Diseases

Nipah virus

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  • Diagnostics availability

  • Commercial diagnostic kits available worldwide

    None.

    For recent updates, check the list of Diagnostics for Animals.

    GAP: Definite gap.

  • Commercial diagnostic kits available in Europe

    None.

    For recent updates, check the list of Diagnostics for Animals.

    GAP: Definite gap.

  • Diagnostic kits validated by International, European or National Standards

    AAHL, NCFAD and FLI have accreditation to perform diagnostic testing. AAHL prepares diagnostic kits for henipaviruses distributed upon request. NCFAD performs testing for henipaviruses under “non-validated tests”.

    HSADDL (NIHSAD) has developed NiV diagnostic preparedness suitable for low containment laboratory (ELISA, real time RT-PCR).

    Antigen lateral flow assay during validation on negative samples in Canada revealed cross reactivity with CMV, and is no longer pursues.

    NIHSAD developed a nucleic acid lateral flow assay which appears to be promising.

    GAPS:

    Lack of positive experimental and field samples for test validation (or even evaluation).

    Possibility to produce and distribute reference sera using low biosafety vaccinations.

  • Diagnostic method(s) described by International, European or National standards

    Details in the OIE Manual of Diagnostic Tests and Vaccines for Terrestrial Animals 2015 chapter 2.1.14 Hendra and Nipah Virus Diseases provides recommendations for the following tests.

    Identification of the agent

    1. Virus isolation and characterisation

    1.1. sampling and submission of specimens

    1.2. isolation in cultured cells

    1.3. Identification: immunostaining and Immuno EM

    2. Viral identification: differentiation of HeV and NiV

    2.1 comparative immunostaining

    2.2. immunofluorescence

    2.3. microtiter neutralization

    3. Molecular methods

    3.1. real-time RT-PCR

    3.2. Conventional RT-PCR and Sanger sequencing

    4. Immunohistochemistry

    Serological tests

    1. Virus neutralisation tests

    2. Enzyme-linked immunosorbent assay

    3. Bead-based assays

    Currently no expectations of validated tests for livestock (or other species).

    Nothing is done in terms of test harmonization. Technology transfer exits: from AAHL to laboratories in Asia (Malaysia mainly); limited transfer from NCFAD to India (Bhopal High Containment Animal Health Laboratory); limited transfer from AAHL to FLI and bilateral transfers between NCFAD and FLI.

    GAPS:

    Restrictions on material transfer due to biosecurity requirements, on import of animal samples for validation purposes or confirmatory testing.

    See above comments on availability of monoclonal antibodies and for generation of reference sera.

    Need for international standards for validation of NiV assays.

  • Commercial potential for diagnostic kits in Europe

    Virtually no requirement in Europe, North America orAustralia. Demand in Asia not known.

    GAPS:

    Lack of financial motivation for the industry to produce henipavirus low biosafety tests for Europe.

    With any incident, the demand could suddenly become huge.

  • DIVA tests required and/or available

    The DIVA would have to most likely target the N antigen, or alternatively P gene coded products depending on level of expression and antigenicity in animals, as well as number of reactors in non-endemic areas. Indirect recombinant N- ELISA and G-ELISA were developed, and is now in stage of diagnostic evaluation.

    GAP: Lack of a DIVA test fit for purpose, in conjunction with vaccine development, but still lack of financial justification for the industry.

  • Opportunities for new developments

    Sequence variation effects molecular diagnostics; both Clifton Beach (2007) and Redlands (2008) Hendra virus strains failed in AAHL Hendra virus specific real-timePCR used at that time.

    Consensus RT-PCR was developed for henipaviruses, however it was evaluated only on four isolates, and no diagnostic evaluation was performed. Real time RT-PCR targeting the N gene of NiV-M is suitable for detection also of NiV-B, which could be in addition confirmed by real-time RT-PCR targeting NiV-B specific region of the F gene.

    It takes almost 14 days to get detectable antibody response against NiV in swine, and therefore early diagnosis based on serology will be less reliable than antigen or molecular tests.

    Isothermal real-time RT-PCR is also promising as a field deployable assay.

    Shedding of NiV in oral fluid starts early post infection and rope sampling can be employed for collection of samples.

    GAPS:

    Due to its nature, real time RT-PCR may not be able to detect all divergent and novel henipavirus strains. Classical RT-PCR followed by sequencing may be more successful in detecting novel strains of henipaviruses. Combination of both approaches may need to be considered.

    There is a need for high throughput antibody assays for outbreak, recovery and surveillance purposes.

    Need to develop operator-safe diagnostics tests and reagents that can be produced in low containment.

  • Vaccines availability

  • Commercial vaccines availability (globally)

    None.

    NOTE: A vaccine for horses against HeV based on soluble HeV G protein is licensed since 2012 in Australia.

  • Commercial vaccines authorised in Europe

    None.

  • Marker vaccines available worldwide

    None.

  • Marker vaccines authorised in Europe

    None.

  • Effectiveness of vaccines / Main shortcomings of current vaccines

    Not applicable.

  • Commercial potential for vaccines in Europe

    Very low at present. Lack of financial motivation for the industry to produce henipavirus vaccine and low biosafety tests forEurope, but with any incident, the demand could suddenly become huge.

  • Regulatory and/or policy challenges to approval

    Need BSL-4 facilities for vaccine efficacy studies.

    GAP:

    Need standard challenge pig model, and correlates of protection;

    Lack of recognition of well established platforms (such as ALVAC) that could help speed up licensing.

  • Commercial feasibility (e.g manufacturing)

    Feasible if subunit or vector platform technology that has already accessed confirmed level for manufacture of marketed products is considered.

