The Hendra Story: A Triumph for Australian Science

Guest post by Erin O’Neill, Visiting Fellow at The Australian National Centre for the Public Awareness of Science

1. THE NATURAL HISTORY OF HENDRA VIRUS

When most people think of Australia, they imagine long coastlines with beautiful beaches, magnificent deep red deserts, the Opera House and cuddly koalas and kangaroos.  The more jelly-legged will profess a concern for sharks (of any kind), snakes, crocodiles, blue ringed octopus, funnel web spiders, jelly fish and possibly cassowaries.

They don’t think of one of the deadliest viruses that humanity has had to reckon with.

In September 1994, a horse trainer in Hendra, Brisbane contracted a virus from his horses.  21 horses were involved, with 18 sufferering respiratory tract infections.  Of those, 14 died.  Seven other horses in the stable also caught the virus.  Of these, 4 survived, two of which were left with mild neurological signs, and 3 were found to have been infected and to have produced an immune response (seroconverted) without showing obvious clinical signs.  Two people caught the disease – a stable hand had a self-curing influenza like illness, and Vic Rail, a 49 year old trainer who died from severe lung inflammation caused by the Hendra virus.  Both men had very close exposure to the sick horses including nursing and handfeeding them during their illness. The disease, infecting horses and humans, was new to both medicine and veterinary science. Given the lethality of the virus, it is unsurprising that the isolation of the virus from the samples collected at Hendra happened in record time.

Within 7 days of hospitalization, Vic Rail needed ventilation.  His condition continued to deteriorate, and he died six days later.

The most significant post-mortem finding was of heavy wet lungs consistent with interstitial pneumonia, but little pathology in other organ systems.  It would seem that he died from an acute attack of the illness, and like his horses, suffered severe respiratory failure.

Just as concerning, and for horse owners, more frightening, was the prospect of the virus having an ability to infect, cause mild illness and then lie dormant in tissues until reactivated.  As it happened, one month before the case of Vic Rail, in August 1994, a 36 year old cane farmer from Mackay, Qld fell ill with an aseptic meningitis-like disease after nursing two of his horses that had been infected with a virus later shown to be Hendra.  His horses died, but he recovered. In September 1995 (13 months later) he was readmitted to hospital suffering irritable mood and low back pain with seizures.  Over the next week he developed a fever and more generalized seizures, and despite treatment with antibacterials, antivirals, corticosteroids and anti-convulsants his fever continued, whereupon he lost consciousness and died 25 days after admission.  The initial illness was possibly due to seroconversion, where there is a burst of viral replication that is then followed by a strong immune response. In the 13 months from the initial seroconversion illness to his final days he potentially could have shed virus.  The most concerning aspect of this is that it is not known where the virus hid itself between the initial seroconversion illness and the young farmer’s terminal disease.

The onset of a Hendra virus infection can look similar to many other diseases, so if you are a horse owner, it can become confusing knowing what to look for in a suspected Hendra case.  Has your horse just got a snotty nose, or is it something worse?  An infected horse may shed virus for about 48 hours before showing significant symptoms, giving the virus a two-day edge on any observant owner or handler.  Once symptoms occur, they tend to look very similar to a range of other disorders and diseases, making it hard to work out what the horse has come down with.  The common symptoms – increases in body temperature, heart rate, and discomfort – could just as easily be colic, a common, but potentially fatal disorder, and one that horse owners rightly live in fear of.  However, by the time any swab samples come back from analysis, the horse will have had the disease for a number of days, and its owners, handlers and vets and other animals will have been unknowingly exposed for that time as well.

Transmission from horse to human requires close contact with the infected horse and its bodily fluids. By practicing very good hygiene (using personal protective equipment (at the very least long shirts, a mask and latex gloves), your chances of avoiding the disease are very good.

The prognosis for an infected horse is very poor: if the disease doesn’t kill the horse, the vet will have to, making Hendra 100% fatal, one way or another.  75% of horses died directly from the virus, while the remaining 25% have been killed.  In humans infected with the disease there is some evidence that the virus can reappear sometime after the initial infection, creating concerns that any horse that recovers may later shed the virus and infect other horses and people.  This is why all surviving infected horses are euthanased. A therapeutic vaccine, one that could be given to the horse after contracting and surviving the initial infection, but preventing recurrence of the disease would be wonderful, but it is probable that the economics of such a vaccine do not justify the effort of developing it.

