This book chronicles the unforgettable account of one of the most severe child abuse cases in California history. It is the story of Dave Pelzer, who was brutally beaten and starved by his emotionally unstable, alcoholic mother: a mother who played tortuous, unpredictable games--games that left him nearly dead.

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He had to learn how to play his mother's games in order to survive because she no longer considered him a son, but a slave; and no longer a boy, but an 'it.' Dave's bed was an old army cot in the basement, and his clothes were torn and raunchy.

When his mother allowed him the luxury of food, it was nothing more than spoiled scraps that even the dogs refused to eat. The outside world knew nothing of his living nightmare. He had nothing or no one to turn to, but his dreams kept him alive--dreams of someone taking care of him, loving him and calling him their son.

Zoonoses are increasingly recognized as an important burden on global public health in the 21 st century. High-resolution, long-term field studies are critical for assessing both the baseline and future risk scenarios in a world of rapid changes.

We have used a three-decade-long field study on hantavirus, a rodent-borne zoonotic pathogen distributed worldwide, coupled with epidemiological data from an endemic area of China, and show that the shift in the ecological dynamics of Hantaan virus was closely linked to environmental fluctuations at the human-wildlife interface. We reveal that environmental forcing, especially rainfall and resource availability, exert important cascading effects on intra-annual variability in the wildlife reservoir dynamics, leading to epidemics that shift between stable and chaotic regimes. Our models demonstrate that bimodal seasonal epidemics result from a powerful seasonality in transmission, generated from interlocking cycles of agricultural phenology and rodent behavior driven by the rainy seasons. Pathogens shared with wildlife cause more than 60% of human infectious diseases. However, there is a scarcity of comprehensive modeling of zoonotic disease dynamics at the wildlife-human interface. Here, we use 30 years of monthly rodent-hantavirus monitoring to show that the complex seasonality in human spillover results from the interplay between an ecological cascade that shapes reservoir infection dynamics and seasonal agricultural cycles that in turn determine human-wildlife contact patterns. Introduction Most emerging infectious diseases are zoonotic, and more than 70% of these originate among wildlife [].

Zoonotic disease emergence and reemergence has been hypothesized to be driven by environmental and anthropological variability at the human-wildlife interface [–]. However, recent reviews of our understanding of the determinants of spillover have shown that a critical knowledge-gap [] exists as we lack empirically validated models of the ecological interactions between humans, wildlife reservoirs and key environmental drivers [,]. In order to untangle the complexity of zoonotic spillover, combined field surveillance and modeling approaches that link the contacts between humans and wildlife with disease dynamics within the wildlife reservoir are essential []. However, such comprehensive investigations are still lacking for almost all zoonotic disease systems [].

Hantaviruses are rodent-borne zoonotic pathogens within the Bunyaviridae family that cause hundreds of thousands of hospitalizations annually on a global scale. Depending on the viral strain in question, which may cause hantavirus pulmonary syndrome (HPS) or hemorrhagic fever with renal syndrome (HFRS), case fatality rates range between 0.5–40% []. Hantavirus is responsible for numerous significant zoonotic outbreaks, including the outbreak of HFRS due to Hantaan virus (HTNV) during the Korean War [], and HPS due to Sin Nombre virus (SNV) in the Four Corners region of the United States in 1993 [] and more recently in Yosemite National Park, California, in 2012 []. Hantaan virus, which is in the clade of hantaviruses that causes HFRS, was first isolated in 1978 [].

Previous analyses of hantavirus infection dynamics suggest that changes in climate [–], environmental condition and/or agricultural activity affect the risk of zoonotic transmission via changes in reservoir dynamics [,], exposure risk [–], or virus stability in the environment [–]. However, HPS/HFRS epidemics do not appear to simply track environmental conditions or rodent dynamics [,].

An integrated picture of host-environment interactions and the resulting hantavirus transmission and spillover is far from clear. China has the highest incidence of HFRS worldwide.

Our study area in central China, Hu County, is one of the main epidemic areas and serves as a national surveillance site to monitor the HFRS situation. Since 1984, a unique longitudinal field study of hantavirus in rodents with additional epidemiological tracking of human incidence has been conducted in the area (). From 1994 onwards, an attempt has been made to control hantavirus transmission through the targeted routine vaccination of adults aged 16 to 60 yrs. Despite these control efforts, the dominant hantavirus (HTNV) continues to infect humans, with dynamics exhibiting clear seasonal and interannual variability as outbreaks invariably coincide with the end of the two rainy seasons ().

