The Successful Elimination of Sylvatic Rabies Using Oral Vaccination of Foxes in Slovenia

Sylvatic rabies was present in Slovenia between 1973 and 2013, with the red fox as the main reservoir of the rabies virus. The first oral rabies vaccination (ORV) control program in foxes started in 1988, using the manual distribution of baits. Significant improvement of fox vaccination was achieved with the aerial distribution of baits, starting in 1995 and successfully finished with the final, fifty-ninth vaccination campaign in 2019. Between 1979 and 2019, a total of 86,471 samples were tested, and 10,975 (12.69%) rabies-positive animals were identified. Within the ORV, two different vaccines were used, containing modified live virus strain Street Alabama Dufferin (SAD) B19 and SAD Bern, while the last ORV campaigns were completed in 2019, with a vaccine containing a genetically modified strain of SPBN GASGAS. Molecular epidemiological studies of 95 rabies-positive samples, originating from red foxes, badgers, cattle, dogs, martens, cats, and horses, revealed a low genetic diversity of circulating strains and high similarity to strains from neighboring countries. During the elimination program, few vaccine-induced rabies cases were detected: three in red foxes and one case in a marten, with no epidemiological relevance. Slovenia has been officially declared a country free of rabies since 2016.     

Review of Oral Rabies Vaccination of Dogs and Its Application in India

Oral rabies vaccines (ORVs) have been in use to successfully control rabies in wildlife since 1978 across Europe and the USA. This review focuses on the potential and need for the use of ORVs in free-roaming dogs to control dog-transmitted rabies in India. Iterative work to improve ORVs over the past four decades has resulted in vaccines that have high safety profiles whilst generating a consistent protective immune response to the rabies virus. The available evidence for safety and efficacy of modern ORVs in dogs and the broad and outspoken support from prominent global public health institutions for their use provides confidence to national authorities considering their use in rabies-endemic regions. India is estimated to have the largest rabies burden of any country and, whilst considerable progress has been made to increase access to human rabies prophylaxis, examples of high-output mass dog vaccination campaigns to eliminate the virus at the source remain limited. Efficiently accessing a large proportion of the dog population through parenteral methods is a considerable challenge due to the large, evasive stray dog population in many settings. Existing parenteral approaches require large skilled dog-catching teams to reach these dogs, which present financial, operational and logistical limitations to achieve 70% dog vaccination coverage in urban settings in a short duration. ORV presents the potential to accelerate the development of approaches to eliminate rabies across large areas of the South Asia region. Here we review the use of ORVs in wildlife and dogs, with specific consideration of the India setting. We also present the results of a risk analysis for a hypothetical campaign using ORV for the vaccination of dogs in an Indian state.     

Study of the dog population and the rabies control activities in the Mirigama area of Sri Lanka

The national health authorities of Sri Lanka have adopted a combined strategy of rabies vaccination and stray dog removal to control endemic dog rabies. Despite the control efforts, an increase of animal and human rabies cases has occurred since 1994. As a consequence, a project to evaluate the national rabies control program has been started and a study focussing on the dog population and rabies control activities in a limited area of Mirigama was conducted. Information on canine abundance and the accessibility of dogs for rabies vaccination was obtained by a household survey, vaccination of dogs against rabies at several vaccination points, collar-marking, and transect line recapture. The number of unvaccinated dogs was estimated by using Bayesian methodology. The estimated number of dogs per square kilometre was 87 (95% credibility interval: 80, 93) for owned dogs and 108 (100, 116) for owned and ownerless dogs. Coverage after the immunisation campaign was 57.6% (53.3, 61.9%) if vaccination at the vaccination points was considered and 66% (60.4, 72.0%) if recently provided vaccination by private veterinarians was also taken into account. The proportion of households with at least one dog vaccinated varied between 59.1 and 94.2% within the catchment area of the different vaccination points. Unvaccinated dogs were puppies (12%), ownerless dogs (57%), and owned dogs, which were not presented for vaccination (31%). In order to improve the rabies immunisation coverage among dogs and to achieve complete elimination of rabies it was recommended that the 95% catchment area of each vaccination point be assessed, the distribution of vaccination points in the vaccination area be redefined if necessary, a system for the vaccination of dogs missing the vaccination campaign for dog owner-specific reasons be established, and an inexpensive marking system be used for vaccinated dogs.     

Emergency vaccination of rabies under limited resources – combating or containing?

