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



Risks: the vaccine


No vaccine is entirely risk-free. The published data on the Hendra virus (HeV) vaccine indicates that while adverse effects do occur, they’re uncommon and are generally short-lived and treatable, most being relatively mild and resolving without intensive treatment. Serious adverse events with this vaccine are considered to be rare.


Serious adverse effects following HeV vaccination have reportedly occurred at a rate of less than 0.04% of doses sold, or less than 1 per 2,500 doses sold:

From mid-2015 to mid-2020, a total of 124 "serious incidents" involving the HeV vaccine were reported to the Adverse Experience Reporting Program of the Australian Pesticides and Veterinary Medicines Authority (APVMA).

Figures provided to the Australian Centre for Disease Preparedness (ACDP, formerly the Australian Animal Health Laboratory) by Zoetis indicated that a total of 317,030 doses were sold between 2016 and 2019.

While the figures don't match perfectly (financial year vs calendar year, and injected vs sold), they give us a general sense of the serious adverse event rate reported for this particular vaccine — emphasis on reported...


However, not all vaccine reactions are identified as such, and not all are reported to the manufacturer or the governing body (the APVMA in Australia).


A 2020 UK study of vaccination practices involving 304 equine vets found the following:

* 66% of vets encountered adverse events in horses vaccinated against influenza (the focus of the study) in the past year, for a total of 2,760 adverse events

* but only 19% of these cases were reported to the governing body

* most reactions were transient; even so, 86% of vets reported vaccine hesitancy from horse owners due to perception of over-vaccination, cost, and concern about adverse events


The perception persists among Australian horse owners that the HeV vaccine causes "lots of problems," including death.


Class Action


A Class Action lawsuit, filed in 2018 against Zoetis by a group of horse owners, is still making its way through the Australian federal courts. The suit basically claims that Zoetis overstated the risks of HeV infection and understated the risks of their HeV vaccine to horse owners and veterinarians. As horses are considered property under the law, the suit is simply claiming financial losses or damages related to adverse effects of the HeV vaccine.


The allegation is that, in their marketing and promotional materials, Zoetis made representations including these:

1. There is a serious risk of horses contracting HeV in all areas of Australia in which flying foxes are present;

2. The HeV vaccine has no serious side effects; and

3. All horses in Australia should be given the HeV vaccine.


The members of the Class Action claim that their horses suffered adverse effects from the HeV vaccine which resulted in losses or damages, including these: reduction in the monetary value of the horse, costs of veterinary treatment, loss of income generated by the horse, loss of opportunity to gain income from the horse, and the replacement value of the horse.


Although the suit has its problems (the claim has been revised several times) and its ultimate success is in doubt, a federal judge has ruled on more than one occasion that the claim has merit and should proceed.


At the present time (May 2022), the case is in mediation.


Incidentally, in 2014 — the same year they filed an application for full approval of their HeV vaccine (which was granted in 2015) —  Zoetis filed an application with the APVMA for approval of an inactivated vaccine against West Nile virus (WNV) strain VM-2, formerly known as Kunjin virus, for use in horses. Is this an example of a solution in search of a problem?


There have been more papers published in veterinary journals on vaccine hesitancy (why horse owners are reluctant to vaccinate against HeV), than there have been on the safety, efficacy, and necessity of the vaccine under ‘field’ conditions (real-world use).


In the one field study that has been published to date on the safety and effectiveness of the HeV vaccine, the study began with 57 horses; by the first annual booster, only 29 horses remained in the study group, and by the second annual booster only 26 horses remained. There are practical reasons for this drop-off, which I'll discuss in a later section. But the simple fact remains that the safety and effectiveness of this vaccine under field conditions were based on data from less than 30 horses.


Even Zoetis states in the product leaflet for their HeV vaccine, "The effectiveness of Equivac HeV vaccine in the face of Hendra virus disease outbreak has not been studied."