Although domestic animals can catch the virus, they are not thought to be the major vectors to humans. Even so, domestic animals associated with an infected horse will also be tested and be put down if positive for the virus. Again, this is done because the virus has the ability to sit sequestered in the body for some time and potentially cause a recurrence of the disease.

By 1996 it had been determined that bats were the most likely natural vector and means of infecting horses.  Bats harbored the virus without showing infection, and the virus could be found in a number of tissues in a bat.  The exact mode of transmission was unknown: transmission via bat saliva, urine, faeces or reproductive fluids transferred onto fruit, grass, water and feed bins was theoretically possible.  All four species of the Australian flying foxes, a type of large fruit bat, may carry the Hendra virus, and about 47% of bats are seropositive to the virus.  That is, they have been exposed to the virus and developed antibodies to it.

In such a vast country, with millions of bats and many thousands of horses, the potential for a large number of human and animal deaths loomed. In 2011, a family pet dog was found to have contracted the virus, thus establishing that dogs could be infected in real world conditions.  It is unknown if the dog contracted it directly from bats, or from the infected horses that were also on the property.

While not absolutely certain, it now seems that the virus needs to be transmitted from the bat to the horse first, and then from the sick horse to the human host. The virus infects the horse, but only certain individual particles are particularly able to be successfully produced in the horse, and then later transmitted to humans, an effect called “passaging”.  This is important, because it means that the horse has to be the intermediate host.  To date, there are no examples of where humans have caught the virus directly from bats (e.g. bat handlers) or animals other than horses.

From flying foxes, to horses, and then on to humans.  It has become obvious from the outbreaks of virus since, that once infected, horses have to be in very close contact with each other and/or humans for the virus to be passed on.  At least one study of 5000 horses showed no sign of the virus, outside of the outbreaks in Mackay and Brisbane.  Another study of humans found that there were no other seropositive individuals among those who had varying degrees of exposure to the infected horses or humans in both the Hendra and Mackay outbreaks described above.

At least part of the reason for the rarity and seeming randomness of Hendra infection is that it is not a particularly robust virus.  However, it is interesting to note that the most likely periods for contracting the virus coincides with the birthing season of Australian fruit bat species.  A bolus of virus delivered via aborted fetuses to a potential new host (the horse) would have a greater chance of surviving in the open environment than virus diluted in saliva, urine or even faeces.

In short, the Hendra Virus is hard to get, but once you have it, it’s hell for humans and a death sentence for horses.

2. MORE ABOUT THE VIRUS

Viruses are intriguing organisms that use an asymmetrical warfare strategy against their hosts. Despite having just a small, single strand of RNA, the Hendra virus is able to conquer the immune systems of much larger and more complex animals in a short period of time.  It does this by hijacking the host cell that it has just infected and forcing it to make many copies of itself, which are then shed by the host to infect others.

The Hendra virus is classified as a small paramyxovirus, which forms part of the Henipavirus family.  It is cousin to another lethal virus called Nipah Virus, which is found in South East Asia.  Like Hendra Virus, Nipah Virus originates in bats, but uses pigs as its bridge to infecting humans.  A more recent addition to the family is a virus called Cedar Virus.  Cedar Virus has been shown to infect ferrets and guinea pigs and initiate an immune response by the host to the virus, but it did cause clinical disease.  These qualities and its similarity to significant aspects of the biology of Hendra and Nipah Virus mean that it may be of use in laboratory studies as it is less lethal and therefore easier to handle in the lab.

From the 1990’s onward, has been suspected that habitat disturbance amplifies the production of Hendra virus by bats.  It is now thought that when that when land is cleared or disturbed, this places further ecological and physiological stress upon the bats, inducing them to shed virus and potentially abort foetuses.  But there is also a multiplying effect on human infection rates: as their habitat disappears, bats are forced to live closer to humans, perhaps the ultimate bad neighbours, and so the opportunity for horses and humans to be exposed to the virus rises greatly.

