Estimating the Global Burden of Endemic Canine Rabies

BackgroundRabies is a notoriously underreported and neglected disease of low-income countries. This study aims to estimate the public health and economic burden of rabies circulating in domestic dog populations, globally and on a country-by-country basis, allowing an objective assessment of how much this preventable disease costs endemic countries.Conclusions/SignificanceThis study demonstrates that investment in dog vaccination, the single most effective way of reducing the disease burden, has been inadequate and that the availability and affordability of PEP needs improving. Collaborative investments by medical and veterinary sectors could dramatically reduce the current large, and unnecessary, burden of rabies on affected communities. Improved surveillance is needed to reduce uncertainty in burden estimates and to monitor the impacts of control efforts.     

Using Serology to Assist with Complicated Post-Exposure Prophylaxis for Rabies and Australian Bat Lyssavirus

Background

Australia uses a protocol combining human rabies immunoglobulin (HRIG) and rabies vaccine for post-exposure prophylaxis (PEP) of rabies and Australian bat lyssavirus (ABLV), with the aim of achieving an antibody titre of ≥0.5 IU/ml, as per World Health Organization (WHO) guidelines, as soon as possible.

Methodology/Principal Findings

We present the course of PEP administration and serological testing for four men with complex requirements. Following dog bites in Thailand, two men (62 years old, 25 years old) received no HRIG and had delayed vaccine courses: 23 days between dose two and three, and 18 days between dose one and two, respectively. Both seroconverted following dose four. Another 62-year-old male, who was HIV-positive (normal CD4 count), also suffered a dog bite and had delayed care receiving IM rabies vaccine on days six and nine in Thailand. Back in Australia, he received three single and one double dose IM vaccines followed by another double dose of vaccine, delivered intradermally and subcutaneously, before seroconverting. A 23-year-old male with a history of allergies received simultaneous HRIG and vaccine following potential ABLV exposure, and developed rash, facial oedema and throat tingling, which was treated with a parenteral antihistamine and tapering dose of steroids. Serology showed he seroconverted following dose four.

Conclusions/Significance

These cases show that PEP can be complicated by exposures in tourist settings where reliable prophylaxis may not be available, where treatment is delayed or deviates from World Health Organization recommendations. Due to the potentially short incubation time of rabies/ABLV, timely prophylaxis after a potential exposure is needed to ensure a prompt and adequate immune response, particularly in patients who are immune-suppressed or who have not received HRIG. Serology should be used to confirm an adequate response to PEP when treatment is delayed or where a concurrent immunosuppressing medical condition or therapy exists.     

Evaluation of Hepatitis A Vaccine in Post-Exposure Prophylaxis,The Netherlands, 2004-2012

Background

The secondary attack rate of hepatitis A virus (HAV) among contacts of cases is up to 50%. Historically, contacts were offered immunoglobulin (IG, a human derived blood product) as post-exposure prophylaxis (PEP). Amid safety concerns about IG, HAV vaccine is increasingly recommended instead. Public health authorities’ recommendations differ, particularly for healthy contacts ≥40 years old, where vaccine efficacy data is limited. We evaluated routine use of HAV vaccine as an alternative to immunoglobulin in PEP, in those considered at low risk of severe infection in the Netherlands.

Methods

Household contacts of acute HAV cases notified in Amsterdam (2004-2012) were invited ≤14 days post-exposure, for baseline anti-HAV testing and PEP according to national guidelines: immunoglobulin if at risk of severe infection, or hepatitis A vaccine if healthy and at low risk (aged <30, or, 30-50 years and vaccinated <8 days post-exposure). Incidence of laboratory confirmed secondary infection in susceptible contacts was assessed 4-8 weeks post-exposure. In a vaccinated subgroup, relative risk (RR) of secondary infection with estimated using Poisson regression.

Results

Of 547 contacts identified, 191 were susceptible to HAV. Per-protocol, 167 (87%) were vaccinated (mean:6.7 days post-exposure, standard deviation(sd)=3.3) and 24 (13%) were given immunoglobulin (mean:9.7 days post-exposure, sd=2.8). At follow-up testing, 8/112 (7%) had a laboratory confirmed infection of whom 7 were symptomatic. All secondary infections occurred in vaccinated contacts, and half were >40 years of age. In healthy contacts vaccinated per-protocol ≤8 days post-exposure, RR_{ref. ≤15 years} of secondary infection in those >40 years was 12.0 (95%CI:1.3-106.7).

Conclusions

Timely administration of HAV vaccine in PEP was feasible and the secondary attack rate was low in those <40 years. Internationally, upper age-limits for post-exposure vaccination vary. Pending larger studies, immunoglobulin should be considered PEP of choice in people >40 years of age and those vulnerable to severe disease.     

