What’s New in Equine Vaccines?

For most of us, equine vaccines seem pretty simple and boring–halter and restrain horse, pop in a needle and release contents, then a short time later the horse will be protected against that disease. But it’s a lot more complicated than that,

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For most of us, equine vaccines seem pretty simple and boring–halter and restrain horse, pop in a needle and release contents, then a short time later the horse will be protected against that disease. But it’s a lot more complicated than that, and the various factors affecting immunity and vaccination provide seemingly limitless possibilities for new technologies and ways to get vaccines into horses.

Lately we’ve heard a lot about the new vectored vaccines (such as Merial’s canarypox-vectored West Nile virus, or WNV, vaccine) and DNA vaccines (such as Fort Dodge’s, or FDAH, DNA WNV vaccine). And there are more possibilities on the way, such as transdermal vaccines (currently used in cats), subunit vaccines, orally delivered vaccines, and several ways to improve currently available vaccines. More on these in a moment.

“People are looking for alternatives to traditional approaches to get the best immunity possible,” says Robert Holland, DVM, PhD, senior technical services veterinarian at Pfizer Animal Health. “Scientists are looking at improving less effective vaccines and exploring new vaccine technologies. We’ve also learned a lot about nutrition, exercise, stress, etc., while trying to find the best way to safely boost immunity (with management techniques, not just vaccines).”

Whether a particular vaccine is new or improved, one thing is for sure: The companies that develop and manufacture vaccines aren’t making products and forgetting about them. Research to better understand the equine immune system and how to optimize it is spread across several countries and countless institutions, all with the goal of keeping more horses healthy in the face of new, old, and mutating disease challenges.

DNA Technology

Fort Dodge’s equine DNA vaccine for WNV is awaiting USDA approval and might become available in 2005, making it the first commercially available DNA vaccine for any species, including humans.

“This is a naked DNA vaccine–not recombined with anything,” says Kevin Hankins, DVM, MBA, a field veterinary consultant at FDAH. “It’s just the DNA of the virus and an adjuvant (which boosts the immune response), unlike current vectored vaccines that require a vector agent. There’s no antigen for the horse to react to, so it’s basically a reaction-free vaccine, and it also gives very rapid protection.”

Steve Chu, DVM, PhD, of Global Research and Development at FDAH, explains that when a virus’ DNA is given to an animal in a vaccine, it is taken up by the body cells to be processed into RNA. The RNA can then be translated into proteins that stimulate antibodies and white blood cell immune response, protecting the vaccinated animal from that disease.

Hankins says, “The minute the DNA starts entering cells, it starts the RNA replicating, so the protection is much more rapid than with vaccines available today. With a DNA vaccine, you can also vaccinate foals at a younger age.”

With traditional vaccines, there has always been a problem with maternal antibodies from colostrum interfering with the foal’s ability to mount an immune response to the vaccine. But naked DNA vaccination is attractive for immunizing foals because it contains no antigens for the maternal antibodies (from colostrum) to block; the maternal antibodies target proteins on the pathogen and DNA is not a protein. “This way the vaccine ‘flies under the radar’ of the maternal antibodies,” explains Hankins.

Once in the foal’s cells, the DNA directs them to make immunogens, which teach the immune system to recognize the pathogen and destroy it. Also, studies in humans and some animal species have shown that when given early in the course of disease, a DNA vaccine can act therapeutically to reduce disease signs and severity, he notes.

DNA vaccines were first presented in 1992. The FDA approved the first DNA vaccines for human trials in 1995, but none have been approved for commercial use. If FDAH’s equine WNV vaccine is approved, this will open the way for other veterinary and human uses for this technology.

DNA vaccines are also being developed to enhance cancer immunotherapy for injection into tumors (such as melanoma), activating the body’s immune system so it can recognize tumor cells. The immune response creates tumor-killing T-cells that can spread to other tumors in the body; injection into a single tumor can thus treat multiple tumors, Hankins explains.

Another DNA vaccine is being developed to fight lymphoma, he adds. This vaccine targets tumors with much more specificity than traditional killed tumor cell vaccines, and it is much cheaper to produce.

Naked DNA has an advantage over whole virus in creating a vaccine, since  DNA is more stable. DNA vaccines might not require refrigeration, and they rarely produce any adverse reactions.

