David Horohov, PhD, chair of the University of Kentucky Department of Veterinary Science, director of the Gluck Equine Research Center and Jes E. and Clementine M. Schlaikjer Chair, gave a talk on vaccination, immunity and immune responses in weanlings at the third session of UK’s annual Equine Research Showcase Feb. 2. Presenting sponsors for the event included BET, Kentucky Performance Products, McCauley’s, Merck, Rood & Riddle Equine Hospital and Tribute Equine Nutrition.
In his talk, Horohov discussed immune responses and their components (antibodies and cellular immunity), types of vaccines administered to horses such as killed, live or vectored/plasmid types and overall factors affecting vaccine responses in these animals.
The Immune System
He first provided background on the immune system, explaining that when we discuss immunity, we generally are discussing responses that are by the immune system.
“One that we’re all familiar with is the production of antibodies by a particular subset of white blood cells and lymphocytes called B cells. These B cells secrete the antibodies that play a major role in protection against a number of infectious and even non-infectious agents, parasitic agents as well. These antibodies can bind to, neutralize, capture and facilitate the removal of various pathogenic organisms from circulation, and so in general they are considered to be the front-line defense of the immune system,” Horohov said.
According to Horohov, this also includes the role of cell mediated immunity, often referred to killer T cells or cytotoxic T cells, another subset of white blood cells. These cells have the capacity to kill virus-infected cells or cells that may be harboring an intercellular bacterium (such as Lawsonia or Rhodococcus equi). They can also kill tumor cells.
He said the other, less talked about portion of the immune response is the helper T cell, the cells that produce various cellular proteins called cytokines and these various cytokines help B cells grow up to become antibodies producing plasma cells. They also help killer T cells develop their cytotoxic activity.
“The cell mediated immunity aspect of the response to an infectious agent or vaccine has to include all three of these components in order for it to be effective. But getting to these steps is actually a fairly difficult process and involves a number of steps,” Horohov said.
Three Stages of Immune Response
Horohov broke down the three stages of the immune response. First is the initial recognition, second the immune expansion and third the effector function, which is where antibodies and cell-mediated immunity come into action.
According to Horohov, there is initially a recognition component that has to occur. This is where an infectious agent or pathogen comes into contact with the body and antigen presenting cells send signals to the rest of the body’s cells that there is something in the body. This is done by passing small parts of the virus across the surface so the other cells will be able to recognize the virus when it makes contact.
“As a result of that recognition, the cells that identify that particular antigen, as we call it at that point, will actually undergo a proliferation or a division so that you’ll start out with initially only a few cells that recognize that specific agent but after many rounds of replication, you could end up with hundreds or thousands of cells that recognize it. Not surprisingly, that replication of those cells is driven by a cytokine that’s produced by T helper cells, called interleukin 2,” Horohov said.
It takes about a week or two for the whole response to occur. Yet with a re-exposure, the memory T cells are able to have a response within a few short days. The key point is that there are several steps along the way to generate the two processes in the immune system, the antibody immunity and cellular immunity. Depending on what is being produced, it is possible to have more of an antibody response versus a cell mediated immunity response. Horohov explained that this is particularly important when you vaccinate an animal.
“The general rule of thumb is that vaccines should stimulate protective immune responses, both antibody and cellular, in the absence of disease. And indeed for the horse, we have a large number of vaccines that are currently available, and many of them are good at inducing protective immunity in the absence of any subsequent disease,” Horohov said.
Live, killed or vector?
The conventional vaccines that we are most familiar with often fall into the broad categories of being an inactivated vaccine or modified live vaccine. Inactive vaccines, one in which the agent itself, whether that be a virus or bacteria, has been killed or inactivated in some manner so that it is incapable of causing infection, but still can cause the induction of an immune response. By contrast, the modified live vaccine is a vaccine that has a live or infectious component to it. The agent has been selected in such a way though that it does not cause disease but is still capable of stimulating an immune response.
Horohov then referenced an article by J.M. Minke, relaying that in 2004-2005 they discussed a second generation of vaccines different from others, referred to as plasmid or vector mediated vaccines. This means that instead of the whole virus being present, it has selected genes or particular pieces of DNA from that agent to stimulate an immune response. This was done with the West Nile Virus (WNV) vaccine.
“I like to tell people that while we are all excited that we have a COVID vaccine that uses messenger RNA and its one of the first of the nucleic acid base vaccines to be used in humans, horses actually beat them by about 10 years in terms of an effective vaccine using a nucleic acid,” Horohov said.
Each one of these vaccine types has its advantages and disadvantages, Horohov said. Inactivated vaccines, which tend to be the most common, while good at stimulating immune responses, those responses are primarily an antibody response. They are less effective in general when it comes to stimulating cell mediated immunity. Advances in technology have increased the ability to do this, but compared to modified live vaccines and vector vaccines, they are overall less effective when looking for that cell mediated response. The protection with these also tends to be short term, and because of the fact this is a killed agent, they also tend to be strain specific. If that strain changes, it means the vaccine must be reformulated.
