animal health consulting

Hendra: why not just go ahead and vaccinate?

Christine King  BVSc, MANZCVS (equine), MVetClinStud

Table of Contents

Summary (key points)

Introduction

Risks

   the virus

   the 'vector' (flying foxes)

   the vaccine

   vaccination status

Benefits

   the vaccine

   experimental study

   vaccine field study

   vaccination status

HeV antibody testing

Letter to the Editor (AVJ)

Final thoughts



So, what are the risks and benefits involved here? First, let’s talk about the risk posed by the virus itself.


Risks: the virus


Hendra virus (HeV) occurs naturally in at least four flying fox ('fruit bat') species in Australia. It rarely causes illness in flying foxes, as they are its natural host. However, HeV can "spill over" into other species and, depending on the species and on individual factors not well understood, it may cause serious illness. Horses are the most commonly affected species. Humans are also susceptible. Dogs can be infected with HeV, although they generally don't show signs of illness and they don't appear to be an important transmission risk for horses or humans.


To date, almost all cases of HeV infection in horses and humans have occurred in coastal Queensland and New South Wales, east of the Great Dividing Range and north of Sydney. However, in 2021 a new HeV variant was identified in flying foxes in Victoria, South Australia, and Western Australia. More on that variant at the end of this page, and more on flying foxes as HeV 'vectors' on the following page.


The virus was first identified in 1994, when it caused an outbreak of serious, and in some cases fatal, illness in several horses in Hendra, QLD. Two people were also infected in that outbreak, which I'll describe in detail in a bit. One person died, the other survived.


Now, to the nuts and bolts...


Mortality rate


In horses, HeV infection is widely assumed to have a high mortality rate; often reported to be ~ 75%,  it was 65% in the first Hendra outbreak.


However, as I'll discuss (with data), investigations surrounding the first HeV outbreak revealed that not every horse who is infected with HeV gets sick, and not every sick horse dies. Asymptomatic infections (infected but not ill) and mild infections (ill then recovered) were surprisingly common in HeV-exposed horses. (Surprising, that is, given all the hype surrounding this "deadly" virus.)


Yes, some horses infected with HeV become very ill, and apparently most of those horses are likely to die. But what is the likelihood that a HeV-infected horse will be severely affected, and what are the risk factors or circumstances involved? In other words, who is highly susceptible, and when or why?  And can we do anything about those individual risk factors?


Currently, we have very little idea; and there seems to be very little interest in finding out. Why bother, when there is a "safe and effective" vaccine available? (And where have we heard that line before?...) In other words, why not just go ahead and vaccinate?


Here's another problem with those mortality statistics: we don't know the actual mortality rate of illness caused by HeV infection in horses, because many of the documented cases were euthanised ("put down"). When done right, euthanasia has a mortality rate of 100%.


No doubt, in many of those cases euthanasia was performed on humane grounds (to prevent further suffering). But I'd be willing to bet that in at least some cases the primary driver will have been "public health" concerns, given the fear surrounding this virus. Who knows how many of those HeV-infected horses would have survived and recovered with timely and appropriate treatment?


Although it is highly speculative at this point, I've written an article which ponders whether ivermectin would be useful in the early treatment of HeV infection in horses, and in the prevention of HeV infection in exposed but still-healthy horses. It's based on the fact that HeV is one of the many viruses inhibited by ivermectin in the lab.


And perhaps at some point there'll be a HeV monoclonal antibody product available for horses as there now is for the treatment and post-exposure prevention of HeV infection in humans.


Although we've been living with HeV for almost 30 years now, we still don’t have much idea about how many horses have been exposed to the virus without becoming ill or who showed only mild signs of disease (most likely attributed to some other cause) and then recovered.


But we do know that, since HeV was first identified in a sick horse in 1994, there have been only 87 confirmed cases of HeV infection in horses, and a further 20 unconfirmed cases, in QLD and NSW combined. For some context, the horse population in these two states is currently estimated to be a little over half a million (509,000 horses in 2019, down from ~ 547,000 in 2016). Since the start of 2016, there have been only 9 confirmed cases and 0 unconfirmed/suspected cases of HeV in horses anywhere.


