Rift Valley Fever Virus, Japanese Encephalitis Virus, and African Swine Fever Virus: Three Transboundary, Vector-Borne, Veterinary Biothreats With Diverse Surveillance, and Response Capacity Needs

Kading, Rebekah C.; Abworo, Edward O.; Hamer, Gabriel L.

doi:10.3389/fvets.2019.00458

REVIEW article

Front. Vet. Sci., 13 December 2019

Sec. Veterinary Infectious Diseases

Volume 6 - 2019 | https://doi.org/10.3389/fvets.2019.00458

This article is part of the Research Topic Emerging Arboviruses View all 23 articles

Rift Valley Fever Virus, Japanese Encephalitis Virus, and African Swine Fever Virus: Three Transboundary, Vector-Borne, Veterinary Biothreats With Diverse Surveillance, and Response Capacity Needs

$\nRebekah C. Kading$ Rebekah C. Kading¹^*

Edward O. Abworo²

Gabriel L. Hamer³

¹Arthropod-Borne Infectious Disease Laboratory, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States
²International Livestock Research Institute, Nairobi, Kenya
³Department of Entomology, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX, United States

Early detection of emerging foreign animal diseases is critical to pathogen surveillance and control programs. Rift valley fever virus (RVFV), Japanese encephalitis virus (JEV), and African swine fever virus (ASFV) represent three taxonomically and ecologically diverse vector-borne viruses with the potential to be introduced to the United States. To promote preparedness for such an event, we reviewed the current surveillance strategies and diagnostic tools in practice around the world for these emerging viruses, and summarized key points pertaining to the availability of existing guidelines and strategic approaches for early detection, surveillance, and disease management activities. We compare and contrast the surveillance and management approaches of these three diverse agents of disease as case studies to emphasize the importance of the ecological context and biology of vectors and vertebrate hosts. The information presented in this review will inform stakeholders of the current state of surveillance approaches against these transboundary foreign animal disease which threaten the United States.

Introduction

Rift Valley fever virus (RVFV), African swine fever virus (ASFV), and Japanese encephalitis virus (JEV), are three vector-borne veterinary pathogens with the potential to invade the United States (US). All of these viruses are notifiable animal diseases (1), and Rift Valley fever (RVF) is also included on the “World Health Organization (WHO) Blueprint of priority pathogens” (2). While these viruses would all have devastating health and economic impacts, the ecological context and potential transmission dynamics of each are quite different and would require unique preparedness and mitigation efforts. All of these agents are capable of vector-borne as well as direct transmission (Table 1). JEV and RVFV are also zoonotic and capable of causing disease in humans, and the potential vector, domestic, and wild animal species involved in enzootic and spillover transmission are variable. Routes of potential entry into the US span importation of infected vectors (all three agents), viremic travelers (RVFV), infected animal products (ASFV), or contaminated fomites (ASFV), hence requiring very different preparedness efforts. This complexity in disease ecology and introduction potential presents a challenge to our health infrastructure to prepare for one or multiple such events.

TABLE 1

Table 1. Similarities and differences among the invasion and establishment of Rift Valley fever virus, Japanese encephalitis virus, and African swine fever virus into the United States.

The risk of introduction and establishment for RVFV, JEV, and ASFV to the US have all been investigated. The emergence of RVFV on the Arabian Peninsula (3) and recent reports of RVFV-infected travelers returning to France and China from areas of active RVFV transmission (4, 5) demonstrate the feasibility of pathogen importation via air travel. Considering five potential pathways of entry, Golnar et al. predicted the most likely introduction would be through an infected human traveler, but invasion of infected mosquitoes by plane or ship also carried quantifiable risk (6). In a separate qualitative analysis, Kasari et al. also concluded that RVFV could feasibly enter the US through several pathways including importation of infected animals, people, vectors, or live virus (7). If introduced, many competent mosquito vectors exist in the US (8, 9), and maintenance of the virus in mosquito populations by vertical transmission is possible (10–12). Deer have recently been shown to be a susceptible amplifying host (13) with viremias capable of infecting blood-feeding mosquitoes, which significantly increases the probability of enzootic establishment (14). Intensive livestock production in the US also creates a vulnerable environment for virus transmission among human and livestock communities by opportunistic mosquito vectors adapted to agricultural environments (15). Barker et al. modeled the potential for RVFV transmission in California considering local vectors, hosts and environmental conditions, but understanding the long-term persistence of RVFV depended on the parameterization of the models with data that were not available at the time this model was developed (16).

