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O Animal, Food and Health Sciences, Australian Animal Health Laboratory, Private Bag 24, Geelong 3220, Australia

ntroduction

Hendra virus (HeV) and Nipah virus (NiV) are uniqueong the paramyxoviruses in that they cause severection in a broad range of animals and fatal disease inh humans and animals (Chua et al., 2000; Geisbert et al.,0; Guillaume et al., 2006; Li et al., 2010; Marsh et al.,1; Westbury et al., 1995; Williamson, 1999; William-

et al., 1998, 2000, 2001; Williamson and Torres-Velez,0). Because of the potential for HeV and NiV to causeere disease in humans and the lack of a vaccine orrapies proven to be effective against disease in humansse viruses are classified as biosafety level 4 (BSL4)nts. Their pathogenicity, presence in a wildlife popula-

and the ease at which they can be propagated, make henipaviruses Select Agents of Concern for Biodefensethe USA Centres of Disease Control and Prevention and

National Institute of Allergy and Infectious Diseases. natural spill-over host for HeV in Australia is the horse;h more than 80 horses know to have been infected,st resulting in fatal disease. All cases of human HeV

have resulted from significant exposure to infected horses.Horses are also susceptible to NiV infection with equinecases, showing similar pathological features to HeVinfections, observed during the NiV outbreak in Malaysia(Hooper et al., 2001; Hooper and Williamson, 2000). Avaccine has been released to prevent HeV infection inhorses. An array of antiviral therapeutics is being exploredand a human monoclonal antibody against HeV glycopro-tein shows great promise for post exposure therapy.

2. History

HeV was first isolated in 1994 from an outbreak of fatalrespiratory disease in racehorses and their trainer inBrisbane, Australia (Murray, 1996; Selvey et al., 1995).Retrospectively investigations confirmed the virus wasalso the cause of death of horses in Mackay, Queensland,earlier in 1994 and subsequently the death of an individualinvolved in 1995 from suspected relapsing encephalitis(Allworth et al., 1995; O’Sullivan and Allworth, 1997;Rogers et al., 1996). Since then there have been sporadiccases of the disease confirmed in horses in Queensland andnorthern New South Wales. Prior to 2011 there were a totalof 14 known ‘spill over’ events, infecting 45 horses and 7humans, all of whom had close contact with an infectedhorse, 4 of the human infections were fatal (Field et al.,

T I C L E I N F O

le history:

ived 11 April 2013

ived in revised form 12 July 2013

pted 5 August 2013

ords:

ipavirus

dra virus

h virus

ipa-like viruses

nosis

A B S T R A C T

The Henipavirus genus represents a group of paramyxoviruses that are some of the

deadliest of known human and veterinary pathogens. Hendra and Nipah viruses are

zoonotic pathogens that can cause respiratory and encephalitic illness in humans with

mortality rates that exceed 70%. Over the past several years, we have seen an increase in

the number of cases and an altered clinical presentation of Hendra virus in naturally

infected horses. Recent increase in the number of cases has also been reported with human

Nipah virus infections in Bangladesh. These factors, along with the recent discovery of

henipa and henipa-like viruses in Africa, Asia and South and Central America adds, a truly

global perspective to this group of emerging viruses.

Crown Copyright � 2013 Published by Elsevier B.V. All rights reserved.

Corresponding author. Tel.: +61 3 5227 5125; fax: +61 3 5227 5555.

E-mail addresses: emma.croser@csiro.au (E.L. Croser),

n.marsh@csiro.au (G.A. Marsh).

Contents lists available at ScienceDirect

Veterinary Microbiology

jo u rn al ho m epag e: ww w.els evier .c o m/lo cat e/vetmic

8-1135/$ – see front matter . Crown Copyright � 2013 Published by Elsevier B.V. All rights reserved.