Background

Rabies is the most important viral zoonosis from a global perspective. Worldwide efforts to combat the disease by oral vaccination of reservoirs have managed to eradicate wildlife rabies in large areas of central Europe and North-America. Thus, repeated vaccination has been discontinued recently on a geographical scale. However, as rabies has not yet been eradicated globally, a serious risk of re-introduction remains. What is the best spatial design for an emergency vaccination program – particularly if resources are limited? Either, we treat a circular area around the detected case and run the risk of infected hosts leaving the limited control area, because a sufficient immunisation level has not yet been built up. Or, initially concentrate the SAME resources in order to establish a protective ring which is more distant from the infected local area, and which then holds out against the challenge of the approaching epidemic.

Methods

We developed a simulation model to contrast the two strategies for emergency vaccination. The spatial-explicit model is based on fox group home-ranges, which facilitates the simulation of rabies spread to larger areas relevant to management. We used individual-based fox groups to follow up the effects of vaccination in a detailed manner. Thus, regionally – bait distribution orientates itself to standard schemes of oral immunisation programs and locally – baits are assigned to individual foxes.

Results

Surprisingly, putting the controlled area ring-like around the outbreak does not outperform the circular area of the same size centred on the outbreak. Only during the very first baitings, does the ring area result in fewer breakouts. But then as rabies is eliminated within the circle area, the respective ring area fails, due to the non-controlled inner part.We attempt to take advantage of the initially fewer breakouts beyond the ring when applying a mixed strategy. Therefore, after a certain number of baitings, the area under control was increased for both strategies towards the same larger circular area. The circle-circle strategy still outperforms the ring-circle strategy and analysis of the spatial-temporal disease spread reveals why: improving control efficacy by means of a mixed strategy is impossible in the field, due to the build-up time of population immunity.

Conclusion

For practical emergency management of a new outbreak of rabies, the ring-like application of oral vaccination is not a favourable strategy at all. Even if initial resources are substantially low and there is a serious risk of rabies cases outside the limited control area, our results suggest circular application instead of ring vaccination.

     

Epidemiologic trends of rabies in domestic animals in southern Thailand, 1994-2008

Rabies and associated risk factors in dogs, cats and cattle (n = 3,454) in southern Thailand during 1994-2008 were evaluated by using a mixed-effect logistic regression model. Overall prevalence was 48%. In dogs, odds of being rabid were 1.7 times higher in unvaccinated dogs than in vaccinated dogs and two times higher in dogs with bite history than in dogs with no known bite history. Similarly, aggressive dogs were more likely to be rabid than non-aggressive dogs. In cattle, aggression, pharyngeal paralysis, hyperactivity, and depression were clinical signs associated with being rabid. Annual fluctuations of the species-specific prevalence of rabies is suggestive of a positive correlation between canine and either feline (r = 0.60, P = 0.05) or bovine rabies (r = 0.78, P = 0.004). Insufficient vaccination coverage led to maintenance of rabies, which could be easily controlled by increased vaccine coverage and public education.     

Renewed Public Health Threat from Emerging Lyssaviruses

Pathogen discovery contributes to our knowledge of bat-borne viruses and is linked to the heightened interest globally in bats as recognised reservoirs of zoonotic agents. The transmission of lyssaviruses from bats-to-humans, domestic animals, or other wildlife species is uncommon, but interest in these pathogens remains due to their ability to cause an acute, progressive, invariably fatal encephalitis in humans. Consequently, the detection and characterisation of bat lyssaviruses continues to expand our knowledge of their phylogroup definition, viral diversity, host species association, geographical distribution, evolution, mechanisms for perpetuation, and the potential routes of transmission. Although the opportunity for lyssavirus cross-species transmission seems rare, adaptation in a new host and the possibility of onward transmission to humans requires continued investigation. Considering the limited efficacy of available rabies biologicals it is important to further our understanding of protective immunity to minimize the threat from these pathogens to public health. Hence, in addition to increased surveillance, the development of a niche pan-lyssavirus vaccine or therapeutic biologics for post-exposure prophylaxis for use against genetically divergent lyssaviruses should be an international priority as these emerging lyssaviruses remain a concern for global public health.     

Oral immunization and protection of raccoons (Procyon lotor) with a vaccinia-rabies glycoprotein recombinant virus vaccine.