Seasonality and dynamics In Hu County, a total of 9,626 HFRS cases were reported from 1984–2014, with the highest incidence of 0.3% occurring in 1984. During the study, 10,598 rodents were captured in 247,408 trap-nights, with a capture rate of 4 rodents per hundred trap-nights. Of the rodent species captured, striped field mice ( Apodemus agrarius, mean capture rate of 2.1) was the most frequently captured species, with 48% (5079/10598) of total captures, followed by brown rats ( Rattus norvegicus, mean capture rate of 0.9), buff-breasted rats ( Rattus flavipectus, mean capture rate of 0.7), Gansu hamsters ( Cansumys canus, mean capture rate of 0.3), and house mice ( Mus musculus, mean capture rate of 0.2) [].

Hantavirus antigen-positive captures were also found in the rodent species: A. Norvegicus, R. Flavipectus, C. Canus, and M. Musculus with positive rates of 6.8% (346/5079), 0.5% (12/2237), 0.2% (4/1702), 0.3% (2/677), and 0.2% (1/493), respectively. Complete S segments of Hantaan virus (HTNV) were obtained from A.

Agrarius and HFRS patients from 1984–2012 (, ) as described both previously and in this study [,]. This result indicates that HTNV, carried by A. Agrarius, is primarily associated with the HFRS cases in Hu County. While other rodent species were relatively rarely infected, these sequences were closely clustered with little antigenic variation from sequences obtained from A. Agrarius even over long periods of time (), indicating that these are spillover infection of HTNV. We therefore chose to explore the epidemics of HFRS by considering its dynamics solely within A.

Agrarius, using field and laboratory studies. We found that HFRS epidemics increased after the rainy seasons, even after the mass vaccination program was initiated in 1994, which was associated with a decrease in the mean number of cases (). This suggests powerful seasonality in wildlife-to-human transmission.

However, while the incidence indicates a clear intra-annual variability with a strong correspondence to A. Agrarius dynamics (R = 0.80, P. Ecological cascades Changes in interannual patterns of epidemics may be linked to changes in potential environment drivers. Environmental variability has cascading effects on wildlife population dynamics [–], through breeding success () and mortality (resource availability and carrying capacity), which may further affect hantavirus dynamics []. We propose a mechanistic mathematical model to explore the response of hantavirus dynamics to environmental fluctuations. The model includes the logistic growth of the rodent reservoir [], where A.

Agrarius population dynamics are influenced by environmental factors affecting both birth and death rates, which are in turn determined by amount of rainfall in the breeding season and the carrying capacity of farmland, respectively (see ). The model supports our dynamical hypothesis, and captures the qualitative pattern of rodent population dynamics (). In particular, the model accurately predicts the unusually low abundance between 2002 and 2005. Our analysis reveals that the exceptional 2002 population crash in autumn breeding could be traced back to a significant food shortage, as crops growing after the spring harvest in our study area were affected by extreme drought in 2002. The extent of this catastrophic drought in the area is illustrated by the temperature vegetation dryness index (TVDI) (). In addition, the mean normalized difference vegetation index (NDVI) for farmland in this region was significantly lower during the drought year of 2002, compared with other years ().

Significantly, drought may be associated with low breeding rate (), and the resulting food shortage may increase mortality for most rodents (), except the brown rat ( R. Norvegicus) which lives in close association with humans and does not rely on farm crops (). Environmental fluctuations, rodent host dynamics, and hantavirus infections. The dynamics of A. Agrarius normally undergoes biennial cycles, which was especially the case in the high population densities of 1984 and 2012.

However, these population oscillations collapsed in 2002, initiating a population decline (). We infer that the life cycle of A. Agrarius in our study area is affected by rainfall and resource availability during the breeding season, and our model was therefore constructed to represent these dynamics (). Bifurcation analysis demonstrates that our model produces stable population dynamics (i.e.

Stable equilibria, in which population numbers remain constant) at low density under low rainfall or drought scenarios, oscillations with 1–2 yrs. Periodicity under normal rainfall, and aperiodic and chaotic dynamics (i.e. Chaos, in which population numbers change erratically) for strong environmental forcing and abundant rainfall (, ). Predicted environmental forcing alters dynamical stability. The magnitude of transmission rate varies with time and corresponds to time-varying contacts between susceptible and infected hosts []. Thus, environmental changes lead wildlife hosts to a critical density threshold, below which the virus cannot invade () [,]. In addition, a decreased carrying capacity is associated with loss of farmland area over time ().

