It 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 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

Cleaveland, Sarah

Hampson, Katie

Lankester, Felix

Lembo, Tiziana

Palmer, Guy

Taylor, Louise

Science

English

PubMed

Enlighten: Publications

Implementing Pasteur's vision for rabies elimination: the evidence base and the needed policy actions

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n       Lankester, F., Hampson, K., Lembo, T., Palmer, G., Taylor, L., and Cleaveland, S. (2014) Implementing Pasteur's vision for rabies elimination. Science, 345 (6204). pp. 1562-1564. ISSN 0036-8075    Copyright © 2014 American Association for the Advancement of Science   http://eprints.gla.ac.uk/97729/       Deposited on:  01 October 2014                   Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk                                sciencemag.org      SCIENCE    VOL. 345  • galley printed 1 October, 2014  • •  For Issue Date: 26 September 2014 1  INSIGHTS  |  PERSPECTIVES SCIENCE GALLEY 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59    INFECTIOUS DISE ASE Implementing Pasteur’s vision  for rabies elimination Human and veterinary health systems must be better integrated. By Felix Lankester,1,2,3* Katie Hampson,3 Tiziana Lembo,3 Guy Palmer,1,2 Louise Taylor,4 and Sarah Cleaveland2,3 It has been 129 years since Louis Pasteur’s experimental protocol saved the life of a child mauled by a rabid dog, despite incom-plete 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 has not been realized. Rabies remains a threat to half the world’s population and kills more than 69,000 peo-ple each year, most of them children (2). We discuss the basis for this neglect and present evidence supporting the feasibility of elimi-nating canine-mediated rabies and the re-quired 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 de-veloped countries. In 2013, the one person diagnosed with rabies in the United States, which was predictably fatal, acquired the in-fection in Guatemala. In Western Europe no cases were reported in 2013; the one per-son 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 im-poverished communities, rabies threatens the world’s most marginalized people. Even in low-income countries, those from more affluent areas rarely die of rabies, as they are likely to promptly access highly effective postexposure prophylaxis (PEP). It is the poor who die; they are more frequently vic-tims 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 meth-ods (5), underdiagnosis and underreporting contribute to rabies neglect. The true inci-dence 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 dis-eases in low-income countries: The afflicted often do not reach medical facilities (4) so are never recorded. For those who attend a medical facility, the similarity of rabies symptoms to other neurologic conditions, including cerebral malaria (6), renders clini-cal diagnosis without laboratory support challenging. Even where laboratory facilities exist, diagnostic samples are rarely collect-ed, 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 in-terventions. Predominant disease burden metrics, such as disability-adjusted live years (DALYs), are important in focusing re-search and intervention agendas. However, decisions should also take into account the availability and effectiveness of control in-terventions 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 consid-ered highly cost-effective (7–9). Although global concerns relating to avi-an influenza have helped bridge medical and veterinary disciplines, a responsibility gap remains for zoonotic diseases not consid-ered a global threat. For rabies, prevention through dog vaccination is the province of veterinary medicine, whereas PEP is the re-sponsibility of physicians and nurses. Budg-ets to address rabies are rarely considered jointly, which results in ever-increasing PEP costs if the disease is not tackled at the ani-mal source. As rabies does not cause a high burden of disease in livestock, compared with many economically important transboundary livestock diseases, dog vac-cination has not been prioritized by veteri-nary services in low-income countries. However, if viewed more broadly as a socie-tal burden, rather than by using a single health or economic metric, the impact of ra-bies and priority for its control is substan-tially elevated (2, 8).  A One Health approach, integrating med-ical and veterinary sectors, is important both to develop appropriate metrics for evaluating the disease burden, and to en-sure shared operational responsibility for zoonosis control and prevention. Although international funding can facilitate this co-ordination (as shown for avian influenza), the most critical requirements are political commitment and building of trust and effec-tive communication between sectors, which need not be prohibitively costly. Establish-ment of an effective interministerial Zoono-tic Disease Unit in Kenya, which has rapidly developed integrated national plans for ra-bies control and elimination, provides a re-cent example of One Health coordination in-volving not only health and veterinary sectors but also wildlife services concerned with the threat that rabies poses to endan-gered wildlife.   ELIMINATION IS ACHIEVABLE. Although rabies virus is a multihost pathogen, the domestic dog remains the principal reser-voir and source of human rabies. The basic reproductive number for rabies (R0, the av-erage number of new cases generated by a single case) is consistently low (R0 < 2) in dog populations worldwide, despite wide variations in population density (10). This suggests that transmission can be relatively easily interrupted through mass dog vac-cination but not through the reduction of dog density, an approach that, despite being the first response to many rabies outbreaks (11), has never been successful (12). A growing body of evidence from Central and South America and pilot projects in Southeast Asia and Africa demonstrate the effectiveness of dog vaccination as a means to prevent human rabies in both high- and low-income countries (13). Annual vaccina-tion coverage of 70% controls and eventual-ly eliminates the disease (Fig. 1) (10).  