In 2009, RNA sequences of three novel viruses in phylogenetic relationship to known henipaviruses were detected in African straw-colored fruit bats (Eidolon helvum) in Ghana. The finding of these novel henipaviruses outside Australia and Asia indicates that the region of potential endemicity of henipaviruses may be worldwide. These African henipaviruses are slowly being characterised.
The henipavirus genome (3' to 5' orientation) and products of the P gene
Henipavirions are pleomorphic (variably shaped), ranging in size from 40 to 600 nm in diameter. They possess a lipid membrane overlying a shell of viral matrix protein. At the core is a single helical strand of genomic RNA tightly bound to N (nucleocapsid) protein and associated with the L (large) and P (phosphoprotein) proteins, which provide RNA polymerase activity during replication.
Embedded within the lipid membrane are spikes of F (fusion) protein trimers and G (attachment) protein tetramers. The function of the G protein is to attach the virus to the surface of a host cell via EFNB2, a highly conserved protein present in many mammals. The structure of the attachment glycoprotein has been determined by X-ray crystallography. The F protein fuses the viral membrane with the host cell membrane, releasing the virion contents into the cell. It also causes infected cells to fuse with neighbouring cells to form large, multinucleated syncytia.
As all mononegaviral genomes, Hendra virus and Nipah virus genomes are non-segmented, single-stranded negative-sense RNA. Both genomes are 18.2 kb in length and contain six genes corresponding to six structural proteins.
In common with other members of the Paramyxoviridae family, the number of nucleotides in the henipavirus genome is a multiple of six, consistent with what is known as the 'rule of six'. Deviation from the rule of six, through mutation or incomplete genome synthesis, leads to inefficient viral replication, probably due to structural constraints imposed by the binding between the RNA and the N protein.
Henipaviruses employ an unusual process called RNA editing to generate multiple proteins from a single gene. The specific process in henipaviruses involves the insertion of extra guanosine residues into the P gene mRNA prior to translation. The number of residues added determines whether the P, V or W proteins are synthesised. The functions of the V and W proteins are unknown, but they may be involved in disrupting host antiviral mechanisms.
Hendra virus (originally called "Equine morbillivirus") was discovered in September 1994 when it caused the deaths of thirteen horses, and a trainer at a training complex at 10 Williams Avenue, Hendra, a suburb of Brisbane in Queensland, Australia.
The index case, a mare called Drama Series, brought in from a paddock in Cannon Hill, was housed with 19 other horses after falling ill, and died two days later. Subsequently, all of the horses became ill, with 13 dying. The remaining six animals were subsequently euthanised as a way of preventing relapsing infection and possible further transmission. The trainer, Victory ('Vic') Rail, and the stable foreman, Ray Unwin, were involved in nursing the index case, and both fell ill with an influenza-like illness within one week of the first horse's death. The stable hand recovered but Rail died of respiratory and kidney failure. The source of the virus was most likely frothy nasal discharge from the index case.
A second outbreak occurred in August 1994 (chronologically preceding the first outbreak) in Mackay 1,000 km north of Brisbane resulting in the deaths of two horses and their owner. The owner, Mark Preston, assisted in necropsies of the horses and within three weeks was admitted to hospital suffering from meningitis. Mr Preston recovered, but 14 months later developed neurologic signs and died. This outbreak was diagnosed retrospectively by the presence of Hendra virus in the brain of the patient.
Flying foxes have been identified as the reservoir host of Hendra Virus. A seroprevalence of 47% is found in the flying foxes, suggesting an endemic infection of the bat population throughout Australia. Horses become infected with Hendra after exposure to bodily fluid from an infected flying fox. This often happens in the form of urine, feces, or masticated fruit covered in the flying fox's saliva when horses are allowed to graze below roosting sites. The seven human cases have all been infected only after contact with sick horses. As a result, veterinarians are particularly at risk for contracting the disease.
Red dots show outbreaks in Queensland
Red dots show outbreaks in New South Wales
As of June 2014, a total of fifty outbreaks of Hendra virus have occurred in Australia, all involving infection of horses. As a result of these events, eighty-three horses have died or been euthanised. A further four died or were euthanised as a result of possible hendra infection.
Case fatality rate in humans is 60% and in horses 75%.