Assessing clinicians’ Post-Exposure Prophylaxis recommendations for rabies virus exposures in Hunan Province,China

BackgroundTimely and appropriate administration of post-exposure prophylaxis (PEP) is an essential component of human rabies prevention programs. We evaluated patient care at rabies clinics in a high-risk county in Hunan Province, China to inform strategies needed to achieve dog-mediated human rabies elimination by 2030.MethodsWe collected information on PEP, staff capacity, and service availability at the 17 rabies clinics in the high-risk county during onsite visits and key staff interviews. Additionally, we conducted observational assessments at five of these clinics, identified through purposive sampling to capture real-time information on patient care during a four-week period. Wound categories assigned by trained observers were considered accurate per national guidelines for comparison purposes. We used the kappa statistic and an alpha level of 0.05 to assess agreement between observers and clinic staff.ResultsIn 2015, the 17 clinics provided PEP to 5,261 patients. Although rabies vaccines were available at all 17 clinics, rabies immune globulin (RIG) was only available at the single urban clinic in the county. During the assessment period in 2016, 196 patients sought care for possible rabies virus exposures. According to observers, 88 (44%) patients had category III wounds, 104 (53%) had category II wounds and 4 (2%) had category I wounds. Observers and PEP clinic staff agreed on approximately half of the assigned wound categories (kappa = 0.55, p-value< 0.001). Agreement for the urban county-level CDC clinic (kappa = 0.93, p-value<0.001) was higher than for the township clinics (kappa = 0.16, p-value = 0.007). Using observer assigned wound categories, 142 (73%) patients received rabies vaccinations and RIG as outlined in the national guidelines.ConclusionRabies PEP services were available at each town of the project county; however, gaps between clinical practice and national rabies guidelines on the use of PEP were identified. We used these findings to develop and implement a training to rabies clinic staff on wound categorization, wound care, and appropriate use of PEP. Additional risk-based approaches for evaluating human rabies virus exposures may be needed as China progresses towards elimination.     

Mitochondrial Dysfunction in Rabies Virus-Infected Human and Canine Brains

Neurochemical Research - Rabies is a fatal encephalitis caused by the Rabies lyssavirus (RABV). The presence of minimal neuropathological changes observed in rabies indicates that neuronal...     

Trends in Animal Rabies Surveillance in the Endemic State of Minas Gerais,Brazil

Rabies is a viral zoonosis affecting mammal species and causes large economic losses. Included among the neglected diseases, it is still insufficiently addressed by governments and the international community, despite formal surveillance and control programs. This study used a dataset of 10,112 rabies diagnoses in animals provided by the Brazilian passive surveillance system from 2001 to 2012. The positivity rate of the tested samples was 26.4%, and a reduction in the total samples sent during the last six years was observed. The kernel density map indicated case concentration in the south region and a decrease in density of rabies cases in the second period studied (2007 to 2012). The directional trend of positive rabies diagnoses remained in the south region, as shown by the standard deviational ellipse. The spatial scan statistic identified three large clusters of positive diagnoses, one in the first period (2001-2006) and two in the second period (2007-2012), indicating an expansion of risk areas. The decrease in rabies cases from 2006 to 2012 does not necessarily reflect lower viral circulation or improvement in actions by epidemiological surveillance; this decrease could indicate a deficiency in epidemiological surveillance during the observation period due to the increase in the silent areas. Surveillance should maintain an increasing or constant number of tests during the years in addition to a reduction in the number of outbreaks of rabies, which would indicate a lower positivity rate. The findings in this study indicate deterioration in the effectiveness of the passive surveillance for rabies. The number of rabies cases, total number of tests performed and positivity rate are good indicators for evaluating passive surveillance. This paper can function as a guide for the assessment and improvement of the actions in passive surveillance of rabies.     

Development of a Mouse Monoclonal Antibody Cocktail for Post-exposure Rabies Prophylaxis in Humans