Types of adverse effects


More on vaccine effectiveness later in this series. Here is a list of the most common adverse effects reported to the APVMA associated with the HeV vaccine (referred to as G Glycoprotein of Hendra Virus, so you'll find it under G). In descending order of prevalence:

* swelling and soreness at the site of injection ('injection site reaction')

* lethargy

* pain (not specified)

* loss of appetite ('anorexia')

* fever ('pyrexia')


I should note that these are typical of equine vaccines, and nothing on that list is unique to the HeV vaccine. They simply indicate that the horse's immune system has been stimulated (perhaps a little overstimulated).


However, a more detailed look at the list of of adverse events reported for this vaccine tells a rather more disturbing story:

Here is what the product leaflet says to vets, under the heading, Side effects:


"Transient swelling may develop at the site of vaccination in some horses but should resolve within one week without treatment.

"In some horses transient post-vaccination reactions including injection site reaction, pain, increase in body temperature, lethargy, inappetance and muscle stiffness have also been observed. Additional reported clinical signs have included urticaria ['hives'], sweating, oedema [tissue fluid accumulation] and colic.

"Clinical signs may vary in severity and occasionally may require veteirnary attention.

"Systemic allergic reactions such as anaphylaxis [which can be fatal] may require parenteral treatment with adrenaline, corticosteroid and antihistamine as appropriate and should be followed by appropriate supportive therapy."


It says nothing about preventing adverse reactions with future doses.


By the way, Zoetis warns that the vaccine should not be used in horses who are sick or immunocompromised. That's standard language for animal vaccines. However, that “fine print" often gets overlooked. So, too, does the fact that the potential for interaction with other vaccines and medications is unknown.


It's worth bearing in mind that the HeV vaccine is still a relatively new vaccine, in relatively limited use (only 10–13% of horses in QLD and NSW, according to one report, and less than 10% nationwide). There's still a lot more data to collect and objectively evaluate.


Vaccine components


Now to the nuts and bolts of the vaccine itself.


The Zoetis HeV vaccine is of a type called a subunit vaccine. It does not contain any live virus, nor even any whole virus, alive or dead.


Soluble G glycoprotein


The HeV vaccine contains a surface protein, called the G glycoprotein or simply G protein, that HeV (and the closely related Nipah virus) uses to attach to the horse's cells — a necessary first step in gaining entry to the cell. This particular component of the virus, and its synthetic counterpart (the 'soluble G protein' in the HeV vaccine), appears to be highly effective at eliciting a protective immune response without much risk.


In the vaccine challenge study, even half the dose used in the commercial vaccine (which contains 100 micrograms of G protein) was protective in the 3 horses in which the lower dose (50 micrograms) was studied.


However, the HeV vaccine also contains one or more proprietary adjuvants (substances designed to "goose" the immune response to the G protein, which Zoetis calls "immunostimulating complex") and thiomersal (thimerosal). That last one first...


Thiomersal


Thiomersal, also known as thimerosal (Zoetis uses both spellings in its various documents), is a mercury-containing substance that is added to many vaccines as a preservative. It's a controversial addition because mercury is a potentially toxic heavy metal that accumulates in the body with repeated exposure. Thiomersal/thimerosal is also a potential allergen.


In the United States and the European Union, thimerosal is no longer used in vaccines intended for use in children.


Adjuvants


Zoetis hides their specific adjuvant formulation behind the word "proprietary," but a 2016 review article of Hendra and Nipah virus vaccine development might have let the cat out of the bag. In describing the development of a HeV soluble G protein subunit vaccine, the authors discussed the use of two adjuvants: Alhydrogel™ (aluminium hydroxide gel) and CpG. Both are used in vaccines to stimulate specific components of the animal's immune response.


Aluminium hydroxide boosts the antibody-mediated immune response to the core vaccine component. However, aluminium is another metal not known to have any physiological function in mammals yet with potentially toxic effects in large amounts.


