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Emergency vaccination of rabies under limited resources – combating or containing?
© Eisinger et al; licensee BioMed Central Ltd. 2005
Received: 21 October 2004
Accepted: 07 March 2005
Published: 07 March 2005
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.
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.
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.
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.
Rabies is life-threatening for humans  and the most important viral zoonosis from a global perspective . In Europe and North-America, wildlife is the main reserve (i.e. foxes or raccoons). Aerial distribution of vaccine filled baits proved to be a method which can be used for controlling rabies in these species, as they are attainable via baits, and an efficient oral rabies virus vaccine is available [3, 4]. Therefore, disease managers have been making huge efforts in rabies control over the last 25 years [2, 5–9]. Long-term and large scale oral vaccination of wildlife eradicated rabies at the regional scale in central Europe and the Americas [10–16]. Consequently, repeated vaccination in these regions has now ended [8, 16, 17] and, eventually, its host populations will be completely susceptible to new rabies infection. Therefore, we must be aware of a reintroduction as long as rabies persists anywhere in the world,  and we have to develop emergency measures designed for a local outbreak in non-immunised wildlife populations. Thus recent contingency planning appears comparable to the situation in the UK at the end of the last century when an introduction from continental Europe was expected [19–23]. A lot of literature is available from that period concerning how a newly introduced rabies epidemic potentially spreads or will be controlled [21, 22, 24, 25]. However, empirical knowledge has been accumulated in the mean time regarding large-scale field application of oral vaccination, recognition of successful strategies or operating population immunity levels, and termination of repeated baiting. It appears worthwhile to exploit these sources, in order to adjust contingency plans for future rabies control in general and the event of rabies re-introduction in particular.
How should disease management react to re-introduction, i.e. detection of an infection within a rabies-freed area? Revitalising country-wide vaccination campaigns appears to be not very well-adapted to detection of a local rabies outbreak . A WHO  recommendation suggests 5,000 sq. km of compact vaccination area as the minimum sustainable strategy, but there are no details regarding the plausible spatial configuration. Field practice demonstrates that modern aerial distribution of vaccine-filled baits performs precisely, even on complex spatial distribution patterns [28, 29].
Thus, alternative control application schemes can be considered as emergency strategies, which 1) are able to restrict the spatial extent of the control area, 2) are able to eradicate the disease and finally, 3) are logistically practicable.
Disease managers usually think of combating an outbreak by immediately controlling all areas at risk . But in an emergency, when the outbreak is very local at first, to what spatial extent must a control area be designed to cover "all areas at risk", or in practice, to what distance might the disease spread until a protective immunisation level has been built up [24, 26, 30]? How can we exclude potential breakouts of infected hosts just before the control measures succeed in the controlled area? The most appealing counter-measure would fence in the epidemic first and eradicate afterwards. The "fence" could be realised by a ring-shaped area of competently vaccinated hosts at an adequate distance from the detected outbreak (see for example ). The host population of such a ring area is already well immunised before first infections will reach the inner border of the ring – hence the outbreak is actually contained. But, the ring approach promises another advantage: Although we BAIT an equally sized area compared to circle application, the larger spatial extent of the ring allows for an increased control area because the outer border of the ring is beyond the circle of respective size. Indeed, the inner part of the ring must not be treated in the beginning which could be important if we have to cope with logistic and/or resource limitations immediately after an outbreak (Vos, pers. comm). While aiming at a serious contingency plan, we still have to analyse the comparability of the two different approaches from the epidemiological discussion: Centred on the detected outbreak, we treat either a circular compact area or the equal-sized area, but arrange it in a ring around an omitted inner part (i.e. equal size of baited area, equal baiting program, equal number of baits and same bait density).
We use an explicit simulation model of the fox-rabies system to compare the different spatial designs of vaccination. We analyse how long the circle or the ring design can keep the rabies epidemic inside the control area. We compare the two spatial designs for the application of mixed strategies, i.e. the definition of most-rewarding-point-in- time, in order to change from ring to circle, as compared to a pure circle strategy. In case of a rabies outbreak in a previously rabies-free region, the results determine which of the strategies should be applied and how to benefit the most from limited resources.
