Mohamad Aljofan. Future Virology. Volume 10, Issue 5. May 2015.
Paramyxoviruses are enveloped viruses with a linear nonsegmented negative sense RNA genome of approximately 15.5 kb in size, clustered with other virus families that are grouped taxonomically in the order Mononegavirales. The family Paramyxoviridae is further classified into two subfamilies Paramyxovirinae and Pneumovirinae, which include not only a number of older, well-studied human and animal pathogens, but also newly emergent ones such as Hendra virus (HeV) and Nipah virus (NiV) and the recently identified member Cedar virus (CedPV). More recently, the screening of African fruit bats identified 19 new henipa-like sequences, which have recently been classified within the Henipaviruses including one full length sequenced virus, Bat Paramyxovirus Eidhel, which suggest potential spillovers in Africa.
Both Hendra virus (HeV) and NiV cause fatal encephalitis and respiratory disease in a wide variety of mammals, including humans. Since their emergence in mid 1990s, HeV and NiV continued to cause sporadic outbreaks in Australia and South East Asia, respectively, resulting in fatal infections. Henipaviruses are distinguished from all other paramyxoviruses particularly by their broad species tropism. In addition to infecting humans, Henipavirus infections can cause fatalities in multiple vertebrate hosts including monkeys, pigs, horses, cats, dogs, ferrets, hamsters and guinea pigs, spanning six mammalian orders.
Bats have been identified or implicated as the natural reservoir host for an increasing number of new and often deadly zoonotic viruses including Henipaviruses. In fact serological sampling of wildlife throughout eastern Queensland revealed that antibodies capable of neutralizing HeV have only been detected in bats of the genus Pteropus and that over 25% of sampled pteropid bats were identified as being seropositive to HeV. However, HeV-positive bats showed no signs or symptoms of the infection. Additionally, horses and pigs are reported to serve as amplifying reservoirs for Hendra and Nipah viruses, respectively, but direct bat-to-human and human-to-human transmission, at least for Nipah virus, has been increasingly documented. Henipaviruses represent the most severe viral zoonosis emerging from bats in recent years causing significant health and economic burdens with a potential of pandemic spread.
Currently, there are no approved and/or licensed therapies for the treatment of human Henipavirus infection. The high morbidity and mortality rates of Henipavirus infection and the lack of any approved or commercially available active or passive therapeutic measures for preventing or treating human Henipavirus infections, makes them a potentially high biosecurity threat. Therefore they are classified as biosafety level 4 (BSL-4) pathogens.
Hendra Virus
The first known case of HeV infection in humans was associated with an outbreak of fatal respiratory disease in horses in 1994 in the Brisbane suburb of Hendra, Queensland, Australia. Consequently a horse trainer died as a result of severe respiratory disease. A stable hand became infected, seroconverted to HeV, but recovered after a brief period of illness. A second human fatality occurred in Mackay, Queensland, following HeV exposure from two horses. The infection could be traced back to exposures in August 1994 from two infected horses which also eventually died.
Scientists in Queensland and at the Commonwealth Scientific and Industrial Research Organisation (CSIRO) Australian Animal Health Laboratory (AAHL) in Geelong, Victoria, had detected a novel virus, subsequently shown to be a previously undescribed virus of the family Paramyxoviridae. The virus was initially named equine morbillivirus, but was later renamed HeV after the Brisbane suburb where the outbreak occurred. Horses were subsequently found to be the amplifying host with only HeV transfer from animals to humans, but no transfer from human to human.
In November 2004, a veterinarian conducting a necropsy on a horse possibly infected with the Hendra virus developed a dry cough, a sore throat, cervical lymphadenopathy and fever. However, he recovered and remained in good health. Later in June 2008, there were five fatal HeV infections in horses at a Queensland veterinary clinic. Two staff members became ill with HeV infections, one of whom died (a veterinarian). In August 2009, a veterinarian who treated two horses also possibly infected with the HeV also became infected with the virus and died 3 weeks later.
In the years immediately following its appearance in 1994, occasional outbreaks of HeV occurred in horses with transfer of the virus to humans as well. However, from 2006, HeV infections were commonly seen on an annual basis in horses in Australia, with an associated incidence of seven cases in humans of which four have been fatal. In 2011, however, (June-October) the dynamics of HeV ‘spillover’ events changed considerably, and an unprecedented 18 independent outbreaks of HeV among horses in Australia were recorded, leading to the death or euthanasia of 23 horses, one dog and the monitoring of more than 60 people for possible HeV infection.
Nonetheless, the outbreak of HeV in 1994 remains the largest single incident. Subsequent incidents have involved smaller numbers of horses. While the virus is highly lethal, it has later been shown to have low transmissibility, and it is believed that the large number of cases in the 1994 outbreak reflected inadvertent human-assisted transmission associated with the trainer’s treatment of the sick and healthy horses. It is possible that without this single large event, HeV may have remained unknown in Australia until more recent times.
Nipah Virus
In 1998/1999, a major outbreak of febrile encephalitis affecting pigs and humans in peninsular Malaysia, resulted in the death of 105 humans and the eventual culling of about a million pigs. In late 1998, additional cases of febrile encephalitis were noted to occur among pig farmers in the neighboring districts. The outbreak had also spread into Singapore through the importation of live pigs from Malaysia.
