More than just vaccine is needed to eliminate brucellosis. Many processes like systemic surveillance and public engagement are also necessary. The following text provides information about components of a One Health disease elimination.

Rationale

Brucellosis control by livestock mass vaccination and subsequent test-and-slaughter is effective and in this way brucellosis has been eliminated in several countries. Yet, its control is stagnating or even re-emerging in many parts of the world, especially in Africa and Asia. Depending on the context, the cross-sector nature of brucellosis involving wildlife, livestock and humans requires a systemic integrated approach when aiming towards elimination. However, the public health and animal health sectors work in too much separation from one another. While research on better vaccines is urgent and on-going, control and elimination of brucellosis is not merely an operational problem. Control and elimination of brucellosis is a science challenge because of complexity in the involved processes and the way in which these processes contribute to fundamental properties of the biology of brucellosis. From a matrix mathematical point of view, a brucellosis intervention aimed at elimination can be considered as a major perturbation leading towards a disease free equilibrium state. Here the different components of a science of brucellosis elimination involving all actors in public and animal health are outlined.

Components of a science of brucellosis elimination

** Pathogen biology in the social-ecological system**
Prior to implementing brucellosis control and elimination activities, the main reservoirs and their population dynamics must be known. The population dynamics of reservoir hosts directly determines the effective reproductive number (R_e) of brucellosis transmission and the persistence of transmission (Racloz et al. 2013). Because of the long incubation period, the role of density dependence and contact networks in brucellosis transmission are not well understood and require more research. In Mongolia, effective reproductive numbers were estimated at 1.2 in small ruminants and 1.7 in cattle and a vaccination coverage of 80% was recommended for the 2000-2010 mass vaccination campaign (Zinsstag et al. 2005a).

A recent study in Mongolia showed that since the end of the socialist period in 1990 the livestock population of goats, cattle and sheep changed in different ways. In particular, the goat population rose sharply because cashmere was the only source of cash income. However, all livestock species suffered heavy losses from snow storm catastrophes in 2001 and 2009. A near doubling of the Mongolian livestock population very likely contributed to the largely ineffective mass vaccination campaign (2000 - 2010) because the number of vaccinations was not sufficiently adjusted to account for the growing number of animals (Shabb et al. 2013). The high human brucellosis seroprevalence in 2012 indicates that brucellosis transmission in Mongolia continues, so an additional mass vaccination was initiated, for which the achieved vaccination coverage is now being systematically assessed (Tsend 2014).

** Social determinants and public engagement
Effective interventions against brucellosis rely on important enabling public conditions. Both public and private veterinary services need to be sufficiently staffed and able to cover the area of intervention. Sufficient human and veterinary laboratory capacity is needed, along with the ability to characterize isolated bacterial strains. Implementing test-and-slaughter control schemes requires sufficient public funding to compensate farmers for culled stock and a relatively corruption-free environment. Above all, a societal consensus is needed, which is only achieved by including all actors in so called ‘transdisciplinary’ stakeholder processes (Hirsch Hadorn et al. 2008). Through this process, all involved stakeholders contribute to identify priority actions and this should create trust between them (Schelling et al. 2007).

Systemic surveillance**
Understanding the disease ecology allows for identification of interventions which have the highest effect. For this purpose, joint animal-human cross-sectional studies provide a snapshot of disease frequencies in the most important reservoir hosts and may indicate the main source of human infection. In a representative study in Kyrgyzstan human seroprevalence was significantly related to sheep seroprevalence but not to goats and cattle (Bonfoh et al. 2012).

Such studies should be complemented by molecular epidemiological studies to ascertain transmission pathways and reservoir hosts. In the Kyrgyz example, brucella melitensis strains were isolated mostly from sheep, with a few from cattle but none from goats. Unfortunately the Kyrgyz health authorities refused to share human strains, which would have documented the sources of the human strains (Kasymbekov et al. 2013). In addition, diagnostic tests are very often not validated properly.

Recent Bayesian analytical work allowed for estimating true seroprevalence for several diagnostic tests without a Gold Standard (Durr et al. 2013). In addition to the validation of diagnostic test, the sheer lack of diagnostic tests in district public health centres contributes to huge underreporting of the disease. The Mongolian authorities have recently adopted a modified Rose Bengal test for human diagnosis confirmation in district health centres.

Mathematical model frameworks: transmission dynamics
Mathematical modelling of the transmission dynamics of brucellosis assists in following up the effectiveness of interventions (Zinsstag et al. 2005a). Such models are the backbone to intervention economic analysis (Roth et al. 2003) and can be used to assess animal-human interfaces. In this example, it can be shown that brucella melitensis seems to be more readily transmitted to humans than brucella abortus. In Mongolia, the small ruminant to human transmission constant was 13 times lower than that between small ruminants, ie one infected small ruminant infected 13 other small ruminants before one person was also infected. Assuming the cattle were mostly infected with brucella abortus, the cattle to human transmission constant was 165 times lower than that between cattle transmission. Such findings are still very rare and need to be further assessed (Zinsstag et al. 2015).

