The Italian experience in the control of rabies. I. Procedural methods

Oral vaccination of foxes associated with their control has been shown to be a rapid and safe method to extinguish enzootic foci of sylvatic rabies and to prevent the entry and spreading of this zoonosis in free zones of Italy. Domestic animals vaccination with live modified vaccines in zones with sylvatic rabies has proved to be highly effective in limiting the cases, recorded only in non-vaccinated animals.     

Current rabies epizootiology

Situation in rabies in the Russian Federation (RF) remains to be tense and is characterized by important specific features. Central Russia and the Moscow region have essential differences in the epizootic situation, the epizootological structure of rabies and other indices as compared with the Russian Federation. In the course of the last 25 years the ecological stereotype of rabies has undergone considerable transformations, becoming natural focal infection with the circulation of the infective agent among wild carnivores, which is now particularly obvious in the Moscow region. In 1998 a sharp rise in rabies morbidity occurred in Central Russia: peak values exceeded average annual values 2 times for the RF, 4 times for Central Russia and more than 10 times for the Moscow region. The situation in rabies in the Moscow region permits to use it as a model in the study of today rabies.     

Skunk rabies in California (1992-2003)--implications for oral rabies vaccination

Skunk-variant rabies is endemic in California (United States), and the development of oral vaccines and baits to vaccinate skunks is in progress. In 2003, the California Department of Public Health (CDPH) began to quantify the impacts of skunk-variant rabies and to assess the feasibility of using oral rabies vaccination (ORV) as a containment measure. The CDPH rabies case data for skunks were spatially depicted and analyzed using a geographic information system. Statewide, rabid skunks (1992-2003) primarily occurred in seven physiographic regions: Central Coast, North Coast, North Sierra, Sacramento Valley, San Francisco Bay and Delta, San Joaquin Valley, and South Sierra. Detailed analysis of rabid skunks in San Luis Obispo (SLO) and Santa Barbara (SB) counties showed that skunk rabies was endemic in the coastal plain of SLO County between 1992 and 2000, but only became epizootic in SB County during 2002. Despite the widespread distribution of striped skunks (Mephitis mephitis) throughout most of California, the skunk rabies variant has not been found in Los Angeles County since 1979. Results imply that future ORV campaigns for skunk-variant rabies in the Pacific Coastal Plain could deter spread from SLO into SB County, as well as deterring the reintroduction of skunk-variant rabies into southern California.     

Vaccination of small Asian mongoose (Herpestes javanicus) against rabies

Oral vaccination of free-ranging wildlife is a promising technique in rabies control. The small Asian mongoose (Herpestes javanicus) is an important reservoir of rabies on several Caribbean islands, but no vaccines have been evaluated for this species. Captive mongooses were used to test the safety and efficacy of the commercially licensed vaccinia-rabies glycoprotein (V-RG) recombinant vaccine and a newly developed genetically engineered oral rabies virus vaccine (SPBNGA-S). In one study using V-RG, no vaccinated animals developed detectable rabies virus-neutralizing antibodies, and all but one died after experimental challenge with rabies virus. In contrast, all animals given SPBNGA-S demonstrated seroconversion within 7 to 14 days after vaccination and survived rabies virus challenge. On the basis of these preliminary results indicating the greater efficacy of SPBNGA-S vs. V-RG vaccine, additional investigations will be necessary to determine the optimal dose and duration of vaccination, as well as incorporation of the SPBNGA-S vaccine into edible bait.     

Epizootiology of skunk rabies in North America

Public health surveillance data from the United States and Canada (1961 to 1982) were analyzed to determine if consistent temporal and spatial patterns in skunk rabies could be identified. Enzootic/epizootic rabies was recognized in 18 states (enzootic states) based on the criteria of greater than or equal to 20 yr of reported skunk rabies and at least 1 yr with a minimum of 50 reported rabid skunks. In other wildlife species, epizootics have been demonstrated to expand along a wave-like front. We hypothesized: if skunk rabies behaved in a similar fashion, states reporting rabid skunks would change over time. No such change was noted. During epizootics the number of counties reporting increased but not the number of states. Within Illinois certain counties were demonstrated to have persistent rabies histories and likely served as enzootic foci. Enzootic states combined prevalence indicated a 6 to 8 yr cycle for epizootics. Data on monthly percent rabies positive (number rabid/total number tested) were available from six states and Canada. Mean distributions were bimodal with winter and spring peaks. The patterns identified for skunk rabies differ from those of other major wildlife vectors and have significance for potential vaccination control regimes.     