In March 1999, a novel virus was isolated from the cerebrospinal fluid of an encephalitic patient from the Sungai Nipah village. Electron microscopy, immunofluorescence and sequence analysis indicated that the new virus was a paramyxovirus, closely related but not identical to HeV. The virus, which was named Nipah after the index case was shown to be associated with high fatality rates of 35-75% in humans and about 5% in pigs. The discovery of Nipah virus (NiV) as the etiological agent responsible for the outbreak in 1999 was a pivotal significant turning point in instituting effective control measures to halt further infections.
In the case of NiV infections, pigs are implicated to be the amplifying hosts and that oral ingestion or aerosol inhalation of mucous or secretion particles is thought to be responsible for pig-to-human transmission of NiV. The disease in pigs was highly contagious and characterized by acute fever and adverse respiratory and clinical nervous sign.
Nipah virus subsequently continued to re-emerge with reports of annual outbreaks of NiV infection, primarily in Bangladesh, but also in India. There have been more than 13 reported outbreaks since its first emergence in Malaysia in 1998, all of which evidently associated with generally significantly higher fatality rates (ranging from 10 to 100%). Furthermore, a very recent outbreak of NiV has been reported in the Philippines in 2014, which highlights the potential widespread of the deadly virus to new regions.
Interestingly, genetic data revealed that NiV isolate from Malaysia and Bangladesh presents two different viral strains and that the Bangladesh isolate is six nucleotides longer than that of the Malaysian, with 92% of overall nucleotide homology. To date, there have been a total of 570 reported cases of NiV infection in humans of which 305 have been fatal.
Clinical Manifestation
The clinicopathological features of human NiV and HeV virus infections appear to be similar. The clinical manifestations may be mild, but if severe, includes acute encephalitic and pulmonary syndromes with high mortality (Table 1). Generally, the pathological features in human acute Henipavirus infections comprise vasculopathy (vasculitis, endothelial multinucleated syncytia, thrombosis), microinfarcts and parenchymal cell infection in the CNS, lung, kidney and other major organs.
Equine HeV infection is characterized by rapid onset of illness including fever and respiratory or neurological syndromes leading to death in most cases. Clinical presentations of human HeV infection include influenza-like illnesses that can progress to pneumonia and encephalitis-type symptoms such as headache, fever and drowsiness, which can progress to convulsion or coma. Seizures have occurred in 23% of all patients, with all but one of these patients having generalized tonic-clonic seizures. This patient had focal motor seizures with secondary generalization. Some of the typical clinical signs include segmental myoclonus, hypertension, tachycardia, areflexia and hypotonia. Other pathological features common to both viruses includes interstitial pneumonia and encephalitis.
The main clinical features of NiV infection at presentation are fever, headache, dizziness, vomiting and reduced levels of consciousness. However, NiV-infected patients also present with severe acute encephalitic syndrome. Some patients also display significant pulmonary manifestations. The encephalitis may present as either acute or late onset. The latter may be difficult to diagnose since exposures may have taken place several months earlier. Pathological evidence suggests viral reactivation confined to the CNS is the cause for the late onset of encephalitis.
Clinical symptoms of NiV infections in pigs have been reported to predominantly be respiratory distress. In pigs, the clinical manifestations of the infections are also known as porcine respiratory and neurologic syndrome as well as barking pig syndrome. Unlike all other animal species, bats that tested positive to HeV showed no signs or symptoms of the disease.
Therapy
Currently, there is no approved/licensed therapy for humans for the treatment of Henipavirus infections. The continual emergence of these pathogens necessitates a strong need for the development of effective therapies. A number of antivirals including small molecules and vaccine candidates were shown to be effective against Henipavirus in vitro , but failed at the in vivo stage. Of note, experimental vaccine development to prevent infection has made significantly greater progress in comparison to its postexposure counterpart.
A Hendra virus vaccine, Equivac HeV® is now available for equine use. This is the only currently licensed means of protection against the deadly disease. The vaccine is a soluble form of a G glycoprotein, which has the critical role of initiating infection by binding to receptors on host cells. This allows, antibody directed against this protein to neutralize the virus. The formal launch of the HeV horse vaccine in November 2012 represents the conclusion of multiple studies conducted in numerous animal infection models over many years. While the vaccine is officially available to be used to protect horses from HeV infection, there is nothing that exists so far against NiV infection.
The drug ribavirin is the only postexposure therapy that has been used to treat HeV and NiV infections in humans. An open-label antiviral trial was performed in 140 patients during the initial outbreak of NiV in Malaysia in 1998. However, the results remain controversial. Additionally, the use of ribavirin as a postexposure treatment in humans, only seems to result in survival rates of one in three cases.
So far, the only potential postexposure treatment for Henipavirus infection is the experimental human monoclonal antibody (mAb) referred to as m 102.4, which targets the ephrin B2- and B3-receptor entry site of the HeV and NiV G glycoproteins. M 102.4 is a potent cross-reactive neutralizing antibody in vitro shown to protect ferrets from lethal NiV challenge and African green monkeys from lethal HeV and NiV challenges. However, it is yet to be tested in humans.