://dx.doi.org/10.1016/j.vetmic.2013.08.002

E.L. Croser, G.A. Marsh / Veterinary Microbiology 167 (2013) 151–158152

2000, 2010; Hanna et al., 2006; Marsh et al., 2010; Playfordet al., 2010; PromedMail, 2009; Selvey et al., 1995; Sullivanet al., 1997). In 2011 there was an unprecedented rise inthe number of HeV outbreaks, with 18 equine outbreaksrecorded between June and October. Hendra virus out-breaks are summarised in Table 1. Investigations intoclimatic and environmental factors in facilitating theincrease in henipavirus spill over events remain incon-clusive (McFarlane et al., 2011; Plowright et al., 2011). Lowmorbidity but high case fatality rates are features of HeVinfection in both horses and humans (Field et al., 2010).

3. New viral discovery and globalisation

HeV and NiV, comprise the genus Henipavirus, in thesubfamily Paramyxovirinae of the family Paramyxoviridae

(Marsh et al., 2012; Wang et al., 2000, 2001). Bats of thegenus Pteropus (fruit bats, also called flying foxes) wereidentified as the reservoir host of henipaviruses (Chuaet al., 2002; Halpin et al., 2000; Marsh et al., 2012).Recently a novel virus, Cedar virus, was isolated fromAustralian fruit bats during HeV surveillance activities.Genome characterisation of this virus identified a close linkto HeV and NiV suggesting this virus should be classified asa third member of Henipavirus genus. CedPV antibodiescross react but do not neutralise HeV or NiV but fullgenome analysis of CedPV shows it is most closely relatedto HeV and NiV than to the henipa-like virus fragmentsdetected in Africa (Marsh et al., 2012). The major geneticdifference between the so far apparently non-pathogenicCedPV, and HeV or NiV lies within the P gene. Unlike HeV,NiV, and almost all other known paramyxoviruses, theCedPV P gene lacks both RNA editing and also the codingcapacity for the V and W proteins. Preliminary studiesindicated that CedPV infection of ferrets and guinea pigswas subclinical, and a more robust type I interferonresponse is induced in human cells compared to thatinduced by HeV (Marsh et al., 2012). The discovery ofCedPV provides an important tool for future research intothe molecular basis of pathogenicity.

Although disease associated with henipaviruses hasonly been recognised in Australia, Malaysia, Singapore,India and Bangladesh, evidence of the presence of henipaor henipa-like viruses in bats has been detected acrossCentral and South America, Africa, Asia, and Oceania(Fig. 1). This includes fruit bats from the Pteropus genus

along with fruit bats from several other genera, insecti-vorous and microbats (as reviewed by Clayton et al., 2013).

4. Transmission

The mode of virus transmission between flying foxes,and ‘spill over’ from flying foxes to other animals, is not yetfully understood but most likely involves exposure to theurine or saliva of an infected bat (Chua et al., 2002; Halpinet al., 2000; Luby and Gurley, 2012). All cases of HeVinfection in humans have arisen from close contact withinfected horses (Field et al., 2010; Murray et al., 1999). Allcases had exposure, either during necropsy of infectedhorses, or from close contact with respiratory secretionsand/or blood from infected horses. In all cases of humaninfection, HeV had not been considered as a differentialdiagnosis for the horse at the time of human exposure. Inone case, human HeV infection is thought to have occurredthrough contact with an as yet asymptomatic infectedhorse in the late incubation period (Field et al., 2010;Playford et al., 2010). In experimental studies in horsesHeV was detected in respiratory secretions, saliva, urineand faeces (Hooper et al., 1997a; Marsh et al., 2011;Williamson et al., 1998). It was also demonstrated that bythe time a horse is showing clinical signs, HeV virus hadspread systemically throughout the body and is present inbody fluids (Marsh et al., 2011). A HeV infected horse canshed HeV genetic material and therefore potentiallyexcrete HeV through nasal/nasopharyngeal secretions,from 2 days after exposure up to and including the timethat it shows clinical signs. Therefore there is the risk ofonward transmission to other susceptible species prior tothe horse developing clinically detectable disease. Trans-mission risk increases with disease progression and ishighest during the terminal stages of disease (Marsh et al.,2011). Horses are likely to be maximally infectious atnecropsy and infectious virus may persist on surfacescontaminated by body fluids at necropsy for a variableperiod (up to several days), depending on environmentalconditions (Marsh et al., 2011; Queensland Biosecurity,2011). However, not all infections are fatal, approximately25% of horses can survive acute infection associated withthe development of virus neutralising antibodies (Murrayet al., 1995; Queensland Biosecurity, 2011; Williamsonet al., 1998). The occupational health and safety andwelfare challenge of caring for horses at BSL4 limit the

Table 1

Summary of Hendra virus disease events in Australia.