This moves hantavirus dynamics into an environmentally forced regime with large fluctuations in infection rate. Transmission at the human-wildlife interface Intervention can explain the discrepancy between rodent dynamics and human infections at interannual timescales. In times of high rodent abundance, the response in number of HFRS cases would be expected to be large. However, the number of HFRS cases was low for 2001 and 2012, despite favorable transmission conditions due to high rodent density (). Our results indicate that these episodes were concurrent with a vaccination-induced reduction in human susceptibility.

This in turn reduced the number of human hantavirus infections and controlled the susceptible population size, even though the overall human population increased in these decades (see Supporting Information). Most notably, a significant decrease in the number of susceptible individuals was observed after the mass vaccination in 2011 (), and the measures implemented successfully averted further epidemics. In addition, the number of HFRS cases were clustered on an annual basis during two time periods: June to July, and October to November ().

The cases peaked and coincided with two important annual agricultural events, the spring and autumn harvest. Maize is sown in late October for the spring harvest at the end of May, and wheat is sown in June for the autumn harvest at the end of September and October.

These agricultural activities coincide with the two rainy seasons (). A second important cycle (shown in ) involves the pregnancy rate of A. Agrarius [], which closely matches the NDVI curve. Apodemus agrarius, which tends to live in agricultural fields, initiates its spring breeding season in April–May, and the autumn breeding season starts in August–September [].

It is interesting to note that the breeding season is closely associated with agricultural activity in Hu County. To summarize, the incidence of HFRS cases peaked during the harvests, when the risk of exposure of farmers to infected rodents in the farmland areas would have increased (, as the average incubation period for HFRS is approximately 3 weeks, ranging from 10 days to 6 weeks []). We estimated the seasonal variation in the transmission rate explicitly by applying the discrete-time susceptible-infected-recovered model to 30 yrs. Of monthly data from the area, and the fit of the full model accounts for 88% of the variability in the HFRS cases (). Discussion Public health scientists and epidemiologists are increasingly challenged to understand how environmental change and anthropogenic trends affect zoonotic disease dynamics at the wildlife-human interface [–]. An effective prevention and control method of zoonotic disease is required, which integrates ecological principles of animal, human, and environmental factors [,].

Our study of how shifts in disease ecology can be forced by environmental and anthropogenic processes sheds critical light on zoonotic dynamics and the persistence of disease []. We have shown the ecological drivers responsible for the cascading effects of environmental variability on HFRS, using a mechanistic mathematical model integrating longitudinal field surveillance, environmental change and epidemiological data. Once the wildlife and virus dynamics are taken into account, a clear picture emerges of the role of environmental variability in zoonoses []. We found support for intra-annual disease cycles driven by seasonal interactions between humans and wildlife, and by an environmentally induced cascade which can switch the dynamics of A. Agrarius abundance between stable and oscillatory []. This in turn affects seasonality in HFRS incidence. Our finding adequately explains the complexity and interrelatedness of the environmental, biological, and anthropogenic dimensions of zoonotic pathogen dynamics.

We have provided support for the hypothesis that environmental forcing, rainfall and related vegetation growth, may induce strong chain reactions [,] in wildlife dynamics and zoonotic epidemics []. Environmental conditions influence survival of the animal reservoir [,] and affect transitions between stability, cycles and chaotic dynamics. This is consistent with numerous field studies showing that an increase in resources would allow the rodent host to survive and reproduce [–], possibly leading to a higher prevalence of infection [,–] and a higher transmission rate among rodent populations with an older age structure [] as hantavirus infection is life-long in natural hosts []. In turn, this could lead to a greater chance of spillover to humans. Various studies cite HFRS as an example of a zoonotic disease which is linked to climate variability and environmental factors [–]. However, general predictions and a supporting model of the effects of environmental change on HFRS dynamics have not yet been empirically tested [,,].

Our results in this study suggest that the proposed mechanism would be valuable in broadening our understanding of human exposure to hantaviruses in general. Anthropogenic forcing has been linked to disease dynamics and relations between wildlife hosts, humans, and pathogens [,].