Four of these outbreaks have spread to humans as a result of direct contact with infected horses. On 26 July 2011 a dog living on the Mt Alford property was reported to have HeV antibodies, the first time an animal other than a flying fox, horse, or human has tested positive outside an experimental situation.
The timing of incidents indicates a seasonal pattern of outbreaks. Initially this was thought to possibly related to the breeding cycle of the little red flying foxes. These species typically give birth between April and May. Subsequently, however, the Spectacled flying fox and the Black flying fox have been identified as the species more likely to be involved in infection spillovers.
Timing of outbreaks also appears more likely during the cooler months when it is possible the temperature and humidity are more favourable to the longer term survival of the virus in the environment.
There is no evidence of transmission to humans directly from bats, and, as such it appears that human infection only occurs via an intermediate host, a horse. Despite this in 2014 the NSW Government approved the destruction of flying fox colonies.
Death of five horses; four died from the Henda virus, the remaining animal recovered but was euthanised because of a government policy that requires all animals with antibodies to be euthanised due to a potential threat to health. Two veterinary workers from the affected property were infected leading to the death of one, veterinary surgeon Ben Cuneen, on 20 August 2008. The second veterinarian was hospitalized after pricking herself with a needle she had used to euthanize the horse that had recovered. A nurse exposed to the disease while assisting Cuneen in caring for the infected horses was also hospitalized. The Biosecurity Queensland website indicates that 8 horses died during this event, however a review of the event indicates that five horses are confirmed to have died from HeV and three of the horses "are regarded as improbable cases of Hendra virus infection...".
Death of four horses. Queensland veterinary surgeon Alister Rodgers tested positive after treating the horses. On 1 September 2009 after two weeks in a coma, he became the fourth person to die from exposure to the virus.
Death of three horses (all confirmed to have died of Hendra) and sero-conversion of a dog. The first horse death on this property occurred on 20 June 2011, although it was not until after the second death on 1 July 2011 that samples taken from the first animal were tested. The third horse was euthanised on 4 July 2011. On 26 July 2011 a dog from this property was reported to have tested positive for HeV antibodies. Reports indicate that this Australian Kelpie, a family companion, will be euthanised in line with government policy. Biosecurity Queensland suggest the dog most likely was exposed to HeV though one of the sick horses. Dusty was euthanised on 31 July 2011 following a second positive antibody test.
One horse euthanised after testing positive. A horse that died on the property one week before may have died of HeV. On 15 October 2011 another horse on the property was euthanised following a positive HeV antibody test.
One horse died. On 27 July it was announced that two other horses on the property, showing clinical signs of the disease, had been euthanised. Two dogs were assessed, and the property was quarantined.
An unvaccinated mare contracted Hendra and had to be euthanased
Events of June-August 2011
In the years 1994-2010, fourteen events were recorded. Between 20 June 2011 and 28 August 2011, a further seventeen events were identified, during which twenty-one horses died.
It's not clear why there has been a sudden increase in the number of spillover events between June and August 2011. Typically HeV spillover events are more common between May and October. This time is sometimes called "Hendra Season", which is a time when there are large numbers of fruit bats of all species congregated in SE Queensland's valuable winter foraging habitat. The weather (warm and humid) is favourable to the survival of henipavirus in the environment.
It is possible flooding in SE Queensland and Northern NSW in December 2010 and January 2011 may have affected the health of the fruit bats. Urine sampling in flying fox camps indicate that a larger proportion of flying foxes than usual are shedding live virus. Biosecurity Queensland's ongoing surveillance usually shows 7% of the animals are shedding live virus. In June and July nearly 30% animals have been reported to be shedding live virus. Present advice is that these events are not being driven by any mutation in HeV itself.
Other suggestions include that an increase in testing has led to an increase in detection. As the actual mode of transmission between bats and horses has not been determined, it is not clear what, if any, factors can increase the chance of infection in horses.
Following the confirmation of a dog with HeV antibodies, on 27 July 2011, the Queensland and NSW governments will boost research funding into the Hendra virus by $6 million to be spent by 2014-2015. This money will be used for research into ecological drivers of infection in the bats and the mechanism of virus transmission between bats and other species. A further 6 million dollars was allocated by the federal government with the funds being split, half for human health investigations and half for animal health and biodiversity research.
