The hendra virus

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Hendra virus is a virus that infects large fruit bats flying foxes. Occasionally the virus can spread from flying foxes to horses and horses can then pass the infection on to humans. A small number of people who had very close contact with infected horses have developed Hendra virus infection. Hendra virus infection has been confirmed in two dogs on properties where horses had been infected with the Hendra virus.

Neither dog was showing signs of illness. There is no evidence of Hendra virus occurring naturally in any other species. Hendra virus was discovered following an outbreak of illness in a large racing stable in the suburb of Hendra, Brisbane in What are the symptoms? After onset of fever, but before development of other clinical signs of illness, HeV RNA was also detected in the oral swab sample.

On the day of euthanasia, genome was detected in oral and nasal swab samples, blood, rectal swab, and urine samples; however, virus was not reisolated from any sample collected before postmortem examination. Viral RNA was detected in all tissues sampled at postmortem examination except cerebrospinal fluid. Reisolation of virus was attempted for all tissues: HeV was recovered from lung, submandibular lymph node, small intestine, large intestine, and adrenal gland.

In a series of vaccine efficacy studies, 10 horses were immunized with HeVsG glycoprotein and then exposed to an otherwise lethal dose of HeV by the oronasal route. Each study also included a pathogenicity control for the virus inoculum. In the first of these, the pathogenicity control was the fourth control horse described above. Together with historical data gathered from 3 horses following their exposure to HeV under equivalent experimental conditions 5 , data from this horse completed the requirements of the Australian Pesticides and Veterinary Medicines Authority for defining the horse infection model.

In subsequent studies, guinea pigs or ferrets were used as pathogenicity controls to maximize the number of vaccinated horses that could be accommodated in the BSL-4 facility. These animals duly displayed signs, lesions, tissue antigen and viral genome distribution, and virus reisolation data consistent with acute HeV infection. Figure 2. Scatter plot showing quantitation of the Hendra virus N gene in nasal swab samples from 1 vaccinated horse V9 and 4 control horses C1—C4 ; controls were challenged but not vaccinatedDays represent In contrast to unvaccinated control horses, vaccinated horses remained clinically healthy during the observation period after exposure to HeV.

Following elective euthanasia at the time of predicted peak viral replication, there was no gross or histologic evidence of HeV infection in vaccinated horses; all tissues examined were negative for viral antigen by immunohistochemistry; and viral genome was not recovered from any tissue, including nasal turbinates, pharynx, and guttural pouch Table 3.

For 9 of 10 vaccinated horses, viral RNA was not detected in daily nasal, oral, or rectal swab specimens or from blood, urine, or feces samples collected before euthanasia, and virus was not reisolated from any of these clinical samples. For 1 V9 of 3 horses exposed to HeV 6 months after completing the vaccination course, low viral gene copy numbers were detected in nasal swab samples collected on postchallenge days 2—4 and 7 Figure 2 ; this finding was consistent with self-limiting local replication.

Virus was not reisolated from these samples. At the time of euthanasia, no rise in antibody titer was detected in any vaccinated horse following exposure to HeV. The formal launch of the HeV horse vaccine in November represents the culmination of multiple studies conducted in several animal infection models over the course of many years.

Studies using Nipah virus in cats 16 , 17 and monkeys 18 and HeV in ferrets 15 provided strong evidence that a HeVsG glycoprotein subunit—based vaccine could prevent not only disease but often infection in animals exposed to otherwise lethal doses of Nipah virus or HeV. Where evidence of low-level virus replication did occur in secretions, it was transient and unaccompanied by the development of clinical illness, and virus was not isolated from the secretions.

The henipavirus surface-expressed G glycoprotein has the critical role of initiating infection by binding to receptors on host cells, and antibodies directed against this protein can neutralize virus Earlier reports have shown that passive immunotherapy with antibody to the G or F glycoprotein of HeV or Nipah virus alone can prevent fulminating disease 20 : G glycoprotein—specific human monoclonal antibody prevented Nipah virus disease in ferrets 21 and HeV infection in African green monkeys 22 ; and F or G glycoprotein—specific monoclonal or polyclonal antibodies prevented HeV and Nipah virus disease in hamsters 23 — Thus it is likely that, as seen for other paramyxoviruses with a viremic infection phase e.

