INFECTIOUS DISEASE Implementing Pasteur’s vision for rabies elimination Human and veterinary health systems must be better integrated if rabies is to be controlled By Felix Lankester,1,2,3* Katie Hampson,3 Tiziana Lembo,3 Guy Palmer,1,2 Louise Taylor,4 Sarah Cleaveland2,3 I t has been 129 years since Louis Pasteur’s experimental protocol saved the life of a child mauled by a rabid dog, despite incomplete understanding of the etiology or mechanisms by which the miracle cure worked (1). The disease has since been well understood, and highly effective vaccines are available, yet Pasteur’s vision for ridding the world of rabies POLICY has not been realized. Rabies remains a threat to half the world’s population and kills more than 69,000 people each year, most of them children (2). We discuss the basis for this neglect and present evidence supporting the feasibility of eliminating canine-mediated rabies and the required policy actions. A NEGLECTED PRIORITY. Because of effec- tive control of rabies in domestic dogs, it is no longer a disease of major concern in developed countries. In 2013, the one person diagnosed with rabies in the United States, 1562 which was predictably fatal, acquired the infection in Guatemala. In Western Europe no cases were reported in 2013; the one person who died of canine-mediated rabies in 2012 was bitten by a dog in India. With more than 95% of human cases occurring in Africa and Asia (3), largely in rural and impoverished communities, rabies threatens the world’s most marginalized people (see the first photo). Even in low-income countries, those from more affluent areas rarely die of rabies, as they are likely to promptly access highly effective post-exposure prophylaxis (PEP). It is the poor who die; they are more frequently victims of rabid dog attacks, they suffer fatal delays in trying to access PEP, or simply cannot afford to pay for it (4). Despite recent developments of simple, rapid, and highly accurate diagnostic methods (5), underdiagnosis and underreporting contribute to rabies neglect. The true incidence of human rabies in Asia and Africa is estimated to be between 20 and 160 times what is officially reported (3). The reasons for this are common among neglected diseases in low-income countries: The afflicted sciencemag.org SCIENCE 26 SEP TEMBER 2014 • VOL 345 ISSUE 6204 Published by AAAS CREDIT: MYANMAR-ROHINGYA/REUTERS/DAMIR SAGOLJ The human cost of rabies. Having not received post-exposure prophylaxis after a dog bite, a 16-year-old boy suffers the terrifying symptoms of rabies. often do not reach medical facilities (4, 6) so are never recorded. For those who attend a medical facility, the similarity of rabies symptoms to other neurologic conditions, including cerebral malaria (7), renders clinical diagnosis without laboratory support challenging. Even where laboratory facilities exist, diagnostic samples are rarely collected, and where a clinical diagnosis is made, many cases are not reported to national or international authorities. Coupled with this structural underdiagnosis and underreporting is the current approach to prioritizing disease interventions. Predominant disease burden metrics, such as disability-adjusted live years (DALYs), are important in focusing research and intervention agendas. However, decisions should also take into account the availability and effectiveness of control interventions and their implementation cost. For rabies, although a DALY score of 1.74 million lost per year is low compared with HIV, malaria, or tuberculosis, highly effective animal vaccines are available to control and eliminate disease in animal reservoirs and to prevent human deaths for a price considered highly cost-effective (8, 9). Although global concerns relating to avian influenza have helped bridge medical and veterinary disciplines, a responsibility gap remains for zoonotic diseases not considered a global threat. For rabies, prevention through dog vaccination is the province of veterinary medicine, whereas PEP is the responsibility of physicians and nurses. Budgets to address rabies are rarely considered jointly, which results in everincreasing PEP costs if the disease is not tackled at the animal source. As rabies does not cause a high burden of disease in livestock, compared with many economically important transboundary livestock diseases, dog vaccination has not been prioritized by veterinary services in low-income countries. However, if viewed more broadly as a societal burden, rather than by using a single health or economic metric, the impact of rabies and priority for its control is substantially elevated (2, 8). A One Health approach, integrating medical and veterinary sectors, is important both to develop appropriate