We evaluated the management strategies with a model of the rabies-fox system which is tailored to emergency control planning. We applied a spatially-explicit, individual-based, time-discrete modelling approach [32–34]. This approach had already proved practical in studying the spread and control of rabies in foxes [26, 35–37] and to provide useful management support . Thus, previous models [26, 35, 36] were enhanced in order to cope with the new question. The rules of rabies dynamics between the fox family groups, as well as individual dispersal of juveniles after maturity, were adopted from the basic model [35, 36]. The spatial unit of a fox group home-range was also maintained because it had proven suitable for studying the disease spread on the regional scale [20, 38, 39]. Group home-ranges are implemented within regular grid cells, and the obtained results would not change if the grid cells were replaced by irregular shaped home-ranges of a given mean-size. This is because the dispersal movements are modelled relative to group home-range size [35, 40, 41] and not in metric measures [36, 42–45]. This approach incorporates an implicit adjustment of the fox density effect . A metric reference to fox densities within central Europe is realised by means of the mean-fox-group home-ranges (i.e. cells) corresponding to 1 sq. km. Compared to previous rabies models which had addressed an introduction of rabies [20, 25, 31, 47, 48], it was necessary to extend the simulation area (i.e. 256 times 256 cells corresponding to ~65.536 sq. km in a central European scenario) in order to allow relevant dimensions of the control area. The representation of the control area by a regular ring or circle within the model is an abstraction. When applied to real landscapes the vaccination areas are non-regular, as they are usually determined by administrative borders, hence certain excess areas must be baited additionally. Thus the geometric simplification in the model represents the required core area, which must at least be covered by the vaccination area defined along administrative units. But, the aim of our study necessitates a further step in scaling down the basic model . The temporal resolution was refined to a weekly time step, since the success of an emergency vaccination depends on the time of introduction of rabies into the fox population, the time until detection of the epidemic, and the timing of the initial vaccination campaign [7, 17, 20]. The model rules were complemented with ecological characteristics of, and disease transmission between, individual foxes of a group. The individual-based representation enables a locally varying immunisation level due to non-homogeneous bait uptake [50, 51] or individual foxes moving across the border of the vaccination area. The effect of these issues might be negligible for vaccination success on a geographical scale,  but it becomes serious for the few rabid animals after an outbreak or a spatially limited vaccination area WITHIN a landscape.
Basic fox population model
Parameters of the model, default values and reference.
Adjusted to 
Adjusted to 
Variable in accordance with simulation experiments
Reproduction is scheduled in the first week of April. All non-empty cells produce a litter of a normally distributed number of cubs with mean of 5.5 and a standard deviation of 1.5 [44, 57, 58, 62–64]. Fox groups which consist of exactly one individual reproduce with 50% probability. This rule accounts for floaters and multiple mating males as well as for non-reproducing males [53, 65, 66].
With these population dynamics, on average 3.5 juveniles per group emerge in the maturity dispersal (Goretzki, pers. comm.). The dispersal occurs for 8 weeks from October to November [64, 67]. Thus, during that phase per time-step one eighth of all cells are selected randomly. Out of each selected cell, all juveniles move consecutively according to the following dispersal algorithm. The dispersing individual is randomly assigned with a main direction from 8 cells of 360 degrees, which is maintained in each step with 50% probability [60, 67–69]. In the remaining steps the individual deviates to the left or to the right by one cell with equal probability (i.e. 25%; see ). The probability to settle in a cell (PSettle) increases with the distance travelled (PSettleDistance; ), but decreases with the number of adult foxes already in there (CrowdingFactor):
PSettle = PSettleDistance(Step) * CrowdingFactor(NumAdultFoxes)
PSettleDistance(Step) = (15% + (1-0.15) * Step/60)
Each fox has a disease state (susceptible, infected, infectious, or immune). The state is updated according to weekly time-steps. If infection was introduced in a cell by neighbourhood contact one adult fox is randomly selected. If this fox is not susceptible but "immune", nothing happens, otherwise its state changes from "susceptible" to "infected". The "infected" fox gets infectious after a negative exponential distribution with a minimum of 2 weeks and an effective mean of 3.5 weeks [71–74]. During the following infectious period of 1 week, a fox can transmit the disease [41, 75]. It is assumed that infected cubs will die of rabies, but can only transmit the infection if their incubation period ends after the dispersal .