Japanese encephalitis virus strains have a history of invasion and establishment among new areas in Asia. Molecular epidemiological evidence suggests that JEV strains are introduced from continental south-east Asia to Japan regularly (17–19). Introductions of JEV within Asia and between Asia and Australia are believed to be through either infected windblown mosquitoes or birds, where the virus then circulates enzootically among native birds and Culex spp. mosquitoes (20–22). Considering seven possible pathways of JEV entry into the US, entry of infected adult mosquitoes through air travel was the most likely scenario, however, the risk of establishment of JEV in the US following this type of introduction was variable (23). Several parameters complicated the establishment in the US, including a relatively short host viremia, unpredictable contact rates between hosts and vectors, particularly near airports, virus strain and genotype differences, and the cross-protection of JEV with other flaviviruses endemic to the US (23). North American Culex mosquitoes have been shown to be competent for infection with JEV under experimental conditions (24, 25). The predictable and stochastic factors influencing an introduction are complex, which makes risk assessment efforts challenging.

African swine fever virus has demonstrated its ability to cross national borders and establish in diverse geographical areas around the globe (26–29). A unique risk for introduction of ASFV is that this DNA virus is exceptionally stable in the environment, and remains viable in animal products. This property opens a potential route of entry not available to RVFV and JEV. If ASFV invades the US, competent vertebrate amplifying hosts as well as transmission-competent soft ticks are known to be present, although many questions remain (30). California, Texas, and Florida were among the states with the highest predicted risk for ASFV introduction through imported swine or swine products (31, 32). Further, these states plus much of the southwestern US were predicted to have increased risk for ASFV establishment should this virus be introduced. Additionally, operational procedures that characterize small-scale and organic pig producers throughout the southern US made these enterprises particularly vulnerable to ASFV circulation given the potential exposure to feral swine or Ornithodoros spp. soft ticks (32).

Preventing establishment of any or all of these viral pathogens would require biosecurity and health infrastructure to have a broad focus able to evaluate the risk of introduction and establishment of these disease agents. For example, monitoring passengers with febrile illness entering via airplane from RVFV-endemic countries, inspecting aircraft entering the US from JEV and RVFV-endemic countries for mosquitoes, testing swine products for ASFV, educating agricultural, wildlife, and veterinary professionals to recognize signs and symptoms of infection with any of these agents, conducting surveillance on a diversity of wildlife species spanning birds, deer, and feral swine, and being prepared to mitigate local vector-borne transmission through mosquito and tick vector control. As an example of extreme caution, the 2019 World Pork Expo to be held in June in Des Moines, Iowa was canceled by the National Pork Producers Council due to the concern for the risk of ASFV infected products or fomites being introduced from infected countries (33). Executing the scope and complexity of these activities effectively with limited resources will make identification and early response to any of these agents particularly challenging. Diagnostic labs in the US testing samples from animals or arthropod vectors do not routinely test for these three agents specifically. Still, an extensive national network of veterinary diagnostic laboratories, and valuable knowledge, guidelines, and diagnostic tools exist for each of these viral pathogens to help prepare for such events. The following sections compile information on the current status of surveillance practices and diagnostic tools in use for RVFV, JEV, and ASFV.

Rift Valley Fever Virus

Rift Valley fever is a notifiable disease to the World Organization for Animal Health (OIE) and is additionally cross-listed as a select agent with the USDA and US Department of Health and Human Services (HHS). Due to the RVF disease severity, sizeable outbreaks, and the significant health and economic impacts, national and international guidelines for RVF surveillance and response activities have been developed.

Surveillance

The ability to predict likely times when an outbreak may occur would provide incredible power toward the timely mobilization of intervention and control measures. For RVF outbreaks in East Africa, a close association between epizootic activity and the occurrence of El Niño has been documented (34), providing an opportunity for monitoring weather patterns as an early indicator of conditions consistent with historic outbreak conditions. In particular, NASA has developed an outbreak risk mapping system for RVFV that inputs a variety of satellite measurements to produce a dynamic map of areas at potential risk of virus transmission. This “Rift Valley Fever Monitor” (35), records monthly RVF risk for Africa and the Middle East based on interpretation of satellite vegetation indices, and is maintained by the USDA and NASA (11, 36). In 2008, the WHO convened a joint meeting of experts with the United Nations Food and Agriculture Organization (FAO) to share experiences and discuss the predictability of forecasting models for RVF, and develop guidelines for improving prediction and response capabilities to RVF outbreaks (37). How these predictive models might translate to environmental risk in the US has been approached (16) but needs further study. Still, the precedent has been set for a potential contribution of climate monitoring and predictive modeling into RVFV outbreak prevention.