While prior research has traditionally focused on land-use change and zoonosis emergence [–], growing evidence indicates that the expansion of ecotones (transitional areas between adjacent ecological systems) can provide opportunities for pathogen spillover [,–]. Our work provides an improved understanding of the mechanistic processes linking anthropogenic environmental change (for instance, land-use change) and disease dynamics. During the study, farmland loss was found to be associated with host resources and carrying capacity, both of which affect wildlife abundance. In addition, over the past three decades there has been a decline in the abundance of A. Agrarius, coinciding with a long-term trend showing a decrease in the incidence of HFRS.

Our results suggest not only the role of environmental seasonality in shaping population fluctuations [,], but also 1) the critical role of human activities, which shape the seasonal dynamics of A. Agrarius by deeply influencing the local rodents’ activity and their life cycles, as well as 2) the role of seasonality in influencing contact between humans and the reservoir host. Apodemus agrarius has adapted to thrive in the ecological landscape created by agriculture. This adaptation amplifies seasonality in both transmission and spillover, which alter the spread of infectious diseases [–]. The estimated seasonality in the transmission rate shows a bimodal distribution, consistent with the seasonal timing of HFRS cases. Given the distinct roles of wildlife and agricultural activity in transmission, a reasonable explanation for this seasonal pattern is the increase in potential contact between rodents and humans in the dry season due to seasonal agricultural activities.

Overall, the combination of both agricultural and seasonal environmental forcing generates a setting in which irregular epidemics arise intrinsically. These findings not only provide evidence for the long-standing hypothesis that environmental change is associated with zoonotic persistence and amplification, but also indicate that the dynamical effects of human-wildlife interactions are dependent on environment-linked processes (). The HFRS vaccination strategy has been effective and has played an important role in reducing the incidence of HFRS in Hu County [,]. Despite this, challenges still remain regarding the prevention and control of HFRS outbreaks.

It should be noted that the incidence of HFRS evidently rebounded after 2010, even with high vaccination coverage []. This may be attributed to many factors and requires a deeper understanding of the drivers of zoonotic disease risk [,]. Taken together with the empirical data on demography and epidemiology, the results suggest that such erratic HFRS epidemics in the study area may have been generated by high amplitude wildlife oscillations interacting with environmental stochasticity and vaccination coverage.

All of this demonstrates that wildlife monitoring and modeling may not only help us to retrospectively understand the dynamics of the system, but may also provide advance warning of an outbreak. Several important limitations of this study should also be acknowledged. First, there is no surveillance data available before 1984, and it is therefore difficult to provide a possible mechanistic explanation for the rodent population peaks in 1984 and 1985. Second, although our rodent surveillance involved constant effort over time, the capture rate was estimated using an unequal number of traps between months. Third, the relationship between environmental variability and the infection rate of wildlife was not considered in the present analysis due to constraints in data availability, and this relationship may have accounted for unexpected outbreaks, e.g. The outbreaks in 1988 and 2011. Future surveillance efforts should include more detailed and frequent sampling of wildlife and hantavirus to improve our knowledge of the association between virus transmission and environmental variability.

Zoonotic diseases significantly impact human health globally, with approximately 1 billion cases and millions of deaths reported each year [], and are persistent public issues around the world. Our longitudinal survey provides evidence that the key to HFRS epidemic control is critical monitoring of wildlife and the environment, combined with mathematical models to forecast outbreaks and the vaccination of farmers at risk. Data The study was located in Hu County (108° E, 34° N) on the Loess Plateau of central China, an area of 1,255 km 2 and a population of approximately 600,000 people (according to the 2013 Chinese national census). We used the official monthly notification data of HFRS cases from Shaanxi Provincial Center for Disease Control and Prevention and associated demographic data available for Hu County between 1984 and 2014.

All HFRS cases were confirmed according to the standard diagnosis set by the Ministry of Health of the People’s Republic of China [], then confirmed by detecting antibodies against hantavirus in human serum samples. Serum samples were sent to the Shaanxi Centre for Disease Control and Prevention (CDC) for the detection of hantavirus-reactive antibodies. Between 1994 and 2014, a vaccination campaign was conducted in the study area. To assess both the vaccine efficacy and the loss of vaccine efficacy with time elapsed since vaccination, we randomly selected a total of 29,359 people from epidemic and non-epidemic villages in Hu County and monitored them []. The health records of each person were investigated, and blood was collected and analyzed by ELISA for the presence of anti-hantavirus IgG specific antibodies. Starting in 1984, surveillance of the rodent host population density in Hu County has been carried out on a monthly basis ().