If there is at least one infected fox in a cell, then the 8 neighbouring cells have a probability of 14% of getting infected [36, 76], i.e. approach of Infection Communities  or 'group infection rate' in .
Mating Contacts (additionally in January and February)
Distribution of baits
Standard vaccination protocol on the regional scale comprises biannual campaigns with 18–20 baits distributed per sq km [7, 10, 11, 13, 17, 79]. Accordingly, two vaccination events are performed in the model: one in the first week of April and one in the second week of September.
The mid cell of the grid receives an external infection during a randomly chosen week of the year. Subsequently, any rabies case will be detected with a probability of 2% [16, 24, 93, 94]. Rabid juvenile foxes will be detected only from August onwards .
First vaccination campaign
If one infected fox is detected, we assume a preparation time of 2 months until the first vaccination campaign is scheduled (Vos, pers. comm.). Further campaigns are performed according to the standard protocol: autumn and spring [7, 17, 79] – with the only exception being that the second campaign will not be performed less than two months after the initial baiting.
Spatial design – ring vs. circle
The relative assessment of the competing spatial designs is based on regular edges. Using the Moore neighbourhood, adjacent and diagonal cells are assumed to have equally scaled distances. The modelled emergency area is always centred on the first detected rabies case ignoring other "infected" cells on the grid.
The parameter vaccination area (PVacArea) corresponds to the maximum amount of cells that could be treated immediately after detection. PVacArea is set to be 6,400, 10,800 or 16,000 cells. The values are selected to provide useful width of the ring area (i.e. 20 km, 30 km or 40 km wide ring areas respectively). The area could be calculated into a necessary amount of baits after scaling the mean area of fox group home-ranges. For instance, in rural Europe fox group density of ~1 per sq. km is agreed [20, 51] which fixes the mean area of the cells in the model at 1 sq. km Thus, the amount of baits per campaign used in the three scenarios is roughly: 128,000, 216,000 or 320,000 respectively when applying 20 baits per sq. km.
The vaccinated area is compact around the detected outbreak and implemented in the model as a solid square. According to PVacArea, the region is 80*80, 104*104 or 126*126 cells respectively.
Simulation experiments are performed on a grid of 256 × 256 which totals 65,536 cells. We ran each simulation scenario 10,000 times to cover stochastic effects.
Experiment 1 – Containment of the epidemic with fixed resources
We assess which strategy performs better at confining the epidemic inside the control area over the short and long term. The frequency of infected foxes outside the control area provides the quantitative measure. The 3 sizes of vaccinated areas (PVacArea) remain constant throughout a simulation run.
Experiment 2 – Search for the optimal switch point from ring to circle strategy with increasing resources
The aim is to identify the strategy or a mixture of strategies which performs best in final eradication of the epidemic. The inner part of the ring has to be baited in the end to achieve eradication. Thus resource limitation is assumed to be eased at some point in time, and the baited area (PVacArea) is doubled afterwards. The resource extension is assumed with a lag of either 1 or up to 5 vaccination campaigns. Again, initial vaccination areas (PVacArea) will have 3 different sizes but they are doubled after the time lag. Technically, the following spatial configuration is applied in this experiment: Either we already start baiting the circle whose surface gets doubled after the time lag. Or, we start baiting the ring of the same size and after the time lag we continue baiting the circle of doubled surface, which of course contains the ring. Hence, the final treated area is always a solid square of 112*112, 146*146 or 178*178 cells respectively. Figure 5(c) shows an example of the configuration.
When parameters of the model were altered, only the quantitative results changed, but neither the qualitative results nor the conclusions did. But there is one noteworthy difference between large-scale and local vaccination concerning immunisation level. In emergency control the relatively small baited areas are surrounded by a susceptible neighbourhood and thus non-immunized foxes will regularly disperse into the baited region and vice versa. Indeed, the immunisation level maintained by the circle or ring strategy was measured lower than for the large-scale application (Fig. 4a), in particular at the edges of the control areas (Fig. 4b). Nevertheless, the resulting immunisation in the model was still sufficient to eradicate rabies locally, which is in agreement with recent findings about potential over-baiting during the past control programs in Europe [15, 50, 82, 106, 107].
