Agricultural intensification, priming for persistence and the emergence of Nipah virus: a lethal bat-borne zoonosis

Abstract

Emerging zoonoses threaten global health, yet the processes by which they emerge are complex and poorly understood. Nipah virus (NiV) is an important threat owing to its broad host and geographical range, high case fatality, potential for human-to-human transmission and lack of effective prevention or therapies. Here, we investigate the origin of the first identified outbreak of NiV encephalitis in Malaysia and Singapore. We analyse data on livestock production from the index site (a commercial pig farm in Malaysia) prior to and during the outbreak, on Malaysian agricultural production, and from surveys of NiV's wildlife reservoir (flying foxes). Our analyses suggest that repeated introduction of NiV from wildlife changed infection dynamics in pigs. Initial viral introduction produced an explosive epizootic that drove itself to extinction but primed the population for enzootic persistence upon reintroduction of the virus. The resultant within-farm persistence permitted regional spread and increased the number of human infections. This study refutes an earlier hypothesis that anomalous El Niño Southern Oscillation-related climatic conditions drove emergence and suggests that priming for persistence drove the emergence of a novel zoonotic pathogen. Thus, we provide empirical evidence for a causative mechanism previously proposed as a precursor to widespread infection with H5N1 avian influenza and other emerging pathogens.

Figure 1.

(a) Epidemiological data from the entire outbreak region, (b) the index farm and (c) evidence of agricultural intensification. (a) Symptomatic Nipah virus cases in Malaysia and Singapore, January 1997–April 1999; data are from the Center for Disease Control and Prevention's Morbidity and Mortality Weekly Reports [7,8], records from the Department of Veterinary Services and the Ministry of Health, Malaysia [16]. Further information on case numbers can be found in the electronic supplementary material. (b) Detection of Nipah virus-induced pre-weaning mortality in the three breeding sections on the index farm. To investigate the timing of Nipah-induced mortality in the three breeding sections, we define a piglet mortality index (PMI) that compares the observed mortality for each litter with expected mortality (based on the number of piglets born and the time from farrow to wean). Here we present average PMI values through time, shown as quantiles of the values observed during the parametrization period; raw litter-level PMI values are shown in the electronic supplementary material. The presence of Nipah virus is suggested when pre-weaning mortality of piglets is significantly greater than expected, and we infer the presence of Nipah virus when significant excess mortality is observed in multiple litters during the same time period or coincident with human cases. The binned PMI values show that significant mortality peaks occurred in the Breeding Nucleus and Breeding section 2 during the time period of the first cluster of human cases in early 1997; individual litters in Breeding section 1 also showed elevated mortality during this time period (electronic supplementary material). Piglet mortality then returned to baseline levels until approximately July 1997, corresponding to the time of the next observed human cases, around which time the virus is likely to have been reintroduced from the flying fox reservoir. Model output analysed in the same manner as the piglet mortality data from the index farm is shown in the electronic supplementary material. (i) Breeding Nucleus; (ii) Breeding section 1; (iii) Breeding section 2. (c) Commercial production of mangoes and domestic pigs in Malaysia, 1961–2005. The drop in both mango (dashed lines) and pig production (solid line) between 1998 and 1999 is because of the depopulation and closing of pig farms in areas infected with Nipah virus. Mangoes on these farms were not harvested and many of the orchards have since been abandoned or converted to other crops. Data are from the Food and Agricultural Organization's Agricultural Production database.

Figure 2.