In the studies reported here, we show that 2 doses of a commercially formulated HeVsG glycoprotein subunit—based vaccine prevented infection in 7 of 7 horses exposed to HeV at least 21 days after the second vaccine dose; this finding is in contrast to that for unvaccinated control horses. Similar results were obtained for 2 of 3 horses exposed to HeV 6 months after vaccination. In the third horse, which also remained clinically healthy, evidence of HeV replication was limited to low-level transient detection of viral genome but not virus from the nasal cavity.

In assessing the field significance of this observation, the following must be noted: the experimental horses were exposed to considerably higher levels of HeV than have been recovered from flying foxes 1 , higher levels of viral genome were routinely found in the nasal secretions of nonimmunized horses, and all human infections have been acquired from animals in which clinical disease developed.

It is reasonable to suggest that the higher transmission risk that is clearly associated with such horses is a consequence of not only increased viral load but also of the illness itself: it is the clinically ill horse that promotes increased human—animal contact through diagnostic investigations and administration of nursing care.

We conclude that the level and pattern of virus replication in the 1 vaccinated horse do not meet the epidemiologic criteria presently associated with transmission of infection to humans. In previous henipavirus vaccine efficacy studies in cats and ferrets, a neutralizing antibody titer of 32 was shown to be protective against the development of clinical disease In the horse efficacy studies, the 3 horses with prechallenge antibody titers of 16 or 32 were similarly protected from clinical illness.

However, we caution that any correlation between antibody titer at the time of exposure to virus and levels of subsequent protection against infection and disease is unlikely to be linear; it is possible that animals with even lower titers will have epidemiologically meaningful protection against HeV exposure occurring in the field, not least because of stimulation of immunological memory.

Additional studies assessing the duration of protection are planned, and the outcome of these will further inform recommendations regarding booster vaccination. As expected, initial uptake of the HeVsG glycoprotein subunit—based vaccine was strongest in the area with the highest perceived risk for HeV infection, namely coastal Queensland, Australia.

In other regions where HeV infection of horses has not been reported, there is understandably more uncertainty regarding the value of vaccination as part of horse preventative health programs. Any reluctance to vaccinate horses against HeV that is based on assessment of risk is probably exacerbated by several factors, including the novelty of the vaccine roll-out process to the Australian horse industry, a mistaken perception that fast-tracking vaccine release involved overlooking key safety and efficacy issues, the lack of published data on safety in pregnant mares, reluctance of certain industry sectors to vaccinate because of import restrictions on HeV-seropositive horses, and cost.

Although it is likely that each of these barriers will diminish over time, our experiences may assist the development of road maps to guide the future release of vaccines against BSL-4 pathogens that are associated with highly sporadic disease events and where the decision to vaccinate is in the hands of the persons whom vaccination was designed to protect.

Several recently emerged zoonotic viruses, including HeV, Nipah, Ebola, and Marburg viruses, are classified as BSL-4 agents because of their ability to cause severe illness or death in humans and because there have been no effective vaccines or postexposure treatments to protect against the diseases they cause.

The vaccine against HeV Equivac HeV is a commercially deployed vaccine developed against a BSL-4 agent and is the only licensed treatment for henipavirus infection. Development of vaccines against BSL-4 agents for use in humans requires that the US Food and Drug Administration implement the animal rule, which requires that such vaccines first be tested for efficacy in at least 2 animal models As a veterinary vaccine, Equivac HeV did not need to meet this requirement, and it was both cheaper and faster to produce than a vaccine intended for human use.

At the same time, the vaccine is expected to provide a substantial health benefit to humans. In so doing, this vaccine encapsulates the spirit of a One Health approach, not just in terms of the interconnectedness of human and animal health but also with respect to environmental health.

One consequence of the recent HeV outbreaks was a move to eradicate bat populations, despite their crucial environmental roles in pollination and reduction of the insect population. Successful deployment of the HeV vaccine, with a targeted reduction in the risk for acute disease events in horses and humans, should help reduce the current momentum toward the setting of control policies with potential adverse effects on the environment.