Focus: Zoonotic Disease: Rabies in Costa Rica – Next Steps Towards Controlling Bat-Borne Rabies After its Elimination in Dogs

Rabies is an acute, progressive encephalitis caused by a lyssavirus, with the highest case fatality of any conventional infectious disease. More than 17 different lyssaviruses have been described, but rabies virus is the most widely distributed and important member of the genus. Globally, tens of thousands of human fatalities still occur each year. Although all mammals are susceptible, most human fatalities are caused by the bites of rabid dogs, within lesser developed countries. A global plan envisions the elimination of human rabies cases caused via dogs by the year 2030. The combination of prophylaxis of exposed humans and mass vaccination of dogs is an essential strategy for such success. Regionally, the Americas are well on the way to meet this goal. As one example of achievement, Costa Rica, a small country within Central America, reported the last autochthonous case of human rabies transmitted by a dog at the end of the 1970s. Today, rabies virus transmitted by the common vampire bat, Desmodus rotundus, as well as other wildlife, remains a major concern for humans, livestock, and other animals throughout the region. This review summarizes the historical occurrence of dog rabies and its elimination in Costa Rica, describes the current occurrence of the disease with a particular focus upon affected livestock, discusses the ecology of the vampire bat as the primary reservoir relevant to management, details the clinical characteristics of recent human rabies cases, and provides suggestions for resolution of global challenges posed by this zoonosis within a One Health context.     

Antibody response to purified chick embryo cell vaccine in equines for production of equine rabies immune globulin

Rabies is endemic in India. The post exposure treatment of class three bite cases, as recommended by the World Health Organization, must involve the use of rabies immunoglobulin as soon as possible and up to the seventh day of start of anti rabies vaccination. The annual requirement in India as projected by the Ministry of Health, Government of India is about 1500 liters of purified anti rabies serum (ERIG). Central Research Institute (CRI), Kasauli, being the sole producer of ERIG in India, an effort was made to increase the production of ERIG by the use of tissue culture vaccine (Human) for primary immunization of equines. It also involved changing the vaccine from horse brain suspension to tissue culture vaccine by eliminating horse sacrifice for antigen preparation. A better immune response was obtained.     

The elimination of fox rabies from Europe: determinants of success and lessons for the future

Despite perceived challenges to controlling an infectious disease in wildlife, oral rabies vaccination (ORV) of foxes has proved a remarkably successful tool and a prime example of a sophisticated strategy to eliminate disease from wildlife reservoirs. During the past three decades, the implementation of ORV programmes in 24 countries has led to the elimination of fox-mediated rabies from vast areas of Western and Central Europe. In this study, we evaluated the efficiency of 22 European ORV programmes between 1978 and 2010. During this period an area of almost 1.9 million km² was targeted at least once with vaccine baits, with control taking between 5 and 26 years depending upon the country. We examined factors influencing effort required both to control and eliminate fox rabies as well as cost-related issues of these programmes. The proportion of land area ever affected by rabies and an index capturing the size and overlap of successive ORV campaigns were identified as factors having statistically significant effects on the number of campaigns required to both control and eliminate rabies. Repeat comprehensive campaigns that are wholly overlapping much more rapidly eliminate infection and are less costly in the long term. Disproportionally greater effort is required in the final phase of an ORV programme, with a median of 11 additional campaigns required to eliminate disease once incidence has been reduced by 90 per cent. If successive ORV campaigns span the entire affected area, rabies will be eliminated more rapidly than if campaigns are implemented in a less comprehensive manner, therefore reducing ORV expenditure in the longer term. These findings should help improve the planning and implementation of ORV programmes, and facilitate future decision-making by veterinary authorities and policy-makers.     

Epizootic characteristic of rabies today

During the 23 year period rabies was registered in the Moscow region in 163 cases among foxes, 22 cases among racoon-like dogs, 92 cases among dogs, 54 cases among cats. In 1991-2000 ten cases of rabies were registered among other wild animal other than foxes and raccoon-like dogs (hares, hedge-hogs, polecats, badgers, hamsters, martens, rats). Under today conditions the generalized epizootological pattern of rabies is characterized by the vector "natural foci-->anthropurgic foci" with wild and domestic animals playing an alternative role in the epizootic process and the circulation of the infective agent. Wild carnivorous animals maintain natural focal infection in time and space, while all domestic animals are a direct or indirect ecological impasse and took no part in the maintenance of the infection. Foxes are the main source of infection for the animals of the anthropurgic cycle: they play a special role in the development of the epizootic situation in the region as the main reservoir and source of the causative agent of rabies as a natural focal infection. Among other wild animals, raccoon-like dogs are involved into epizootic and epidemic chains. Dogs are the main objects to be infected in the anthropurgic cycles, while cats--a progressing group of risk. During the period of 25 years a decrease in the probability of natural rabies was noted.     