The HeV vaccine has been on the market since August 2015 (in limited use from November 2012, granted full approval 3 years later), but its uptake by horse owners has been quite low. It's been estimated that only 10–13% of the horse population in QLD and NSW were vaccinated against HeV between 2016 and 2019. In addition, seasonal and annual variations in flying fox health and activity result in variable HeV risk from year to year, so it's difficult to make any definitive statements about the number of cases in relation to HeV vaccination.


In other words, we don’t know much about individual susceptibility to the disease nor about how prevalent naturally acquired immunity to the virus may be in the horse population.


Naturally acquired immunity (as distinct from vaccine induced immunity) develops when individuals encounter the virus naturally and, whether or not they show any signs of illness, they mount an appropriate immune response which is protective against later encounters with the virus.


Immunity, whether naturally acquired or vaccine induced, has two components:

1. Production of specific antibodies, (called humoral immunity) and

2. Cell-mediated immunity, which includes...

(a) immediate action by immune cells, and

(b) maintenance of immunological memory, which can last a lifetime.


Both are equally important, but because it’s the easier thing to measure, the focus has all been on the level of antibodies in the horse's blood.


The amount of specific antibody in the bloodstream is usually reported as a titre (the result is obtained by titration using serial dilutions). According to the vaccine challenge study I'll discuss later, a HeV antibody titre of between 1:16 and 1:32, often written simply as 16–32, is considered protective against illness and viral shedding.


Generally, titres are conducted on the cell-free, liquid portion of the blood: the serum or plasma. Thus antibody testing is also referred to as serology.


Naturally acquired immunity


Except for when HeV first made an appearance in 1994, there have been no large serologic (serum antibody) surveys of horses in areas where HeV outbreaks have occurred, so we don’t know how common it is for horses to develop natural immunity without showing signs of HeV infection or only mild signs that are attributed to some other cause.


From the limited data that are available, horses do develop natural immunity following HeV infection which may be expected to be protective against future exposure.


A 2018 study of diagnostic methods included blood test results from 19 horses naturally infected with HeV during various outbreaks in Queensland between 1994 and 2012 (i.e., before the HeV vaccine was available). In 8 horses, only 1 blood sample was available, but the other 11 horses had at least 2 blood samples, taken about 1 week apart.


Of the 8 horses with single results, 7 horses had a titre of at least 16. (As a reminder, a titre of 16–32 was protective against illness and viral shedding in the HeV vaccine challenge study.)


In the 11 horses with 2 or more results, all 11 horses (100%) had a titre of 16 or higher in at least 1 sample. Eight horses (73%) had titres of over 100, and 7 horses (64%) had titres of over 500, in at least 1 sample. One horse had a titre of more than 2,000 in all 4 of its blood samples.


(The higher the titre, the more antibody there is in the blood sample:. That's because the more times you can dilute a sample and it still have a virus-neutralising effect, the more antibody there must have been in the original sample.)


Overall, 18 of the 19 horses (95%) had a titre of 16 or higher, and 14 of the 19 horses (74%) had a titre of 32 or higher, in at least 1 sample. Of the 11 horses with 2 or more samples, 8 horses had much higher titres in their second sample, indicating a vigorous immune response with active antibody production in the week between samples 1 and 2.


The health status of these horses was not reported, as it wasn't important to the study goals. The samples were described simply as "Post-infection" serum from "equine HeV infection cases." In experimental studies and in naturally occurring HeV infections, the horses who have become very ill and have died or been euthanised have all died within a few days of showing signs of illness, sometimes within 24 hours. There is generally not enough time for them to mount a vigorous antibody response, and they generally don't survive long enough for a second serum sample to be collected a week later. So, we may reasonably assume that at least 11 of the 19 horses in this study were survivors.


In summary, horses naturally infected with HeV do indeed mount an immune response that can be expected to be protective agaainst future HeV exposure.