Furthermore, the increasing evidence for henipaviruses and henipa-like viruses in bats in other areas 30 — 32 raises the possibility of future henipavirus outbreaks. The current HeVsG glycoprotein vaccine technology provides a platform for the rapid development of related vaccines to counter future emergent threats. Dr Middleton, a veterinarian with a PhD in pathology, works as a senior principal research scientist.

Her research interest is the pathogenesis of emerging infectious diseases including highly pathogenic avian influenza viruses, henipaviruses, severe acute respiratory syndrome, and bat-borne viruses in reservoir and spillover hosts. Two of the biological criteria that differentiate HeV and NiV from other paramyxoviruses are their wide host range and the virulence that they display in their hosts. The susceptibility to henipavirus infection of a range of mammalian species and the similarity in patterns of susceptibility to infection by HeV and NiV are now known to be due, at least in part, to the fact that both viruses use ephrin B2 as a cell receptor, a remarkably conserved surface glycoprotein of ancient lineage and widespread distribution among vertebrates.

The widespread cellular distribution of ephrin B2, especially in vascular endothelial cells, also provides an explanation for one of the most frequently observed outcomes of henipavirus infection, namely systemic involvement of endothelial cells. However, it remains to be seen if ephrin B2 will be the universal henipavirus receptor used by all species and all naturally occurring HeV and NiV strains, or variants such as those implicated in the outbreaks of disease in Bangladesh where human-to-human transmission has been documented.

The recent molecular investigations have also revealed several other factors that probably contribute to virulence. The cleavage of the F protein by cathepsin L, a ubiquitous endosomal protease with a cleavage site that is unique among viral glycoproteins, facilitates virus dissemination in vivo.

The widespread distribution of the protease among organs might also be crucial in the transmission of infectious virus within and between species. It is tempting to speculate that the virulence of henipaviruses is due at least in part to the multifaceted P-gene strategy that these viruses have developed to inhibit the IFN system, a strategy that is novel amongst the paramyxoviruses, having both cytoplasmic and nuclear components.

Several important questions have been raised by recent and varied in vitro studies on HeV and NiV. An appreciation of the factors that contribute to the virulence of henipaviruses in terrestrial hosts versus the outcome of virus infection of flying foxes might provide crucial clues. Is ephrin B2 the receptor in bats? In light of the highly conserved nature of murine and human ephrin B2 proteins, especially in the ectodomain, there will probably be significant homology in the ephrin B2 homologue from flying foxes.

Does the ubiquity of cathepsin L, the F protease cleavage enzyme, extend to a range of flying-fox cells and tissues? Do henipaviruses use the same range of P-gene products to inhibit IFN in bats? If henipaviruses inhibit dsRNA signalling and IFN signalling in chiropteran cells, their limited replication observed in flying foxes could be due to other factors such as the nature, density and location of the bat cell receptors or the ability of the viral C protein to inhibit viral RNA synthesis in bat cells more effectively than has been observed in mammalian cells The C protein encoded by the respirovirus P gene has been shown to downregulate viral genome amplification , and transcription , Alternatively, given the well known propensity of bats to tolerate infection with a wide range of viruses in the absence of clinical symptoms, more generic methods could be operative, such as the inhibition of virus replication by lectins such as mannose-binding protein and galectin-1 Refs , Galectin-1, an endogenous lectin secreted by various cell types, has been shown to inhibit henipavirus envelope-glycoprotein-mediated cell fusion, probably by aberrantly oligomerizing NiV F and G glycoproteins In addition to this direct effect on virus replication, galectin-1 might also act indirectly to limit NiV replication because it enhances dendritic-cell production of proinflammatory cytokines such as interleukin 6 IL-6 , which has an essential role in the final differentiation of B cells into antibody-secreting cells The capacity of henipavirus P-gene products to abrogate the STAT-dependent ILsignalling pathway in terrestrial or chiropteran cells remains to be determined.