Raccoon rabies: the re-emergence of an epizootic in a densely populated area

Investigation of sporadic or isolated cases of rabies was encouraged in the 1950s by the implementation of a national surveillance system for reporting of rabies cases. Low level enzootic disease was recognized in several wild species during this period, including a small focus of rabies in raccoons in Florida. Phylogenetic analysis of the virus transmitted by rabid raccoons and reconstruction of the early history of raccoon rabies in the United States suggests that rabies was present in these animals long before its recognition by the public health community and that the emergence of raccoon rabies as a major threat to public health was the result of several natural and human-mediated events. In recent years, reports of raccoon-human contact and rabies in raccoons have increased as changes in human demographics and land development have concentrated raccoon populations in urban and suburban settings. In addition to the natural spread of rabies from Florida to raccoon populations in Georgia, Alabama, South Carolina and North Carolina, a separate focus in the northeastern states is believed to have been caused by the translocation of raccoons from the southeast to Virginia and West Virginia. Oral vaccination of wild species may be an important adjunct to traditional rabies control measures in the management of this disease in the future.     

Proposal for changing the ministerial instructions for antirabies prophylaxis in the light of the experience of the Centro Antirabbico di Roma

Records of clinical assistance and of post-exposure antirabies prophylaxis from 4820 outpatients who attended the Antirabies Center of Rome following animal bites in 1986 were analysed. We observed a high proportion of people submitted to active immunization (44% received at least one shot of HDCV vaccine) in spite of the fact that rabies is absent from Central Italy since many decades in both wild and domestic animals. These considerations suggest the opportunity of a major revision of the official recommendations for rabies prevention, and we feel that different policies should be adopted in rabies enzootic areas (such as Northern Italy) compared to those where the risk is only potential. Immunization should be avoided after bites by rodents; passive immunization should be added to the vaccine after bites by wild animals in enzootic areas, while bites by cats and dogs, even uncaptured, will not be necessarily followed by vaccination in non enzootic areas.     

Oral rabies vaccination of dogs—Experiences from a field trial in Namibia

Dog-mediated rabies is responsible for tens of thousands of human deaths annually, and in resource-constrained settings, vaccinating dogs to control the disease at source remains challenging. Currently, rabies elimination efforts rely on mass dog vaccination by the parenteral route. To increase the herd immunity, free-roaming and stray dogs need to be specifically addressed in the vaccination campaigns, with oral rabies vaccination (ORV) of dogs being a possible solution. Using a third-generation vaccine and a standardized egg-flavoured bait, bait uptake and vaccination was assessed under field conditions in Namibia. During this trial, both veterinary staff as well as dog owners expressed their appreciation to this approach of vaccination. Of 1,115 dogs offered a bait, 90% (n = 1,006, 95%CI:91–94) consumed the bait and 72.9% (n = 813, 95%CI:70.2–75.4) of dogs were assessed as being vaccinated by direct observation, while for 11.7% (n = 130, 95%CI:9.9–17.7) the status was recorded as “unkown” and 15.4% (n = 172, 95%CI: 13.4–17.7) were considered as being not vaccinated. Smaller dogs and dogs offered a bait with multiple other dogs had significantly higher vaccination rates, while other factors, e.g. sex, confinement status and time had no influence. The favorable results of this first large-scale field trial further support the strategic integration of ORV into dog rabies control programmes. Given the acceptance of the egg-flavored bait under various settings worldwide, ORV of dogs could become a game-changer in countries, where control strategies using parenteral vaccination alone failed to reach sufficient vaccination coverage in the dog population.     

Cost-effectiveness of the national dog rabies prevention and control program in Mexico, 1990–2015