Experiment 1: Containing with fixed resources
In all scenarios we found noteworthy frequency of rabies infections spreading beyond the vaccinated area (Fig. 6a). For the medium amount of resources, about 1% of all simulation runs ended up with breakouts after 2 years. Independent of the amount of applied resources in the long run, the ring strategy performs worse than the circle strategy. In the ring strategy the number of rabies cases rises quickly (Fig. 6b) and the epidemic is not eradicated. On the other hand, by distributing the same resources in the circle strategy, the epidemic often gets eradicated (Fig. 6c). Only for the first two vaccination campaigns the ring strategy performs better in containing rabies.
Experiment 2: Eradication with increasing resources
According to Figure 10 we expect at least one mixed strategy (switching from ring to circle after k baitings) to perform better than the continuous circle approach. Following this idea, we conducted experiment 2: The initial strategy is changed after k vaccination campaigns towards a circle application. In practice, the change could commence when resource limitations are overridden. Thus resources are doubled after the switch and the final circular control areas are IDENTICAL for all mixed strategies, i.e. ring-circle and circle-circle.
Expert knowledge and biological data about the host, the epidemiology of the infection or even the efficacy of management measures are quite often vague in the sense that they are never measured, they are examined with highly differing results or they are even difficult to sample precisely [52, 108]. Nevertheless, it is necessary to overcome these uncertainties because management decisions have to be made . Usually, modelling studies tend to select one particular configuration and substantiate the parameter choice with the help of logical arguments. We suggest an approach that is oriented to robust conclusions for practical management in terms of different or even antagonistic model assumptions. There are initial studies in the literature [109, 110] which opt for the development of a more general methodology. The approach parallels standard techniques of model validation or sensitivity analysis. But we are no longer troubleshooting at the level of particular values which the model acquires in relation to slight changes in assumed parameters. We are only interested in changes at the level of conclusions made for management application, i.e. whether there are hypothetical scenarios which could falsify the management decision just derived from the model results. That is how practical management often performs . Thus, while targeting useful support for these decisions, we have already covered the need for 'robustness' during the shaping of our management proposal.
We compared two spatial strategies of local emergency vaccination for controlling a rabies outbreak. One refers to the immediate control of infection within a smaller treated area. The alternative was theorised to overcome the drawback of a spatially limited strategy by providing equal resources in a ring around the affected area which contains the infection at the cost of more cases in the centre.
Simulation of the two spatial strategies revealed the true dynamics of the models. The ring strategy in general does not outperform the circle strategy. The predicted advantage of the ring strategy can only be found in the short term (Fig. 6a). Therefore, we determined mixed strategies and searched for the most rewarding point in time for switching between the ring strategy, which was better in the short term, and the circle strategy, which was better in the long term (Fig. 10).
Why aren't we able to identify the switch point as suggested by the risk analysis? Figure 10 actually proposes a switch around the third campaign. However, no matter which point we chose for switching from ring to circle in experiment 2, we did not find a clear advantage at all for the mixed strategy. There is only one plausible reason for this disagreement between the mind and the simulation model. The switch between the two strategies comprises a time lag until the protection level is reached inside the ring, i.e. until the inner part of the former ring actually acts like a circle. Our qualitative risk assessment (Fig. 9) assumes a perfect change between strategies. In practice however, we have to consider the temporal delay of building up population immunity which was shown to be at least 2 vaccination campaigns [16, 87, 91–93, 104] in noteworthy agreement with our simulations (Fig. 4a). Thus the change in strategy has to take place two baitings in advance of the theoretical suggestion in order to profit with the mixed strategy. But the ideal switch point found in the simulation is around the 3rd baiting campaign (Fig. 10). After subtracting the building up time of 2 vaccination campaigns in practice we need to change at baiting 1, i.e. we must apply the circle strategy from the very beginning.
Consequently, in the field we cannot benefit from the alternative baiting scheme and hence are forced to focus contingency planning on a compact control area around the detected outbreak. After testing the respective models, we can reject a-priori any pure vaccination field trial that attempts to distribute vaccine baits with a ring-like strategy.