The development of a range of anti-IFN strategies by henipaviruses might have evolved to maximize virus replication under conditions of restricted growth in bats. Finally, the ability to conduct these studies using recombinant molecular biological techniques on otherwise highly pathogenic and dangerous viruses has provided important information on the biology of HeV and NiV, which should prove exploitable in the near future and offer new or novel approaches in treating or preventing henipavirus infection.

Viruses in the family Paramyxoviridae are classified in two subfamilies, Paramyxovirinae and Pneumovirinae. The latter subfamily contains two genera, Pneumovirus and Metapneumovirus.

The number of genera in the Paramyxovirinae was increased in from three Respirovirus, Morbillivirus and Rubulavirus to five by the addition of two new genera, Avulavirus and Henipavirus The Avulavirus genus contains avian paramyxoviruses that were previously classified in the Rubulavirus genus, and the Henipavirus genus was created to accommodate Hendra virus and Nipah virus. The phylogenetic tree shown here is based on an alignment of the deduced amino-acid sequence of the N gene of selected Paramyxovirinae subfamily members using the Neighbour-Joining method see the genome organization of henipaviruses in Fig.

Viruses are grouped according to genus and abbreviated as follows. Despite the high prevalence of antibodies to henipaviruses, particularly in Australian pteropids, neither Hendra virus HeV nor Nipah virus NiV has been associated with any naturally occurring disease of flying foxes. The subclinical nature of HeV infection of pteropids has been confirmed by experimental infection of several species of Australian flying foxes , A comparison of the pathology observed in henipavirus-infected chiropteran and terrestrial mammals provides some insights into the different clinical outcomes of infection.

Viral antigen is detected in syncytial cells in vascular endothelium and, in the case of NiV infection, in bronchial and alveolar epithelium. Henipaviruses are readily recovered from nasopharyngeal secretions, urine and internal organs including lung and brain 21 , By contrast, infection of flying foxes with doses of HeV consistently shown to be lethal in horses generated only sporadic vasculitis in the lung, spleen, meninges, kidney and gastrointestinal tract, and only in a proportion of infected bats , Viral antigen is detected in the tunica media rather than endothelial cells.

In infected pregnant flying foxes, antigen is observed in similar locations and in the placenta Two observations might explain the lack of systemic disease in flying foxes. First, the presence of antigen in the tunica media rather than endothelial cells indicates that the latter might be spared from infection, therefore reducing the clinical effects associated with vasculitis. Second, the striking reduction in the level of antigen in flying foxes compared to horses and cats indicates that factors not found in terrestrial mammals that limit the ability of HeV to replicate could be at play in flying foxes.

Despite rigorous sampling regimes, virus has been isolated only infrequently, and where isolation was successful, positive sources included urine and the foetus, heart, placenta, kidney and spleen of two pregnant bats , The paramyxovirus P gene encodes several proteins by means of internal translation-initiation sites, overlapping reading frames and an unusual transcription process in which one or more non-templated G nucleotides are inserted at a conserved editing site, resulting in a shift of reading frame during translation The figure shows a schematic representation of mRNAs transcribed from the P gene of henipaviruses compared with those of morbilliviruses, respiroviruses and rubulaviruses.

In henipaviruses a and respiroviruses and morbilliviruses b , the unedited P-gene transcript encodes the P protein, and the V protein is generated by a separate transcript containing a single G nucleotide inserted at the editing site. Insertion of two G residues generates a transcript encoding a protein usually called W.

V and W proteins share their amino termini with the P protein. Compared with morbilliviruses and rubulaviruses, henipaviruses have an N-terminal —amino-acid extension that might have evolved to better equip the viruses to antagonize the cellular interferon response see text. The P, V and W proteins have unique C-terminal domains. In the P protein, this region is essential for viral RNA synthesis and contains sites for binding to the N and L proteins in ribonucleoproteins.

The C-terminal domain of the V protein is highly conserved among paramyxoviruses and contains seven perfectly conserved cysteine residues.

