In Europe, the elimination of wildlife rabies using oral rabies vaccination [ORV] of foxes for more than 30 years has been a success story. Since a comprehensive review on the scope of the different oral rabies vaccine baits distributed across Europe has not been available yet, we evaluated the use of different vaccine baits over the entire period of ORV [1978–2014]. Our findings provide valuable insights into the complexity of ORV programs in terms of vaccine related issues. More than 10 oral vaccines against rabies were used over the past four decades. Depending on many factors, the extent to which oral rabies virus vaccines were used varied considerably resulting in huge differences in the number of vaccine doses disseminated in ORV campaigns as well as in large spatial and temporal overlaps. Although vaccine virus strains derived from the SAD rabies virus isolate were the most widely used, the success of ORV campaigns in Europe cannot be assigned to a single oral rabies virus vaccine alone. Rather, the successful elimination of fox rabies is the result of an interaction of different key components of ORV campaigns, i. e. vaccine strain, vaccine bait and strategy of distribution.
Elimination of infectious diseases from wildlife populations is a major challenge. Thus, until a few decades ago, elimination of wildlife-mediated rabies from Europe was considered wishful thinking. This paralleled the results of early conventional control measures aimed at stopping the expansion of fox rabies in Europe [1,2]. Almost all attempts to reduce the fox population below a threshold, where the chain of infection would be interrupted and the epidemic would fade out, using intensive culling, poisoning, and trapping failed [3]. Moreover, scientists, veterinary and public health authorities came to understand that focusing on reduction of the fox population evidently was counterproductive as it disrupted the social and spatial organization of foxes, thereby increasing contact rates and disease incidence [3,4]. The development of attenuated oral rabies virus vaccines in the second half of the 20th century provided a unique opportunity to target elimination of the infection circulating in European wildlife [5,6]. Concerted inter-sectorial applied research activities in a few European countries such as Switzerland, Germany and France pioneered the basic techniques for a suitable strategy for oral rabies vaccination (ORV) of foxes. These included the type of baits, timing of vaccination campaigns, bait delivery densities, adequate modes of bait distribution, and duration and monitoring of ORV campaigns [2,7]. What started as a small but ground-breaking field trial in Switzerland in 1978 [8] soon became the most widely-used model for controlling and eliminating a zoonosis in its wildlife reservoir host. Triggered by promising results of first field trials in the 1980s and accelerated by a strong political commitment of European governments and the co-financing policy of the European Union (EU) for member states and neighboring non-EU countries [9], many rabies affected European countries implemented long-term ORV programs [10]. However, it was not until further scientific and technical achievements, e. g. the development of manufacturing methods for baits and the application of computer supported automatic aerial distribution equipment for baits were made that large-scale vaccination campaigns became possible [2,11]. Despite perceived challenges and individual setbacks at national or international levels [10,12], the current rabies situation provides an impressive testimony of the efficiency and future potential of wildlife vaccination [2,13]. Within the past 30 years the overall rabies incidence in Europe decreased by approximately 80% compared to the peak year 1984 during which 24,315 rabies cases were reported (www. who-rabies-bulletin. org). Furthermore, the disease was completely eliminated from Western and Central Europe [2,13,14]. The proportion of landscape 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 control and eliminate rabies [13]. Highly potent and safe oral rabies vaccines have been the key for the elimination of wildlife rabies in Europe and several regions of North America [10,15]. All rabies vaccines used for oral immunization of wildlife in Europe are based on live replication-competent vaccine viruses [15]. The first generation vaccines were attenuated rabies viruses developed by conventional in vivo and/or in vitro serial passaging of virulent field virus isolates resulting in e. g. SAD Bern, SAD B19, SAD P5/88, Vnukovo-32, or RV-97 [16–19]. The second generation was developed by selection of monoclonal antibody escape mutants, e. g. SAD VA1, SAG1, or SAG2 [20–23]. Later, site-directed mutagenesis [reverse genetics] led to the development of a third generation of oral rabies vaccines, e. g. ERA G333 [24]. Finally, a recombinant vaccinia virus expressing the rabies virus glycoprotein from the ERA strain [V-RG] [25,26] has been used. The progenitor of almost all attenuated rabies virus-based vaccines currently in use in Europe is the vaccine virus strain SAD Bern [27], a derivative of the original SAD (Street Alabama Dufferin) virus isolated from a rabid dog in 1935 in the US [28]. The limited available information on the use of those vaccines in ORV programs in Europe [7,29,30] resulted in speculations whether the efficiency of ORV programs in Europe can be attributed to a single vaccine only or whether certain vaccines are more efficient than others under field conditions. However, a comprehensive review of the scope of oral rabies virus vaccines distributed across Europe had not been available. We therefore evaluated the spatio-temporal use of different oral rabies virus vaccines in individual European ORV programs over the past 37 years.