Our findings are not contradicted by the successful application of cordon-sanitaire vaccination at borders of large-scale vaccination areas in the field [17, 27, 111–115]. In fact, the basic difference between a ring-like vaccination around a new outbreak and the cordon-sanitaire is the aim of control: In the outbreak situation we do not need to accept the rabies inside the ring, but in the second, the border situation, we have to. Rabies persists "on the other side" of the cordon, i.e. if neighbouring countries have not (successfully) combated the disease. Although the ring-like emergency vaccination does provide some protection for the surrounding area in the same manner in which the cordon-sanitaire vaccination does, in the emergency situation we aim for ultimate eradication, and in order to achieve this, our results clearly require the treatment of a compact circle-like control area.
The only threat for success of control is the migration of infected foxes from the limited area under treatment into the non-vaccinated surroundings. We cannot limit the distance infected foxes disperse, but we can reduce the number of them by means of the control itself. It is the circle strategy in which the number of rabies infections is lowered right from the beginning.
Geometry of circle vs. ring. Gain in the maximum distance from the point of outbreak by using a ring instead of a circle. Presented scenarios with input parameters framed. Bold – respective calculations for scenarios not presented. Smaller inner non-vaccinated area reduces the gain, whereas a large inner radius reduces the thickness (i.e. protective ability) of the ring.
Vaccinated area [km2]
ring thickness [km]
ring – inner radius [km]
ring – outer radius [km]
circle – outer radius [km]
If the ring design strategically loses, i.e. in eradicating rabies, are there other benefits which outweigh the disadvantage? There are two other potential benefits to consider: economy and public health. With modern aerial bait disposal controlled by the GPS, logistic costs do not differ substantially between the two spatial designs (Mürke, pers. comm.). The cost is mainly linked to the total number of baits needed for the program. However, we demonstrated that in the ring design the time lag until the spared inner part is vaccinated directly adds to the time until eradication (Fig. 11b). This increases the cost of the ring design as compared to the earlier eradication in the circle design.
The remaining public health issue is the principal objective [7, 71, 116]. Eradication of the disease is the only method for achieving this objective . However, within the inner part of the ring the epidemic roams freely and thus imposes a risk to humans and livestock which makes it less competitive than the compact circle approach. Additionally, eradication takes longer and thus the threat to public health is prolonged. Consequently, we can rule out the ring as a non-viable approach in terms of eradication, economy and public health.
In all respects we concluded that the circle performs better. But we still have to deal with possible early breakouts. Whilst zero risk strategies perhaps represent political demand, they are probably neither possible nor the most cost-effective approach. However, additional measures could be applied for an improvement of the performance of the circle strategy and will be considered in the ongoing analysis: Firstly, better monitoring programs could lower the time until detection of an outbreak, which consequently leads to an earlier eradication. Secondly, it is not clear whether immediate vaccination with a risk of imperfect placement performs better than waiting with the first vaccination until a monitoring program has provided a better understanding of the spatial extent of the outbreak. Thirdly, circles baited with spatially varying density of baits could provide both, the required fast suppression of the epidemic and the largest possible control area (see  for a combined simulation of poisoning and ring vaccination). And finally, follow-up programs can be designed. Indeed, the circle strategy with a control area of 10.800 sq. km has already provided a very low likelihood of breakouts. Thus, the strategic approach could extend the initial circular area to a non-circular control area (but still vaccinated on a regular basis), according to detected breakouts. Raised awareness after the reintroduction of rabies and particular border surveillance around the baited area, would guarantee fast detection of breakouts. Thus, we recognise the need for a more detailed cost-benefit, which explores the cost of extensions of the control area, versus the benefit of reducing the amount of resources applied to the initial hazard area.
If vaccination is the only approved measure for fighting a rabies outbreak within a completely susceptible fox population, then the only feasible contingency plan is to vaccinate a compact area centred on the epidemic. The ring strategy which leaves an inner part non-vaccinated must be ruled out in all concerns: strategically, since it under-performs in eradication levels, economically, since eradication takes longer and public health, since it allows more cases of rabies.
Yet even in the circle strategy, there remains some risk of early breakouts of rabies from the control area. Thus, further studies should concentrate on optimizing the emergency strategy concerning timing and benefits of additional monitoring programs. Furthermore, a detailed cost-benefit analysis of potential strategic alternatives is needed in order to improve the outcome of a contingency plan.
DE was partly funded by Impfstoffwerke Dessau-Tornau GmbH. We gratefully acknowledge improvements according to referees' comments.
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