a highly fatal disease that is endemic in Nigeria. The poor community awareness and knowledge of canine rabies have thwarted the realization of zero deaths from dog mediated human rabies. This study aimed to assess the awareness and knowledge of canine rabies in Kwara state. A total of 1,460 questionnaires were administered to respondents in the three senatorial zones of the state using open data kit (ODK) on mobile phones between September 2019 to January 2020. The rabies awareness rate was 38.1%. The mean knowledge score was 3.78 ± 2.15. Only 10.6% (n = 59/557) of the respondents had satisfactory knowledge of canine rabies. Respondents had poor knowledge of the mode of transmission, symptoms, prevention, and the control measures needed to eliminate canine rabies. Only 20.1% of respondents owned at least a dog. Dog owners were 3.85× (95% CI: 2.89, 5.13; p < 0.01) more likely to be aware of canine rabies and were 1.78× (95% CI: 1.22-2.60; p = 0.003) more likely to have satisfactory knowledge about canine rabies than non-dog owners. Respondents with tertiary education were at least 6.81× (95% CI: 4.24, 10.92; p < 0.01) more likely to be aware of rabies than respondents with no formal education. The findings of this study showed very low awareness and knowledge of canine rabies among residents of Kwara state. Mass sensitization of the populace on the dangers of rabies should be intensified. Such interventions should be targeted at the general public and dog owners.

Regional and age difference of human rabies prevalence of the past fourteen years in China.

OBJECTIVE: The aim of this study is to describe the epidemiological characteristics about regional and age difference of human rabies in the past fourteen years in China, and provide a reliable epidemiology basis for further control and prevention of human rabies. METHODS: The database of "China Public Health Science Data Center" affiliated Chinese CDC was searched with the key words of "rabies" or "epidemiology" or "morbidity" or "mortality" from 2004 to 2018 and the corresponding data about human rabies cases was collected referred to regional and age difference for describing the epidemiological characteristics of human rabies. RESULTS: In this study, a total of nearly 26,315 rabies cases (1754 ± 253) and 25,691 rabies-related deaths (1712 ± 255) (Mean ± SE) were reported, and a decreasing trend about the morbidity and mortality of human rabies existed from 0.2039 and 0.2039 (1/100,000) in 2004 to 0.0304 and 0.0295 in 2018. Otherwise, regional difference of human rabies prevalence significantly existed, and juvenile and middle-aged population especially in 50-60 years old were more easily attacked and infected with rabies (all p < 0.05). CONCLUSION: This study proved that human rabies still is a major public health problem in China though a decreasing trend about the morbidity and mortality of human rabies existed in the past fourteen years.

Improving dog bite victim survey and estimation of annual human deaths due to suspected rabies cases in three selected Liberian cities and environs, 2008-2017.

Rabies remains a public health challenge of unknown magnitude in Liberia in spite of the goal of ensuring that no human in the country dies of rabies by 2030. The annual prevalence of Dog Bite Victims (DBVs) and true load of Annual Human Deaths (AHDs) due to rabies were not known. We investigated three selected cities of Liberia for annual prevalence of DBVs and true load of AHD due to suspected rabies, using 10-year retrospective record, 2008-2017 obtained from Buchanan, Gbarnga, and Voinjama, three socio-economically important cities in post-conflict Liberia. Data were sourced at County Reference Hospitals and at the Liberia National Institute of Health for these cities and their local environs. In addition, household questionnaire survey was used to identify and audit data quality for unreported DBVs, and treatment received from traditional caregivers. The proportion was used to audit the 10-year data on unreported DBVs in the cities. Descriptive statistics was used to summarize annual DBVs over the 10-year period in the three cities, respectively. A standardized clinical decision tree model was used to estimate AHDs due to suspected rabies. Based on questionnaire survey, 140/365, 148/375 and 146/350 DBVs did not visit any orthodox health facility in Buchanan, Gbarnga and Voinjama cities, respectively in 2014. An estimated total of 559 DBVs died of suspected rabies in the three cities and their environs during the 10-year period. Mean yearly prevalence of DBVs was 179±106.82, 393±257.85 and 76.9±38.11 per 100,000 population, while mean AHDs due to suspected rabies was 14.3±8.47, 35.5±23.25, and 6.1±3.21 per 100,000 population in Buchanan, Gbarnga, and Voinjama cities, respectively. The present findings provide annual prevalence of suspected rabies cases, corrected for under-reporting in three selected cities of Liberia. The findings would be useful in planning for stepwise actions towards rabies elimination, ensuring that no human dies of rabies in Liberia by 2030.

Inflammatory response and MAPK and NF-κB pathway activation induced by natural street rabies virus infection in the brain tissues of dogs and humans.