Year No of disease events Horse cases Human cases Human deaths

1994 2 22 3 2

1999 1 1 – –

2004 2 2 1 –

2006 2 2 – –

2007 2 2 – –

2008 2 8 2 1

2009 2 6 1 1

2010 1 1 – –

2011 18 23 – –

2012 8 10 – –

2013a 7 7 – –a Up until 10th July 2013.

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E.L. Croser, G.A. Marsh / Veterinary Microbiology 167 (2013) 151–158 153

ber of henipavirus studies that can be performed inses. It is not feasible at BSL4, and the risks too great at aer biosafety level, to maintain horses that have

vived the acute infection to study the potential forl recrudescence. Serosurveys of wildlife carers whodle injured and sick flying foxes have shown no

dence of HeV spreading directly from bat to humanswak, 1995).Some seasonality to HeV spill over events is observed,h an overlap of late stage pregnancy and birthing periodflying foxes and/or the dry season (McFarlane et al.,1). However, HeV excretion in bat urine occurs yearnd (Field et al., 2011) suggesting other factors inition to the presence of the virus are importanttributors to spill over events. Investigations intoatic and environmental factors in facilitating spill

r events prior to 2011 were inconclusive (McFarlanel., 2011; Plowright et al., 2011). Some evidence exists ofitive associations between pregnancy and HeV status oft bats, ecological stress and HeV status, incidenttion and proximity to flying fox roosts and between

iods of lower rainfall and HeV incidents (Field et al.,2). In 2011, the cluster of 18 HeV incidents over a 3nth period was a dramatic departure from previousr’s occasional sporadic spill-over events. The location of

incidents expanded the known southern and westerlyge of disease occurrence by over 300 and 200 kmpectively (Field et al., 2012). Multiple host andironmental factors are proposed responsible. Flying

viral excretion levels were substantially higher anddding was more prolonged than in the previous 3 yearsld et al., 2011, 2012) and it is hypothesised thatitional environmental factors such as decreased food

ource availability and climatic conditions, prolonged

survival of the virus in the environment, pasture state andhorse behaviour all contributed (Field et al., 2012). A moremoderate increase in incidents has continued this trendwith and additional 12 outbreaks occurring betweenJanuary 2012 and July 2013 (Queensland Government,2013). The increased incidence of outbreaks in horses hasnot been associated with further cases of human infection.This is probably due to increased awareness in horseowners and veterinarians fostering earlier consideration ofHeV as a differential diagnosis and therefore increasedimplementation of risk minimising protocols (Field et al.,2012).

The genetic relatedness of HeV recovered from horsesand flying foxes during spill over events supports thesuggestion that different outbreaks result from indepen-dent spill over events from the fruit bat population,consistent with the presence of ‘quasispecies’ within thebat population (Marsh et al., 2010; Smith et al., 2011),rather than being associated with correlating to aparticular HeV strain.

Serological studies (Field et al., 2001; Mills et al., 2009)confirmed observations (Parashar et al., 2000) that dogswere commonly infected with NiV during the Malaysianoutbreak. Only two dogs were necropsied during theMalaysian outbreak (Hooper et al., 2001). One waseuthanased after exhibiting clinical signs similar to caninedistemper virus (a paramyxovirus of the genus Morbilli-

virus) including fever, conjunctivitis, and respiratorydistress with mucopurulent nasal discharge. In July2011, the first reported case of HeV antibody detectionin a dog outside of an experimental setting occurred(PromedMail, 2009). The dog lived on a property whereHeV infection had been confirmed in horses. It wasreported that the dog did not show any clinical signs of