As the demand for rabies post-exposure prophylaxis (PEP) treatments has increased exponentially in recent years, the limited supply of human and equine rabies immunoglobulin (HRIG and ERIG) has failed to provide the required passive immune component in PEP in countries where canine rabies is endemic. Replacement of HRIG and ERIG with a potentially cheaper and efficacious alternative biological for treatment of rabies in humans, therefore, remains a high priority. In this study, we set out to assess a mouse monoclonal antibody (MoMAb) cocktail with the ultimate goal to develop a product at the lowest possible cost that can be used in developing countries as a replacement for RIG in PEP. Five MoMAbs, E559.9.14, 1112-1, 62-71-3, M727-5-1, and M777-16-3, were selected from available panels based on stringent criteria, such as biological activity, neutralizing potency, binding specificity, spectrum of neutralization of lyssaviruses, and history of each hybridoma. Four of these MoMAbs recognize epitopes in antigenic site II and one recognizes an epitope in antigenic site III on the rabies virus (RABV) glycoprotein, as determined by nucleotide sequence analysis of the glycoprotein gene of unique MoMAb neutralization-escape mutants. The MoMAbs were produced under Good Laboratory Practice (GLP) conditions. Unique combinations (cocktails) were prepared, using different concentrations of the MoMAbs that were capable of targeting non-overlapping epitopes of antigenic sites II and III. Blind in vitro efficacy studies showed the MoMab cocktails neutralized a broad spectrum of lyssaviruses except for lyssaviruses belonging to phylogroups II and III. In vivo, MoMAb cocktails resulted in protection as a component of PEP that was comparable to HRIG. In conclusion, all three novel combinations of MoMAbs were shown to have equal efficacy to HRIG and therefore could be considered a potentially less expensive alternative biological agent for use in PEP and prevention of rabies in humans.     

Transmission Dynamics and Prospects for the Elimination of Canine Rabies

Rabies has been eliminated from domestic dog populations in Western Europe and North America, but continues to kill many thousands of people throughout Africa and Asia every year. A quantitative understanding of transmission dynamics in domestic dog populations provides critical information to assess whether global elimination of canine rabies is possible. We report extensive observations of individual rabid animals in Tanzania and generate a uniquely detailed analysis of transmission biology, which explains important epidemiological features, including the level of variation in epidemic trajectories. We found that the basic reproductive number for rabies, R₀, is very low in our study area in rural Africa (~1.2) and throughout its historic global range (<2). This finding provides strong support for the feasibility of controlling endemic canine rabies by vaccination, even near wildlife areas with large wild carnivore populations. However, we show that rapid turnover of domestic dog populations has been a major obstacle to successful control in developing countries, thus regular pulse vaccinations will be required to maintain population-level immunity between campaigns. Nonetheless our analyses suggest that with sustained, international commitment, global elimination of rabies from domestic dog populations, the most dangerous vector to humans, is a realistic goal.     

Establishment of a Canine Rabies Burden in Haiti through the Implementation of a Novel Surveillance Program

The Republic of Haiti is one of only several countries in the Western Hemisphere in which canine rabies is still endemic. Estimation methods have predicted that 130 human deaths occur per year, yet existing surveillance mechanisms have detected few of these rabies cases. Likewise, canine rabies surveillance capacity has had only limited capacity, detecting only two rabid dogs per year, on average. In 2013, Haiti initiated a community-based animal rabies surveillance program comprised of two components: active community bite investigation and passive animal rabies investigation. From January 2013 –December 2014, 778 rabies suspect animals were reported for investigation. Rabies was laboratory-confirmed in 70 animals (9%) and an additional 36 cases were identified based on clinical diagnosis (5%), representing an 18-fold increase in reporting of rabid animals compared to the three years before the program was implemented. Dogs were the most frequent rabid animal (90%). Testing and observation ruled out rabies in 61% of animals investigated. A total of 639 bite victims were reported to the program and an additional 364 bite victims who had not sought medical care were identified during the course of investigations. Only 31% of people with likely rabies exposures had initiated rabies post-exposure prophylaxis prior to the investigation. Rabies is a neglected disease in-part due to a lack of surveillance and understanding about the burden. The surveillance methods employed by this program established a much higher burden of canine rabies in Haiti than previously recognized. The active, community-based bite investigations identified numerous additional rabies exposures and bite victims were referred for appropriate medical care, averting potential human rabies deaths. The use of community-based rabies surveillance programs such as HARSP should be considered in canine rabies endemic countries.     

Transmission of Novel Influenza A(H1N1) in Households with Post-Exposure Antiviral Prophylaxis

Background

Despite impressive advances in our understanding of the biology of novel influenza A(H1N1) virus, little is as yet known about its transmission efficiency in close contact places such as households, schools, and workplaces. These are widely believed to be key in supporting propagating spread, and it is therefore of importance to assess the transmission levels of the virus in such settings.