In 2014, the African Union-InterAfrican Bureau for Animal Resources (AU-IBAR) published a framework to support consistency and coordination of disease control activities, referred to as the “Standard Methods and Procedures (SMPs) for control of RVF in the Greater Horn of Africa” (38). The overall approach concerning the development of these SMPs relies on the coordination of disease prevention and control activities in each participating region (i.e., Greater Horn of Africa) to a set of regional minimum standards and procedures that align with the OIE standards (38). This SMP document provides valuable information on surveillance and epidemiology, diagnosis and laboratory detection, disease control, disease reporting and information management, RVF and trade, and risk analysis and risk mapping, and is supported by specific Standard Operating Procedures (SOPs) for each subject area in accordance with the structure and capabilities of each nation.

Of particular relevance to a potential introduction of RVFV to the US, the AU-IBAR SMP document lists recommendations for surveillance approaches in areas which have not yet reported RVFV activity, in order to promote early detection and rapid response to a virus introduction. Among these recommendations are a combination of passive (continuous) and active surveillance (as needed, according to perceived risk) (38) (Table 2). Passive surveillance would involve the distribution of educational materials to veterinary personnel, and syndromic surveillance conducted by veterinarians, livestock handlers, and wildlife agencies. A specific reporting network is outlined for when suspicious cases are identified. Active surveillance would include serosurveillance, syndromic surveillance, and the regular monitoring of RVFV antibody levels in sentinel herds or flocks. Enhanced vector surveillance is recommended during interepidemic activities, to monitor for increased virus infection rates in mosquito populations. Supporting these surveillance activities should be administrative preparations, such as capacity building and training, and development of a policy framework to support surveillance activities (38).

TABLE 2

Table 2. Guidelines and control recommendations for Rift Valley fever virus, Japanese encephalitis virus, and African swine fever virus.

The rapid deployment of available vaccines may aid considerably in curtailing virus circulation. RVF vaccines currently being deployed under emergency circumstances in Africa include the formalin-inactivated attenuated Smithburn strain. The Smithburn strain vaccine is “recommended for use in pregnant animals and in RVF-free countries experiencing outbreaks” (47); even though multiple boosters may be required. At the time of this writing, there is no RVF vaccine approved for human or veterinary use in the US, however RVF vaccine research and development is being pursued (48–51). If the decision to vaccinate is made, the vaccine must meet the standards in the “OIE Manual of Standards for Diagnostic Tests and Vaccines.” The final decision to vaccinate will be made by the US Department of Agriculture (USDA) Animal Plant Health Inspection service (APHIS) VS Deputy Administrator (US Chief Veterinary Officer) (40). Once vaccination is implemented, the ability to differentiate among infected and vaccinated animals (DIVA) will be essential in order to assess vaccine coverage as compared with virus exposure levels (48, 52).

The USDA APHIS has published “The Foreign Animal Disease Preparedness and Response Plan (FAD PReP)—Disease Response Strategy: Rift Valley Fever” (2013) (40) (Table 2). This document is intended to provide responders with the critical information necessary to mount an effective response effort against RVF in domestic livestock in the US (40). This document recommends approaches to disease control and eradication in the event of an introduction, including the roles and responsibilities of US government agencies (40). These control and eradication strategies are based on four epidemiological principles: “1. Prevent contact between RVFV and susceptible animals (i.e., quarantine and movement control), 2. Stop the production of RVFV by infected or exposed animals, 3. Stop the production of RVFV by insect vectors (i.e., vector surveillance and control), and 4. Increase the disease resistance of susceptible animals to RVFV (i.e., vaccination)” (40). Vector surveillance is only considered in the context of an outbreak and rapid response situation in these guidelines, and not as a potential strategy for early detection. Because of the diverse infrastructure for how vector surveillance and control is managed, these decisions would be left to the agency responsible for conducting vector surveillance activities at the county or municipal government level (40). While these guidelines take some important first steps in providing a framework for priority activities by responsible parties, additional planning is needed to determine mechanisms for inter-agency collaboration during surveillance and response efforts, and identify capacity gaps for implementation of this strategic plan on the ground in an emergency situation. Further, no plan is outlined for conducting pre-introduction surveillance activities, either active or passive, as is detailed in the USAID plan (38). These gaps should be addressed for diseases, such as RVFV which are considered serious risks for introduction.