metrics for evaluating the disease burden, and to ensure shared operational responsibility for zoonosis control and prevention. Although international funding can facilitate this coordination (as shown for avian influenza), the most critical requirements are political commitment and building of trust and effective communication between sectors, which need not be prohibitively costly. Establishment of an effective interministerial Zoonotic Disease Unit in Kenya, which has rapidly developed Downloaded from http://science.sciencemag.org/ on July 18, 2016 INSIGHTS P E R S P E C T I V E S 180 0.10 140 istered (2, 3). To realize these savings, initial external financing may be needed to support investments in dog vaccination. However, to ensure sustainability, financing strategies need to involve governments and to have flexibility to encourage community engagement and to exploit new approaches to enhance cost-effectiveness, such as linking dog vaccination with other healthdelivery platforms. Although rabies virus is a multihost pathogen, the domestic dog 100 0.00 remains the principal reservoir and 0 20 40 60 80 source of human rabies. The basic ACROSS DISCIPLINES AND BORVaccination coverage (%) reproductive number for rabies DERS. The only infectious diseases (R0, the average number of new Impact of dog vaccination coverage on rabies outbreak probability and deliberately eradicated worldwide, cases generated by a single case) cost. The left axis and the dashed blue line show the probability of an outbreak smallpox and rinderpest, were is consistently low (R0 < 2) in dog of 10 or more cases being seeded by an introduced case under different levels within the exclusive domains of populations worldwide, despite of vaccination coverage. The right axis and solid red line indicate the total human and veterinary medicine, wide variations in population dencosts (U.S.$) per km2 of rabies control with increasing vaccination coverage. respectively. Eliminating canine sity (10). This suggests that transVaccination coverage of 70% of the canine population reduces outbreak rabies as a public health burden mission can be relatively easily probability close to zero and is cost-effective. Cost data from (9), probability will require a One Health approach interrupted through mass dog vacdata from (10). integrated across sectors. This has cination (see the chart). In contrast, proven much easier to advocate although reducing dog density has been the scale elimination is a realistic goal. This in theory than to achieve in practice. Many first response to many rabies outbreaks (11), has been demonstrated by the reduction in low-income countries face a considerable it has never been successful (12). canine rabies by around 99% across Latin challenge in coordinating and integrating A growing body of evidence from CenAmerica, with elimination targets for the reactivities across decentralized and fragtral and South America and pilot projects gion set for 2015 (17). mented veterinary and health care systems. in Southeast Asia and Africa demonstrate Is elimination of canine rabies economiThis is exacerbated by a lack of linked reguthe effectiveness of dog vaccination for precally feasible? Empirical and theoretical latory policies. venting human rabies in both high- and studies of mass dog vaccination campaigns Although growing scientific evidence is low-income countries (13). Annual vaccinain low-income countries reveal that vaccinataddressing misperceptions about canine ration coverage of 70% controls and eventuing dogs against rabies is cost-effective up to bies epidemiology and control, progress in ally eliminates the disease (see the second the critical 70% vaccination coverage threshmany countries is still hampered by lack of photo) (10). old (9), is significantly less expensive over political commitment and financing mechDespite misperceptions of large “stray” the long-term than providing PEP to bite anisms. Pilot projects in Africa and Asia, dog populations, a high proportion of dogs victims, and can result in substantial savings which have supported initial investments in are accessible for highly efficacious parento the public health sector (8, 9, 18). These dog rabies control, demonstrate the power teral vaccination campaigns (14). Less than savings will be particularly relevant in Asia, of catalytic funding to achieve operational 11% of the dog population has been identiwhere currently 90% of global PEP is adminprogress, and allow veterinary and health fied as ownerless in Zimbabwe, Chad, Tanzania, and South Africa (15). In densely populated Asian settings, where community dogs are common, techniques for vaccinating free-roaming dogs have been successfully applied (11). Studies of rabies epidemiology in the Serengeti National Park in Tanzania and the surrounding communities demonstrate that domestic dogs, not wildlife, drive rabies transmission dynamics (16). Where dog rabies has been locally eliminated, the disease disappears in all species (15). This generates confidence that control of canine rabies is epidemiologically achievable and that large- PHOTO: FELIX LANKESTER 1 Paul G. Allen School for Global Animal Health, Washington State University, Pullman, WA 99164, USA. 2School of Life Sciences and Bioengineering, Nelson Mandela African Institution of Science and Technology, Arusha, Tanzania. 