The mathematical analysis of an elimination intervention provides a tool to validate fundamental properties of transmission dynamics like the threshold population below which brucellosis transmission is interrupted. For the pastoral system in Mongolia we estimated that the threshold density to interrupt transmission for cattle was 1.2 (min. 0.6; max. 8) cows/km² and for small ruminants it was about 6.8 (min. 4.5; max. 21) small ruminants/km² (Racloz et al. 2013). Mathematical models of brucellosis should be combined with molecular strain characterization using full sequencing to address the risk of reintroduction into a previously brucellosis free zone.

Equity effectiveness
The effectiveness of an intervention is a multiplicative rather than additive process: for example, the product of the vaccine efficacy times the achieved coverage. The coverage, in other words, the proportion of animals effectively reached by a mass vaccination, is determined by the vaccine availability, accessibility, affordability, acceptability and adequacy. Further, it depends on the service provider compliance and the adherence to the mass vaccination by the animal holder (Obrist et al. 2007). An understanding of the determinants of the effectiveness of an intervention requires a close interdisciplinary collaboration between, among others, vaccine biology, health systems research, health economics, social and cultural sciences and animal health. Even if all intervention factors have a relatively high performance, they are all related to each other in a multiplicative way (Zinsstag et al. 2011a).

This may lead to very low community effectiveness, which falls below the threshold to interrupt the transmission of brucellosis. Nonetheless, the detailed understanding of the intervention factors is critical for achieving a successful intervention (Zinsstag et al. 2011b). Understanding the effectiveness of an intervention is a core element of the science of brucellosis elimination. Novel quantitative models of intervention effectiveness should allow for identification of the most sensitive effectiveness factors, which need to be harnessed to make an intervention successful.

From our research on dog rabies elimination in African cities and brucellosis control in Mongolia, we have learned that above all, the monitoring and evaluation of vaccination coverage is a critical element for the follow up of an effective intervention. Often, the basic principles of random sampling proportional to size are not understood and it is insufficient if vaccination coverage assessments are only done in vaccinated herds. A basic epidemiological understanding is essential for successful implementation of a mass vaccination campaign. Vaccination coverage data, ie the proportion of effectively vaccinated animals, combined with field epidemiological seroprevalence and sequence data from isolated strains can be used to validate the effectiveness of the intervention as predicted by models like the ones cited above (Zinsstag et al. 2005a).

Intervention methods
The choice of intervention methods depends on the prevalence of the disease and the available funds. It is well established that mass vaccination of livestock is recommended in settings where brucellosis seroprevalence is above 1% (Zinsstag et al. 2012). Below this, a test-and-slaughter method is recommended, whereby seropositive animals would be culled after systematic sampling. However, one should bear in mind that most developing countries would not be able to compensate farmers for culled stock and the existing levels of corruption would probably not allow for successful implementation of such schemes. Intervention methods must be carefully analysed within a given political and socio-economic context.

Cross-sector economic analyses provide a societal perspective which could lead to sharing of intervention costs between, for example, the livestock and public health sectors (Roth et al. 2003). To achieve elimination, novel financing instruments could be examined like development impact bonds (DIB) which are currently investigated for the elimination of sleeping sickness (trypanosoma brucei rhodesiense) in Uganda. With DIBs, the risks are shared between national governments, institutional donors and private investors (Zinsstag et al. 2007). Another precedent is the successful elimination of rinderpest which could be re-invigorated for the elimination of livestock brucellosis, at least in areas with negligible wildlife reservoirs.

The way forward

Brucellosis elimination is also achievable in developing countries. Above all, it requires a societal consensus addressing issues like compensation or intervention types which should not be decided over the heads of livestock owners. Successful examples of disease elimination shows that all actors need to be involved from the start, as all of them play important roles. Specifically, the public health and animal health sectors should work as closely together as possible (Zinsstag et al. 2015, Zinsstag et al. 2005b).

Regional approaches, for example involving Mongolia, China and Russia, will also be needed to address issues of cross border transmission, and, in this way, brucellosis control would probably make a significant practical contribution to the create trust and peace building. The proposed science of brucellosis elimination does not stand alone, it should learn from other initiatives, like the science of malaria eradication or the science of rabies elimination (Zinsstag 2013).

Further orientations could aim at combining, for example brucellosis and echinococcosis mass vaccination. One could also think about a locally adapted extended farm package including dog rabies, echinococcosis, brucellosis, anthrax, and FMD. Brucellosis can be eliminated, but we need to all work together in an evidence based systemic way.

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References

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Durr, S. et al. (2013). Bayesian estimation of the seroprevalence of brucellosis in humans and livestock in Kyrgyzstan, in: Revue Scientifique Et Technique, 32(3), 801-15.

Hirsch Hadorn, G. et al. (2008). Handbook of Transdisciplinary Research, London, Springer.

Kasymbekov, J. et al. (2013). Molecular epidemiology and antibiotic susceptibility of livestock Brucella melitensis isolates from Naryn Oblast, Kyrgyzstan, in: PLoS Neglected Tropical Diseases, 7(2), e2047.

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Zinsstag, J. et al. (2007). Human Benefits of Animal Interventions for Zoonosis Control, in: Emerging infectious diseases 13(4), 527-531.

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Zinsstag, J. et al. (2015). One Health. The Theory and Practice of Integrated Health approaches, Wallingford, CABI.

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