    GAP: Consider specific negotiations and filing for already recognized technology platforms.

  • Opportunity for barrier protection

  • Opportunity for new developments

    Two vaccines are in the pipeline and reachable: canarypox-based NiV vaccine, and recombinant subunit soluble HeV G glycoprotein vaccine (sG). Vaccines for pigs in areas with a high density of fruit bats may be advantageous, but would have the disadvantage of masking infection and complicating surveillance. Malaysia made a decision not to seek or use vaccines post outbreak, preferring freedom without vaccination. The major need for a vaccine would be to assist in control of an extensive outbreak of Nipah virus in swine that cannot be controlled by stamping out. If vaccination were to be contemplated marker vaccines would be useful to enable the differentiation of infected form vaccinated pigs.

    HeV sG glycoprotein based vaccine can protect cats, ferrets and African green monkeys against NiV challenge and protect ferrets, horses and African green monkeys against HeV challenge, but offered only partial protection against HeV and no protection against NiV in swine.Use of a different adjuvant showed promise for efficacy in swine.

    Vaccine for swine has to elicit both antibody and CMI response.

    GAPS:

    One dose vaccine regimen with a short onset of immunity and a known duration of immunity is needed. (Need onset of immunity and DOI data to ensure best use of vaccines in disease outbreak situation)

    Although conditionally licensed emergency vaccines would be first available, field safety studies and efficacy studies based on serological follow-up, can be performed under special authorisations with proven technology platforms, and this can allow full licensure and stockpiles.

  • Pharmaceutical availability

  • Current therapy (curative and preventive)

    None available at present.

  • Future therapy

    Several studies have been conducted to evaluate a human monoclonal antibody therapy for human use, and is presently under pre-clinical development. Peptides that compete for the fusion protein receptor side have been tested successfully in laboratory animals.

    GAPS:

    Human use only.

    No studies targeting swine conducted or considered. It is unlikely that treatment of single animals would be considered.

  • Commercial potential for pharmaceuticals in Europe

    Low (due to zoonotic nature of henipaviruses, even companion animals will be euthanized if infected).

    GAP: Human use only: lack of financial justification for the industry.

  • Regulatory and/or policy challenges to approval

    None apart from the cost of authorisations.

    GAP: Human use only: consider specific negotiations and filing for already recognized technology platfors products .

  • Commercial feasibility (e.g manufacturing)

    Feasible mid-term.

    GAP: Human use only: lack of financial justification for the industry.

  • Opportunities for new developments

    Limited. Possibility of use of recombinant human adenovirus 5 vector coding for swine IFN-type I could be explored in combination with vaccination to elicit rapid protection and to quickly stop shedding as one of the outbreak control measures.

    GAP: Human use only: lack of financial justification for the industry.

  • New developments for diagnostic tests

  • Requirements for diagnostics development

    Desired Diagnostic Test Profile:

    1. Screening tests that will detect all henipaviruses

    2. Strain specific tests to identify separate NiV strains

    3. Direct tests for control and eradication

    4. Indirect tests for post-control monitoring

    5. Rapid test

    6. >95% specificity

    7. >95% sensitivity

    8. Pen-side test

    9. DIVA Compatible

    10. Field validated

    11. Easy to perform/easily train

    12. Scalable

    13. Reasonable cost

    GAPS:

    As before, lack of financial motivation for the industry to produce henipavirus low biosafety tests for Europe, but with any incident, the demand could suddenly become huge.

    Collection of low biosafety reference sera against various isolates, that could be obtained with experimental recombined vaccines.

  • Time to develop new or improved diagnostics

    Long term for antigen detection, however adaptation of molecular tests to new virus variants could be rapid.

    Classical serological tests with low biosecurity (recombinant) reagents could be reasonably quick.

    GAP: financial incentive.

  • Cost of developing new or improved diagnostics and their validation

    For classical tests, and especially using low biosecurity platforms and reagents, the costs would be within expected classical range.

    GAP: formalized structured worldwide network for validation and ring trials.

  • Research requirements for new or improved diagnostics

    Develop a panel of reference standards for both molecular and serologic tests that can be made available to all of the laboratories performing diagnostic tests for henipaviruses. This panel should also include monoclonal antibodies and recombinant antigens that will be freely available as low biosecurity reagents.

    Develop broadly reactive PCR assays targeting highly conserved genetic targets within the henipaviruses. Evaluate the relative sensitivity and specificity of the currently used PCR assays.

    Develop field tests (both protein- and nucleic acid-based) to detect henipaviruses.

    Explore new antigen detection assays, including antigen capture, Loop Mediated Isothermal Amplification Protocol (LAMP), and nanotechnology.

    Develop species specific reagents to improve the quality of serologic assays.

    Evaluate the relative sensitivity and specificity of molecular and serologic tests, especially new serologic tests that could replace serum neutralization titers (SNT) and meet DIVA (differentiate infected from vaccinated animals) requirements.

    Explore the use of serological assays based on recombinant antigens that could be produced at BSL-2.

    Develop species independent serologic assays using recombinant antigens.

    GAP: formalized structured worldwide network for validation and reference (panel development) and assay harmonization.

  • Technology to determine virus freedom in animals

    Recombinant N protein ELISA appears to be most promising but other DIVA tests to be considered.

    GAP: Formalized structured worldwide network for validation of acceptable thresholds with cross-validated tests.