1. The global distribution of henipa and henipa-like viruses. Red: countries where henipavirus outbreaks have occurred. Dark blue: countries where

ipavirus has been isolated. Light blue: countries where RNA from a henipavirus or henipa-like virus has been discovered. Yellow: countries with

logical evidence of henipavirus exposure. Green: countries where there is both serological evidence of exposure and henipavirus RNA has been

overed. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

E.L. Croser, G.A. Marsh / Veterinary Microbiology 167 (2013) 151–158154

illness. In July 2013 HeV infection was confirmed in seconddog, this dog was also from a property where HeV infectionhad claimed a horse. Currently, HeV infection dynamics indogs is being investigated, with particular emphasis beingplaced on the potential for dogs to shed infectious virus(Deborah Middleton, CSIRO, personal communication). InAustralia, because of the unknown risk of diseaserecrudescence, it is the policy that any animal shown tobe infected with HeV is euthanased (Queensland Biose-curity, 2011).

Ecological drivers of pathogen spill over are undoubt-edly complex and cross disciplinary approaches arerequired for increased understanding. Different epidemio-logical modelling systems are being applied in order tobetter understand and predict disease emergence (Hay-man et al., 2013; Plowright et al., 2011). The recentcharacterisation of the immune transcriptome of theAustralian flying fox, Pteropus alecto (Papenfuss et al.,2012; Zhang et al., 2013) identified genes involved inantiviral immunity in the bat and should direct furtherinvestigations into understanding the control of viralreplication in bats.

5. Human infection

Whilst there have only been 7 cases of human HeVinfection, there have been over 500 cases of human NiVinfection. HeV and NiV infection in humans appear to besimilar. Infection is characterised by an acute influenza-like illness which may progress to pneumonia (Selveyet al., 1995) or encephalitis with a high mortality rate(Chua et al., 1999; Goh et al., 2000; Hanna et al., 2006;Playford et al., 2010; Wong et al., 2002, 2009). Somepatients following an initial recovery suffer relapsing, orlate-onset encephalitis months to years after the initialinfection (Allworth et al., 1995; O’Sullivan and Allworth,1997; Tan et al., 2002).

The incubation period ranges from a few days up to 14days (Goh et al., 2000; Hanna et al., 2006; Playford et al.,2010; Selvey et al., 1995). Mild symptoms include fever,headache, myalgia and drowsiness. Neurological signsinclude headache, confusion, dizziness, abnormal reflexes,hypertension and tachycardia and seizures progressing toan altered level of consciousness and coma (as reviewed byWong and Tan, 2012). In the NiV Malaysia outbreak, allpatients with normal level of consciousness recoveredfully over the course of 2 weeks, whereas, only 15% ofpatients with a reduced level of consciousness recovered.Of these survivors, approximately three-quarters recov-ered fully, but one quarter had residual neurologicaldeficits (Chua, 2003; Goh et al., 2000). Some patientspresented with a cough, pneumonia and may progress toacute respiratory distress syndrome (Goh et al., 2000;Selvey et al., 1995). Vomiting and diarrhoea wereoccasionally reported in patients with NiV infection(Hossain et al., 2008).

Although there are only 3 cases of people surviving HeVinfection to study, in these patients virus was shed for 5–6weeks post exposure with no evidence of shedding afterthis time (Taylor et al., 2012). Anti-henipavirus antibodiesdevelop in cerebrospinal fluid (CSF) and serum. IgM

appears by 2 weeks post infection and is present forseveral months in recovered patients. IgG seroconversionoccurs from 3 weeks post infection and may be present foryears (Hanna et al., 2006; O’Sullivan and Allworth, 1997;Selvey et al., 1995; Tan and Tan, 2001; Wong and Tan,2012).