Animal rabies control has been frustrated by the existence of multiple wildlife reservoirs and the lack of efficacious oral vaccines. In this investigation, raccoons fed a vaccinia-rabies glycoprotein recombinant virus in a sponge bait developed rabies virus-neutralizing antibody (0.6-54.0 units) and resisted street rabies virus infection 28 and 205 days after feeding. Additional raccoons immunized by oral infusion with attenuated antigenic variants of rabies virus strains CVS-11 and ERA failed to develop rabies virus-neutralizing antibody. This work demonstrates the feasibility of a recombinant virus vaccine containing the rabies glycoprotein gene for immunization of raccoons, and possibly other wildlife, to obtain long-term protection against rabies.     

狂犬病口服疫苗对消除人间狂犬病的重要作用北大核心CSCD

狂犬病严重威胁人类生命,控制狂犬病需要从病毒的源头着手。在狂犬病毒的多种宿主中,犬科动物所占比例最大。因此,消除狂犬病的关键是对犬的免疫覆盖率达到70%以上。事实证明,通过注射灭活疫苗对犬只形成免疫屏障是一件困难的事情。采用口服疫苗策略控制野生动物狂犬病的成功案例给大家提供了新的思路,因此世界卫生组织建议采用狂犬病口服疫苗对犬进行免疫,用以提高犬只的免疫覆盖率,从而达到2030年消除和控制狂犬病的目的。     

A recombinant human adenovirus vaccine against rabies

Rabies continues to be a serious problem in both developed and developing nations due to the reservoir of rabies virus in wildlife vectors. The control and worldwide eradication of rabies depends on the development of safe, effective, and economical vaccines that might be used in preexposure vaccination programs for humans and animals. To this end an infectious human adenovirus type 5 recombinant virus that contains the rabies glycoprotein gene, and which may serve as the prototype for a new class of vaccines against rabies, was constructed and tested. This recombinant, when administered by either the parenteral or oronasal route, was highly effective in eliciting good levels of rabies-neutralizing antibodies in the sera of dogs and mice. Mice immunized by the recombinant virus were protected from lethal intracerebral challenge with rabies virus.     

Feline and Canine Rabies in New York State,USA

In New York State, domestic animals are no longer considered rabies vector species, but given their ubiquity with humans, rabies cases in dogs and cats often result in multiple individuals requiring post-exposure prophylaxis. For over a decade, the New York State rabies laboratory has variant-typed these domestic animals to aid in epidemiological investigations, determine exposures, and generate demographic data. We produced a data set that outlined vaccination status, ownership, and rabies results. Our data demonstrate that a large percentage of felines submitted for rabies testing were not vaccinated or did not have a current rabies vaccination, while canines were largely vaccinated. Despite massive vaccination campaigns, free clinics, and education, these companion animals still occasionally contract rabies. Barring translocation events, we note that rabies-positive cats and dogs in New York State have exclusively contracted a raccoon variant. While the United States has made tremendous strides in reducing its rabies burden, we hope these data will encourage responsible pet ownership including rabies vaccinations to reduce unnecessary animal mortality, long quarantines, and post-exposure prophylaxis in humans.     

History of Rabies Incidence and Rabies Control in Serbia in Support of the Zero by 2030 Campaign to Eliminate Dog-Mediated Human Rabies

Urban (principally canine-mediated) rabies has been a public health risk for people living in Serbia for centuries. The first legal act in urban rabies prevention in Serbia was established in 1834 by introducing high taxes for pet dog owners. Five years later in 1839, the first set of literature describing rabies prevention was issued by the health department from The Serbian Ministry of Interior. An overview of cauterization of rabies wounds was presented as the principal method of rabies post exposure prophylaxis. In 1890, a human rabies vaccination was introduced in Serbia with the royal government directive which ordered patients to be treated at the Pasteur Institute in Budapest in receipt of rabies vaccination. Urban (canine) rabies was eliminated during the 1980s, but sylvatic (principally fox-mediated) rabies still prevailed. The last human rabies case was recorded in the Province of Kosovo and Metohija in 1980. Sylvatic rabies in Serbia is in the final stages of elimination by orally vaccinating foxes (Vulpes vulpes). The only published finding of a lyssavirus among Serbian bats was made in 1954 by Dr Milan Nikolić in the vicinity of Novi Sad. In 2006, a comprehensive two-year active surveillance program of lyssaviruses in bats in Serbia was undertaken. In this single study, all of the bats from Serbia tested negative for a lyssavirus.     