  • New developments for vaccines

  • Requirements for vaccines development / main characteristics for improved vaccines

    Desired Vaccine Profile

    1. Highly efficacious: prevent transmission; efficacy in all age animal target hosts, including maternal antibody override; cross protection across all henipavirus strains; quick onset of immunity; multiple animal target hosts; one year duration of immunity

    2. Safe in all age animal target hosts; no reversion to virulence for live vaccines

    3. One dose

    4. Safe vaccine strain for manufacturing (low biosecurity)

    4. DIVA compatible

    5. Manufacturing method yields high number of doses

    6. Rapid speed of production and scale-up

    7. Reasonable cost

    8. Short withdrawal period for food consumption

    9. Long shelf life

    10. Not needing a cold chain for distribution

  • Time to develop new or improved vaccines

    Two vaccines are in the pipeline that could be developed within four years with proper funding and support given to commercial partners: canarypox-based NiV vaccine, and recombinant subunit soluble HeV G glycoprotein vaccine (sG).

    GAP: Regulatory timelines often exceed technical timelines; EU would have to accept field efficacies based on serological follow-up.

  • Cost of developing new or improved vaccines and their validation

    Using proven low biosecurity platforms, the costs would be within expected classical range.

    GAPS:

    As before, lack of financial motivation for the industry, but with any incident, the demand could suddenly become huge.

    Consider stockpiles.

  • Research requirements for new or improved vaccines

    A comprehensive vaccine research program to deliver next generation NiV vaccines and specifically design strategies for control in priority susceptible hosts: domestic pigs and feral swine.

    GAPS:

    Determine early events of NiV infection, immune evasion and identify determinants for virulence and host susceptibility.

    Develop the basic knowledge of the mechanisms NiV uses to evade the innate immune response.

    Need to evaluate whether recrudescence and/or persistent infections occur in pig and if so the effectiveness of vaccines in preventing this phenomenon.

    Ensure large cross-protection with different isolates now and in the future.

  • New developments for pharmaceuticals

  • Requirements for pharmaceuticals development

    Rapid protection against viral replication until vaccine is 1. able to induce a protective immune response (outbreak control measure) or 2. the animals are slaughtered.

    GAPS:

    1. Human use only (human mAb m102.4; postexposure therapy for HeV/NiV completed Phase I trial in Australia).

    2. Pilot study conducted with Ad5-IFN in swine was not successful. More studies are needed.

  • Time to develop new or improved pharmaceuticals

    Not applicable.

    GAP: Human use only.

  • Cost of developing new or improved pharmaceuticals and their validation

    Not applicable.

    GAP: Human use only.

  • Research requirements for new or improved pharmaceuticals

    Need to test effectiveness of Human Adenovirus 5 vectored Type 1 interferon against NiV infection of pigs.

    GAP: Pilot study conducted with Ad5-IFN alpha in swine was not successful. More studies are needed (e.g. IFN-lambda).

Disease details

  • Description and characteristics

  • Pathogen

    Hendra virus (HeV) and Nipah virus (NiV) along with non-pathogenic Cedar virus form genus Henipavirus, in the subfamily Paramyxovirinae, family Paramyxoviridae.

  • Variability of the disease

    There are two clades/genotypes of NiV: M (Malaysia) and B (Bangladesh). Overall, henipaviruses appear to be genetically relatively stable, with specific geographical distribution (e.g. NiV was not detected in areas with HeV, and vice versa). HeV isolates from Australia have not shown the genetic variation seen with NiV.

    Henipaviruses have a wide host range, unlike most of the other members of the family Paramyxoviridae. The henipavirus receptors ephrin-B2 and ephrin-B3, members of a family of receptor tyrosine kinase ligands, are highly conserved across vertebrate species, a contributing factor to the wide host range. Henipaviruses can infect and cause disease across 6 mammalian orders including humans, monkeys, pigs, horses, cats, dogs, ferrets, hamsters and guinea pigs.

    However for NiV in livestock there is a clear evidence only for infections in pigs and horses.

    GAP: Classification of henipaviruses needs to be developed (to assist epidemiological investigations).

  • Stability of the agent/pathogen in the environment

    Experiments suggest that NiV can survive up to 4 days in fruit juice or fruit bat urine, in neutral pH. Henipaviruses are highly sensitive to higher temperatures (37oC) and desiccation. Nipah virus is readily inactivated by soaps, detergents and many disinfectants. Routine cleaning and disinfection with sodium hypochlorite or commercially available disinfectants is expected to be effective. Sodium hypochlorite was recommended for the disinfection of pig farms in Malaysia.

    There is a permanent natural reservoir (bats) in endemic countries from where the virus periodically re-emerges.

    GAP: Although extrapolation of information regarding physical and chemical susceptibilities from that available for other (enveloped) paramyxoviruses would be reasonable, regulatory authorities would appreciate more information specific to NiV and HeV.

  • Species involved

  • Animal infected/carrier/disease

    NiV emerged in 1999 as the cause of outbreaks of respiratory and neurological disease affecting a number of animal species. During the Malaysian outbreak NiV infections in humans were transmitted from infected pigs, as were infections in dogs, cats, and horses. There is indirect evidence of NiV transmission from a cow, goats and pigs to people in Bangladesh. NiV disease is often fatal in all the above species, except swine. A carrier state has not been documented, but recrudescence of disease is well documented in people.

    India has conducted a geographically comprehensive survey of limited number fo samples collected from swine (including West Bengal). All 1709 samples tested negative for NiV antibodies (unpublished).

    GAPS: There is lack of knowledge on:

    - the pathogenesis of infection in ruminants and its significance in terms of disease and transmission.

    - the pathogenesis of recrudescence of disease in any species, or even its possibility.