Prevention, detection and treatment
Three main approaches are currently followed to reduce the risk to humans.
Vaccine for horses.
In November 2012, a vaccine became available for horses. The vaccine is to be used in horses only, since, according to CSIRO veterinary pathologist Dr Deborah Middleton, breaking the transmission cycle from flying foxes to horses prevents it from passing to humans, as well as, "a vaccine for people would take many more years."
By December 2014, about 300 000 doses had been administered to more than 100 000 horses. About 3 in 1000 had reported incidents; the majority being localised swelling at the injection site. There had been no reported deaths.
Nipah virus and Hendra virus are closely related paramyxoviruses that emerged from bats during the 1990s to cause deadly outbreaks in humans and domesticated animals. National Institute of Allergy and Infectious Diseases (NIAID)-supported investigators developed vaccines for Nipah and Hendra virus based on the soluble G-glycoproteins of the viruses formulated with adjuvants. Both vaccines have been shown[who?] to induce strong neutralizing antibodies in different laboratory animals.
Trials began in 2015 to evaluate a monoclonal antibody to be used as a possible complementary treatment for humans exposed to Hendra virus infected horses.
When considering any zoonosis, one must understand the social, ecological, and biological contributions that may be facilitating this spillover. Hendra virus is believed to be partially seasonally related. For, there is a suggested correlation between breeding time and an increase in incidences of Hendra virus in flying fox bats.
Additionally, recent research suggests that the upsurge in deforestation within Australia may be leading to an increase in incidences of Hendra virus. Flying fox bats tend to feed in trees during a large part of the year. However, due to the lack of specific fruit trees within the area, these bats are having to relocate and thereby are coming into contact with horses more often. The two most recent outbreaks of Hendra virus in 2011 and 2013 appear to be related to an increased level of nutritional stress among the bats as well as relocation of bat populations. Work is currently being done to increase vaccination among horses as well as replant these important forests as feeding grounds for the flying fox bats. Through these measures, the goal is to decrease the incidences of the highly fatal Hendra virus.
Flying foxes experimentally infected with the Hendra virus develop a viraemia and shed the virus in their urine, faeces and saliva for approximately one week. There is no other indication of an illness in them. Symptoms of Hendra virus infection of humans may be respiratory, including hemorrhage and edema of the lungs, or in some cases viral meningitis. In horses, infection usually causes pulmonary oedema, congestion and / or neurological signs.
Ephrin B2 has been identified as the main receptor for the henipaviruses.
Viruses of this genus can only be studied in a BSL4 compliant laboratory.
Pteropus vampyrus (large flying fox), one of the natural reservoirs of Nipah virus
The first cases of Nipah virus infection were identified in 1998, when an outbreak of neurological and respiratory disease on pig farms in peninsular Malaysia resulted in 265 human cases, including 105 human deaths. The virus itself was isolated the following year in 1999. This outbreak resulted in the culling of one million pigs. In Singapore, 11 cases, including one death, occurred in abattoir workers exposed to pigs imported from the affected Malaysian farms. The Nipah virus has been classified by the Centers for Disease Control and Prevention as a Category C agent. The name "Nipah" refers to the place, Sungai Nipah in Port Dickson, Negeri Sembilan, the source of the human case from which Nipah virus was first isolated. Nipah virus is one of several viruses identified by WHO as a likely cause of a future epidemic in a new plan developed after the Ebola epidemic for urgent research and development before and during an epidemic toward new diagnostic tests, vaccines and medicines.
The outbreak was originally mistaken for Japanese encephalitis, but physicians in the area noted that persons who had been vaccinated against Japanese encephalitis were not protected in the epidemic, and the number of cases among adults was unusual. Despite the fact that these observations were recorded in the first month of the outbreak, the Ministry of Health failed to react accordingly, and instead launched a nationwide campaign to educate people on the dangers of Japanese encephalitis and its vector, Culex mosquitoes.
Symptoms of infection from the Malaysian outbreak were primarily encephalitic in humans and respiratory in pigs. Later outbreaks have caused respiratory illness in humans, increasing the likelihood of human-to-human transmission and indicating the existence of more dangerous strains of the virus.
Based on seroprevalence data and virus isolations, the primary reservoir for Nipah virus was identified as Pteropid fruit bats, including Pteropus vampyrus (large flying fox), and Pteropus hypomelanus (small flying fox), both of which occur in Malaysia.