DNA vaccines can be made quickly once a new virus is isolated, which is very handy when faced with a new disease outbreak or epidemic. “If a new disease appears, we can rapidly develop a vaccine just by getting the DNA from the virus and growing it in a culture,” explains Hankins. “It goes through a washing process to purify it, then an adjuvant is added, and that’s your vaccine.”

For instance, in both the WNV outbreak in North America and the SARS (severe acquired respiratory syndrome) in China, the DNA components for use in clinical testing became available four to six months after the antigen gene sequences were discovered. By contrast, traditional vaccines usually take two to three years to safely develop, Hankins notes.

The WNV equine vaccine, if approved, will be given intramuscularly in two initial doses three to four weeks apart, with an annual booster thereafter, he says. If this vaccine is approved for use in horses, a human WNV vaccine will probably be approved in the next few years.

Another DNA-based vaccine generating a lot of discussion in the equine immunology research world is Merial’s therapeutic melanoma vaccine for dogs. “Many in the equine world are interested in trying this with gray horses, so this will be clearly under experimental consideration for this important disease,” says Bob Nordgren, PhD, head of research, development, and technology acquisitions at Merial.

Vectored Vaccines

“Vectored vaccines are another hot area,” says David Horohov, PhD, William Robert Mills Chair of Equine Infectious Diseases at the University of Kentucky’s Gluck Equine Research Center. With a vectored vaccine, a specific piece of DNA from the pathogen against which you want immunity is carried into the animal’s cells by a carrier or vector that does not cause disease itself.

Along with the canarypox-vectored WNV vaccine (Recombitek) Merial already markets, Merial also has a canarypox-vectored influenza vaccine based on the same technology in use in Europe. This product is in field testing for U.S. approval, says Nordgren. At the field testing stage of the approval process, he says, a product is usually about six months away from approval.

“We have wonderful data with this product in Europe, with a publication (The Veterinary Record, 156 (12)) reporting short-onset protection with a single shot application and a one-year duration of immunity with three shots, with broad-spectrum protection against strains that have broken through conventional products,” says Jules Minke, DVM, PhD, Project Leader Biologicals at Merial.

New Delivery Methods

Transdermal (through/into the skin)–“There is lots of potential for immunity via skin; the potential for generating response there is very exciting,” says Horohov. “Any kind of IM immunization is painful, there’s no getting around that. You’re introducing things into the muscle body, where there is damage, inflammation, pain, and soreness due just to the method. Transdermal delivery avoids this issue.”

Merial is currently marketing a transdermal vaccine against feline leukemia, which is delivered with their Vet Jet system. The device pushes liquid medication through small punctures in the skin that are about the diameter of a human hair.

“We’re really excited about how transdermal vaccines are working in companion animals, although horse applications are currently in the research stages,” says Nordgren. “One thing we’ve found is extraordinarily important with transdermal vaccines is adjusting the application for each species. We’re trying to derive optimal immune response for the host and antigen in question, limit dose volume, and improve safety.”

Intradermal administration puts the antigen where the dendritic cells are, which Nordgren says are “what everyone has decided are the key immune cells, and they’re really rich in the intradermal space. They orchestrate the whole immune response, initiating the appropriate immune cascade (to best combat a particular pathogen, which might be a cell-mediated or antibody response, etc.)

“We have nothing pending approval now, but it certainly holds great promise, particularly for DNA-based vaccines,” he says.

Oral delivery–“One of the things that’s always interesting to me is that in humans, there has been great interest in orals to avoid sticking small children. But veterinary medicine is just the opposite–it’s easier to just stick an animal than to get him to swallow it!” notes Horohov. “The problem with oral vaccines is this–are you sure they got enough? Did they swallow or spit it out?

“I think for some (vaccine) applications, oral would be the best delivery method, such as for Salmonella or other intestinal parasites,” he adds. “There’s lots of interest in using attenuated Salmonella as a vector, including in the horse. The thing about it is that it’s an invasive organism in the intestinal tract, which could be very useful (to gain access to the bloodstream). But you’d have to use strains that aren’t as pathogenic (disease-causing); then they might not be as effective (at stimulating an immune response).

“There’s a real possibility of orals with horses and other species in the future; viral/bacterial/yeast-mediated delivery are all possibilities,” he adds.

Subunit Vaccines

Subunit vaccines are those including only a part of the pathogen being vaccinated against, such as a particular protein or group of proteins. Subunit vaccines are being researched for several pathogens, particularly against those for which serologic testing can be confounding (such as equine infectious anemia, EIA, or equine protozoal myeloencephalitis), says Horohov.