BackgroundRabies is a viral zoonosis that imposes a substantial disease and economic burden in many developing countries. Dogs are the primary source of rabies transmission; eliminating dog rabies reduces the risk of exposure in humans significantly. Through mass annual dog rabies vaccination campaigns, the national program of rabies control in Mexico progressively reduced rabies cases in dogs and humans since 1990. In 2019, the World Health Organization validated Mexico for eliminating rabies as a public health problem. Using a governmental perspective, we retrospectively assessed the economic costs, effectiveness, and cost-effectiveness of the national program of rabies control in Mexico, 1990–2015.MethodologyCombining various data sources, including administrative records, national statistics, and scientific literature, we retrospectively compared the current scenario of annual dog vaccination campaigns and post-exposure prophylaxis (PEP) with a counterfactual scenario without an annual dog vaccination campaign but including PEP. The counterfactual scenario was estimated using a mathematical model of dog rabies transmission (RabiesEcon). We performed a thorough sensitivity analysis of the main results.Principal findingsResults suggest that in 1990 through 2015, the national dog rabies vaccination program in Mexico prevented about 13,000 human rabies deaths, at an incremental cost (MXN 2015) of $4,700 million (USD 300 million). We estimated an average cost of $360,000 (USD 23,000) per human rabies death averted, $6,500 (USD 410) per additional year-of-life, and $3,000 (USD 190) per dog rabies death averted. Results were robust to several counterfactual scenarios, including high and low rabies transmission scenarios and various assumptions about potential costs without mass dog rabies vaccination campaigns.ConclusionsAnnual dog rabies vaccination campaigns have eliminated the transmission of dog-to-dog rabies and dog-mediated human rabies deaths in Mexico. According to World Health Organization standards, our results show that the national program of rabies control in Mexico has been highly cost-effective.     

The Feasibility of Canine Rabies Elimination in Africa: Dispelling Doubts with Data

Background

Canine rabies causes many thousands of human deaths every year in Africa, and continues to increase throughout much of the continent.

Methodology/Principal Findings

This paper identifies four common reasons given for the lack of effective canine rabies control in Africa: (a) a low priority given for disease control as a result of lack of awareness of the rabies burden; (b) epidemiological constraints such as uncertainties about the required levels of vaccination coverage and the possibility of sustained cycles of infection in wildlife; (c) operational constraints including accessibility of dogs for vaccination and insufficient knowledge of dog population sizes for planning of vaccination campaigns; and (d) limited resources for implementation of rabies surveillance and control. We address each of these issues in turn, presenting data from field studies and modelling approaches used in Tanzania, including burden of disease evaluations, detailed epidemiological studies, operational data from vaccination campaigns in different demographic and ecological settings, and economic analyses of the cost-effectiveness of dog vaccination for human rabies prevention.

Conclusions/Significance

We conclude that there are no insurmountable problems to canine rabies control in most of Africa; that elimination of canine rabies is epidemiologically and practically feasible through mass vaccination of domestic dogs; and that domestic dog vaccination provides a cost-effective approach to the prevention and elimination of human rabies deaths.     

Modeling control of rabies outbreaks in red fox populations to evaluate culling,vaccination, and vaccination combined with fertility control

A predictive model of spread and control of rabies in red fox (Vulpes vulpes) populations was used to evaluate efficacy of culling, oral vaccination, and oral vaccination and fertility control (V + FC) as rabies control strategies. In addition, effects of season, fox population density, and a delay in starting control were modeled. At fox densities of 0.5 fox families/km2 or greater, a single oral vaccination campaign with bait uptake rates of less than 50% resulted in ineffective rabies control. An uptake rate of at least 80% was required to give a better than 80% chance of eliminating rabies. Vaccination was least effective at controlling rabies if applied 1 or 2 mo before the foxes gave birth. Seasonal timing of poison or V + FC had little effect on efficacy, which was always more successful than the oral vaccination alone. The longer the delay between the simulated start of the rabies infection and the application of a single vaccination campaign, the less successful was the control, particularly at the higher fox densities tested. At a fox density of 0.25 families/km2, all the strategies were equally successful at eliminating rabies. At higher fox densities V + FC was slightly less successful than culling, whereas vaccination-only was considerably less successful. The sole use of vaccination is not considered a viable control method for areas with high fox densities. The model suggests that an area of culling centered on the disease focus, plus an outer ring of vaccine or V + FC, could be the best strategy to control a point-source wildlife rabies outbreak.     

Incentives Increase Participation in Mass Dog Rabies Vaccination Clinics and Methods of Coverage Estimation Are Assessed to Be Accurate