In both humans and animal models the characteristicpathological feature of HeV and NiV infection is dissemi-nated vasculitis with endothelial syncytia (Wong et al.,2002). Viral antigen is present within the endotheliumincluding in syncytia and the smooth muscle of the vesselwall (Wong et al., 2002). Damage to the vascular wallresults in thrombosis and perivascular haemorrhage.Thrombosis of vessels leads to decreased perfusion withinthe dependent tissues resulting in ischaemic necrosis,oedema and inflammation throughout multiple organs.Viral inclusions, antigen and RNA are also present withinparenchymal cells adjacent to lesions, for example, inneuroglial cells, renal tubular epithelium, pneumocytes inthe alveoli of the lung, neuronal necrosis is also a feature(Wong et al., 2009; Wong and Tan, 2012). In addition toendothelial and organ damage there is extensive lymphoidnecrosis.

Relapsing encephalitis appears distinct from the acuteencephalitic infection. The lesions of encephalitis in theacute phase, as expected with haematogenous dissemina-tion, are small, discreet, multiple and widely distributed(Wong et al., 2009; Wong and Tan, 2012), consistent withbeing a result of ischaemic injury and a sequelae of thesystemic vasculopathy. Whereas the lesions in relapsingencephalitis are confined to the central nervous system(CNS) and there is no evidence of vascular pathology (Tanet al., 2002; Wong, 2010). Affected areas are moreextensive and comprised of necrosis, oedema and inflam-mation (macrophages, plasma cells and lymphocytes).There is prominent perivascular cuffing and gliosis inadjacent areas accompanying severe and widespreadmeningitis. Viral inclusions, antigen and RNA werepresent, mainly in neurones, ependyma and possibly glialcells and inflammatory cells in cases of relapsingencephalitis, as they are in acute encephalitis cases, butinfective virus is not able to be re-isolated from relapsingcases. It is surmised that relapsing encephalitis resultsfrom viral recrudescence from foci of virus surviving in theCNS since the initial acute infection and similarities aredrawn to Measles virus encephalitis (subacute sclerosingpanencephalitis, SSPE) (Tan et al., 2002; Wong, 2010).

6. Clinical presentation and factors affecting diseasecourse in animals

Up until 2008, the clinical syndrome associated withHeV infection in horses was predominately associated witha rapidly progressive febrile illness culminating infulminating respiratory disease (Selvey et al., 1995). Someof the early cases did exhibit some neurological signs butthese were only mild, consisting of muscle twitching andrestlessness (Rogers et al., 1996; Williamson et al., 1998).In contrast, the 2008 outbreak in the Brisbane suburb ofRedlands affected 5 horses and presented primarily asneurological disease (Field et al., 2010). Signs included

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E.L. Croser, G.A. Marsh / Veterinary Microbiology 167 (2013) 151–158 155

xia, depression, disorientation, extreme hypersensitiv-when approached, head tilt, facial nerve paralysis,ling, head pressing, stranguria and recumbent periods.s change in the clinical presentation of Hendra infectionhorses may have delayed its recognition. In thisbreak two humans were infected and both sufferedephalitis, in one person this was fatal (Playford et al.,0).

The genetic makeup of isolates did not appear the causethe different clinical presentation. Isolates obtained

infected horses from 1994 to 2010 were compared exhibited little genetic variation (<1%) (Marsh et al.,0) and, in addition, horses experimentally infectedh the Redlands 2008 strain (Hendra virus/Australia/se/2008/Redlands, GenBank accession no. HM044317)ibited clinical signs comparable to those seen in theial outbreak with the ‘‘classical’’ 1994 strain (Hendras/Australia/horse/1994/Hendra, GenBank accession

AF017149) (Marsh et al., 2011). Accordingly, theerences in presentation in the Redlands outbreak weretulated to occur either due to a difference in exposuree, or route of infection, or to merely reflect thectrum of possible clinical manifestations of diseaseld et al., 2010).

Parallels can be drawn between horses and experi-ntally infected cats where HeV infection culminated inere respiratory disease from both non-parenteral (oral

nasal) and parenteral (subcutaneous) routes ofosure with a similar disease course (Hooper et al.,7b; Westbury et al., 1995, 1996), although, it was notedt intranasal and oral exposure resulted in more severemonary lesions (Hooper et al., 1997b). While CNSons were present (Middleton et al., 2002) the severity of

respiratory disease overshadowed any neurologicalase.