  • Human infected/disease

    NiV causes encephalitis and a pulmonary syndrome in humans, with case/fatality rate reaching up to 90% in some outbreaks. Most prominent pathological lesions are a diffuse vasculitis and involvement of the brainstem. Virus was detected also in lung and kidneys. Different transmission patterns and case fatality rates were observed between the Malaysian and theBangladesh (India) outbreaks. InSouth Asia person-to-person transmission can frequently occur whereas this was not identified inMalaysia. The disease is acute, but in one human case of HeV and significant numbers of human cases of NiV relapsing encephalitis has been reported ranging from 1 to 2 month to as long as 4 years after the acute phase. HeV and NiV diseases are quite similar and are thought to have a similar pathogenesis.

    GAP: Little is known about human NiV pathogenesis, with most data available from the Malaysian outbreak or cases of HeV disease.

  • Vector cyclical/non-cyclical

    Fruit bats, mainly from genus Pteropus; non-cyclical.

  • Reservoir (animal, environment)

    Fruit bats (flying foxes) in the genus Pteropus are the natural hosts for NiV and HeV. Fruit bat populations inSoutheast Asia are being disrupted by various factors that may alter their foraging patterns and behaviour, and bring them into closer contact with domesticated animals and humans. Serological surveys show seroprevalances up to 20% to NiV in Malaysian pteropid bats. Antibodies to NiV or putative closely related viruses have subsequently been detected in pteropid bats inBangladesh,Cambodia,Indonesia,Madagascar,Thailand, and in African fruit bats inGhana, and several insectivorous bat species inChina. NiV has been isolated from flying foxes fromMalaysia andCambodia. NiV RNA has been detected by polymerase chain reaction (PCR) in pteropid bat urine, saliva and blood in Thailand, Ghana and Indonesia (Daniels personal comm.). Fruit bats live in large colonies where more than half the population may be sero-positive. The size of the populations is probably sufficient to maintain the virus as an acute infection.

    Currently Luminex detection of anti-G antibodies is used in the bat surveillance (AAHL), and by other investigators. The N-antibody detection could be considered, if deemed critical for sensitivity of detection, however problems with specificity could arise.

    GAPS:

    Little is known about bat immunology, ecology, and the maintenance of transmission of NiV in bats and bat population. Availability of reagents is very limited. (This is an area of active research at AAHL).

    Nipah like viruses (genomic sequences) were identified in large areas of African continent.

    Potential of wild boar/feral swine as a NiV reservoir is not known.

  • Description of infection & disease in natural hosts

  • Transmissibility

    Swine

    Currently it is unclear how the virus is transmitted from bats to pigs. However, it is suspected that fruit trees close to pig confinement areas are foraged by the bats and the virus is spread by this close proximity (urine or saliva on partially eaten fruit).

    In a swine herd close range transmissibility of NiV is highly efficient, likely via droplets, ingestion, or direct contact.

    Fine aerosol transmission is unknown, but not suspected over larger distances. Movement of infected pigs was considered the main mean of dispersal of NiV infection in Malaysia.

    GAPS:

    Why Nipah virus periodically transmitted from the bat reservoir host to domesticated animals is not precisely known;

    Knowledge about routes of infection, susceptibility and the likely infectious dose, intra- and interspecies transmission of NiV in all known susceptible species (pigs, dogs, cats, goats, cattle, horses). Such information is important in outbreak control.

    No information on transmission via fomites, or possibility of NiV being shed into milk.

    No knowledge on minimum infectious dose for humans, bats, pigs, etc.

  • Pathogenic life cycle stages

    Not applicable.

  • Signs/Morbidity

    NiV infection of pigs is highly contagious, with clinical signs not significantly different from several more common pig diseases. The severity of disease appeared to be age dependent, increasing with age. Peracute mortalities were reported in boars and sows. An outbreak of NiV in swine may thus not be noticed for a period of time sufficient to permit further spread of the virus. Observations made during the Malaysian outbreak investigation, confirmed during experimental infections, that NiV infection of pigs is characterised by fever with respiratory involvement. In animals showing disease, nervous signs have been frequently reported, but many infections are subclinical. Some infected animals display an unusual cough, described as barking cough. However this description is also used in cases of swine influenza, and would not be pathognomonic. Secondary bacterial infections may also mask underlying NiV infection (based on experimental data). Abortions were reported in sows.

    NiV affects companion animals. Natural infection of dogs with NiV causes a distemper-like syndrome with a high mortality rates; there is serological evidence that some dogs survive the infection. Field infections were reported in cats and horses, with fatalities observed in both species. Experimentally NiV causes a disease in guinea pigs, ferrets and hamsters, all of them often kept as pets.

    GAP: Further pathogenesis studies would be useful to address aspects on which information is not well developed.

  • Incubation period

    The incubation period of NiV in pigs has been reported as 7-14 days, but may be as short as four days. In experimentally infected pigs, shedding is detected at 2 dpi. In experimentally inoculated cats and ferrets, incubation periods of six to eight or ten days, respectively, have been reported

  • Mortality

    NiV caused low mortality in swine, the maximum reported mortality during the outbreak in Malaysia was 5%. However the experimental model using nasal inoculation of about 105-6 PFU/animal is reaching a 40% mortality rate.

    Oral inoculation with 104 PFU/animal resulted in shedding and protective immune reponse, but no apparent clinical disease.

  • Shedding kinetic patterns

    Pigs shed Nipah virus in respiratory secretions and saliva based on virus isolation from 2 until about 14 dpi in experimental infections. Nasal shedding based on detection of viral RNA was detected between 2 and 17 dpi. Virus was not detected in urine in the experimentally infected pigs, but this shedding route cannot be excluded, as virus was detected in kidneys from field swine cases.

    GAP: Consider evaluating survival of the virus in semen.

  • Mechanism of pathogenicity

    The molecular determinants of virulence are unknown. (For some other paramyxoviruses, amino acid sequence at the cleavage site of the F protein is considered to be a major virulence factor.)