In this study we show that incentives (dog collars and owner wristbands) are effective at increasing owner participation in mass dog rabies vaccination clinics and we conclude that household questionnaire surveys and the mark-re-sight (transect survey) method for estimating post-vaccination coverage are accurate when all dogs, including puppies, are included. Incentives were distributed during central-point rabies vaccination clinics in northern Tanzania to quantify their effect on owner participation. In villages where incentives were handed out participation increased, with an average of 34 more dogs being vaccinated. Through economies of scale, this represents a reduction in the cost-per-dog of $0.47. This represents the price-threshold under which the cost of the incentive used must fall to be economically viable. Additionally, vaccination coverage levels were determined in ten villages through the gold-standard village-wide census technique, as well as through two cheaper and quicker methods (randomized household questionnaire and the transect survey). Cost data were also collected. Both non-gold standard methods were found to be accurate when puppies were included in the calculations, although the transect survey and the household questionnaire survey over- and under-estimated the coverage respectively. Given that additional demographic data can be collected through the household questionnaire survey, and that its estimate of coverage is more conservative, we recommend this method. Despite the use of incentives the average vaccination coverage was below the 70% threshold for eliminating rabies. We discuss the reasons and suggest solutions to improve coverage. Given recent international targets to eliminate rabies, this study provides valuable and timely data to help improve mass dog vaccination programs in Africa and elsewhere.     

Application of the GARC Data Logger—a custom-developed data collection device—to capture and monitor mass dog vaccination campaigns in Namibia

Domestic dogs are responsible for 99% of all cases of human rabies and thus, mass dog vaccination has been demonstrated to be the most effective approach towards the elimination of dog-mediated human rabies. Namibia demonstrated the feasibility of this approach by applying government-led strategic rabies vaccination campaigns to reduce both human and dog rabies incidences in the Northern Communal Areas of Namibia since 2016. The lessons learnt using paper-based form for data capturing and management of mass dog vaccination campaign during the pilot and roll out phase of the project (2016–2018) led to the implementation of a simple and accurate data collection tool in the second phase (2019–2022) of the rabies elimination program. In this paper, we describe the implementation of such custom-developed vaccination tracking device, i.e. the Global Alliance for Rabies Control (GARC) Data Logger (GDL), and the integration of the collected data into a website-based rabies surveillance system (Rabies Epidemiological Bulletin—REB) during 2019 and 2020 campaigns. A total of 10,037 dogs and 520 cats were vaccinated during the 2019 campaign and 13,219 dogs and 1,044 cats during the 2020 campaign. The vaccination data were recorded with the GDL and visualized via REB. Subsequent GIS-analysis using gridded population data revealed a suboptimal vaccination coverage in the great majority of grid cells (82%) with a vaccination coverage below 50%. Spatial regression analysis identified the number of schools, estimated human density, and adult dog population were associated with the vaccination performance. However, there was an inverse correlation to human densities. Nonetheless, the use of the GDL improved data capturing and monitoring capacity of the campaign, enabling the Namibian government to improve strategies for the vaccination of at-risk areas towards achieving adequate vaccination coverage which would effectively break the transmission of rabies.     

The use of an E1-deleted, replication-defective adenovirus recombinant expressing the rabies virus glycoprotein for early vaccination of mice against rabies virus.

An E1-deleted, replication-defective adenovirus recombinant of the human strain 5 expressing the rabies virus glycoprotein, termed Adrab.gp, was tested in young mice. Mice immunized at birth with the Adrab.gp construct developed antibodies to rabies virus and cytokine-secreting lymphocytes and were protected against subsequent challenge. Maternal immunity to rabies virus strongly interferes with vaccination of the offspring with a traditional inactivated rabies virus vaccine. The immune response to the rabies virus glycoprotein, as presented by the Adrab.gp vaccine, on the other hand, was not impaired by maternal immunity. Even neonatal immunization of mice born to rabies virus-immune dams with Adrab.gp construct resulted in a long-lasting protective immune response to rabies virus, suggesting that this type of vaccine could be useful for immunization shortly after birth. Nevertheless, pups born to Adrab.gp virus-immune dams showed an impaired immune response to the rabies virus glycoprotein upon vaccination with the Adrab.gp virus, indicating that maternal immunity to the vaccine carrier affected the offspring's immune response to rabies virus.     

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.     

浓缩狂犬病疫苗接种后不良反应与血清抗体水平分析

报导了≥２．５ＩＵ浓缩狂苗人体接种后的不良反应其反应率为１．３１％与以往未浓缩常规苗的反应率为０．７３％比较两者具有显著性差异（Ｘ２＝６．９４,Ｐ＜０．０１）,浓缩苗以注射１～３针时的不良反应多,临床表现以局部极痛、红肿、瘙痒、急性荨麻疹和过敏性休克等。但其血清抗体阳转率７天时为４０．０％以上,１４天时为１００％,而常规苗仅是４０．０％,抗体滴度浓缩苗第７天时达到有效保护水平（中和试验）。显示了其抗体产生早,水平高特点,关于如何减少浓缩狂苗不良反应问题,作者提出了几点建议