“Modified live vaccines are at a greater advantage because they effectively induce antibody and cell mediated immunity, and because they mimic the natural process, they enable a response more consistent with the natural process. These vaccines tend to have longer term protection and are also cross reactive, so slight variations that may occur as a result of virus mutations can actually be covered by the broader cross reactivity. The concern with these vaccines is always that because they are live and susceptible to mutations, they could revert to virulence,” Horohov said.
Vector vaccines, Horohov said, are kind of the best of both worlds. They’re capable of inducing both potent antibody as well as cell mediated immune responses. It’s thought that they offer longer term protection, more akin to what you see with the live vaccine. Though there isn’t enough data to fully confirm that, research is appearing to show that to be true. They also tend to be very specific since they are evolved from exact antigens related to the pathogen that is being protected against. That is both good and bad. It reduces some of the cross reactivities that may not be wanted, but if the virus mutates, it is also possible to lose effectiveness.
“Most important of all is that they are very difficult to generate. Indeed, part of the excitement now about the COVID vaccine is that it was done so quickly; it was quite the accomplishment actually,” Horohov said.
Genetics and Other Factors
There are several factors that come into play on how the vaccine actually affects the horse. The vaccine may work well for one, but not well for another, and that can be due to a wide variety of things.
“One we always talk about is genetics. Indeed there are genes that regulate the immune response itself, they regulate the production of the various factors that are needed, regulate the behavior of the cells themselves, so certainly there could be genetic differences,” Horohov said.
Genetics play an evident role in vaccine effectiveness because they are seen easily in responsiveness to vaccinations between species. This likely results from the differences (polymorphisms) in immune-related genes. The question that arises is which genes in particular?
“Well right now we are only just beginning to get a grasp on which particular genes are involved and some of the DNA technology that has been developed over the past 10 years or so that has been used to identify which particular genes play a role in regulating specific immune responses,” Horohov said.
While it may be possible to identify these genes, Horohov poses the question of “What could you do with this information?” Topics discussed in the past have been more frequent vaccinations, improving vaccines as a whole or different vaccine, and some go as far as creating personalized vaccines.
“These things sounded fairly farfetched a couple years ago are now a real possibility due to advances we are seeing,” Horohov said.
Other, factors can also come into play when discussing vaccine responses.
“We also know that there are other external factors such as stress that play a role. Particularly, when we talk about weanlings and when we start vaccinating them, this is an important factor to consider,” Horohov said.
Stress doesn’t have to be dramatic to an extent, Horohov explained. Types of stress that occur can be physical, social and nutritional.
“Well, if you think about all three of these things, that’s exactly what happens when you wean these little guys. You’re subjecting them to a physical trauma, subjecting them to a social stress because they are being moved away from their moms into crowds of other youth and individuals they may not recognize, and of course there’s a nutritional change that’s occurring at the same time. It’s no surprise we’re probably seeing stress in our animals,” Horohov said.
The consequence of those stressors is the reduction in immune function. It can also increase the susceptibility of infection. Importantly, it decreases responsiveness to vaccines.
A study done a couple of years ago by Amanda Adams, PhD, MARSTM Equestrian Fellow and associate professor at the Gluck Equine Research Center, then in Horohov’s laboratory, investigated weaning effects on the CMI (cell mediated immunity) response in foals. Her research found that weaning did reduce the CMI response, and the immunomodulating treatment used showed no effect in the horses studied.
The third and final factor affecting immune responses in these horses is age. Age is known to be a factor because of the varying responses received from weanlings and adult horses, and the timeframes to vaccinate both of them. A study undertaken on giving vaccines to foals versus weanlings showed that regardless the type of vaccination, there was no effect on the foals. Horohov said he thinks this has to do with the fact the fact that the foal’s initial antibody is provided by the mare.
Because of the nature of the equine placenta, no maternal antibody is transferred to the foal in utero. But after birth, colostrum in the milk provides the foal with maternal antibodies that confer production against various infectious agents. These maternal antibodies decay within four months, leaving the foals susceptible to infection. If the foals are vaccinated during this period of time, a situation known as maternal interference can occur.
“Maternal interference is defined as the suppressive effect of passively transferred maternal antibodies on the production of protective antibodies by the neonate in response to vaccination. This is the reason why when you look at the AAEP recommendations for foal vaccination, you see quite specifically that there are two sets of recommendations they give you. One, if the foals are from mares that are vaccinated, there is a timing recommendation that says the foal’s first dose should be at around 5-6 months of age. However, if the foal is from an unvaccinated mare, they recommend giving the first dose as soon as possible and then a booster,” Horohov said.
Take-home message
“Vaccination remains a cost-effective method to prevent infectious diseases. Multiple vaccines are available which each have advantages and limitations and host factors can affect vaccine performance and adverse reactions as well, reasons for that are due to genetics, stress and age,” Horohov said.
~ reprinted with permission, UK College of Ag, Food & Environment