The transmission of Nipah virus from flying foxes to pigs is thought to be due to an increasing overlap between bat habitats and piggeries in peninsular Malaysia. At the index farm, fruit orchards were in close proximity to the piggery, allowing the spillage of urine, faeces and partially eaten fruit onto the pigs. Retrospective studies demonstrate that viral spillover into pigs may have been occurring in Malaysia since 1996 without detection. During 1998, viral spread was aided by the transfer of infected pigs to other farms, where new outbreaks occurred.
The most likely origin of this virus was in 1947 (95% credible interval: 1888-1988). There are two clades of this virus--one with its origin in 1995 (95% credible interval: 1985-2002) and a second with its origin in 1985 (95% credible interval: 1971-1996). The mutation rate was estimated to be 6.5 × 10-4 substitution/site/year (95% credible interval: 2.3 × 10-4 -1.18 × 10-3), similar to other RNA viruses.
Locations of henipavirus outbreaks (red stars-Hendra virus; blue stars-Nipah virus) and distribution of henipavirus flying fox reservoirs (red shading-Hendra virus; blue shading-Nipah virus)
Eight more outbreaks of Nipah virus have occurred since 1998, all within Bangladesh and neighbouring parts of India. The outbreak sites lie within the range of Pteropus species (Pteropus giganteus). As with Hendra virus, the timing of the outbreaks indicates a seasonal effect. Cases occurring in Bangladesh during the winters of 2001, 2003, and 2004 were determined to have been caused by the Nipah virus. In February 2011, a Nipah outbreak began at Hatibandha Upazila in the Lalmonirhat District of northern Bangladesh. As of 7 February 2011 there had been 24 cases and 17 deaths in this outbreak.
2001 January 31-23 February, Siliguri, India: 66 cases with a 74% mortality rate. 75% of patients were either hospital staff or had visited one of the other patients in hospital, indicating person-to-person transmission.
2004 January - February, Manikganj and Rajbari districts, Bangladesh: 42 cases with 14 fatalities (33% mortality).
2004 19 February - 16 April, Faridpur District, Bangladesh: 36 cases with 27 fatalities (75% mortality). 92% of cases involved close contact with at least one other person infected with Nipah virus. Two cases involved a single short exposure to an ill patient, including a rickshaw driver who transported a patient to hospital. In addition, at least six cases involved acute respiratory distress syndrome, which has not been reported previously for Nipah virus illness in humans.
2005 January, Tangail District, Bangladesh: 12 cases with 11 fatalities (92% mortality). The virus was probably contracted from drinking date palm juice contaminated by fruit bat droppings or saliva.
2007 February - May, Nadia District, India: up to 50 suspected cases with 3-5 fatalities. The outbreak site borders the Bangladesh district of Kushtia where eight cases of Nipah virus encephalitis with five fatalities occurred during March and April 2007. This was preceded by an outbreak in Thakurgaon during January and February affecting seven people with three deaths. All three outbreaks showed evidence of person-to-person transmission.
2008 February - March, Manikganj and Rajbari districts, Bangladesh: Nine cases with eight fatalities.
2010 January, Bhanga subdistrict, Faridpur, Bangladesh: Eight cases with seven fatalities. During March, one physician of Faridpur Medical College Hospital caring for confirmed Nipah cases died
2011 February: An outbreak of Nipah Virus occurred at Hatibandha, Lalmonirhat, Bangladesh. The deaths of 21 schoolchildren due to Nipah virus infection were recorded on 4 February 2011. IEDCR confirmed the infection was due to this virus. Local schools were closed for one week to prevent the spread of the virus. People were also requested to avoid consumption of uncooked fruits and fruit products. Such foods, contaminated with urine or saliva from infected fruit bats, were the most likely source of this outbreak.
2018 May: Deaths of seventeen people in Perambra near Calicut, Kerala, India were confirmed to be due to the virus. Treatment using antivirals such as Ribavirin was initiated.
2019 June: A 23-year-old student was admitted into hospital with Nipah virus infection at Kochi in Kerala. Health Minister of Kerala, K. K. Shailaja confirmed that 86 people who have had recent interactions with the patient were under observation. This included two nurses who treated the patient, and had fever and sore throat. The situation was monitored and precautionary steps were taken to control the spread of virus by the Central and State Government.