In each month between 1984 and 2014, rodent trapping was carried out in the fields (farmland or wasteland, 3 km away from villages, which are the habitats for the important rodent reservoirs) in Hu County for three consecutive nights at 9 trapping sites, according to standard protocol from the Chinese Center for Disease Control and Prevention. Snap-traps (medium-sized steel rodent trap, brand name: Golden Cat, Guixi Mousetrap Factory, Jiangxi, China) were baited with peanuts, set each night, and recovered in the morning. At the trapping site, traps were set as 4 parallel lines of 25 traps each and were spaced at 5 m intervals. The trapped rodents were identified to species by species identification experts according to previously described criteria []. All rodents were accessioned to the Shaanxi CDC [84HX001-13HX141], and retained as voucher specimens for each species. Lung tissues were removed from the trapped rodents and stored immediately at –196°C, and then transported to the biosafety level-2 (BSL-2) laboratory of Shaanxi CDC for processing. The frozen lungs were sliced with a cryostat (Leica CM1950) and preserved in a refrigerator at –80°C.

Tissues and serum specimens for serological or molecular tests were handled during the various laboratory procedures in class II type A2 biosafety cabinets. The average monthly NDVI, an index of the amount and productivity of vegetation, was derived from satellite data and was generated as follows: NDVI = (NIR—VIS)/(NIR + VIS), where VIS and NIR stand for the spectral reflectance measurements acquired in the visible (red) and near-infrared regions, respectively []. NDVI values for farmland were obtained from 9 sampling sites () during 1984–2014 using AVHRR GIMMS 15-day composite NDVI products []. The TVDI, based on an empirical parameterization of the relationship between surface temperature and NDVI, was used in monitoring soil moisture and drought regionally []. The TVDI is estimated using the following equation: TVDI = ( T s— T s min)/( Ts max— T s min), where T s is the observed land surface temperature at a given pixel, and T s min is the minimum surface temperature in the triangle ( T s min = a 1 + b 1(NDVI)). T s max is the maximum surface temperature observation for a given NDVI ( T s max = a 2 + b 2(NDVI)). A 1 and a 2 are the intercepts, and b 1 and b 2 are the slopes for the dry and wet edges.

The value for TVDI is higher for dry conditions and lower for wet conditions, and varies between 0 and 1. Climatic data, including temperature and rainfall, were obtained from a local meteorological station from 1984–2014. Land-use change During the study, the major crop production in Hu County was spring wheat and autumn maize, occupying most of the local farmland. We used the phenology of local crop production, together with the spectral features of satellite images, to select Landsat images (with a resolution of 30 m) from March to May and September to October in order to extract the areas of cropland in the Hu area in 1984, 1995, 2001, 2004, 2010 and 2014.

A support vector machine (SVM) of supervised classification was applied to perform the classification process in ENVI v4.3 []. The accuracy assessment of land cover classification using ground truth images by region of interest tools (ROI) indicated a Kappa coefficient of 0.98 on average. Detection of hantavirus antigen Viral antigens in lungs were detected by using direct immuno-fluorescent assay as described previously []. Lung tissue samples were cut into 7–8 μm sections on a freezing microtome and fixed in acetone after air drying for at least 30 min. 100μl of FITC-labeled anti-SEOV/L99 or HTNV/76–118 hantavirus nucleoprotein typing monoclonal antibody [] was pipetted onto each slide. Tissues were incubated at 37°C for 1 hour and washed five times with 0.02 M phosphate buffered saline (PBS). The samples were considered positive when yellow-green fluorescing hantavirus particles were seen under fluorescence microscopy.

RT–PCR and sequencing Total RNA was extracted from rodent lung tissue with the TRIzol reagent (Invitrogen, USA) and RNeasy mini kit (Qiagen, Germany), the viral RNAs from the sera of patients were extracted using the QIAamp viral RNA mini kit (Qiagen, Germany) according to the manufacturer’s instructions. CDNAs were synthesized from 5 μg total RNA with the RevertAid first strand cDNA synthesis kit (Fermentas, Canada) in the presence of random hexamers primer according to the manufacturer’s instructions. The partial S segment sequences were obtained by PCR as described previously []. The PCR products were gel purified using QIAquick Gel Extraction kit (Qiagen, Hilden, Germany), according to the manufacturer’s instructions. DNA sequencing was performed with the Big Dye Termination Sequencing kit on the ABI-PRISM3730 genetic analyzer (Applied Biosystems, Carlsbad, CA, USA) and sequences () were submitted to GenBank (accession nos., KY283955–KY283956).