Is Henipavirus a History Yet?
Well, the simple answer is no. The successful development of an HeV vaccine will surely assist in reducing the human, animal and environmental effects of the deadly virus, but it is presently not capable of eradicating it forever. While the vaccine is the first and only means currently available to protect the lives of horses, veterinarians and horse owners, it is not sufficient by itself to end its threat. Thus future efforts should be directed toward antiviral development.
The ultimate therapy to reduce the impact of such relatively rare infections would be a postexposure treatment, as vaccination for these diseases is unlikely to be made mandatory for either human or animal use to end the virus threat. Despite the availability of an HeV vaccine for over 2 years, the virus has continued to re-emerge with the latest outbreak in June 2014 at a farm in New South Wales, Australia.
The Hendra virus has emerged in horses and is able to transmit to humans. In theory, vaccinating horses will stop the infection cycle. However, this will only be effective if the HeV infection cycle is confined to a defined area where horse movements are controlled and all horses have been immunized. This scenario can never be the case in Australia, where a number of national and international horse races take place every year. Also, it is not likely that all horses could ever be immunized for a variety of reasons. This includes the probability of low horse owner compliance or willingness to vaccinate horses that are not in close proximity to affected regions. Despite a favorable safety profile of the vaccine, many owners are reluctant to introduce new vaccines to their horses, particularly to a virus that could somewhat be thought of having isolated and limited incidents.
Furthermore, the potential of HeV to infect other species raises the prospect that horse vaccination against HeV may not necessarily limit its spread to humans (with the reports of domestic animals testing positive for HeV infections including; two dogs, one dog in Queensland, 2011 and one in NSW, 2013). Additionally, novel henipa-like virus sequence, called Mojiang paramyxovirus, has been identified in rats ( Rattus flavipectus ) in China, expanding the natural hosts for these enigmatic viruses to another species different from bats. Also other species, which includes cats, pigs, guinea pigs and ferrets have developed HeV infection under laboratory conditions, prove that these and other animal species may also be susceptible to natural HeV infection, and hence an HeV vaccine for horses will not likely end the fight as yet. Another interesting point, which will take the fight against Henipaviruses and the like to a new level, is to test and see whether other species such as insects are susceptible to such viral infections and whether they have played a role in their spread.
Notwithstanding the availability of potential candidates for the treatment of NiV infection including m102.4, there will be many years before these candidates become available for human use. However, most of the NiV affected areas such as those in Bangladesh and India are poor, isolated and that a treatment for NiV infection is not a priority. Furthermore, a treatment for a rare infection in areas where water and food are considered rare commodities is unlikely to gain a momentum to become a national need. Thus, the lack of the urgency factor for such infections will probably delay both development and availability.
Conclusion
The availability of an equine vaccine and an experimental postexposure therapy suggests that the worst might be over. However, until an effective antiviral therapy is approved, Henipaviruses will continue to possess significant health risks to humans. Hence, to facilitate the speed of discovery of a suitable and effective therapy, research efforts for the discovery of treatments for rare infections such as Henipaviruses should be directed toward postexposure therapy rather than vaccination. Such a focus will likely yield effective and more suitable treatments capable of overcoming vaccine limitations.
Future Perspective
The continual emergence of Henipaviruses signifies the potential threat that these viruses possess to public health, which will remain high unless appropriate therapy is established. Hence, there is an urgent need for the development of new therapeutics to treat these potentially lethal infections. However, based on the current research efforts and discoveries, particularly the experimental monoclonal antibody (m102.4) and the Hendra virus vaccine (Equivac HeV), I am quite optimistic that potential antihenipavirus therapeutics will soon (within approximately 10 years) become a reality and that the war against Henipavirus will be declared a victory.
| Table 1. Clinicopathological manifestation of Henipavirus infections. | |||||
| Humans | Horses | Swine | |||
| Pulmonary | |||||
| Influenza-like illnesses | Febrile respiratory disease | Nonproductive cough | |||
| Hypoxemia | Copious frothy nasal discharge | Pyrexia | |||
| Diffused alveolar] | Congestion | Forced respiration | |||
| Cough | Pulmonary edema | Drooping of the tongue | |||
| Atypical pneumonia | Hemorrhage | ||||
| Acute respiratory distress syndrome | |||||
| Neurological | |||||
| Hypertension | Facial swelling | Head pressing | |||
| Confusion | Disorientation | Agitation | |||
| Motor deficit | Ataxia | Tetanus-like spasms | |||
| Seizures | Facial paralysis | Seizures | |||
| Reduced consciousness | Head tilt | Pharyngeal muscle paralysis | |||
| Areflexia | Circling | Frothy salivation | |||
| Hypotonia | Head pressing | Rear leg weakness | |||
| Abnormal pupillary and doll’s eye reflex | Stranguria | Muscle spasm | |||
| Tachycardia | Myoclonic twitches | Uncoordinated gait | |||
| Meningism | |||||
| Late onset of encephalitis | |||||