    Infection of cells has been show to occur by virus attachment to specific cellular receptor followed by membrane fusion. The receptors for the henipaviruses are the ephrin-B2 and ephrin-B3 host cell proteins. Ephrin-B2 is highly expressed on neurons, smooth muscle, arterial endothelial cells and capillaries, which closely parallels the known tissue tropism of HeV and NiV in vivo. Ephrin-B3 is also widely expressed but particularly in specific regions of the central nervous system and may facilitate pathogenesis in certain neural subsets.

    Syncytial cells containing viral antigen are seen in small blood vessels, lymphatic vessels and the respiratory epithelium. The presence of appropriate P gene products may modulate virulence by antagonizing the cellular interferon response.

    AAHL performed the first experimental inoculations of pigs with NiV, and their findings were supported and further expanded by follow up experiments at NCFAD. The experimental challenge studies in piglets conducted at NCFAD demonstrated neurological signs in a number of inoculated pigs (both published and unpublished data). The rest of the pigs remained clinically healthy. NiV was detected in the respiratory system (nasal turbinates, nasopharynx, trachea, bronchus, and lung), the lymphoreticular system (endothelial cells of blood and lymphatic vessels), submandibular and bronchiolar lymph nodes, tonsil, and spleen, with observed necrosis or lymphocyte depletion in lymphoid tissues, most importantly in lymph nodes. NiV presence was confirmed in the nervous system of both sick and apparently healthy animals (cranial nerves, trigeminal ganglion, brain, and cerebrospinal fluid). The NCFAD studies suggest that NiV invades the porcine host central nervous system via cranial nerves after initial virus replication in the upper respiratory tract (namely the oronasal cavity), and also by crossing the blood-brain barrier as a result of viremia. Secondary bacterial infections, mostly in cerebrospinal fluid, were detected in a number of animals, some of them requiring euthanasia . NiV infects a number of immune cells in swine including lymphocytes. This may be different from other species, where passive adherence of the virus to the lymphocytes was proposed.

    NiV was not detected in muscle tissue of experimentally infected pigs.

    Protective immune response in pigs requires both humoral and CMI arm.

    There appear to be some differences in pathogenesis and shedding pattern between NiV-M and NiV-B in pigs (Weingartl, oral communication).

    GAPS:

    Behaviour of the Bangladesh isolates in swine were recently evaluated. Reporting of results in pending.

    Studies needed on potential immuno-modulation due to NiV infection in swine (e.g. delay in antibody production may have consequences for diagnostics).

    Further studies needed on infection in various cell types, including cells of the immune system, and bat cells.

    Use of infectious clones to study virulence determinants is being done to low extent at NCFAD using rescued viruses developed by M.Yoneda and C.Kai.

  • Zoonotic potential

  • Reported incidence in humans

    Between September 1998 and April 1999, NiV appeared in the human population in Malaysia causing fatal encephalitides with associated pulmonary disease. In the original outbreak, there were 265 reported cases with 40% fatality rate. The virus had spread in pigs without its significance being recognized. Following the human infections, over one million pigs were culled to stop spread of the disease. Subsequently smaller, more frequent outbreaks are occurring in Bangladesh and India, with the average of 77% mortality rate. Small outbreaks continue to occur in Bangladesh on seasonal basis.

  • Risk of occurence in humans, populations at risk, specific risk factors

    Two high risk factors have been identified. In Malaysia, being in contact with infected swine, especially with diseased swine body fluids but also via husbandry practices such as feeding and handling of pigs, thus being exposed at close range to droplets from their respiratory tract was the significant factor. In Bangladesh and India, a primary risk factor is ingestion of the virus by drinking raw palm sap, followed by human-to-human (including nosocomial) transmission. The transmission requires close contact with live (or even dead) infected people. NiV was detected in human respiratory secretions.

    GAP: Knowledge about the possible routes of infection in people and the likely infectious dose by each route, Such information is important in developing recommendations for prevention of infection. Studies in relevant animal models should be considered.

  • Symptoms described in humans

    Severe, rapidly progressive fatal encephalitis in humans was observed in Malaysia, with 40 % of patients also suffering from pulmonary syndrome. In Bangladesh most of the patients suffer from severe pulmonary edema in addition to encephalitis.

    GAP: Lack of knowledge of the factors leading to relapse in humans, including the possibility of long term infection. Again the feasibility of studies in an animal model should be considered.

  • Estimated level of under-reporting in humans

    Moderate and depends on the diagnostic capacity in an affected country.

    Active surveillance in 6 hospitals in Bangladesh.

  • Likelihood of spread in humans

    Although person-to-person transmission has been documented, the virus does not seem to be highly contagious among humans (e.g. in comparison with influenza). Humans can shed Nipah virus in upper respiratory secretions.

    GAPS:

    Possibility of super-spreaders needs to be investigated.

    Possibility of criminal spreading at least in short clusters of terrorist attacks is a distinct possibility, for example by aerosolization in confined public spaces, or through infection of pigs.

  • Impact on animal welfare and biodiversity

  • Both disease and prevention/control measures related

    Moderate disease in pigs which may show no symptoms and which will recover.

    There will be major impact on animal welfare during outbreaks, when movement of pigs will be restricted due to quarantine. Slaughter of healthy pigs for humane reasons may be necessary (Linked to the structure of the swine industry in the affected region).

    GAP: General gap for other swine diseases as well where quarantine is a control tool – development of a structure to deal with restriction in animal movement.

  • Endangered wild species affected or not (estimation for Europe / worldwide)

    Does not appear to cause disease in the reservoir hosts.