Deterministic model results illustrating Nipah virus dynamics in the growing section of the index farm. Individuals are characterized as belonging to one of five states: susceptible (S), immune—maternal antibodies (A), immune—recovered from infection (R), exposed (E) and infectious (I). The top panels illustrate the infection/immunity profile of the growing section following (a) initial introduction of the virus and (b) subsequent introduction. The population profile is normalized by the capacity of the growing section (see the electronic supplementary material). The qualitative difference in infection dynamics results primarily from the prevalence of maternal antibodies in the young pig population. (c,d) Following the initial introduction of the virus (c), the rate of replenishment of the susceptible population in the growing section (solid blue line) declines, as many individuals are immune, having been infected while in the breeding sections. The rate at which individuals are infected (green line) declines in consequence. When the virus is reintroduced (d), many individuals entering the growing section have maternal antibodies. Loss of maternal antibodies after entry into the growing section provides a source of susceptibles independent of the presence of infection (blue line), allowing the virus to persist. Infection dynamics are qualitatively similar for a wide range of transmission parameters. The results shown were produced using the following combination of transmission parameters: ɛ = 0.5, σ = 0.01 and R₀ = 10. Analogous results for introduction into a vaccinated population are shown in the electronic supplementary material.

Figure 3.

Results from an individual-based model of Nipah virus dynamics on the index farm: proportion of epidemics leading to enzootic circulation of Nipah virus on the index farm, with and without reintroduction of the virus. Simulations show that most epidemics produced by initial introduction of the virus drive themselves to extinction by depleting the susceptible population (blue line); however, a single reintroduction of the virus is most often sufficient to produce a subsequent epizootic that leads to persistent circulation. Here, we define persistence as circulation of the virus from the time of introduction (or reintroduction) until the farm was depopulated. Analogous results for a wide range of values for the unknown transmission parameters are shown in the electronic supplementary material.

Figure 4.

Nipah virus serology and flying fox distribution in peninsular Malaysia. The flying fox density in each state is expected to correlate with two indices that describe the hunting level within the state relative to a null expectation, as described in the electronic supplementary material. Hunting indices > 1 indicate a higher than expected hunting level and are expected to correlate with relatively high flying fox densities. Known flying fox roost locations tend to be located in states with relatively high hunting indices. Nipah virus serology results are given for all sampling sites throughout peninsular Malaysia; seroreactive bats (white) were found at all sampling sites. PP, Pulau Penang; KL, Kuala Lumpur.

Figure 5.

Complex causality of Nipah virus emergence in Malaysia. Each rectangle represents a component cause of emergence. Grey rectangles represent ‘realized’ component causes that were present in Malaysia, whereas white rectangles represent ‘potential’ component causes that did not occur. Boxes surrounding multiple component causes indicate complete or near-complete synergy between these causes. Arrows indicate that some component causes can bring about other component causes (creating a causal pathway), or can lead directly to an outcome of interest (phase I or phase II emergence, highlighted in red). We refer to component causes that brought about another component cause that had been a missing link in the causal pathway as ‘drivers’ (highlighted in dark blue). Alternative pathways that would have been sufficient to produce both phases of emergence—had they occurred—are indicated by dashed arrows. Specifically, introduction of Nipah virus into an area with extremely dense pig-farming activity (such as Port Dickson in Negeri Sembilan or Sabang Perai Utara in Pulau Penang) probably could have resulted in viral persistence without priming and reintroduction. However, these areas lacked factors further up the causal pathway: the absence of Pteropus bats in these areas prevented viral introduction prior to the establishment of an alternative source of infection (e.g. persistent viral circulation on the index farm in Kinta, Perak). Similarly, if Nipah virus in Malaysia had resulted in human-to-human transmission, an alternative causal pathway could have produced incident human cases outside the area of transmission from flying foxes, as was seen in the Faridpur outbreak in Bangladesh in 2004 [34], but there is no evidence that such human-to-human transmission occurred in Malaysia [35]. The causal pathway that was realized in Malaysia most probably involved (i) the creation of a pathway for transmission from bats to pigs via agricultural intensification (i.e. dual-use agriculture, or the practice of planting fruit trees on land used for livestock production, and increased fruit production through time) and (ii) repeated introduction of the virus into a high-turnover commercial pig population in Perak that led to viral persistence and set the stage for phase II of the emergence process. FF, flying fox.