Data-Driven Management—A Dynamic Occupancy Approach to Enhanced Rabies Surveillance Prioritization

Rabies lyssavirus (RABV) is enzootic in raccoons across the eastern United States. Intensive management of RABV by oral rabies vaccination (ORV) has prevented its spread westward and shown evidence of local elimination in raccoon populations of the northeastern US. The USDA, Wildlife Services, National Rabies Management Program (NRMP) collaborates with other agencies to implement broad-scale ORV and conducts extensive monitoring to measure the effectiveness of the management. Enhanced Rabies Surveillance (ERS) was initiated during 2005 and updated in 2016 to direct surveillance efforts toward higher-value specimens by assigning points to different methods of encountering specimens for collection (strange-acting, roadkill, surveillance-trapped, etc.; specimen point values ranged from 1 to 15). We used the 2016–2019 data to re-evaluate the point values using a dynamic occupancy model. Additionally, we used ERS data from 2012–2015 and 2016–2019 to examine the impact that the point system had on surveillance data. Implementation of a point system increased positivity rates among specimens by 64%, indicating a substantial increase in the efficiency of the ERS to detect wildlife rabies. Our re-evaluation found that most points accurately reflect the value of the surveillance specimens. The notable exception was that samples from animals found dead were considerably more valuable for rabies detection than originally considered (original points = 5, new points = 20). This work demonstrates how specimen prioritization strategies can be used to refine and improve ERS in support of wildlife rabies management.     

中国狂犬病口服疫苗的研究进展及其应用的紧迫性

中国科学家早在上世纪80年代开始研究狂犬病动物口服疫苗,获得数株毒力减弱的疫苗株,并进行过犬的口服免疫实验和大规模安全性和保护效果的现场观察。其中有几株减毒株的弱毒特征、遗传稳定性和免疫性与WHO认可并广泛应用的动物口服疫苗毒种相似。消除狂犬病的关键措施是对犬进行大面积免疫达到免疫覆盖率70%以上,中国犬的数量多达亿头,而且多数为散养犬,以常规的注射免疫很难达到这个水平。对犬实施口服免疫提高免疫率也是WHO和狂犬病专家积亟提倡和推荐的。中国已有多株减毒株,国家应充分发挥它们的作用,在人力、物力、财政上予以大力支持,完善这些候选株以便尽快得到批准应用,从而达到全球2030年消除人间狂犬病的目标。     

Isolation and Characterization of Cross-Reactive Human Monoclonal Antibodies That Potently Neutralize Australian Bat Lyssavirus Variants and Other Phylogroup 1 Lyssaviruses

Australian bat lyssavirus (ABLV) is a rhabdovirus that circulates in four species of pteropid bats (ABLVp) and the yellow-bellied sheath-tailed bat (ABLVs) in mainland Australia. In the three confirmed human cases of ABLV, rabies illness preceded fatality. As with rabies virus (RABV), post-exposure prophylaxis (PEP) for potential ABLV infections consists of wound cleansing, administration of the rabies vaccine and injection of rabies immunoglobulin (RIG) proximal to the wound. Despite the efficacy of PEP, the inaccessibility of human RIG (HRIG) in the developing world and the high immunogenicity of equine RIG (ERIG) has led to consideration of human monoclonal antibodies (hmAbs) as a passive immunization option that offers enhanced safety and specificity. Using a recombinant vesicular stomatitis virus (rVSV) expressing the glycoprotein (G) protein of ABLVs and phage display, we identified two hmAbs, A6 and F11, which completely neutralize ABLVs/ABLVp, and RABV at concentrations ranging from 0.39 and 6.25 µg/mL and 0.19 and 0.39 µg/mL respectively. A6 and F11 recognize overlapping epitopes in the lyssavirus G protein, effectively neutralizing phylogroup 1 lyssaviruses, while having little effect on phylogroup 2 and non-grouped diverse lyssaviruses. These results suggest that A6 and F11 could be effective therapeutic and diagnostic tools for phylogroup 1 lyssavirus infections.     

福建省狂犬病毒的N基因序列分析

目的了解福建省狂犬病毒流行毒株的基因分型和遗传进化关系,以及流行毒株与疫苗株在N基因核苷酸和氨基酸水平的差异。方法采集福建省不同时间、不同地区的犬脑组织标本共89份,通过RT-nested-PCR扩增、纯化、克隆、测序,获得19条包含N基因全长的序列,采用生物学软件进行序列整理分析。结果根据N基因核苷酸和推导的氨基酸的同源性,把福建省已知狂犬病毒分为3个群组,群组间具有显著的地域分布特征,各群组内部N基因核苷酸和氨基酸同源性分别在99.7%～100%和98.9%～100%之间,群组间N基因核苷酸和氨基酸同源性在86.4%～89.3%和95.3%～98.4%之间。福建省狂犬病毒的流行毒株与目前使用的各种疫苗株N基因序列同源性在86.5%～98.9%之间。结论福建省境内存在表观健康犬携带狂犬病毒现象,福建省已知狂犬病毒流行毒株均属于基因I型,可分为3个群组。从N基因序列的分析上看,我省目前使用疫苗能有效地保护流行毒株的感染。     