    GAP: Susceptibility of European species of bats not known.

  • Slaughter necessity according to EU rules or other regions

    Animals with NiV infections are generally slaughtered to prevent human infections.

    GAPS:

    Availability of alternative measures to slaughter.

    Tools to slow down spread/control the outbreak in swine while depopulating large numbers of animals are not available.

    Provide for efficient financial compensations to encourage immediate declaration.

  • Geographical distribution and spread

  • Current occurence/distribution

    NiV infections of human and domestic animals have been documented in Malaysia, Bangladesh and northern India. Cases were also reported in abattoir workers in Singapore processing pigs from Malaysia. This virus has been isolated from bats in Cambodia, and seropositive and RNA-positive bats have been reported widely across the range of the Pteropid species and in a fruit bat from West Africa. Although Nipah virus should be considered endemic in Southeast Asia, outbreaks seem to cluster in certain geographic areas. See 2.4.

    Swine sero-surveillance in West Bengal appears to be negative so far (out of 328 pig 8 serum samples cross reacting with NiV N-antigen could be false positive). Attempts to ship the sera for confirmation testing not successful. About 50% of bat sera from this region tested positive for NiV-like antibodies, however 475 bat urine samples and 180 swine samples (nasal swabs, lung, spleen) tested negative by RT-PCR targeting the N gene.

    GAP: Knowledge on serological cross-reactions with other henipa- or morbilliviruses in bats is improving (Luminex assays - ecological studies by several groups).

  • Epizootic/endemic- if epidemic frequency of outbreaks

    NiV emerges periodically to affect humans, pigs and occasionally other domesticated animals.

  • Seasonality

    Yes. HeV outbreaks are seasonal, assumed to be linked to life cycle – biology of the bat vector. In Bangladesh in addition human behaviour contributes to seasonality – outbreaks linked to date palm sap collection season (December – May).

    GAP: Knowledge of NiV shedding and recrudescence in bats (stress related, e.g. pregnancy or birthing?).

  • Speed of spatial spread during an outbreak

    May be rapid due to movement of infected animals (prior to the detection of the disease, illegal movements during the outbreak).

    GAP: Possibility of spread by fomites? (Implications for quarantine measures)

  • Transboundary potential of the disease

    High. The NiV has spread across geographical areas and due to wide range of bat reservoir. Potentially spread by pig movements.

  • Route of Transmission

  • Usual mode of transmission (introduction, means of spread)

    The route of transmission from bats to domesticated animals is uncertain, but pigs might be infected by eating fruit that has been contaminated with bat saliva or urine, by drinking contaminated water, or by eating aborted bat foetuses or birth products. Pigs shed NiV in respiratory secretions and saliva. During the Malaysian outbreak, transmission on a farm seemed to occur by large droplets and direct contact with respiratory secretions and coughed up sputum.

  • Occasional mode of transmission

    Unknown but although NiV has not been found to date in urine, it was detected in kidneys and exposure to pig urine may be a risk factor for infection. Anecdotal evidence suggests that vertical transmission may occur across the placenta. Transmission in semen and iatrogenic spread by re-used needles has also been suggested.

    GAP: Presence of NiV in swine urine or semen not determined or excluded.

  • Conditions that favour spread

    Close contact between fruit bats and pigs in particular. No treatment for sap.

  • Detection and Immune response to infection

  • Mechanism of host response

    Immune evasion mechanisms

    The NiV uses unusual processes called RNA editing and internal translational initiation to generate multiple proteins from the phosphoprotein (P) gene, resulting in 4 proteins (P, C, V, and W) that function in inhibiting Type I interferon pathways:

    NiV P, V, and W have individually been shown to bind STAT1, effectively preventing signaling in type I IFN-stimulated cells.

    Both V and W protein localize to the cytoplasm in investigated swine cells; in number of human/other species cell types the W protein localizes to the nucleus.

    The C protein can partially rescue replication of an IFN-sensitive virus, but the mechanism is unknown.

    Nuclear localization of W enables it to inhibit both dsRNA and TLR 3 (IRF-3 dependent) IFN-b induction pathways.

    A single point mutation in the V protein abrogates its ability to inhibit of IFN signaling.

    The V proteins of paramyxoviruses interact with the intracellular helicase Mda-5, and inhibits its IFN-b induction, but not with RIG-I

    Protective immunity

    The G and F glycoproteins induce neutralizing antibodies that protect against NiV or HeV challenge and infection.

    GAPS:

    Innate immunity and immunosuppression:

    - Activation and/or evasion of the innate immune response and cellular immune response not known in pigs

    - Need studies in NiV infected cells and other animal models

    - Identify targets for antiviral agents

    - Cytokine response to infection in cell lines of target species origin

    Protective immunity:

    - Need to define correlates of protection

    - Study cellular response and cellular targets

  • Immunological basis of diagnosis

    Detection of anti-N, anti-G or anti-F antibodies by ELISA, virus neutralization assays (immunostaining, microtiter plaque assays, etc.) and Luminex; immunohistochemistry assays are based on antibodies against the N protein or immune anti-NiV serum.

    GAPS:

    Quick and easy pen-side tests that can be produced and used in low biosafety environments are needed.

    DIVA is essential in vaccinated animals.

  • Main means of prevention, detection and control

  • Sanitary measures

    Avoid unprotected contact with potentially infected pigs; respiratory personal protective equipment in addition to other protective clothing (gloves, boots, Tyvek suit or coveralls) essential for access to suspected farms.

    Unpasteurized juices should be not be drunk, and fruit should be washed thoroughly, peeled or cooked. Good personal hygiene, including hand washing, also reduces the risk of infection.