The clinical spectrum of HeV and NiV disease in bothans and other animals does indeed present as a

ctrum of respiratory and/or neurological disease, withors such as age and dose of virus described aserminates of variable disease presentation in animals.llenge dose influences disease course in non-humanates (Geisbert et al., 2012). Monkeys exposed to lower

es of NiV (<102 PFU) survived longer and exhibited morerological disease whereas monkeys infected with higheres (>105 PFU) succumbed earlier and primarily frompiratory disease. However, these experiments have usedntra-tracheal route of exposure: this is unlikely to mimicoute of natural infection and does not allow forestigation of alternative routes of CNS invasion, namely

olfactory or peripheral cranial nerve routes as proposedpigs (Weingartl et al., 2005), guinea pigs (Williamsonl., 2001), hamsters (Munster et al., 2012) and mice (Dupsal., 2012). Similar to the African green monkey, in

sters infected with HeV and NiV, clinical signs andase progression correlated with the infective dose and

re similar regardless of route (intraperitoneal or intra-al) (Guillaume et al., 2009; Rockx et al., 2011). Hamstersculated with 105 TCID50 succumbed within 5 days withte respiratory distress, whereas those inoculated with

TCID50 developed milder respiratory disease whichgressed to neurological disease and death by day 12

(Rockx et al., 2011). At the lower dose rate animals infectedIN with HeV succumbed significantly earlier (day 7) thanthose infected with NiV (day 12), the HeV infected groupexhibited respiratory and neurological signs whereas theNiV infected group only exhibited neurological signs (Rockxet al., 2011). Alternatively in HeV infection of ferrets, therewere no differences in distribution or severity of lesions seenat different infective doses (Pallister et al., 2011).

In pigs the disease presentation of NiV infection differswith age. A febrile respiratory illness with epistaxis,dyspnoea and coughing is predominately seen in youngerpigs while neurological signs including agitation, musclefasiculations, ataxia, paresis, and seizures predominatelyoccur in older pigs (Mohd Nor et al., 2000). Interestingly inthe case of HeV infection, but not seen in NiV infection, agealso appeared to influence susceptibility in hamsters andmice. Eleven-week old hamsters had a longer diseasecourse than 7-week old hamsters and required a 10-foldhigher dose to achieve 100% mortality (Guillaume et al.,2006, 2009). This resistance with increasing age wasmirrored in a mouse knock out model of HeV (Dhondt et al.,2013) but conversely it was found that only significantlyolder wild type mice (12 months of age) consistentlydevelop HeV encephalitis (Dups et al., 2012).

7. Differences in viral distribution

While the lesions of NiV infection in pigs are similar tothose reported for horses and humans (Hooper et al., 2001;Middleton et al., 2002) there have been some small, butinteresting, species differences discovered which wouldcontribute to differences in pathogenesis. Viral antigen,viral RNA and recoverable virus was present withinporcine peripheral blood mononuclear cells (monocytes,NK cells and CD8+ T lymphocytes) (Stachowiak andWeingartl, 2012), in comparison, in humans and hamstersNiV is only mechanically carried through the blood bythese cells (Mathieu et al., 2011). Clinical signs ofdepression and respiratory disease were more severe inexperimental Hendra infection in pigs than those reportedwith NiV infection (Li et al., 2010; Middleton et al., 2002).Interestingly, unlike with NiV, HeV was limited to therespiratory tract and associated lymph nodes (Li et al.,2010). NiV replicates within the tracheal epithelium inhamsters (Guillaume et al., 2009; Rockx et al., 2011) andcats (Middleton et al., 2002), this is not seen with HeV andan increase in respiratory secretion may account for thedifferences seen in transmissibility between NiV and HeV.