The C-terminal domain of the W protein is frequently short because of the presence of a stop codon soon after the editing site, but in henipaviruses the W-specific domain is 43 amino acids in length, compared with 55 for the V-protein C-terminal domain The P genes of henipaviruses, morbilliviruses and most respiroviruses contain a second short discrete overlapping reading frame upstream of the editing site, which in P, V and W mRNAs encodes the C protein.

The structure of the P gene differs in rubulaviruses c , where the primary transcript encodes the V protein, and transcripts with two G nucleotides inserted at the editing site generate the P protein. We thank A. Hyatt, F. Filippi and I. Pritchard for help with figures. Fogarty International Center. They are interested in emerging zoonoses, particularly the interaction of the Biosafety Level 4 pathogens Hendra virus and Nipah virus with their wildlife hosts and the livestock species they infect.

Christopher Broder is a molecular virologist, with complementary interests in the interaction of henipaviruses with cells and in vaccines and therapeutics. Newcastle disease virus. Tioman virus. Tupaia virus. Bryan T. National Center for Biotechnology Information , U. Nat Rev Microbiol.

Eaton , 1 Christopher C. Christopher C. Author information Copyright and License information Disclaimer. Eaton, Email: ua. Corresponding author. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source.

This article has been cited by other articles in PMC. Abstract Hendra virus and Nipah virus are highly pathogenic paramyxoviruses that have recently emerged from flying foxes to cause serious disease outbreaks in humans and livestock in Australia, Malaysia, Singapore and Bangladesh.

Main Hendra virus HeV and Nipah virus NiV join a growing list of viruses for which bats have been implicated as the natural host, a list that started with rabies virus in Ref.

Open in a separate window. Figure 1. Flying foxes, their distribution and the locations of disease outbreaks caused by Hendra virus and Nipah virus. Figure 2. Structure of henipaviruses and their genomes. Figure 3. Figure 4. Interferon IFN signalling. Box 1 Classification of henipaviruses Viruses in the family Paramyxoviridae are classified in two subfamilies, Paramyxovirinae and Pneumovirinae.

Box 2 Henipavirus infection in flying foxes Despite the high prevalence of antibodies to henipaviruses, particularly in Australian pteropids, neither Hendra virus HeV nor Nipah virus NiV has been associated with any naturally occurring disease of flying foxes.

Box 3 The henipavirus P gene The paramyxovirus P gene encodes several proteins by means of internal translation-initiation sites, overlapping reading frames and an unusual transcription process in which one or more non-templated G nucleotides are inserted at a conserved editing site, resulting in a shift of reading frame during translation Acknowledgements We thank A.

Glossary Zoonotic A zoonotic infection is an infection of animals that can be transmitted to humans. Biosafety Level 4 BSL4. BSL4 is the highest safety rating for laboratories, used for handling agents that pose a high risk of life-threatening disease and for which there is no vaccine or therapy.

Type II membrane glycoproteins Transmembrane glycoproteins with a cytoplasmic N terminus. Fc region The region of an antibody that is responsible for binding to antibody receptors FcR on cells and the C1q component of complement. Tunica media All blood vessels, except capillaries, comprise three layers surrounding a central lumen: the outer tunica adventitia, the inner tunica intima and the middle tunica media.

The tunica media is composed predominantly of smooth muscle and also contains autonomic nerves. Type I membrane protein A single-pass transmembrane protein that contains an N-terminal lumenal domain with carbohydrate moieties and a C-terminal cytoplasmic domain.

Clathrin A structural protein that polymerizes into polyhedral lattices to form a membrane coat around vesicles involved in membrane transport in both the endocytic and biosynthetic pathways.

Nuclear-localization signal A positively charged region of a protein that is responsible for directing its transport through nuclear-membrane pores and into the nucleus. Proteasomes Most of the degradation of cytosolic and nuclear proteins in eukaryotic cells is catalysed by multi-subunit proteases known as proteasomes.

Targeting of proteins to proteasomes most often occurs through the attachment of multiple ubiquitin tags. Competing interests The authors declare no competing financial interests.

References 1. Sulkin SE, Allen R. Virus Infections in Bats. Li W, et al. Bats are natural reservoirs of SARS-like coronaviruses.