BACKGROUND: Street rabies virus (RABV) usually infects hosts at peripheral sites and migrates from motor or sensory nerves to the central nervous system. Several studies have found that inflammation is mild in a mouse model of street RABV infection. However, the pathogenetic mechanisms of street RABV in naturally infected dogs or humans are not well understood. METHODS: Brain tissues collected from 3 dogs and 3 humans were used; these tissue samples were collected under the natural condition of rabies-induced death. The inflammatory response and pathway activation in the brain tissue samples of dogs and humans were evaluated by HE, IHC, ARY006, WB and ELISA. The clinical isolate street RABV strains CGS-17 and CXZ-15 from 30 six-week-old ICR mice were used to construct the mouse infection model presented here. RESULTS: Neuronal degeneration and increased lymphocyte infiltration in the cerebral cortex, especially marked activation of microglia, formation of glial nodules, and neuronophagy, were observed in the dogs and humans infected with the street RABV strains. The various levels of proinflammatory chemokines, particularly CXCL1, CXCL12, CCL2, and CCL5, were increased significantly in the context of infection with street RABV strains in dogs and humans in relation to healthy controls, and the levels of MAPK and NF-κB phosphorylation were also increased in dogs and humans with natural infection. We also found that the degrees of pathological change, inflammatory response, MAPK and NF-κB signaling pathway activation were obviously increased during natural infection in dogs and humans compared with artificial model infection in mice. CONCLUSION: The data obtained here provide direct evidence for the RABV-induced activation of the inflammatory response in a dog infection model, which is a relatively accurate reflection of the pathogenic mechanism of human street RABV infection. These observations provide insight into the precise roles of underlying mechanisms in fatal natural RABV infection.

Knowledge, attitude and practice (KAP) survey of canine rabies in Khyber Pakhtunkhwa and Punjab Province of Pakistan.

BACKGROUND: This study aimed to assess the extent of knowledge and understanding of rabies disease in rural and urban communities of Pakistan. It also identified malpractices after suspected dog bite that might pose a risk for humans contracting rabies. METHODS: A cross-sectional study was conducted (n = 1466) on people having different age groups and educational levels in four different geographic regions of Punjab and Khyber Pakhtunkhwa provinces in Pakistan. Knowledge, attitude, and practices of people were assessed using a structured questionnaire. We used a bivariate and multivariate analysis to study the association between rabies related mortalities in near or extended family members and different risk behaviors. RESULTS: Our results demonstrate that the majority of the juvenile population (less than 18 years of age) were not aware of the clinical signs of rabies in animals. 75% of the total respondents were not vaccinated against rabies, 60% did not seek a doctor's advice after a suspected animal bite, and 55% had inadequate health care facilities for rabies patients in local hospitals. Respondents that had pets at home had not vaccinated (38%; p < 0.05; odds ratio 1.58) themselves against rabies due to lack of knowledge and awareness of pre-exposure prophylaxis for rabies (51%; p < 0.05; odds ratio 1.25). They also tend to not visit doctor after suspected bite (52%; p < 0.05; odds ratio 1.97), which may had resulted in more deaths (65%; p < 0.05; odds ratio 1.73) of someone in their near or extended family due to rabies. CONCLUSIONS: Lack of knowledge about the nature of rabies disease and prophylaxis has contributed to increase of rabies related deaths. Inadequate health care facilities and poor attitude of not seeking medical attention after suspected dog bite are the major reasons of rabies related deaths. These findings could help in devising a targeted management strategy and awareness program to control and reduce the incidence of human rabies related deaths in Pakistan.

Interferon-Inducible GTPase 1 Impedes the Dimerization of Rabies Virus Phosphoprotein and Restricts Viral Replication.