Methodology/Principal Findings

We estimate the transmissibility of novel influenza A(H1N1) in 47 households in the Netherlands using stochastic epidemic models. All households contained a laboratory confirmed index case, and antiviral drugs (oseltamivir) were given to both the index case and other households members within 24 hours after detection of the index case. Among the 109 household contacts there were 9 secondary infections in 7 households. The overall estimated secondary attack rate is low (0.075, 95%CI: 0.037–0.13). There is statistical evidence indicating that older persons are less susceptible to infection than younger persons (relative susceptibility of older persons: 0.11, 95%CI: 0.024–0.43. Notably, the secondary attack rate from an older to a younger person is 0.35 (95%CI: 0.14–0.61) when using an age classification of ≤12 versus >12 years, and 0.28 (95%CI: 0.12–0.50) when using an age classification of ≤18 versus >18 years.

Conclusions/Significance

Our results indicate that the overall household transmission levels of novel influenza A(H1N1) in antiviral-treated households were low in the early stage of the epidemic. The relatively high rate of adult-to-child transmission indicates that control measures focused on this transmission route will be most effective in minimizing the total number of infections.     

Designing Programs for Eliminating Canine Rabies from Islands: Bali,Indonesia as a Case Study

Background

Canine rabies is one of the most important and feared zoonotic diseases in the world. In some regions rabies elimination is being successfully coordinated, whereas in others rabies is endemic and continues to spread to uninfected areas. As epidemics emerge, both accepted and contentious control methods are used, as questions remain over the most effective strategy to eliminate rabies. The Indonesian island of Bali was rabies-free until 2008 when an epidemic in domestic dogs began, resulting in the deaths of over 100 people. Here we analyze data from the epidemic and compare the effectiveness of control methods at eliminating rabies.

Methodology/Principal Findings

Using data from Bali, we estimated the basic reproductive number, R ₀, of rabies in dogs, to be ∼1·2, almost identical to that obtained in ten–fold less dense dog populations and suggesting rabies will not be effectively controlled by reducing dog density. We then developed a model to compare options for mass dog vaccination. Comprehensive high coverage was the single most important factor for achieving elimination, with omission of even small areas (<0.5% of the dog population) jeopardizing success. Parameterizing the model with data from the 2010 and 2011 vaccination campaigns, we show that a comprehensive high coverage campaign in 2012 would likely result in elimination, saving ∼550 human lives and ∼$15 million in prophylaxis costs over the next ten years.

Conclusions/Significance

The elimination of rabies from Bali will not be achieved through achievable reductions in dog density. To ensure elimination, concerted high coverage, repeated, mass dog vaccination campaigns are necessary and the cooperation of all regions of the island is critical. Momentum is building towards development of a strategy for the global elimination of canine rabies, and this study offers valuable new insights about the dynamics and control of this disease, with immediate practical relevance.     

Endemic bird species and conservation in the Cerrado Region, South America

A general overview of the largest South American savanna region, the Cerrado Region, is presented. Using simple approaches, I analyse the distribution of the bird species endemic to this region in order to test the hypothesis that areas harbouring local aggregates of restricted-range endemics have remained stable during the successive Quaternary climatic-vegetational changes. This hypothesis seems not to be generally valid for birds of the Cerrado Region, as restricted-range endemic species exist both in areas that remained stable (Central Goia´s Plateau) and areas that remain unstable (Araguaya and Parana~ River valleys, Espinhac¸o Plateau) during the Late Pleistocene. I also discuss some aspects of the conservation in the Cerrado Region, and suggest that the dry forests of the River Parana~ Valley, Goia´s, must be considered the area with the highest priority for the creation of new reserves in the Cerrado Region.     

Reducing Cost of Rabies Post Exposure Prophylaxis: Experience of a Tertiary Care Hospital in Pakistan

Background

Rabies is a uniformly fatal disease, but preventable by timely and correct use of post exposure prophylaxis (PEP). Unfortunately, many health care facilities in Pakistan do not carry modern life-saving vaccines and rabies immunoglobulin (RIG), assuming them to be prohibitively expensive and unsafe. Consequently, Emergency Department (ED) health care professionals remain untrained in its application and refer patients out to other hospitals. The conventional Essen regimen requires five vials of cell culture vaccine (CCV) per patient, whereas Thai Red Cross intradermal (TRC-id) regimen requires only one vial per patient, and gives equal seroconversion as compared with Essen regimen.

Methodology/Principal Findings

This study documents the cost savings in using the Thai Red Cross intradermal regimen with cell culture vaccine instead of the customary 5-dose Essen intramuscular regimen for eligible bite victims. All patients presenting to the Indus Hospital ED between July 2013 to June 2014 with animal bites received WHO recommended PEP. WHO Category 2 bites received intradermal vaccine alone, while Category 3 victims received vaccine plus wound infiltration with Equine RIG. Patients were counseled, and subsequent doses of the vaccine administered on days 3, 7 and 28. Throughput of cases, consumption utilization of vaccine and ERIG and the cost per patient were recorded.