Experimental studies in pigs described the temporalinfection pathway of NiV and have been supported bylatter work in hamsters (Guillaume et al., 2009; Rockxet al., 2011). Oronasal exposure to virus is followed byreplication in the oropharynx with sequential spread to theupper respiratory tract epithelium and submandibularlymph nodes, then the lower respiratory tract andadditional lymphoid tissues (Weingartl et al., 2005). Viralantigen was present within the olfactory nerve by day 3post infection. The trigeminal, hypoglossal and theglossopharyngeal nerves also stained positively for viralantigen by day 6. The presence of viral antigen in thegranular cells of the olfactory bulb indicated the virus

E.L. Croser, G.A. Marsh / Veterinary Microbiology 167 (2013) 151–158156

enters the brain via olfactory pathways. However, fromthis study it remains to be clarified whether theirhypothesis of viral anterograde spread from cranial nervesto the brain is occurring, or whether the findings at thelater of the time points actually reflect centrifugal spreadfrom the brain. Recently studies in a mouse (Dups et al.,2012) and hamster (Munster et al., 2012) model havefurther elucidated the olfactory pathway of henipavirusinfection. NiV entry into the CNS was rapid (within 4 days)and coincided with the occurrence of respiratory disease,suggesting that the initial entry of NiV into the CNS occurssimultaneously with, rather than as a result of, systemicvirus replication (Munster et al., 2012). This alternativepathway for infection of the CNS is a plausible ‘naturalroute of infection’ and has implications for therapeuticeffectiveness. Future animal model experiments, espe-cially those dealing with therapeutic efficacy, should takethe olfactory route into account and challenge accordingly.

8. Vaccines and therapeutics

There are no licensed or proven effective antiviraltherapies available to treat human henipavirus infections(Mahalingam et al., 2012). Ribavirin and chloroquine havenot been effective in animal models (Freiberg et al., 2010;Georges-Courbot et al., 2006; Pallister et al., 2009; Rockxet al., 2010) but an open label trial of the use of ribavirin inencephalitic patients during the Malaysian NiV outbreaksuggested the drug reduced mortality (Chua, 2003) but thishas not been an effective treatment in human Hendra viruscases (Mahalingam et al., 2012; Playford et al., 2010). Themost promising post exposure therapy is passive immu-notherapy with the human monoclonal antibody 102.4,against the Hendra virus glycoprotein (G) protein (Bossartet al., 2009, 2011). This was unsuccessful when trialled inone human Hendra virus infected patient, however, factorswhich are likely to have contributed to treatment failurewere that the patient was already suffering from severeencephalitis and at the time of his illness there was only asmall (likely insufficient) dose available for administration(Mahalingam et al., 2012). The effectiveness of intrave-nously administered monoclonal antibody in preventingdisease caused by the newly described olfactory pathwayroute of CNS is questionable.

In November 2012 a commercial HeV sub-unit vaccinefor horses was released. The vaccine induces neutralisingantibody which protects horses from lethal Hendra viruschallenge, eliminates viral shedding and prevents viralreplication in tissues (Deborah Middleton, CSIRO, personalcommunication). Not only does this protect the health ofthe horse, but more importantly breaks the chain oftransmission, reducing the risk to people in contact withhorses and will hopefully act to reverse the very real trend(Mendez et al., 2012) of Australian veterinarians leavingequine practice.

9. Conclusion

With the detection of numerous henipa-like virussequences in Central and South America, Africa, Asia,

numbers of bat species, the geographical range ofhenipa-like viruses and the risk of these viruses enteringand spreading in the human population can no longer beconsidered confined to the Asia-Pacific region. Infection inother spill-over hosts is plausible with unknown potentialconsequences. Furthering our understanding of the eco-logical drivers of pathogen spill over and continuing thesearch for new effective anti-viral therapies is important tomitigating future disease outbreaks. In Australia spill-overinfections of HeV in horses are continuing. It is hopeddisease awareness, preparedness and vaccine uptakeamong the horse owning community will continue toincrease reducing the chances of further horse infectionand resultant human exposure.

Conflict of interest

Neither author (Emma Croser or Glenn Marsh) has afinancial or personal relationship with other people ororganisations that could inappropriately influence or biasthe review paper entitled ‘‘The changing face of Henipa-virus: a review’’.

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