The study region encompassed all countries in Europe that implemented ORV programs on their territories between 1978 and 2014 (Fig 1). The standard ORV approach applied typically comprised of (i) performance of ORV campaigns twice a year (spring and autumn), (ii) an average bait density of 20–25 baits/km2, (iii) aerial and manual (mainly at the beginning of ORV, later complementary) distribution of vaccine baits, and (iv) a flight line distance of 500 to 2000 m in case of aerial distribution of baits [13]. In a few exceptions ORV campaigns were only conducted once a year (Italy, 1984) or additional campaigns were conducted either in summer or in winter (France, Germany 2005, Italy 2009) or at short intervals (Germany, 2005; Italy, 2010) [31,32]. As part of the terms of reference as a WHO Collaborating Centre for Rabies Surveillance and Research, data related to ORV programs of individual European countries for the past 37 years were collected from three different sources including (i) information provided by veterinary or other competent authorities (list of contributors to the WHO Rabies Bulletin Europe, http: //www. who-rabies-bulletin. org) upon request, (ii) presentations of members states given at meetings the Standing Committee on the Food Chain and Animal Health—Section:" Animal health and animal welfare" (SCFCAH) [http: //ec. europa. eu/food/committees/regulatory/scfcah/animal_health/index_en. htm], and (iii) official websites of competent authorities of European countries concerned. For each ORV campaign (spring, summer, autumn, winter or other) carried out during the observation period data comprised information on the size of vaccination areas, the timing of vaccination campaigns, bait density, mode of bait distribution, and oral rabies vaccine strains used. The size and location of individual vaccination areas was either requested as shape files or, if not available, as scanned maps from publications or presentations [13]. For countries that implemented ORV programs during the review period we established a GIS database with individual campaign based datasets using ArcGIS software [Esri Inc. , version 10. 2. , Redlands, California, USA]. Maps of vaccination areas that were not available as shape files were digitalized, converted into the GIS databases as previously described [33], and subsequently sent to competent authorities or rabies experts of the respective European countries for validation and revision, if necessary. Information on the oral rabies vaccines used was assigned to any individual vaccination area or sub-region (national units of territories) therein. Data of the entire observation period were subsequently stratified, compiled and displayed in maps. Using ArcGIS analysis tools we calculated the size of the area exclusively vaccinated in Europe with a single oral rabies vaccine or with multiple vaccines by considering vaccine combinations. For each oral rabies vaccine used during the observation period we also calculated the area in which it was used. The total number of vaccine baits for each individual vaccine distributed in Europe was computed based on the size of the cumulative vaccine-specific vaccination areas and an assumed average bait density of 20 baits/km2.