Conclusions/Significance

Government hospitals in Pakistan are generally underfinanced and cannot afford treatment of the enormous burden of dog bite victims. Hence, patients are either not treated at all, or asked to purchase their own vaccine, which most cannot afford, resulting in neglect and high incidence of rabies deaths. TRC-id regimen reduced the cost of vaccine to 1/5^th of Essen regimen and is strongly recommended for institutions with large throughput. Training ED staff would save lives through a safe, effective and affordable technique.     

Essential Role of T Cells in the Postexposure Prophylaxis of Rabies in Mice

Athymic nude mice injected intramuscularly with a street strain of rabies virus were not protected against rabies by postexposure administration of beta-propiolactone-inactivated rabies vaccine. In contrast, their normal littermates were completely protected from death by the same vaccination regimens. Nude mice did not produce IgG antibody as a result of the vaccine during the test period of 15 days, whereas normal littermates produced IgG antibody from day 5 after vaccination. However, passive immunization with antirabies hyperimmune mouse ascites showed that antibody was completely ineffective in protecting either nude mice or their normal littermates against rabies when given later than 2 days after infection. No significant difference in the induction of circulating interferon by the vaccination was noted in these mice. Passive transfer of immune spleen cells to nude mice immediately after infection resulted in 30 to 37.5% protection of the mice. Passively transferred spleen cells did not produce detectable amounts of neutralizing antibody in the recipient mice except on day 2 after the transfer, when a low level of antibody was detected. These observations demonstrate the essential role of T cells in the postexposure prophylaxis of rabies in mice. The mechanisms of the failure of postexposure vaccination in nude mice are discussed.     

Implementation of an Intersectoral Program to Eliminate Human and Canine Rabies: The Bohol Rabies Prevention and Elimination Project

Background

The province of Bohol, located in the Visayas islands region in the Philippines has a human population of 1.13 million and was the 4th highest region for human rabies deaths in the country, averaging 10 per year, prior to the initiation of the Bohol Rabies Prevention and Elimination Project (BRPEP).

Aims

The BRPEP was initiated in 2007 with the goal of building a sustainable program that would prevent human rabies by eliminating rabies at its source, in dogs, by 2010. This goal was in line with the Philippine National Rabies Program whose objective is to eliminate rabies by 2020.

Methods

The intersectoral BRPEP was launched in 2007 and integrated the expertise and resources from the sectors of agriculture, public health and safety, education, environment, legal affairs, interior and local government. The program included: increasing local community involvement; implementing dog population control; conducting mass dog vaccination; improving dog bite management; instituting veterinary quarantine; and improving diagnostic capability, surveillance and monitoring. Funding was secured from the national government, provincial, municipal and village units, dog owners, NGOs, the regional office of the WHO, the UBS Optimus Foundation, and the Global Alliance for Rabies Control. The BRPEP was managed by the Bohol Rabies Prevention and Eradication Council (BRPEC) under the jurisdiction of the Governor of Bohol. Parallel organizations were created at the municipal level and village level. Community volunteers facilitated the institution of the program. Dog population surveys were conducted to plan for sufficient resources to vaccinate the required 70% of the dogs living in the province. Two island-wide mass vaccination campaigns were conducted followed by “catch up” vaccination campaigns. Registration of dogs was implemented including a small fee that was rolled back into the program to maintain sustainability. Children were educated by introducing rabies prevention modules into all elementary schools in Bohol. Existing public health legislation at the national, provincial, and municipal level strengthened the enforcement of activities. A Knowledge, Attitude and Practices (KAP) survey was conducted in 2009 to evaluate the educational knowledge of the population. Increased surveillance was instituted to ensure that dogs traveling into and out of the province were vaccinated against rabies. Human and animal cases of rabies were reported to provincial and national authorities.

Key Results

Within the first 18 months of the BRPEP, human rabies deaths had decreased annually from 0.77 to 0.37 to zero per 100,000 population from 2007–2009. Between October 2008 and November 2010 no human and animal cases were detected. Increased surveillance on the island detected one suspected human rabies case in November 2010 and one confirmed case of canine rabies in April 2011. Two mass vaccination campaigns conducted in 2007 and 2008 successfully registered and vaccinated 44% and 70% of the dogs on the island. The additional surveillance activities enabled a mobilization of mop up vaccination activities in the region where the human and canine case was located. Due to the increased effective and continuous surveillance activities, rabies was stopped before it could spread to other areas on the island. The program costs totaled USD 450,000. Registration fees collected to maintain the program amounted to USD 105,740 and were re-allocated back into the community to sustain the program.