In December of 2006, the “APHIS Centers for Epidemiology and Animal Health in Fort Collins, Colorado,” hosted a working group meeting comprised of representatives from several academic institutions and government agencies to discuss the state of research and preparedness for RVF (53). Participants presented and discussed key research areas to improve the national capacity to respond to an introduction of RVFV, including more research regarding the relative importance of North American mosquitoes to transmission of RVFV, and the role of wildlife species to enzootic maintenance of RVFV circulation. Since the time of this publication, additional research has been conducted on the vector competence of North American mosquito vectors for RVFV (8, 9, 15), and the susceptibility of deer (13). Discussion was held on interagency cooperation and collaboration during outbreak events. On the response side, organized vector control in the US is principally concentrated in larger cities with high human densities. Rural landscapes where the enzootic cycle of RVFV is likely to amplify and spill-over into human and animals generally lacks organized vector control. Vector control in large rural landscapes often relies on partnerships with military capability (54). Similarly, there is a deficit in veterinary surveillance, and the tools to perform this type of surveillance safely. Veterinary surveillance is and will be very important for early detection of invasive vectors and pathogens. As an example, observations of Myiasis in Florida key deer populations in 2016 led to the discovery of an invasion of the screw worm fly, Cochliomyia hominivorax (Coquerel), which had been eradicated from the US since 1959 (55). Re-eradication of this fly was declared in March of 2017, after 35 releases of sterile flies (55). Participants of the RVF Working Group recommended training relevant professionals “to recognize the early signs of an RVF epizootic or epidemic,” and identified a shortage in high containment biosafety laboratories to safely conduct the necessary research (53).

Diagnostic Tools

The diagnostic tests for identification of RVFV listed in the “OIE Manual of Diagnostic Tests and Vaccines for Terrestrial Animals (2012)” include virus isolation, reverse transcriptase polymerase chain reaction (RT-PCR)-based assays, an agar gel immunodiffusion (AGID) assay, an enzyme-linked immunosorbant assay (ELISA), and immunohistochemistry (40, 44). Mansfield et al. comprehensively reviewed clinical diagnostic methods for RVFV infection as well as advancements in vaccine development (56). Therefore, only some representative assays for these widely-used techniques are highlighted below:

Serological Diagnosis

VanVuren and Paweska developed an ELISA based on the capture of the nucleocapsid protein (NP) (57). Alternatively, a monoclonal antibody-based competitive ELISA developed by Kim et al. for the detected antibodies against RVFV in goats and cattle with a sensitivity/specificity of 94.7/99.7% between 9 and 11 days post-inoculation (58). A multiplex fluorescence microsphere immunoassay (FMIA) also detected cattle and sheep IgM and IgG antibodies to the RVFV glycoprotein, non-structural proteins, and nucleoprotein (59). They also reported that the “N protein was the best target for early detection of infection” (59). A novel lateral flow strip test has recently been developed based on detection of the N protein, for use as a pen side diagnostic (60). Importantly, McElroy et al. developed an ELISA that can be used to differentiate infected from those that had been vaccinated a ΔNSm/ΔNSs double-mutant vaccine (48, 52).

The MAGPIX^® and the Luminex xMAP platforms have also been used to simultaneously detect IgG antibodies against a multitude of key emerging viral species and families including RVFV (61, 62). Therefore, many options exist for pathogen detection, depending on the goals of the surveillance program and institutional capabilities.

Molecular Detection

qRT-PCR

Bird et al. developed a robust pan-RVF virus quantitative RT-PCR assay (63). Primers and a probe were designed from the genome alignments of 40 virus isolates derived from representative vector and vertebrate hosts over time. This assay was successfully validated on human RVF clinical samples, and has clinical diagnostic capabilities out to at least 10 days post-symptom-onset. The assay developed by Wilson et al. amplifies the L and M segments as confirmatory targets, and includes a third target gene, NSs, which is deleted in multiple vaccine candidates (64). This approach will be tremendously advantageous for simultaneously monitoring vaccine coverage vs. virus spread.