3Boyd Orr Centre for Population and Ecosystem Health, Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow G12 8QQ, UK. 4Global Alliance for Rabies Control, Manhattan, KS 66502, USA. *E-mail: lankesterf@vetmed.wsu.edu A mass dog rabies vaccination clinic in Tanzania. This makeshift clinic was set up by the Serengeti Health Initiative. SCIENCE sciencemag.org 26 SEP TEMBER 2014 • VOL 345 ISSUE 6204 Published by AAAS 1563 Downloaded from http://science.sciencemag.org/ on July 18, 2016 220 0.20 Cost/km2 (U.S.$) ELIMINATION IS ACHIEVABLE. Efect of dog vaccination on rabies and cost Probability of outbreak integrated national plans for rabies control and elimination, provides a recent example of One Health coordination involving not only health and veterinary sectors but also wildlife services concerned with the threat that rabies poses to endangered wildlife. INSIGHTS P E R S P E C T I V E S Water’s place in Au catalysis Water plays a key role in gold-catalyzed CO oxidation T water and the gold surface or the gold-support interface can oxidize CO, enhancing catalytic activity relative to the hydroxylfree surface (6–9). Different authors have pointed to either cationic gold (6, 7) or metallic gold (8, 9) taking part in this activation process. Others have proposed that the generation of a hydroperoxyl-like surface intermediate via the interaction of water with O2 on the surface of the gold particle may facilitate CO oxidation (10, 11). The diversity of proposed active sites and mechanisms has done little to resolve the debate surrounding water-enhanced CO oxidation. Rather than becoming clearer over time, many aspects of this process have become more perplexing. 10.1126/science.1256306 26 SEP TEMBER 2014 • VOL 345 ISSUE 6204 sciencemag.org SCIENCE 1. G. Geison, The Private Science of Louis Pasteur (Princeton Univ. Press, Princeton, NJ, 1995). 2. S. Shwiff et al., Antiviral Res. 98, 352 (2013). 3. D. L. Knobel et al., Bull. World Health Organ. 83, 360 (2005). 4. K. Hampson et al., PLOS Negl. Dis. 2, e339 (2008). 5. T. Lembo et al., Emerg. Infect. Dis. 12, 310 (2006). 6. W. Suraweera et al.; Million Death Study Collaborators, PLOS Negl. Trop. Dis. 6, e1847 (2012). 7. M. Mallewa et al., Emerg. Infect. Dis. 13, 136 (2007). 8. J. Zinsstag et al., Proc. Natl. Acad. Sci. U.S.A. 106, 14996 (2009). 9. M. C. Fitzpatrick et al., Ann. Intern. Med. 160, 91 (2014). 10. K. Hampson et al., PLOS Biol. 7, e53 (2009). 11. A. A. G. Putra et al., Emerg. Infect. Dis. 19, 648 (2013). 12. M. K. Morters et al., J. Anim. Ecol. 82, 6 (2013). 13. T. Lembo et al., Dogs, Zoonoses, and Public Health, C. N. L. Macpherson, F.-X. Meslin, A. I. Wandeler, Eds. (CAB International, Wallingford, UK, ed. 2, 2013), pp. 205–258. 14. S. L. Davlin, H. M. Vonville, Vaccine 30, 3492 (2012). 15. T. Lembo et al., PLOS Negl. Trop. Dis. 4, e626 (2010). 16. T. Lembo et al., J. Appl. Ecol. 45, 1246 (2008). 17. M. A. Vigilato et al., Philos. Trans. R. Soc. Lond. B Biol. Sci. 368, 20120143 (2013). 18. S. E. Townsend et al., PLOS Negl. Trop. Dis. 7, e2372 (2013). ACKNOWLEDGMENTS K.H. is supported by the Wellcome Trust (095787/Z/11/Z), and L.T. by the UBS Optimus Foundation. Opinions, findings, conclusions, and recommendations are those of the authors and do not necessarily reflect the views of the supporting institutions. Published by AAAS Downloaded from http://science.sciencemag.org/ on July 18, 2016 By Gregory M. Mullen1 and C. Buddie Mullins1,2 he discovery of highly active gold catalysts for CO oxidation (CO + ½O2 → CO2) about 25 years ago (1) ignited substantial interest in the use of gold as a catalyst. Yet, this seemingly simple reaction has proven to be quite complicated. No consensus exists regarding the mechanism by which gold catalyzes CO oxidation. Confounding the understanding of this process was the discovery that incorporation of minute quantities of water in the reactant feed stream can increase catalytic activity by up to several orders of magnitude (2). Many conflicting reports have been proposed for the role of water in the CO oxidation reaction. On page 1599 of this issue, Saavedra et al. (3) present a