The first reactive step was to try and kill or remove as many bats as possible (it would be too much to ask for humans to perhaps modify their behavior!).  But it’s pretty much impossible to do it, silly to even try (although I’m sure some did), and a waste of time, money and effort.  Bats are also a very important part of the ecosystem as they are important pollinators of native species of plants and crops.

So what to do?  You would think that a lethal unknown virus, transmitted by unknown means was impetus enough to support vital research into the biology of the virus, and the chances of a cure or vaccine.  While there was an initial flurry of work to identify the virus and its vectors, research stalled due to lack of interest – there had been no outbreak for a while to keep the virus fresh in the minds of the public and government.  During that time, the Nipah Virus had appeared in Malaysia.  It was found that its preferred vector for transmission to humans was the domestic pig.  It causes respiratory illness in the pigs and fever and encephalitis (inflammation of the brain) in people.  Through farmed pigs, Nipah Virus has claimed the lives of over 100 people in one outbreak alone.

The hiatus in funding ended with pictures of the planes flying into the Twin Towers in September 2001.  This changed the view of the American Congress towards funding for antiviral and vaccination methods against potential bioweapons.  The search for a vaccine for Hendra was now back on the table.

3.HOW DOES THE VACCINE WORK?

The Hendra vaccine works by setting up an immune response against the G Protein of the virus.  This protein is responsible for permitting entry of the virus into the host cell by a ‘lock and key’ type of mechanism.  If the G Protein of the virus, the ‘key’, is blocked by antibodies formed in response to the vaccine, then it cannot open the lock, and a cell cannot be infected.  You can tell if a horse has been vaccinated because it will be positive for antibodies against the Hendra virus G protein.  If a horse has been infected with the real virus, the horse will show positive for antibodies against the whole panoply of Hendra virus proteins.  These differences can be detected and clinical decisions made accordingly.  This is critical, as Australia exports a lot of horses overseas temporarily and permanently, and is a substantial exporter of horsemeat as well.  Some countries (UAE, China, Hong Kong, and Japan) will not take our live (or dead) animals if they have Hendra antibodies.  However, this is subject to ongoing negotiation, and it is reasonable to expect that this will change.

It’s a work in progress.  The vaccine has only been available for a few months, but awareness in the equine community, even in areas that are not obviously affected by Hendra (such as Tasmania) is high.

Equally important and successful has be the way in which the community has been made aware of the implications of infection with Hendra, and how the vaccine rollout is working.  Over time, it is likely that vaccination against Hendra will be mandatory for horses competing in larger events that attract horses from interstate.

One major concern for breeders has been the potential effects of the vaccine on pregnant mares.  Because the vaccine only contains a particular subunit of the virus (G protein), not the whole virus, it is very safe.  However, various studies are underway to determine if there is an increased chance of side effects in the mare of the foals.  It is possible, but given the low reactivity and side effect profile of the vaccine to date, it is unlikely.

Importantly, the Hendra vaccine sets a precedent:  it is the first successful vaccine to a Biosafety Level 4 virus.  Biosafety Level 4 is the strictest form of biosafety on the planet.  There is only one such lab  – in Geelong, Australia, – and it’s the type of lab you see in the movies. The scientists are suited up with their own air supply.  Indeed, fiction caught up with the Henipah Virus family, when the director of the movie “Contagion” based their fictional virus on the Nipah Virus.  While most of the pathogens that CSIRO work with in that lab are not infectious to humans, their containment is essential to protect animals and plants in the environment.  A recent advance has been the discovery of the related “Cedar Virus”.  It is not as deadly as the Nipah or Hendra Viruses, and so it may be more easily manipulated in laboratory work.

Like the eradication of Smallpox, the vaccines against Papilloma Virus and the fight against HIV, the story of the Hendra Virus is another success for Australian Research. Virologists and ecologists, vaccine biologists, veterinarians and medical doctors have come together and demonstrated how successful a multidisciplinary strategy can be.

It’s a story that deserves to be told to the world.

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