Lau SK, et al. Severe acute respiratory syndrome coronavirus-like virus in Chinese horseshoe bats. Natl Acad. Hall L, Richards G. Philbey AW, et al. An apparently new virus family Paramyxoviridae infectious for pigs, humans, and fruit bats.

Molecular characterization of Menangle virus, a novel paramyxovirus which infects pigs, fruit bats, and humans. Chua KB, et al. Tioman virus, a novel paramyxovirus isolated from fruit bats in Malaysia. Bat parainfluenza virus. Immunological, chemical, and physical properties. Characterization of Mapuera virus: structure, proteins and nucleotide sequence of the gene encoding the nucleocapsid protein.

Wang LF, et al. Molecular biology of Hendra and Nipah viruses. Microbes Infect. Harcourt BH, et al. Molecular characterization of Nipah virus, a newly emergent paramyxovirus. The exceptionally large genome of Hendra virus: support for creation of a new genus within the family Paramyxoviridae. Molecular characterization of the polymerase gene and genomic termini of Nipah virus. Isolation and molecular characterization of a novel cytopathogenic paramyxovirus from tree shrews.

The government fast-tracked its release in November , allowing Zoetis to market it under a so-called minor-use permit, which required veterinarians to administer it in order to collect safety and efficacy data. Since the release, 20 horses have died of Hendra. None of them were vaccinated. Down at the end of the street, we saw three thoroughbreds clop-clopping down the pavement behind their strappers, out for their afternoon walk. Reid, who is 70, still practices horse medicine, but he also remains deeply involved in Hendra-related research and policy.

Back in , he flew to the Australian capital of Canberra to plead with Parliament to fund the vaccine trials. A nti-vaccine movements have existed for almost as long as there have been vaccines. Since the s, when the threat of childhood diseases began to wane, anti-vaxxers have raised the alarm about potentially toxic ingredients in vaccines, and about unproven side effects such as autism, irritable bowel syndrome, and neurological problems.

These fears, amplified by social media, have led to declines in vaccination coverage and outbreaks of measles, mumps, and whooping cough in the affluent, educated communities where anti-vaccination sentiment tends to concentrate. Similarly inflated concerns have begun to turn some pet owners away from mainstream veterinary medicine.

An article last year in the Brooklyn Paper quoted a vet who had an owner refuse to vaccinate her dog for fear it would develop autism. No anti-vaccine movement among animal owners has ever gained quite as much traction—or posed such a threat—as the one surrounding the Hendra cases in Australia. But when horse owners began to feel that they were being forced to do something that might just harm the animals they loved, a full-fledged anti-Hendra-vaccine movement blossomed.

Sullivan was told that in order for her horses to receive veterinary treatment, she would need to have them vaccinated against Hendra.

When she tried to ride him, they bled. In September , Sullivan took Appeal to the University of Queensland at Gatton, where a veterinarian named Andrew Van Eps diagnosed him with an autoimmune disease called coronary band dystrophy.

Sullivan had heard murmurings online about adverse reactions, and she became convinced that the vaccine was responsible. The time frame. His feet after the booster. You see things I saw the change. I know Her suspicions were reinforced when Van Eps advised her not to give Appeal any further vaccinations.

To date, the Australian Pesticides and Veterinary Medicines Authority has recorded probable or possible vaccine reactions from the half-million doses of vaccine that have been administered, a figure that places it among the safest vaccines sold.

These reactions range from mild swelling and muscle stiffness to colic. In addition to serious side effects, horse owners have also expressed concerns that the vaccine impacts performance in track races and endurance rides.

Peter Reid recently published a study of thoroughbred horses that showed no performance differences. These statistics hold little sway with vaccine opponents, who see a conspiracy at every turn. Horse owners began attacking other horse owners. It has not been proven percent safe. The brunt of the anger of vaccine skeptics has been reserved for veterinarians, some of whom began refusing to treat unvaccinated horses or attend unvaccinated events.

Vaccine opponents argued that because the virus is so hard to catch, vets should just put on masks and protective gear. Excrement-related puns followed. That page also featured screenshots of posts from anti-vaxxers, marking them up like failing exams. I n , tensions reached a breaking point.