For a detailed description of the laboratory methods used, see Ma et al. Serological assays Human serum samples were tested for IgG antibodies against hantavirus by ELISA. Briefly, the serum samples were diluted 1:10 in PBS and incubated on a microtiter plate containing hantavirus recombinant nucleoprotein. After incubation at 37°C for 1 hour, the plate was washed six times with PBS containing 0.05% Tween 20 (PBST), then peroxidase-labeled goat anti-human IgG (Millipore, Bedford, MA) at a dilution of 1:10,000 was added. After the incubation and washing steps (described above), tetramethylbenzidine (TMB) and hydrogen peroxide (H 2O 2) substrate was added and incubated at 37°C for 10 mins. The reaction was stopped by adding 1 M H 2SO 4 and the plates were read on a microplate reader at 450 nm. A net absorbance value of >0.15 was considered positive.

Phylogenetic analysis Neighbor-joining trees of hantaviral S segment sequences were constructed using a GTR + I + Γ4 model in PAUP v4.0b10 []. The best-fit phylogenetic model was determined by Modeltest v3.7 [].

To assess the robustness of the tree topology, a set of 100 pseudoreplicates was generated and used in bootstrap analyses with the maximum likelihood (ML) method implemented in PHYML [] and the neighbor-joining method implemented in PAUP v4.0b10. A Bayesian phylogenetic tree (10 million generations) was also constructed using MrBayes v3.2 []. Trees were highly congruent to those produced above.

Fitting the TSIR model and ecological fluctuations We modelled the HFRS epidemics in Hu County (1984–2014) using a discrete-time susceptible-infected-recovered (TSIR) model with age structure []. We estimated the seasonality for the HFRS transmission rate by fitting the 30-year-long time series of observed monthly cases using this TSIR model in a Bayesian state-space framework to account for uncertainty in the observation [].

New infections were drawn from the pool of susceptible individuals, along with information on births, deaths, and vaccinations. Rings Of Saturn Dingir Album Download on this page. As the natural time scale for the disease is ~1 month [], we used this as the time interval in our model.

The number of people susceptible to disease in month t+1 is given as S t+1 = B t + S t −D t− V t− I t + λ R t. B t and D t represent the number of human births and deaths during the time period, respectively. V is the number of vaccinated individuals based on medical records, and R is the number of immune individuals.

Λ is the proportion of vaccinated people who lost their immunity per month, based on 20 years of surveillance. Susceptible individuals were divided into three different age groups (0–15 yrs., 16–60 yrs., and 61–100 yrs.) according to disease characteristics, and each individual was also kept track of over the study period ().

The number of people aged 16–60 yrs. Accounted for more than 90% of the total cases in the study area, and as the vaccine was only provided to this group () we assumed that the highest risk of infection was for this age group. Ram Amritvani By Anuradha Paudwal Free Download there. Additional information is given in the Supporting Information. In the model, the force of infection can be expressed as: β t ( NR t/ N t)( IR t), where N t is the current human population size at time t, IR and NR indicate the number of infected and total rodent hosts, and β t the month-specific transmission rate from rodents to human beings. The overall human HFRS epidemic dynamics are thus given. (1) where α allows for the nonlinearities generated by the heterogeneity of the contacts between rodents and humans []. The parameter τ represents low, random abundances when no animals were caught or no infected animals were caught.

Here β t = β 0(1 + β 1cos(2π t)), where β 0 is the average transmission rate and β 1 denotes the amplitude of variation around β 0 []. To represent the roles of intrinsic feedbacks from environmental forcing, we proposed an environment-based wildlife dynamic model. The dynamic change of host population can be mathematically represented as.