Rabies, caused by rabies virus (RABV), is an ancient zoonosis and still a major public health problem for humans, especially in developing countries. RABV can be recognized by specific innate recognition receptors, resulting in the production of hundreds of interferon-stimulated genes (ISGs), which can inhibit viral replication at different stages. Interferon-inducible GTPase 1 (IIGP1) is a mouse-specific ISG and belongs to the immunity-related GTPases (IRGs) family. IIGP is reported to constrain intracellular parasite infection by disrupting the parasitophorous vacuole membrane. However, the role of IIGP1 in restricting viral replication has not been reported. In this present study, we found that IIGP1 was upregulated in cells and mouse brains upon RABV infection. Overexpression of IIGP1 limited RABV replication in cell lines and reduced viral pathogenicity in a mouse model. Consistently, deficiency of IIGP1 enhanced RABV replication in different parts of mouse brains. Furthermore, we found that IIGP1 could interact with RABV phosphoprotein (P protein). Mutation and immunoprecipitation analyses revealed that the Y128 site of P protein is critical for its interaction with IIGP1. Further study demonstrated that this interaction impeded the dimerization of P protein and thus suppressed RABV replication. Collectively, our findings for the first reveal a novel role of IIGP1 in restricting a typical neurotropic virus, RABV, which will provide fresh insight into the function of this mouse-specific ISG.IMPORTANCE Interferon and its downstream products, ISGs, are essential in defending against pathogen invasion. One of the ISGs, IIGP1, has been found to constrain intracellular parasite infection by disrupting their vacuole membranes. However, the role of IIGP1 in limiting viral infection is unclear. In this study, we show that infection with a typical neurotropic virus, RABV, can induce upregulation of IIGP1, which, in turn, suppresses RABV by interacting with its phosphoprotein (P protein) and thus blocking the dimerization of P protein. Our study provides the first evidence that IIGP1 functions in limiting viral infection and provides a basis for comprehensive understanding of this important ISG.

Intracerebral transfection of anti-rabies virus antibodies is an effective therapy for rabies.

Rabies is a neurological disease with 100% lethality. Some of the rare human patients who survived after multiple drug treatment had severe sequelae. The present study showed that after 48 h of RABV inoculation, mice injected intracerebrally with anti-RABV F (ab')2 plus Bioporter® showed 70% survival compared to the control group, suggesting that transfection of anti-RABV antibodies to the brain may prevent or delay the spread of RABV at an early stage of infection. This result may provide important protocol results in intracellular antibody delivery to prevent the fatal outcome of the disease.

RABIES IMMUNOGLOBULIN: Brief history and recent experiences in Côte d'Ivoire.

BACKGROUND: Rabies is a fatal viral zoonosis mainly transmitted via dog bites. The estimated 59'000 annual deaths caused by the disease are preventable through correct and timely administration of post-exposure prophylaxis (PEP). PEP should be initiated as soon as possible after an exposure to a rabies suspected animal and consists of a course of active vaccinations and administration of rabies immunoglobulin (RIG) in case of severe exposure. However, RIG is not accessible in most rabies endemic countries and its impact on survival in combination with modern vaccines and its cost-effectiveness is unclear. We examined the effect of equine RIG (eRIG) in a field-trial in Côte d'Ivoire, a developing country with low but chronic rabies burden and persistent lack of RIG, similar to a majority of rabies endemic countries attempting elimination of the disease. METHODS: Data from 3367 patients attending anti-rabies centers (Centres Anti-Rabiques, CARs) of the National Institute for Public Hygiene (Institut National d'Hygiène Publique, INHP) in the departments of Bouaké and San Pédro in Côte d'Ivoire was prospectively collected between April 2016 and March 2018. We identified 1594 patients at risk of rabies infection as eligible for RIG administration. Depending on local availability of eRIG and vaccination protocol applied, PEP consisted of active immunization only (non-eRIG group, n = 1145) or active and passive immunization (eRIG group, n = 449). Patients were followed-up by phone interviews at least 15 months after their exposure to assess for rabies suspected deaths. RESULTS: Follow-up data was available for 641 patients in the non-eRIG group (56%) and 242 in the eRIG group (54%). Three suspected or possible rabies deaths occurred in each of the two groups, corresponding to a possible rabies mortality of 1.2% (95% CI 0.3-3.6%) in the eRIG group and 0.5% (95% CI 0.1-1.4%) in the non-eRIG group. The difference in proportions was small and not statistically significant (0.7%, p = 0.21). Deaths in both groups were associated with treatment delay after exposure and non-compliance to PEP protocol. No death occurred after correct and timely active immunization independent of eRIG administration. CONCLUSION: The provision of eRIG did not lead to a measurable reduction of rabies burden in our study population. This underlines that improved access to active vaccines will be effective in reducing rabies deaths even if access to eRIG remains difficult in developing countries. A possible benefit of eRIG administration for severely exposed patients cannot be excluded based on these results.

Health economic assessment of a rabies pre-exposure prophylaxis program compared with post-exposure prophylaxis alone in high-risk age groups in the Philippines.

OBJECTIVES: Once symptoms appear, rabies is almost always fatal and accounts for 200-300 deaths annually in the Philippines. Available rabies vaccines can be administered either in pre- exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). After exposure, PrEP-immunized individuals require fewer doses of PEP and no rabies immunoglobulin. METHODS: A static decision-tree model was developed to assess cost-effectiveness of a PrEP+PEP program vs PEP alone. Philippines-specific data for people seeking medical advice at the Research Institute for Tropical Medicine between July 2015 and June 2016 were used in the model, together with data from published literature. RESULTS: Over a 20-year period, in a cohort of 1 million 5-year-old children in the Philippines, PrEP+PEP was expected to prevent 297 deaths compared with PEP alone. From both payer and societal perspectives, the resulting incremental cost-effectiveness ratios were 36 035 (US$759; 2016 US$ conversion) and 18 663 (US$393) Philippine Pesos (PHP) - quality-adjusted life-years gained - respectively, which are both below the willingness-to-pay threshold of PHP140 255 (US$2 953). CONCLUSION: These data suggest that a universal PrEP program targeting 5-year-olds would be cost-effective in the Philippines.