“The question has always been ‘How do you vaccinate populations when that could make them positive on serologic testing?’ This is what you’re trying to avoid,” he explains. “Can one derive a subunit type vaccine to differentiate horses that are infected from those that are vaccinated?”

The difference between the naturally encountered pathogen and the version in the vaccine might just be a single protein. This could be deleting a protein, changing it, or adding one for marker purposes.

“This is primarily of interest for surveillance purposes or if someone buys a horse (without knowing his history) and wants to know if he’s been exposed or vaccinated,” Horohov says. “Over the years, the most interest has been with EIA. African horse sickness was another one that generated a lot of interest in Europe at one time.”

Genes to Maximize Response

We’re always looking for ways to help vaccines boost a horse’s immune system. One approach that could possibly help horses (and is currently being researched in mice and cattle) is adding cytokine genes to vaccines to increase the body’s production of natural immunostimulants.

“You use a cytokine gene to push the immune system in the direction you want it to go,” explains Horohov. “It’s sort of like a fancy adjuvant, which boosts all over response; this is more like a specific adjuvant (to stimulate a particular part of the immune system, such as antibodies only if that is the most effective action against the pathogen in question, or cell-mediated immunity only).

“This is still very much in the research stage,” he adds. “On paper, it looks like it should work, but reality is often a far different thing.”

Improving Current Vaccines

Often we think that when a vaccine lands on the shelf, the company that produced it is done with it, but that’s not the case–constant improvement of vaccine products is more a rule than an exception. The goals of improving a vaccine include better immune response, more relevant strains, and fewer adverse reactions.

“The companies don’t get enough credit–they continue to monitor and modify vaccines and work with people like me to see what can be done to make them even better,” opines Horohov. “These are costly things to do, and it’s an ongoing effort. This is why we have better vaccines than we did 10-15 years ago. They’re still working to improve their products, and that’s important. (Improving modified live vaccines) is probably our most active area (of immunology at Gluck and elsewhere) right now.”

What is involved in improving a vaccine? “We’re looking at modifying vaccines by mixing new strains in or using things that are modified in different ways,” he explains. “The big problem is that it’s a lot like Goldilocks and the three bears–it can’t be too hot or cold, but just right. That’s the trick with modified lives, that they do what you want them to do without the disadvantages of real infection.” The pathogen in the vaccine must be robust enough to replicate in the animal and thus stimulate the immune system to act against it, but weak enough that it doesn’t make the animal sick.

Traditionally, Horohov explains, a modified live vaccine is created by culturing the virus in the lab under various conditions and testing what survives. “When you do that a number of times and the virus mutates, you’re selecting for viruses that grow well in culture,” Horohov explains. “They often don’t do quite as well going back into the natural host. It’s more of an art than science approach, because it’s really difficult to know what modifications were made (throughout the packaging and mutation process).

“What we’d like to do is look at the pathogen and know what proteins are involved in pathogenesis (disease-causing ability), so we can limit pathogenesis, but still stimulate full immunity,” he says. “Ultimately what it comes down to is genetic mapping of an agent to determine where the susceptible genes are to lead to a less pathogenic organism.”

Another approach is to adapt the pathogen to a different environment. An example that is already in use in horses, and might have future uses, is cold-adapted pathogens (Flu-Avert by Intervet is one). These are well suited for respiratory applications, in which a pathogen might be adapted so it can’t survive in normal equine body temperatures, but can live and replicate in the slightly cooler environment of the upper respiratory tract. Thus, it stimulates local immunity in the respiratory tract–the first line of defense for these pathogens–without causing disease elsewhere in the body.

“For something like WNV, this has no use, because (WNV) is injected in or near the bloodstream (where it would enter the body with natural infection from a mosquito bite) where it will be at the core body temperature,” says Horohov. “It wouldn’t replicate at all, and would be essentially inactivated–then it wouldn’t stimulate good immunity. I think, for the most part, cold-adapted pathogens will always be developed with an eye towards respiratory applications. An interesting one might be equine herpesvirus; since EHV is typically spread as a respiratory disease, (an effective cold-adapted vaccine) would be a very attractive vaccine indeed.”


Take-Home Message

With so many available and upcoming options available to maximize immunity, we can expect tomorrow’s horses to have better protection against disease than many might have thought possible. New and mutating pathogens will continue to attack, but vaccine manufacturers and researchers are meeting the challenge

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