Isothermal Amplification

Recently, isothermal nucleic acid amplification methods have gained popularity for their ability to more rapidly detect pathogen nucleic acids directly in a clinical or field sample, and not necessarily require RNA extraction. Eular et al. developed an “isothermal ‘recombinase polymerase amplification (RPA)' assay” on an “ESEquant tubescanner device.” While lacking in sensitivity compared to qRT-PCR, the portability of this system could be a potential tool for field, pen side or bedside diagnostics (65).

Nanotrap Particles

One innovative new approach to sample preparation, which also addresses sensitivity issues that might arise during surveillance, is the use of nanotrap particles to improve the detection of RVFV in low-titer samples by ~100-fold (66). Inactivation of RVFV by detergents or heat treatments did not affect the efficacy of virus binding to nanotrap particles, demonstrating that field samples can be safely inactivated and processed with nanotrap enrichment method to maximize sensitivity and maintain safety precautions (66).

Multiplex Pathogen Detection

Rather than focus on specific detection of RVFV, there are several multiplex assays that incorporate RVFV into the testing panel. Fajfr et al. developed multiplex assays targeting hemorrhagic filoviruses, arenaviruses, and bunyaviruses including RVFV, using previously-published primers (67). These assays are optimized for several types of real-time PCR instruments, including a portable “Ruggedized Advanced Pathogen Identification Device (R.A.P.I.D.)” (Idaho Technology, Inc.). Liu et al. developed a real-time PCR-based TaqMan array card (TAC) that can screen up to eight samples within 3 h for up to 26 agents simultaneously (68). The comprehensive panel includes 15 viruses, eight bacteria, and three protozoa (68). Another multiplex platform is the Lawrence Livermore Microbial Detection Array which “detects 10,261 species of microbes including 4,219 viruses, 5,367 bacteria, 293 archaebacteria, 265 fungi, and 117 protozoa”; RVFV spiked into Culex mosquitoes were successfully detected by the platform (69).

BSL-2 Reagent Production

The select agent status of RVFV limits the tests and control material that can be handled by veterinary diagnostic laboratories that operate at BSL-2. Therefore, Drolet et al. “modified an existing one-step real-time RT-PCR (rRT-PCR) assay for quick virus inactivation and use in BSL-2 laboratories” (70). Further, an immunohistochemical (IHC) assay was developed for use by BSL-2 laboratories, using antiserum against recombinant RVFV-nucleocapsid (N) (70). These advancements provide necessary diagnostic tools to public health and veterinary labs to safely test samples for RVFV and thereby enhance capacity for rapid disease detection and response activities for this high containment pathogen.

Diagnostic Considerations

When considering a diagnosis of RVF in animals in the US, the symptoms observed tend to be non-specific. Therefore, the below diseases are recommended to comprise the testing panel for diagnosis: anthrax, bacterial septicemias, bluetongue, brucellosis, heartwater, ephemeral fever, enterotoxemia of sheep, Nairobi sheep disease, ovine enzootic abortion, peste des petits ruminants, toxic plants, trichomonosis, vibriosis, and Wesselsbron disease (40). Due to biosafety and biosecurity concerns, aerosolization potential, and select agent status, diagnostic testing for suspected RVF cases would be performed at the Foreign Animal Disease Diagnostic Laboratory (FADDL), part of the National Veterinary Services Laboratories (NVSL) (40).

Japanese Encephalitis

Globally, Japanese encephalitis virus (JEV) is one of the most prevalent encephalitic arboviruses, mainly found in eastern and southern regions of Asia (71). Japanese encephalitis virus is primarily recognized as a human pathogen, but affects animal health as well. This virus is transmitted enzootically among mosquitoes (i.e., Culex tritaeniorhynchus), swine and wading birds, which serve as amplification hosts (72). Adult pigs are typically asymptomatic to JEV infection, however the virus is known to cause severe reproductive complications and fetal abnormalities among infected swine (41). Infection of horses with JEV has also been documented (73). People are exposed to JEV through the bite of an infectious mosquito but are considered dead-end hosts, as there is no human-to-human transmission. Japanese encephalitis virus is comprised of five genotypes (GI–GV) which are classified according to the phylogeny of the envelope (E) gene (74), with emergence and circulation of different genotypes alerting public health professionals throughout areas of endemicity. Commercial vaccines are available for humans (75), and pigs and horses (76), however veterinary vaccines for JEV are relatively less available than human vaccines (41).