CpG (Cytosine and Guanine triphospate deoxynucleotides with a phosphodiester link) is a short, single-stranded, synthetic DNA molecule that is used in vaccines as an immunostimulant. Specifically, it mimics the presence of pathogens (disease-causing microbes) such as viruses. Its 'pathogen-associated molecular pattern' is recognised by a couple of different types of immune cells (B lymphocytes and dendritic cells) that have specific roles in a targeted immune response to invaders such as viruses.


We don't know the exact formulation of the proprietary adjuvant used in the HeV vaccine; the company simply identifies it as "Immune Stimulating Complex" in APVMA documents.


If present, either of these substances may be responsible for the adverse effects that occur after vaccine administration in some horses, because either can result in an exaggerated inflammatory or allergic response to the vaccine.


Note that an exaggerated inflammatory response is also at the heart of severe illness and death in fatal HeV infections.


We have long needed more research into vaccine-associated illness and individual susceptibility to vaccine reactions in animals. These issues are such a problem in cats, for example, that adjuvant-free vaccines have been developed for use in dogs and cats. In this regard, equine vaccine research and development is way behind, and we urgently need to catch up.


Minimising vaccine reactions


Typically, vets manage horses who have had vaccine reactions in the past by pre-treating them with an anti-inflammatory drug (usually an antihistamine or nonsteroidal anti-inflammatory drug) at their next booster. Usually, that is an effective approach when the horse simply must be vaccinated for whatever reason.


However, a reasonable alternative with HeV is to weigh the risk of exposure/infection against the risk of a potentially severe vaccine reaction, and, if appropriate, use avoidance measures to manage the horse's risk of infection instead.


Cell-mediated immunity can last a lifetime, and it's an under-appreciated aspect of both naturally-acquired and vaccine-induced immunity.


The point of booster vaccination is to maintain a protective level of the specific antibody in the bloodstream, particularly during periods of high risk. However, low or even undetectable amounts of HeV antibody in the horse's blood do not necessarily mean that the horse is unprotected.


If the horse has ever encountered HeV or its G protein (i.e., HeV vaccine) in the past, it will have some immunological memory which can be activated to ramp up HeV antibody production when the horse is next exposed to HeV.


The issue then is one of 'dose' (i.e., how many viral particles has the horse inhaled or swallowed): can the horse make enough virus-neutralising antibodies in time to block the exponential growth of HeV in the body? And can the rest of the horse's arsenal of immune responses deal with the virus in the meantime?


Here is where avoidance measures support the horse's innate and adaptive immune response to help protect the horse from the severest consequences of viral exposure.


And as I mentioned earlier, I speculate in a separate article that ivermectin may be a useful antiviral agent in horses exposed to HeV, as this virus is one of the many that are inhibited by ivermectin in the laboratory.


Until we know who is most susceptible to vaccine reactions and why, every horse is potentially at the same risk (of vaccine reaction). Even though that risk may be low, it's not zero. Knowing how your horse responds to other vaccines (e.g., tetanus, strangles) and to other invaders such as biting insects may provide a clue as to the likelihood of your horse having a potentially severe reaction to the HeV vaccine.


A Nipah virus vaccine, containing the HeV soluble glycoprotein adjuvanted with aluminium hydroxide (sound familiar?), is currently in human phase I clinical trials in the US. This study examines the safety and 'immunogenicity' (elicited immune response) of various dosages in adults. The vaccine is trademarked already as HenipaVax (Auro Vaccines LLC). The study was expected to be completed in October 2021, although no data have been published yet (May 2022).


A recently completed study of a HeV-specific antibody product in 40 healthy volunteers showed it to be safe for use in the treatment of HeV infection in humans. In fact, it has already been used in at least 13 people in Queensland since its development in 2010.


The argument that we must vaccinate horses to protect humans is losing ground by the day.



Read on...


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

Last updated 29 May 2022.


back

to article main page