云南省狂犬病病人和犬类感染狂犬病病毒及M基因序列分析

目的 调查云南省部分地区狂犬病病人和疫点犬群携带狂犬病病毒(rabies virus, RABV)状况及RABV膜基质蛋白(matrixprotein, M)基因序列分析,为狂犬病防控提供科学依据。方法 2008-2009年在云南省采集犬脑组织标本606份,狂犬病病人唾液8份,脑脊液1份,用直接免疫荧光试验检测RABV抗原,用RT-PCR检测RABV核酸,对阳性标本进行M基因序列测定和分析。结果 所有标本经检测,RABV抗原和/或核酸阳性16份,其中疫点扑杀的貌似健康犬脑组织3.10%(10/323),狂犬病病人唾液5份、脑脊液1份。狗肉餐馆屠宰犬的脑组织283份均为阴性。云南16株RABV的M基因核苷酸和氨基酸同源性分别为88.5%~100%和85.2%~99.5%。它们与中国人用疫苗株aG核苷酸和氨基酸同源性分别为83.9%~85.7%和82.3%~93.6%;与人用疫苗株CTN181核苷酸和氨基酸同源性分别为99%~99.7%和98.5%~99%。系统进化分析表明,云南16株RABV均属基因Ⅰ型并可分为进化Ⅰ和Ⅱ群并分别与泰国等东南亚国家和相邻省份流行株具有较近的亲缘关系。结论 云南省狂犬病流行与周边省份和东南亚地区的狂犬病传播扩散有一定关系;狂犬病疫点部分貌似健康犬携带RABV并具有传染源意义;云南狂犬病病毒株M基因与我国人用狂犬病疫苗CTN株的同源性和亲缘关系较近,但与aG株同源性存在。     

Rabies in France: an update

INTRODUCTION: In 1996, rabies was responsible for more than 35,000 deaths worldwide. Three cases of human rabies that had been contracted abroad were diagnosed in France during the same year. Cases notified in 1997 followed exposure outside the country. Fox, bat, and dog rabies are reviewed on the basis of the latest epidemiological data obtained in France. CURRENT KNOWLEDGE AND KEY POINTS: Two cases of fox rabies diagnosed in 1998 occurred at the border between France and Germany, thus preventing five French departments bordering Germany from being officially declared rabies-free in 1999. The campaigns for oral immunization of foxes that are led since 1986 are responsible for the decrease in rabies incidence. Though not well known, bat rabies is a reality in France, involving either European virus strains (five cases all over the country) or African virus strains that are carried along by imported tropical bats. Dogs rabies is also today an imported disease. FUTURE PROSPECTS AND PROJECTS: The decrease in risk for rabies has resulted from the conjunction of multiple efforts: extensive programs aimed at oral vaccination of foxes in France and its neighboring countries, efficient epidemiological survey, sanitary controls at borders, ban on importing tropical bats. Furthermore, recommendations for preventive pre-exposure immunization have recently been changed, leading to modifications of the French licensing form.     

Rabies in Europe: An epidemiological and clinical update

Rabies is a vaccine preventable zoonotic disease with a significant mortality burden worldwide. Several years of vaccination campaigns in wildlife animals have now achieved the control of rabies in Western Europe through a vaccination belt in front of endemic Eastern European countries. Nevertheless, rabies could be imported both by travellers from areas without an active public control of the disease or by animals coming from areas where the virus circulates in wildlife fauna. The knowledge of the current world epidemiology combined with a high index of clinical suspicion are needed to reach a diagnosis of rabies, especially in case of atypical presentation or without a history of animal exposure. The pre-travel counselling to people visiting highly endemic areas is essential to give information on how to reduce exposure to potential sources of infection and to select those subjects who could benefit from pre-travel vaccination. Rabies is almost invariably fatal, but the prompt administration of a vaccine course combined with anti-rabies immunoglobulins significantly reduces the probability to develop life-threatening consequences. In this review, we give a brief epidemiological and clinical update about rabies in Europe.