compelling mechanism that ties together the conclusions of many of these reports. There are two key questions regarding water-enhanced CO oxidation on gold catalysts. Does water enhance the reaction by promoting the decomposition of surface intermediates or by assisting in the activation of reactants? And is the active site of the catalyst associated with the gold particle surface or the gold-support interface? A few reports have suggested that incorporation of water into the feed Where water fits in. Many ideas have been proposed for the role stream for CO oxidation promotes of water in gold-catalyzed CO oxidation. The results reported by the decomposition of surface inSaavedra et al. indicate that water adsorbed at the gold-support termediates (4, 5). Such an effect interface plays a key role in this process. could reduce catalyst deactivation, leading to enhanced activity. For example, Saavedra et al. explored the water-enhydroxyl groups located on the supporting hanced CO oxidation reaction on a titaniamaterial near the gold-support interface supported gold catalyst. This system has may abstract hydrogen from a reactive inbeen very well studied, but the authors were termediate on the gold surface, resulting in nevertheless able to make novel observations the formation of water and a more stable with a relatively simple technique. They conintermediate that blocks the active site (4). trolled the amount of water on the catalyst Inclusion of water in the feed stream would surface by gently drying the material while reverse this process by driving equilibmonitoring adsorbed water and hydroxyl rium toward regeneration of the hydroxyl species with infrared (IR) spectroscopy. Regroups on the support and the less stable moval of weakly adsorbed water from the intermediate. surface resulted in a substantial decrease in Alternatively, water may assist in the acactivity for CO oxidation. Furthermore, the tivation of reactant species on the catalyst authors observed a large kinetic isotope efsurface. A number of potential active sites 1 McKetta Department of Chemical Engineering, University and mechanisms exist for this type of proof Texas at Austin, Austin, TX 78712, USA. 2Department of cess. Studies have proposed that hydroxyl Chemistry, University of Texas at Austin, Austin, TX 78712, USA. E-mail: mullins@che.utexas.edu species produced by interactions between REFERENCES AND NOTES 1564 CHEMISTRY ILLUSTRATION: P. HUEY/SCIENCE services to move away from short-term or emergency responses toward a more coordinated and proactive program of disease prevention and control. Work is needed to determine how best to scale up from such pilot studies to the national and regional programs that will be needed for eventual elimination. International human and animal health organizations can play an important support role, for example, establishing mechanisms to ensure the affordable supply of human and animal vaccines and their effective cross-sectoral use. An enduring challenge for global elimination is the ability to work effectively across national boundaries. This has been achieved successfully in the Americas through the REDIPRA network (Directors of National Rabies Control Programs), with specific budgets for cross-border control and the transparent sharing of surveillance and budgetary information resulting in a collective commitment to a public good, as well as constructive peer pressure. Newer regional rabies networks in Asia and Africa could develop along the same lines. Successful rabies control programs in KwaZulu-Natal, South Africa, supported through pilot funding, have resulted in transboundary networks and initiatives in neighboring countries. Initial success provides momentum for further success. Canine rabies elimination meets all the criteria for a global health priority: It is epidemiologically and logistically feasible, costeffective, and socially equitable. Pasteur’s vision is within our reach—we only need to move the hand forward to grasp it. ■ Implementing Pasteur's vision for rabies elimination Felix Lankester, Katie Hampson, Tiziana Lembo, Guy Palmer, Louise Taylor and Sarah Cleaveland (September 25, 2014) Science 345 (6204), 1562-1564. [doi: 10.1126/science.1256306] This copy is for your personal, non-commercial use only. Article Tools Permissions Visit the online version of this article to access the personalization and article tools: http://science.sciencemag.org/content/345/6204/1562 Obtain information about reproducing this article: http://www.sciencemag.org/about/permissions.dtl Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2016 by the American Association for the Advancement of Science; all rights reserved. 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