Artesunate enhances the immune response of rabies vaccine as an adjuvant.

Rabies is an ancient zoonosis that continues to be an important health problem worldwide. Vaccination with rabies vaccine is the most important strategy to prevent rabies. Adjuvants contribute to the immune response of viral vaccine. The aim of this study was to investigate whether artemisinin derivatives artesunate and dihydroartemisinin could enhance the immunogenicity of inactivated rabies virus in mice. Administration of artesunate or dihydroartemisinin by intramuscular injection at a dose of 5 mg/kg did not cause body weight loss and unusual symptoms in mice. Mice were immunized with inactivated CVS-11 or inactivated rHEP-dG together with either artesunate or dihydroartemisinin through intramuscular injection. Blood samples were collected to investigate the virus-neutralizing antibody (VNA) titers, and challenge assays were then conducted. The results showed that the rabies VNA titers in mice co-treated with artesunate rather than dihydroartemisinin were significantly higher than in the control animals treated with the phosphate buffered saline (PBS). In addition, mice co-treated with artesunate survived from lethal rabies virus challenge compared with those treated with PBS. In contrast, co-treatment with dihydroartemisinin did not improve the survival rate of the challenged mice. The findings indicate that artesunate could be used as a new candidate adjuvant for rabies vaccination.

Wound-only injection of rabies immunoglobulin (RIG) saves lives and costs less than a dollar per patient by "pooling strategy".

Since 2008, we in Himachal Pradesh have used a "pooling strategy" to help patients save money by pooling vials of antirabies vaccine at a centralized hospital and sharing them using the intradermal technique. In 2014, there was an acute shortage of rabies immunoglobulins (RIG) and two patients died after four injections of rabies vaccine were administered without RIG, which was not commercially available. After an extensive literature review and technical and ethical committee clearances, in June 2014 we started to infiltrate equine RIG (eRIG) into wound/s only without the recommended systemic intramuscular (IM) injection. WHO recommended this technique in 2018. During the four-year period June 2014 to June 2018, 7506 of 10,830 patients exposed to suspected rabid animals were injected with eRIG in and around the wounds in a single clinic at DDU Hospital Shimla without any adverse outcomes. The average volume of eRIG used per patient was 0.75 mL and cost US$ 0.75. Of the 80% of patients who were followed up, all were healthy at the end of a year, including 26 patients bitten by laboratory-confirmed rabid dogs. The reaction rate after PEP administration also declined significantly. Since February 2018, Himachal has started following the new WHO recommendations on PEP regimens of three intradermal antirabies vaccines instead of four, thereby saving hundreds of vaccine vials that became useful during shortages of rabies vaccine in India. To date, more than 700 vaccine vials have been saved in a single clinic at DDU hospital during the past 6 months alone. Not giving PEP to patients who have consumed raw milk from a suspected rabid cow has also saved 62 vials. Currently, 90 "pooling centers" have been established for sharing of vaccine and eRIG vials in Himachal State, generating huge savings that have enabled the government to provide PEP free of charge to all. The new WHO guidelines are a positive step towards a rabies-free world by 2030.

A chimpanzee adenoviral vector-based rabies vaccine protects beagle dogs from lethal rabies virus challenge.

Rabies continues to poses serious threats to the public health in many countries. The development of novel inexpensive, safe and effective vaccines has become a high priority for rabies control worldwide. We previously generated a novel recombinant rabies vaccine by cloning rabies virus glycoprotein into a chimpanzee adenoviral vector, termed ChAd68-Gp. The present study evaluated the immune responses and protection afforded by this vaccine in beagle dogs. The results demonstrated that intramuscular immunization with both low-dose and high-dose of ChAd68-Gp induced strong immune responses and provided complete protection in beagles even at low-dose. However, when administered orally, high-dose vaccination was protective while low-dose vaccination was ineffective. Further investigation indicated that the low-pH value of gastric juice in the stomach of beagles might decompose the adenovirus. Therefore, suitable formulation for adenovirus-based oral vaccine should be considered and developed. The chimpanzee adenovirus-vectored rabies vaccine ChAd68-Gp warrants extensive test for clinical application.