Rabies is considered one of the most dangerous but neglected diseases in developing countries, with the greatest burden in the poorest rural communities where 15 million people need PEP every year [28]. In China, rabies is thought to be under-reported or under-recognized, resulting in an under-estimation of the true disease burden [7].The State Council issued official notices in 2009 and 2012 underlining rabies control as a priority with control objectives between 2015 and 2020 [29,30]. Our study highlighted both the strengths and gaps in the rabies control efforts in China. Despite the decline in human rabies cases at the national level since 2008, especially successful control in historically high-incidence provinces, China has to face a new complication that rabies started to spread from high-incidence regions towards low-incidence regions, as evidenced in our statistical and phylogeographic analyses.
Our findings reveal that the higher temperature, the higher risk of human rabies, which is consistent with the observed peak season in Summer and Autumn. Such seasonality is not surprising, as people tend to wear less and have more outdoor activities (in the absence of indoor air-conditioning in rural areas) in warm and hot weather, and hence have more frequent contact with canines, irascibility of which is sensitive to high temperatures. It also seems reasonable that the male incidence is far higher than the female incidence, as in rural China men tend to have more outdoor activities than women due to cultural factors [31]. The newly-established endemic counties or hotspots mostly occurred in the west or north to the previous endemic areas and represented a trend of spreading of the virus from the southern and eastern regions to the northern and western regions (Fig. (Fig.3,3, ,4).4). Such movement might be explained by the fact that interventions were implemented in baseline high-incidence regions over the years [32] whereas the baseline low-incidence regions started to suffer the increasing burden of rabies in the absence of interventions.
Our analyses revealed the importance of improving the education level and economic status in reducing human rabies incidence in mainland China, and partially explained why farmers, students, and pre-school children are the high risk groups [11]. It is believed that the unawareness of rabies risk and the high price of the rabies PEP are the main reasons for the high incidence in the population with low education and low income [8].The decreasing incidence in rural areas of high-incidence provinces might be partially due to recent efforts in educational campaign about rabies and the introduction of new rural cooperative medical subsidies for PEP costs [32]. In addition, the health services and medical standards for rabies diagnosis and treatment are believed to be other key factors affecting human rabies incidence. For example, the country’s investment in training health professionals on PEP and increasing access to PEP in the countryside likely contributed to the decrease in human rabies cases after 2007 [7,32]. In this study, however, we were not able to quantify the contribution of any intervention due to the lack of data. However, we urge relevant agencies and organizations to extend these intervention programs to rural areas with historical low incidences, in particular around the hotspots we identified.
The rapid economic development in China has greatly encouraged the ownership and transportation of domestic dogs, yet the vaccination of dogs is left far behind [11,32], facilitating the rabies spread. With the help of phylogeographic analysis, some long-distance spread events were detected and support the geographic dispersion pattern found in our epidemiological investigation. Clade I of rabies, especially Clade I-G, was found to dominate recent spread across provinces. These results suggest that the movement of hotspots of human rabies may be a consequence of long distance instead of cross-border migration of hosts. However, interpretation of these results should be cautious as potential sampling bias of sequences could distort the underlying truth. Additionally, although having contributed to most rabies epidemics in the past decade, Clade II was playing a less significant role in the epidemic since 2009. The emergence of the Clade I and the gradual displacement of Clade II are also obvious in recent studies [3,6,33,34]. Our phylodynamic analyses highlight the importance of closely monitoring Clade I in the future and the need to strengthen canine rabies surveillance, to regulate interprovincial animal trade, and to intervene promptly upon detection of canine rabies outbreaks. The usefulness of efficient surveillance on canine rabies is also evidenced by our identification of the positive association of human rabies outbreaks with the canine counterparts at a two-month lag.
While some developed countries, such as the United States and Western European countries had achieved their goal of eliminating human rabies cases, most developing countries, especially those in Africa and Asia, continue to suffer from the burden of rabies and account for 95% of global human cases [35,36]. The magnitudes and epidemiological patterns of rabies differ from country to country [37]. Taking countries bordering China for example, India has the highest rate of human rabies in the world, and its rabies incidence has been nearly constant for a decade. Thailand is moving towards low endemic status, and Indonesia sees increase in incidence and expansion in range. Despite these differences, these countries share some common risk factors, e.g., educational level, economic status and canine rabies [35,36]. A certain level of internationally coordinated efforts such as communication about successful control experiences may be helpful towards global elimination of human rabies [37].
Our study shares some similar limitations with previous studies. The data were collected from a passive surveillance system, which may underreport cases of human rabies especially in rural and remote areas. If underreporting is truly more severe in rural and remote areas where socioeconomic and educational levels are usually lower, the magnitude of the impact of GDP and education levels might have been underestimated. However, this underreporting should have small influence on our results for clustering and expansion of the epidemics, as the hotspots identified in this study are of large scale and encompass both developed and underdeveloped areas. The lack of some highly relevant data such as dog density and dog vaccine coverage also limited our understanding of the true effects of the available risk factors and the driving reason for the declining trend of the overall epidemic. Additionally, GDP per capita and average education years used in our panel Poisson regression were from a single year instead of all the study years. Nevertheless, these data were usually relatively stable over a few years, and spatial heterogeneity generally dominates over temporal changes. Moreover, Bayesian CAR could be used in the panel Poisson model to account for spatial and temporal correlations due to similarity in unmeasured risk factors, which is subject to future research [38]. Finally, despite the large geographic coverage of the sequences used in our phylogeographic analysis, the lack of a sufficient number of sequences at some high-incidence locations such as Guangdong may have led to an incomplete picture of the genotypic distribution and spread of rabies in mainland China.
Overall, we outlined a clear picture of the epidemic patterns of human rabies in China using a multi-disciplinary spatiotemporal analytical approach, and this approach is an integral part in the design of effective elimination strategies for human rabies [35]. We reiterate that control efforts should focus on not only the high-incidence areas but also the low-incidence and emerging areas in order to achieve the goal of rabies elimination by 2020 [13]. The enhanced surveillance of human rabies cases, effective intervention programs, and efficient cooperation among relevant agencies have worked together to achieve the success in rabies control in high-incidence areas since 2007 [32,39,40]. Elimination of rabies is feasible and can be cost effective [41,42]. However, the new challenge of geographic expansion of the rabies epidemic needs to be addressed together with traditional challenges, e.g., the canine immunization coverage may be far below 70%, a critical threshold for interrupting rabies virus circulation in the dog population [1]. We recommend supplementing current control strategies with the allocation of appropriate amount of intervention resources to low-incidence areas, especially areas with limited access to educational and economic development.