Individual susceptibility


The question of individual susceptibility is even harder to get a handle on. As I mentioned earlier, there are considerable species differences in susceptibility to HeV infection. Flying foxes infected with HeV rarely show signs of infection, whereas experimental infection in ferrets (a species that is highly susceptible to HeV) causes a massive systemic inflammatory response, similar to that seen in horses and humans who have succumbed to HeV infection.


From a review published in 2022: "Different mechanisms have evolved in fruit bats permitting them to efficiently control the Henipavirus infection [e.g., HeV]. These mechanisms likely allow bats to establish an adequate equilibrium between viral tolerance and antiviral defense, enabling them thus to avoid both uncontrollable virus expansion as well as immunopathology linked to excessive antiviral responses."


In other words, there is a balance between viral tolerance and antiviral defense that prevents disease in infected bats. Understanding these natural mechanisms may help us develop targeted antiviral therapies for use in horses and other at-risk species.


However, according to the Queensland government, "[s]everal hundred people have been exposed to Hendra virus infected horses but have not been infected."  Does that mean they did not come in direct contact with the virus (no infection, so no illness) or that they encountered the virus but did not become ill (asymptomatic infection)?


Either way, might the risk of HeV to horses and humans have been consistently overstated?  Are we really all at risk and all at equal risk?  Or is the individual risk posed by HeV far more nuanced than we've been led to believe?


Perhaps it's comparing apples to orangutans, but COVID-19 might provide a useful analogy. When this novel virus (SARS-CoV-2) came along, our individual responses ranged from none (no illness, asyptomatic infection) to death!  Most people experienced only a mild to moderate, cold- or flu-like illness and recovered with just symptomatic treatment at home. Those who became seriously ill and needed to be hospitalised typically had a massive systemic inflammatory response (a 'cytokine storm') which, in some cases, was overwhelming and fatal.


While it's true that SARS-CoV-2 was a completely novel virus in 2019, a significant proportion (20–50%) of the population already had some cross-protection from other human coronaviruses that had long been in circulation. (Coronaviruses are among the large collection of viruses that can cause the common cold.) When present, this cross-protection no doubt dampened the severity of COVID-19.


Cedar virus or Cedar paramyxovirus (CedPV) is a nonpathogenic or benign virus that is closely related to both the Hendra and Nipah viruses, all three belonging to the genus Henipavirus. Co-infection with HeV and CedPV has been documented in Australian flying foxes. Is it possible that prior exposure to Cedar virus (from flying foxes) may likewise cross-protect against HeV infection in some horses?


The limited data we have on naturally occurring HeV infection in horses suggests a similarly broad spectrum of responses. Not all horses naturally infected with HeV become ill, and not all horses who do become ill will die. Those who have died have had signs of a massive and overwhelming systemic inflammatory response (a 'cytokine storm').


Here are two excerpts from a report of the first HeV outbreak (occurring in the Brisbane suburb of Hendra in 1994); the emphasis (bold text) is mine:


"Two weeks before the [racehorse] trainer's illness, on September 7, two horses had been moved to the Hendra stable from a spelling paddock in Cannon Hill (6 km). One of these, a pregnant mare, was sick and died within 2 days. The other horse was subsequently moved on and never became sick.


"By September 26, 13 horses had died: the mare; 10 other horses in the Hendra stable; one horse, which had very close contact with horses in the Hendra stable, on a neighboring property; and one which had been transported from the stable to another site (150 km).


"Four Hendra horses and three others (one in an adjacent stable, one moved to Kenilworth, and one to Samford) were later considered to have been exposed and recovered from the illness. Some of these horses were asymptomatic. Nine Hendra horses have remained unaffected."


...


"Serologic [serum antibody] testing of all horses on quarantined properties and within 1 km of the Hendra stable, and a sample of horses from the rest of Queensland was undertaken... In the entire horse survey [1,964 horses], only seven horses, all from the Hendra property and the adjoining stables, were positive. Four of these animals had been clinically affected, but three were asymptomatic."