  • Mechanical and biological control

    Good biosecurity is important in preventing infections on pig farms; strategies should target routes of contact with other pigs as well as fruit bats. Fruit tree plantations should be removed from areas where pigs are kept. Wire screens can help prevent contact with bats when pigs are raised in open-sided pig sheds. Run-off from the roof should be prevented from entering pig pens.

    Mass culling of seropositive animals may be necessary. Quarantines were also important in containing an outbreak; inMalaysia, Transmission on fomites is also possible; re-used vaccination needles may have contributed to the spread of the virus inMalaysia. During an outbreak, fomites and equipment should be cleaned and disinfected. In addition, dogs and cats should be prevented from contacting infected pigs or roaming between farms.

    GAP: Mass culling represents a major logistical problem for humane and environmental reasons, also due to the dangerous zoonotic nature of the agent. Carcass disposal – biosafety concerns.

  • Diagnostic tools

    Diagnosis of NiV infection is by virus isolation, detection of viral RNA or demonstration of viral antigen in tissue collected at necropsy. Specific antibody can also be useful particularly in pigs where NiV infection may go unnoticed. Retrospective serology has been applied to the diagnosis of human infections. Demonstration of specific antibody to NiV in either animals or humans is of diagnostic significance because of the rarity of infection and the serious zoonotic implication of transmission of infection.

    GAP: Individual cases can be submitted to AAHL (OIE Reference Laboratory), however this set up is not suitable for high throughput screening at the onset of an outbreak. AAHL established a high throughput serology laboratory in Malaysia (35,000 sera tested in 3 months) and can assist. CDC Atlanta is a collaborating OIE Centre for NiV.

  • Vaccines

    There are no vaccines currently available for NiV (in swine) although promising results were reported from independent experiments in swine, cats, and hamsters.

    There is a proposal to use NiV sG to be developed as vaccine for NiV in swine (efficacy testing will be performed at CSIRO).

    GAP: Low financial motivation for the industry to produce henipavirus vaccines or therapeutics for Europe. However CEPI announced major funding for human NiV vaccine.

  • Therapeutics

    No specific treatment is available for veterinary purposes. A human monoclonal antibody (m102.4) that is NiV and HeV cross-reactive is available for compassionate use in lab personnel or other individuals exposed to NiV or HeV. It has been used in several people in Australia in HeV exposed individuals, and once in the USA in a NiV exposed individual. The antibody is in pre-clinical development.

    GAP: Gap in development of therapeutics, although their use would be problematic given biosecurity concerns regarding exposed animals: antibody based passive immunotherapy should be considered only for humans.

  • Biosecurity measures effective as a preventive measure

    NiV must be handled at biosafety level 4. It is important that samples from suspect animals are consigned to laboratories under biologically secure conditions according to international regulations.

    GAP: Development of diagnostic tests suitable for low containment laboratories, including reagent production (See sections “Immunological basis of diagnosis” and “Diagnostic tools”).

  • Border/trade/movement control sufficient for control

    Control of farms in an infected area; standstill on animal movements; international ban on meat and meat products can be expected.

    GAP: General negotiation mechanisms and agreements have to be in place (also for other zoonotic diseases): legal power to enforce quarantine, lead on investigation, implementation of sanitary check points.

  • Prevention tools

    Preventing infections in pigs can decrease the risk of infection for humans.

    GAP: Indoor housing of swine with biosecurity precautions; non-kill vector control such as removal of fruit trees from the vicinity of pig farms.

  • Surveillance

    Early recognition of infected pigs prevents disease in other animals and humans.

  • Past experiences on success (and failures) of prevention, control, eradication in regions outside Europe

    Effective control inMalaysia involved initially depopulation followed by national serosurveillance to identify remaining infected farms. Longer term measures included continuing serosurveillance and ensuring separation between pigs and fruit bats through removing fruit trees from farms.

    Depopulation: the control of NiV in pig populations through stamping out is complex due to the zoonotic nature of the agent. In addition, depopulation may be logistically difficult and very expensive in areas with high pig densities. National surveillance identified remaining infected farms after the outbreak, and subsequently demonstrated freedom of disease.

  • Costs of above measures

    High due to the extent and nature of the swine industry and due to zoonotic nature of the agent. Costs of surveillance and culling, communications, compensations, etc.

  • Disease information from the WOAH

  • Disease notifiable to the WOAH

    NiV encephalitis is an OIE listed disease. No reports in 2008/ 2009/ 2010/ or 2011 were made to the OIE. In 2014 an outbreak of henipavirus in horses suspected to be NiV was reported in Philippines.

  • WOAH Terrestrial Animal Health Code

    No.

  • Socio-economic impact

  • Zoonosis: impact on affected individuals and/or aggregated DALY figures

    Geographic impact is limited to those areas with fruit bat populations in Asia.

    Serologic studies suggest that some human infections are asymptomatic. In the Malaysian outbreak, the subclinical infection rate was estimated to be 8%-15%. The case fatality rate during the Malaysian outbreak was 40% and in the variousBangladesh outbreaks has varied from 25% to approximately 100%; the overall case fatality rate for all outbreaks inBangladesh between 2001 and February 2011 is 77%. Among surviving patients, an estimated 25% have residual neurological deficits. Nearly 10% of the patients in the Malaysian outbreak had late onset encephalitis with a case fatality rate of 18%.

    GAPS:

    Implications of the detection of infection in African fruit bats have not been assessed.

    Criminal use of the virus as biological weapon would have devastating consequences.

  • Zoonosis: cost of treatment and control of the disease in humans

    Unknown, but expected to be significant, especially if outbreak investigation is considered. Only symptomatic treatment is available.

