Hendra: why not just go ahead and vaccinate?

Risks

So, what are the risks and benefits involved here?

The virus

First, let’s talk about the risk posed by HeV itself. In horses, disease caused by HeV has a high mortality rate (reportedly about 75%) — in identified cases. However, we don't know the actual mortality rate, because some of the documented cases of HeV infection in horses were euthanised for public health reasons. Who knows how many of those horses would have survived and recovered?

Although we've been living with HeV for at least 25 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.

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

Naturally acquired immunity (as distinct from vaccine-induced immunity) develops when individuals encounter the virus and, whether or not they show any signs of infection, they mount an appropriate immune response which is protective against future encounters with the virus.
 
Immunity, whether naturally acquired or vaccine induced, has two components:
1. Production of virus-specific antibodies, and
2. Cell-mediated immunity, which includes direct action by immune cells, and maintenance of immunological memory ('cell memory'), which can last a lifetime.
 
Both are equally important, but because it’s the easiest thing to measure, the focus has been on the production of virus-specific antibodies. The amount of antibody in the bloodstream is usually reported as a titre (titration using serial dilutions). According to the vaccine challenge study, a HeV antibody titre of between 1:16 and 1:32, often written simply as 16–32, is considered protective.

Except for when HeV first made an appearance in 1994, there have been no large serologic surveys of horses in areas where HeV outbreaks have occurred (coastal Qld and NSW), 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 exposure 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 a vaccine was available). In 8 horses, only one blood sample was available, but the other 11 horses had at least two blood samples, taken about 1 week apart.
 
Of the 8 horses with single results, 7 horses had a titre of at least 16. (For reference, a titre of 16–32 was protective against illness 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 one sample. Eight horses (73%) had titres of over 100, and 7 horses (64%) had titres of over 500, in at least one sample. One horse had a titre of more than 2,000 in all 4 of its blood samples.
 
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 one sample. Eight of the 11 horses with two or more samples 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.
 
In short, horses naturally infected with HeV do indeed mount an immune response that can be expected to be protective agaainst future HeV exposure.

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

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 contact with the virus or that they encountered the virus but did not become ill? Either way, might the risk of this virus to horses and humans have been consistently overstated? Could the individual risk posed by this virus be far more nuanced than we've been led to believe?

Perhaps it's comparing apples and orangutans, but COVID-19 might provide a useful analogy. None of us had any immunity to this novel virus (SARS-CoV-2) when it came along, yet our individual responses have ranged from none (no illness, 'asyptomatic' infection) to death! Most people have experienced only a mild to moderate, cold/flu-like illness and have recovered without specific treatment. The people who have become seriously ill and needed to be hospitalised have typically had a massive systemic inflammatory response (a 'cytokine storm') which, in some cases, was overwhelming and fatal.

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.

Here are two excerpts from a report of the first Hendra outbreak to be described (occurring in the Brisbane suburb of Hendra in 1994):

"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 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 survived.

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?

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 co-infection with other viruses 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, just as they do with COVID-19 in humans. Yet all of the focus has been on vaccination. 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 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?

Until we know who is most susceptible and why, and who is already protected through naturally acquired immunity, every horse is potentially at the same risk. This "one size fits all" approach underpins the blanket recommendation to vaccinate every horse against HeV.

Read on...

UPDATE July 2021

There is a newer strain of HeV in Australia that is not detectable using the current HeV exclusion test (polymerase chain reaction, or PCR). It 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 test result. This new variant (HeV-var) has since been found in grey-headed flying-foxes in South Australia, Victoria, and Western Australia.

But while the 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 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 really lack is a commercial laboratory test for this new strain.

Risks

Benefits

HeV antibody testing

Final thoughts

© Christine M. King, 2021. All rights reserved. Last updated 20 July 2021.