In all, 20 horses in that first outbreak were identified as having HeV infection; 13 died (65%) and 7 recovered (35%). Of the two people who became ill in that outbreak, one died and the other recovered.


To date, there have been only 7 confirmed cases of HeV infection in humans; 4 died and 3 recovered.


It is important to underscore the high mortality rate in horses who become seriously ill from naturally acquired HeV infection. Postmortem examinations of horses who died from naturally acquired HeV infection or were euthanised after experimental HeV infection have consistently revealed the widespread organ and tissue damage caused by a massive systemic inflammatory response.


Might we be able to short-circuit this systemic inflammatory response if we get to it early enough, as can be done for patients with COVID-19?  Probably so.


But it is equally important to note that not all horses succumb to this disease.


Why is that? Is it just about the number of viral particles the horse comes in contact with, or is there some component of the individual's immune response involved as well?


Although it's highly controversial and hotly debated, there is some suggestion that chronic infection with other viruses (unrelated to coronaviruses) increases the likelihood that a patient with COVID-19 will develop severe illness. The reasoning is that chronic viral infection alters the patient's immune status to one of chronic inflammation (upregulation of inflammatory cytokines) and a dysregulated immune response (increased potential for a 'cytokine storm').


The factors that make one horse susceptible to illness and death, while another recovers or doesn't even become ill, urgently need investigation. Yet almost all of the focus has been on vaccination (and a little on preventing exposure to flying fox urine). This is a very short-sighted approach, particularly in this era of personalised medicine.


Incidentally, these same factors may also play a role in determining which horses have vaccine reactions, and how severe those reactions may be. More on that later in the series.


In short, we don’t know how much risk HeV poses to an individual horse. It is clear that some horses become seriously ill and may die when they encounter the virus. But for what percentage of horses is that true? And who are they; what are their characteristics, and might we be able to identify them before they become ill?


Until we know who is most susceptible and why (or under what circumstances), and who is already protected through naturally acquired immunity, every horse is considered to be at the same risk. This "one size fits all" approach underpins the current blanket recommendation to vaccinate every horse against HeV.


This "all are at risk, and all at equal risk" mindset is demonstrably untrue for COVID-19, and for influenza and any number of other viruses, and it is clearly untrue for HeV as well. I'll talk more about the risks posed by the HeV vaccine, and how individual susceptibility fits into that, later in the series.


New HeV variant


Before I go on to discuss the 'vector' (flying foxes), I want to note that there is a new strain of HeV now in circulation. It was first reported in May, 2021. It doesn't appear to be any worse than the original virus, but it is notable because it is not detectable using the current HeV exclusion test.


The HeV exclusion test is a highly specific polymerase chain reaction (PCR) that is based on the genome of the original virus. There is only ~ 83% genetic similarity between this variant and the original strain of HeV, which is why the current HeV exclusion test misses it.


This variant was first identified in samples from a horse near Gympie, QLD, who was euthanised after showing signs consistent with HeV yet with a negative HeV exclusion test. The horse died in 2015, but the new HeV variant wasn't definitively proven to be the cause until 2021.


The variant, called HeV-var or HeV-g2, has since been found in flying foxes in Victoria, South Australia, and Western Australia. In October 2021, it was confirmed as the cause of rapidly worsening neurologic disease in a horse near Newcastle, NSW.


The HeV vaccination status of the QLD case was not specified, but the NSW case was unvaccinated.


The good news is that, while the current exclusion test for the original — and still predominant — HeV strain will not detect this new variant, the HeV vaccine is expected to be protective in horses, and the HeV monoclonal antibody treatment developed for human use following HeV exposure is expected to be protective in people. In addition, I expect ivermectin to be effective against both strains of HeV.


So, all we lack is a commercial laboratory test for this new strain, and that is already underway.


Read on...


© Christine M. King, 2021, 2022. All rights reserved.

Last updated 29 May 2022.


back

to article main page