  • Direct impact (a) on production

    Natural outbreaks appear limited primarily to pigs, but also horses, dogs and cats.

    In pigs, asymptomatic infections appear to be common. Mortality in field low apart from newborn piglets, where it may be linked to inability of the sow to nurse. Severe cases with stamping out close the farm.

    GAP: The bio-threat circumstance of NiV because of its expansive and known host range from natural and experimental infections may require consideration of cattle, sheep and goats.

  • Direct impact (b) cost of private and public control measures

    Direct impact on farms and the pig industry, or any affected industry such as the horse industry, will be significant as this an OIE reportable disease and the first intervention will be very likely culling. Implementation of quarantine and standstill on animal movement will have severe impact on animal welfare: due to current structure of swine industry, stop in animal movement will lead to overcrowding of facilities, and depopulation will have to be implemented for humane reasons.

    Culling of seropositive herds will likely be also implemented, and can be expensive.

  • Indirect impact

    High. There is a high disruption to pig meat production in the affected areas, with implications for employment, poverty and food availability or market distortions. Public health scare. The cost of control measures is high and requires whole of government responses to deal with environmental issues and compliance issues as well as the immediate demand of destocking.

  • Trade implications

  • Impact on international trade/exports from the EU

    High. Importing countries would stop trade. No standards are currently set in the OIE Terrestrial Animal Health Code, making negotiations difficult.

    GAP: Develop (international) regulations and agreement.

  • Impact on EU intra-community trade

    None at present but high in the case of an outbreak.

  • Impact on national trade

    None at present but high in the case of an outbreak.

  • Main perceived obstacles for effective prevention and control

    Since European bats are considered unlikely to be a reservoir host prevention and control are nor major EU concerns, where the normal processes of management of any potential trade in live animals should be adequate. Concerns on surveillance, vaccines, depopulation, and diagnostic tests are summarized in their respective sections above.

    GAPS:

    No consideration given to development of prevention and control measures and (international) strategies.

    No prevention and control measures in place.

  • Main perceived facilitators for effective prevention and control

    Diagnostic capability, and vaccination program in specific regions linked to risk assessment; availability of both human and veterinary vaccine for non-enzootic areas.

    GAPS:

    The availability of safe laboratory diagnostic tests is limited and non –existent in low biosafety conditions: see Sections “Immunological basis of diagnosis”, “Diagnostic tools” and “Biosecurity measures”.

    Availability of human vaccine and serotherapy stocks for personnel during potential outbreaks would secure much better responses.

  • Links to climate

    Seasonal cycle linked to climate

    Yes. See section “Seasonality”.

  • Distribution of disease or vector linked to climate

    Yes. Habitat range of bat species serving as a reservoir for NiV can expand or change due to climate or other ecological changes.

  • Outbreaks linked to extreme weather

    Potentially, as per considerations in section “Distribution of disease or vector linked to climate”above.

  • Sensitivity of disease or vectors to the effects of global climate change (climate/environment/land use)

    Not directly but could be linked to the availability of food for the fruit bats.

Risk

  • A zoonosis limited to certain countries linked to infection in fruit bats. Should the virus mutate or move into other species which could act as reservoir hosts then there is potential for problems to develop.

    Criminal use of henipaviruses as biological weapons is possible with devastating consequences, their highly pathogenic nature and broad host range makes them a significant bio-threat agent to both humans and livestock.

    One of the main concerns related to NiV is the ease with which it can be grown and its potential for biological warfare or terrorism. Because of the high specificity of the issue, the independent expert community is small and could easily be built into a formalized structured worldwide network for validation of products and measures.

Main critical gaps

Conclusion

  • NiV is re-emerging virus responsible for previously unrecognized fatal diseases in animals and humans in Asia. Fruit bats are the natural hosts of the virus. The emergence of NiV appears to have been the result of exposure of new hosts precipitated by certain environmental and behavioural changes. NiV transmission from infected pig herds has led to serious outbreaks of disease in human populations. Control is dependent largely on measures taken to reduce the risk of infection of pigs and the culling and disposal of infected animals.

    In-depth knowledge concerning many aspects of the distribution, epidemiology, pathogenesis and control of NiV is lacking.

    Main GAP: Lack of financial justification for the industry, with no stockpile policy in EU.

Sources of information

  • Expert group composition

    Expert group members are included where permission has been given

    Weingartl Hana, National Center for Foreign Animal Disease, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada - [Leader]

    Balkema-Buschman Anne, Friedrich-Loeffler-Institut; Bundesforschungsinstitut für Tiergesundheit; Federal Research Institute for Animal Health, Südufer 10 | 17493 Greifswald - Insel Riems

    Broder Chris C., Department of Microbiology and Immunology, B4106; Uniformed Services University 4301 Jones Bridge Rd, Bethesda, MD 20814-4799

    Epstein Jonathan H., EcoHealth Alliance; 460 West 34th Street – 17th floor; New York, NY 10001

    Gay Cyril; Agriculture Research Services, US Department of Agriculture, USA

    Marsh Glenn A., Australian Animal Health Laboratory, CSIRO Health and Biosecurity, Geelong, VIC, Australia

    Pickering Brad, National Center for Foreign Animal Disease, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada

    Raut Ashwin A., ICAR-National Institute of High Security Animal Diseases (ICAR-NIHSAD), OIE Reference Laboratory for Avian Influenza, Anandnagar, Bhopal-462021 (India)

    Roth James A., Center for Food Security and Public Health, Institute for International Cooperation in Animal Biologics, College of Veterinary Medicine, Iowa State University, Ames, Iowa

  • Date of submission by expert group

    30 November 2017

  • Name of reviewers

    Project Management Board