2019 July: 338 people were kept under observation and 17 of them in isolation by the Health Department of Kerala. After undergoing treatment for 54 days at a private hospital, the 23-year-old student was discharged. On 23 July, the Kerala government declared Ernakulam district to be Nipah-free.
Nipah virus has been isolated from Lyle's flying fox (Pteropus lylei) in Cambodia and viral RNA found in urine and saliva from P. lylei and Horsfield's roundleaf bat (Hipposideros larvatus) in Thailand. Infective virus has also been isolated from environmental samples of bat urine and partially eaten fruit in Malaysia.Antibodies to henipaviruses have also been found in fruit bats in Madagascar (Pteropus rufus, Eidolon dupreanum) and Ghana (Eidolon helvum) indicating a wide geographic distribution of the viruses. No infection of humans or other species have been observed in Cambodia, Thailand or Africa as of May 2018.
Now in 4 June 2019, the virus is again spotted in Kerala, India
Ephrin B2 has been identified as the main receptor for the henipaviruses.
Cedar Virus (CedV) was first identified in pteropid urine during work on Hendra virus undertaken in Queensland in 2009.
Although the virus is reported to be very similar to both Hendra and Nipah viruses, it does not cause illness in laboratory animals usually susceptible to paramyxoviruses. Animals were able to mount an effective response and create effective antibodies.
The scientists who identified the virus report:
Hendra and Nipah viruses are 2 highly pathogenic paramyxoviruses that have emerged from bats within the last two decades. Both are capable of causing fatal disease in both humans and many mammal species. Serological and molecular evidence for henipa-like viruses have been reported from numerous locations including Asia and Africa, however, until now no successful isolation of these viruses have been reported. This paper reports the isolation of a novel paramyxovirus, named Cedar virus, from fruit bats in Australia. Full genome sequencing of this virus suggests a close relationship with the henipaviruses. Antibodies to Cedar virus were shown to cross react with, but not cross neutralize Hendra or Nipah virus. Despite this close relationship, when Cedar virus was tested in experimental challenge models in ferrets and guinea pigs, we identified virus replication and generation of neutralizing antibodies, but no clinical disease was observed. As such, this virus provides a useful reference for future reverse genetics experiments to determine the molecular basis of the pathogenicity of the henipaviruses.
Causes of emergence
The emergence of henipaviruses parallels the emergence of other zoonotic viruses in recent decades. SARS coronavirus, Australian bat lyssavirus, Menangle virus and probably Ebola virus and Marburg virus are also harbored by bats and are capable of infecting a variety of other species. The emergence of each of these viruses has been linked to an increase in contact between bats and humans, sometimes involving an intermediate domestic animal host. The increased contact is driven both by human encroachment into the bats' territory (in the case of Nipah, specifically pigpens in said territory) and by movement of bats towards human populations due to changes in food distribution and loss of habitat.
There is evidence that habitat loss for flying foxes, both in South Asia and Australia (particularly along the east coast) as well as encroachment of human dwellings and agriculture into the remaining habitats, is creating greater overlap of human and flying fox distributions.
^Pain, Stephanie (17 October 2015). "The real batman". New Scientist. 228 (3043): 47. Bibcode:2015NewSc.228...47P. doi:10.1016/s0262-4079(15)31425-1. Last year, the government of New South Wales sanctioned the destruction of colonies of flying foxes. Why? In 1996, Hendra virus was discovered in Australia.
^Field, HE; Barratt, PC; Hughes, RJ; Shield, J; Sullivan, ND (2000). "A fatal case of Hendra virus infection in a horse in north Queensland: clinical and epidemiological features". Australian Veterinary Journal. 78 (4): 279-80. doi:10.1111/j.1751-0813.2000.tb11758.x. PMID10840578.
^Lai-Meng Looi; Kaw-Bing Chua (2007). "Lessons from the Nipah virus outbreak in Malaysia"(PDF). Department of Pathology, University of Malaya and National Public Health Laboratory of the Ministry of Health, Malaysia. 29 (2): 63-67. Archived(PDF) from the original on 30 August 2019 – via The Malaysian Journal of Pathology.