Despite misperceptions of large “stray” dog populations, a high proportion of dogs are accessible for highly efficacious paren-1Paul 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 & Technology, Arusha, Tanzania. 3Boyd Orr Centre for Population and Ecosystem Health, Institute of Biodiversity, Animal Health & Comparative Medicine, University of Glasgow, Glasgow G12 8QQ, UK. 4Global Alliance for Rabies Control, Manhattan, KS 66502 USA. *E-mail: lankesterf@vetmed.wsu.edu                                   sciencemag.org      SCIENCE    VOL. 345  • galley printed 1 October, 2014  • •  For Issue Date: 26 September 2014 2  1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59    teral vaccination campaigns (14). Less than 11% of the dog population has been identi-fied as ownerless in Zimbabwe, Chad, Tan-zania, and South Africa (15). In densely populated Asian settings, where community dogs are common, techniques for vaccinat-ing free-roaming dogs have been successful-ly 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 ra-bies has been locally eliminated, the disease disappears in all species (15). This gener-ates confidence that control of canine rabies is epidemiologically achievable and that large-scale elimination is a realistic goal. This has been demonstrated by the reduc-tion in canine rabies by around 99% across Latin America, with elimination targets for the region set for 2015 (17). Is elimination of canine rabies economi-cally feasible? Empirical and theoretical studies of mass dog vaccination campaigns in low-income countries reveal that vac-cinating dogs against rabies is cost-effective up to the critical 70% vaccination coverage threshold (Fig. 1) (9), is significantly less expensive over the long-term than provid-ing PEP to bite victims, and can result in substantial savings to the public health sec-tor (8, 9, 18). These savings will be particu-larly relevant in Asia where currently 90% of global PEP is administered (2, 3). To real-ize these savings, initial external financing may be needed to support investments in dog vaccination. However, to ensure sus-tainability, financing strategies need to in-volve governments and to have flexibility to encourage community engagement and to exploit new approaches to enhance cost-effectiveness, such as linking dog vaccina-tion with other health delivery platforms.   ACROSS DISCIPLINES AND BORDERS. The only infectious diseases deliberately eradi-cated worldwide, smallpox and rinderpest, were within exclusive domains of human and veterinary medicine, respectively. Elim-inating canine rabies as a public health bur-den will require a One Health approach in-tegrated across sectors. This has proven much easier to advocate in theory than to achieve in practice. Many low-income coun-tries face a considerable challenge in coor-dinating and integrating activities across decentralized and fragmented veterinary and health care systems. This is exacerbated by a lack of linked regulatory policies.  Although growing scientific evidence is addressing misperceptions about canine ra-bies epidemiology and control, progress in many countries is still hampered by lack of political commitment and financing mecha-nisms. Pilot projects in Africa and Asia, which have supported initial investments in dog rabies control, demonstrate the power of catalytic funding to achieve operational progress, and allow veterinary and health services to move away from short-term or emergency responses toward a more coor-dinated 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 ani-mal health organizations can play an im-portant support role, for example, establish-ing mechanisms to ensure the affordable supply of human and animal vaccines and their effective cross-sectoral use.  An enduring challenge for global elimi-nation 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 budg-ets for cross-border control and the transparent sharing of surveillance and budgetary in-formation resulting in a collec-tive 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 re-sulted in transboundary networks and initi-atives in neighboring countries. Initial suc-cess provides momentum for further suc-cess. Canine rabies elimination meets all the criteria for a global health priority: It is epi-demiologically and logistically feasible, cost-effective, and socially equitable. Pasteur’s vi-sion is within our reach—we only need to move the hand forward to grasp it. REFERENCES AND NOTES  1. G. Geison, The Private Science of Louis Pasteur (Princeton Univ. Press, Princeton, NJ, 1995).  2. S. Shwiff, K. Hampson, A. Anderson, Antivi-ral 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. M. Mallewa et al., Emerg. Infect. Dis. 13, 136 (2007).   7. C. Rupprecht et al., in Towards the Elimina-tion of Rabies in Eurasia, B. Dodet, A. R. Fooks, T. Müller, N. Tordo, Eds. (Karger, Ba-sel, 2008), pp. 95–121.  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, Wall-ingford, 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. 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 institu-tions.   10.1126/science.1256306  Fig. 1. Impact of dog vaccination coverage on rabies outbreak probability and cost. The left-hand axis and the dashed blue line show the probability of an outbreak of 10 or more cases being seeded by an introduced case under different levels of vaccination coverage. The right-hand axis and solid red line indicate the total costs per km2 (U.S.$) of rabies control with increasing vaccination coverage. Vaccination coverage of 70% of the canine population reduces outbreak prob-                               sciencemag.org      SCIENCE    VOL. 345  • galley printed 1 October, 2014  • •  For Issue Date: 26 September 2014 3  1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59    ability close to zero and is cost-effective. Cost data from (9), probability data from (10).     

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Implementing Pasteur's vision for rabies elimination: the evidence base and the needed policy actions

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