(2) Hosts grow and die seasonally at rates b seas and d seas respectively, which are time-varying parameters influenced by extrinsic drivers. B seas and d seas contain both the basic components b cons and d cons, and an environmental component (influenced by rainfall and the NDVI for farmland). Seasonality has been observed in the birth and pregnancy rates of A. An increase in the number of births during the wet season has been suggested [], and this was observed in the Chencang district from 1984 to 1987, 10 km away from Hu County, corresponding to a greater percentage of pregnant females during the wet seasons (). Assuming that an increased pregnancy rate is associated with rainfall, we estimated the time-varying seasonal birth rates by monthly rainfall, and set the seasonal birth index, r t, at a value of 0 (non-breeding season) or 1 (breeding season) according to data provided by reference []. K t is the time-varying carrying capacity, determined by the area of farmland (see Supporting Information).

To reduce the dimensionality of the model, we ignored sex and age heterogeneity among A. S1 Fig Hantaan virus (HTNV) of S segment sequences in China. (A) Map of China, showing the distribution of the S segment of HTNV; the red dot is our study area. (B) Genetic map of HTNV; the HTNV strains present in our study area from 1984 to 2012 are clustered in one branch. (C) Phylogenetic tree of HTNV. The tree was inferred with the Bayesian method using MrBayes.

Numerical values at each node indicate posterior probabilities; only values greater than 70% are shown. Sequences obtained from the study area are shown in the red boxes. S5 Fig Predictions of the regression model. Observed versus simulated NDVI value for farmland (R 2 = 0.81).

The grey dots indicate actual observations, the red dots indicate simulated data from 1984 to 2003, and the blue dots indicate cross validation for 2004–2014. The predictions are one-step ahead predictions, meaning that the data points at time t provide the input for the predictions at time t + 1 (see Eq. The model predictions use the same time interval of 1 month as the time series data. S7 Fig Capture rate, infection rate and human cases. (A) Monthly infected rate against the capture rate threshold observed. The vertical line shows the location of the threshold. Capture rate is expressed as number of rodents caught per 100 trap nights, infection rates represent the number of captured rodents that carry hantavirus per 100 trap-nights.

(B) Annual dynamics of HFRS outbreaks and A. Agrarius population abundance (red bar) and HFRS cases (blue bar) decreased after the drought in 2002 (orange arrow).

S8 Fig Population susceptible to hantavirus over time in Hu County, 1984–2014. (A) The predicted population of Hu County that was susceptible (black line) to hantavirus during the time period 1984–2014. The orange line represents the number of vaccinated individuals based on annual records, and the green line is the total population size. (B) Loss of vaccine efficacy over time.

The rate of loss of vaccine efficacy was plotted against the amount of time since the last vaccine dose was received, based on data from our longitudinal studies. The best fit of the logarithmic relationship is shown.

These estimates show a logarithmic increase in loss of vaccine efficacy over time since the last vaccine dose was received (orange), consistent with a loss in efficacy of 0.02% per year. S9 Fig Demography of the vaccine recipients in the study area, 1978–2014. (A) The monthly number of births in Hu County. The numbers are averaged for each year. (B) The monthly number of deaths. (C) The age distribution of HFRS cases and the population demography in Hu County.

The vaccine was provided to people aged 16–60 yrs. As people in this age group accounted for more than 90% of the total cases in the study area, and the Pharmacopeia of the People’s Republic of China (2005) specified that vaccines could only be administered to people between 16 and 60 years of age.

We thank Sari C. Cunningham for her valuable comments and help. We also thank the many hundreds of CDC staff and local health workers in Shaanxi Province who collected data during 1984–2014.

We thank Xiaoling Lu, Jianhui Qu and Xin Tan, who provided valuable assistance in the field (Hu Center for Disease Control and Prevention). Hailong Chen helped gather the data used in this paper (Xi’an Center for Disease Control and Prevention). Shen Li, Jing Wei, Jianhua Dong and Li Wang arranged for the serological testing conducted at the Special Pathogens Branch Laboratory at Shaanxi Provincial Center for Disease Control and Prevention.

Jiandong Li provided valuable assistance in the field (Chinese Center for Disease Control and Prevention). Funding Statement Funding has been provided by the National Key Research and Development Program of China (2016YFA0600104),; Health industry research special funds for public welfare projects (201502020),; the National Natural Science Foundation of China (81673234, 41271099),; Ministry of Science and Technology, China, the National Research Program (2012CB955501, 2012AA12A407),; Shaanxi Provincial Projects for Serious Disease Prevention and Control (065),; and the Science and Technology Project of Shaanxi Province (2014A7, 2013K12-04-02),. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.