During the past 37 years, 30 European countries implemented ORV programs. In autumn 1978, Switzerland conducted the first European ORV campaign ever; the last country to join efforts to eliminate fox-mediated rabies was Albania in 2014. In seven countries, ORV programs were discontinued and re-initiated either due to re-infection, establishment of a vaccination belt (cordon sanitaire) as a result of unfavorable rabies situation in neighboring regions, or budget constraints. During the review period 10 countries successfully eliminated fox and raccoon dog-mediated rabies from their territory using ORV (Fig 1). Since 1978, the total area ever vaccinated encompassed 2. 5 million km2, within which a total of ten different attenuated rabies virus-based vaccine strains and one recombinant vaccine were used [Fig 2]. In the early days of ORV in Europe (1978–1984) baits consisted of chicken heads each containing a sachet made of plastic and aluminum foil with 1. 8 ml SAD vaccine. Since the development of novel manufactured baits in 1983, later almost all vaccine baits in Europe (SAD P5/88, SAD B19, SAD Berne, V-RG, SAG-1, SAG-2, SAD VA1) have used fish meal as attractant, while the carrier substance differed between the baits (paraffin, polymer, coconut fat). Bait casings usually contained 150 mg of tetracycline as a biomarker. About 1. 52 million km2 (60. 8%) of the total area comprising different regions in 25 countries were exclusively vaccinated with a single representative of the available 11 vaccines strains. In contrast, in 702,482 km2 (28. 1%) and 278,415 km2 (11. 1%) of the area, two and three, or more than three vaccines were distributed, respectively, over the complete time span of ORV in Europe (Tables 1–3). When the size of vaccination areas covered in all individual vaccination campaigns in respective countries between 1978 and 2014 (Fig 1) was summarized, the cumulative vaccination area encompassed 33. 25 million km2. Assuming an average bait density of 20 baits/km2, the estimated total number of vaccine baits distributed between 1978 and 2014 amounts to 665 million (Fig 3). The spatio-temporal use of the different vaccine strains varied considerably. The temporal use of the different vaccine strains is depicted in Fig 4. With a time span of 35 and 32 years of application and an area of 1. 96 and 1. 12 million km2 covered with at least a single campaign by SAD Bern and SAD B19, respectively, these two vaccines were the most widely used throughout Europe. V-RG, SAD P5/88 and SAG2 had been used to a much more limited extent. Although having been authorized for more than 20 years, the area ever vaccinated with vaccine baits of those three vaccine strains comprised 0. 54,0. 31 and 0. 21 million km2, respectively (Fig 5A–5D). In contrast, the remaining vaccine strains were only used at a minor scale during a shorter period of time (<11 years) (Figs 3 and 6A and 6B) with a limited number of baits distributed in the field.
We show that the extent to which oral rabies virus vaccines were used in Europe varies considerably in space and time. Next to the type of vaccine virus strains used, there is significant difference in the number of vaccine doses distributed in ORV campaigns as well as tremendous spatial and temporal overlap. Although SAD derived vaccine virus strains are the most widely used, the success of ORV campaigns in Europe cannot be attributed to a single oral rabies virus vaccine or a specific group of vaccines (e. g. first vs. second generation vaccines or modified live vs. recombinant vaccines). Result are likely due to the interaction of different key components, programs and strategies, including adequate distribution of efficacious vaccine-baits that led to the elimination of fox rabies from vast areas of Europe [13].
Oral rabies vaccination [ORV] is the pre-eminent example of successful vaccination of wildlife populations which has resulted in virtual elimination of fox-mediated rabies from large parts of Western and Central Europe. This achievement is unprecedented in history. Attractive species-specific baits, efficient vaccination strategy, and highly potent and safe oral rabies vaccines have been instrumental for the success. Numerous oral rabies vaccines for wildlife have been developed over the past four decades. However, information on the use of those vaccines in operational ORV programs in Europe that exists has until now not been fully publicly accessible. Here, we provide the first comprehensive review of the spatio-temporal use of oral rabies vaccines over the entire period of ORV [1978–2014]. Although ‘first generation’ vaccine virus strains derived from the SAD rabies isolate are the most widely used, the results do not support significant differences in efficacy of these strains under field conditions nor can success of ORV be attributed solely to one vaccine type. In contrast, vaccination strategy is of major importance. Our analyses could help in the development of adequate rabies control strategies by documenting the importance of vaccination strategy, in which oral rabies vaccines are only one contributing component among other parameters.
Spatio-temporal Use of Oral Rabies Vaccines in Fox Rabies Elimination Programmes in Europe