In a perfect world, every vaccination would result in proper immunization, immune stimulation and disease protection, regardless of the status of an animal's age, immune competency, nutrition, health or stress level. Of course, the vaccine would also have to withstand any heat, cold, freezing, thawing, poor reconstitution and contamination.
In light of the fact that this perfect situation isn't likely to happen in the foreseeable future, it's important to understand why vaccines fail so that we can manage controllable factors and use them in a more strategic manner.
Vaccines stimulate immune responses, so that seems to be the logical place to start. At the time of vaccination, the immune response will be influenced by the other things going on in that animal's life. "When we do vaccination-challenge experiments that the USDA requires, we buy very clean animals and keep them under ideal conditions, make sure they have no parasites, vaccinate and then challenge them to show what the vaccine will do under those conditions," explains Jim Roth, DVM, PhD, Iowa State University. "In the real world, animals might already have a concurrent infection, be parasitized or have all kinds of complicating factors. You can't test every vaccine under those conditions. But those situations can alter the response to the vaccine."
For example, parasitism stimulates a T-helper-2 response. If a parasitized animal is given the same vaccine as an animal that is not parasitized, the parasitized animal is probably going to end up producing more of a T-helper-2 response and less of a desirable T-helper-1 response. "That might be why BRSV vaccines sometimes end up leading to allergies -- an allergy to the BRSV rather than protection," says Roth. "We have to remember our vaccination-challenge studies required by USDA are artificial. If we raised all of our cattle like we do in vaccination-challenge studies, we probably wouldn't have respiratory disease. The vaccination response is complicated by many different management factors."
Nutrition and stress
|Energy and protein synthesis are critical for immune function; if the ration doesn't provide adequate protein and energy, immunity will suffer.|
Poor nutrition, sickness and stress situations are a drain on the immune system, yet we try to vaccinate our way out of problems during stressful times and then wonder why they don't always work. The easiest thing to do is to point to the vaccine.
"It's a fascinating situation because the vaccines we call ‘commodities" are now distinguished as the factor that caused the problem," says Breck Hunsaker, DVM, PhD, Horton Research, Wellington, Colo. "It's a threshold situation. We beat these cattle up nutritionally, pump diesel fumes into them for 24 hours, hold them off feed and water while they're in the marketing channels and commingle them. We do these things but say the vaccine fails. I have a hard time with that concept. I think all of these risk factors contribute to the perceived failure. It warrants a deeper and more thorough investigation and a lot of opportunity for education of our clients."
John Ellis, DVM, PhD, University of Saskatchewan, agrees. "How dumb are we? Why are we vaccinating animals under highly stressed situations? Poultry is ahead in that aspect, and swine is getting there. But because the cattle industry is structured as it is, we're not there." Ellis would like to see aerosol delivery of vaccine, such as fogging a truckload of calves as immune system priming, and "you probably don't need to worry about much after that."
Preconditioning is an example of a sometimes controversial topic. "The challenge we have in the beef industry is showing the economic advantage of preconditioning because it's confounded by so many other things," notes Hunsaker. "It's confounded by management and genetics, and then if we precondition on top of that, we can show a benefit. But if our management is suboptimal from an immunologic perspective, we don't benefit, so some will say preconditioning doesn't work. We need sound management to establish the groundwork to allow preconditioning to provide that benefit. So, we still try to figure out how to make this work in spite of suboptimal management."
Nutrition is the foundation of all health, and when we immunize animals, we need to have them on an appropriate plane of nutrition, adds Mark Hardesty, DVM, Maria Stein Animal Clinic, Maria Stein, Ohio. "You'd think that on a high-producing dairy, that wouldn't be an issue, but it is," he says. "The ration is correct on paper, but there certainly could be individuals suffering from acidosis -- individuals that, because of our feed-bunk management, aren't getting the intake. We need the protein and the energy for immunity to occur. All of the immunity we're talking about is made of proteins, and we need the protein synthesis."
How we use vaccines can be another problem. Vaccines are licensed one at a time. If it's a five-way viral vaccine, for instance, it's licensed for that use alone. If it's a bacterial vaccine with an adjuvant, it should work when used alone. "In the real world, we give two or three or four vaccines at the same time," explains Roth. "They have the potential to conflict with each other. I haven't seen a lot of proof that that occurs, but the dogma would say it's true. If one vaccine needs to stimulate a T-helper-1 response and the other needs to stimulate a T-helper-2 response, the immune system has trouble doing both at the same time. You can't test every vaccine in combination with every other vaccine in all the different life experiences cattle have. We have to do experiments on one vaccine at a time to get the USDA license, but keep in mind you can get interference with vaccines that aren't licensed to be used together."
Roth's advice to veterinary students is that if they have a particular disease problem in an animal -- of any species -- focus the vaccination on that specific disease problem. "When there's nothing else bad going on in that animal's life, go ahead and give the other vaccines. If you put all your vaccines in at once, you might get a suboptimal response to the disease currently causing the most trouble."
Some people are leery of vaccines because they can cause immune suppression and depression. "Through the new technologies -- genetic engineering, recombinant vaccines -- it should be possible to produce a vaccine that gives you the efficacy of a modified-live vaccine but doesn't have the immune suppression," says Roth.
Hunsaker collaborated on research done at the University of Nebraska where they looked for systemic replication of the vaccine virus in lymphoid tissue in vaccinated animals. They found some but less than in unvaccinated controls, and the vaccinated animals were protected when they were challenged later. When vaccinated, some suppression in lymphocyte numbers were observed, but not to the extent of calling it a classic lymphopenia. "We looked at the range between 4,000 and 12,000, and we had about 6,000 per mL," recalls Hunsaker. "We do see some mild transient suppression of lymphocyte numbers. We have replication in the lymphoid tissues, but it may not be clinically immunosuppressive where they are more susceptible to other agents."
Roth explains that most of the time animals won't be "on the edge" when being vaccinated, and that a small decrease in immunity is not a problem, However, "if you have a group that is on the edge, it can tip them over."
And what can put them on the edge is concurrent disease at the time of vaccination. Hardesty sees fewer vaccine breaks and failures than he used to, but when he does, he commonly finds concurrent disease situations, such as Salmonella or acidosis, that may interfere with proper immunization. "We see more breaks with groups of cattle or calves that we get in that come with unknown histories."
For example, a warmer-than-usual and wet January was not a good time for calves to come in, but they came in anyway, says Hardesty, and they came in coughing. "They should have been vaccinated two weeks earlier, but we don't know if they were."
Hardesty likes to vaccinate on arrival, but because the calves were coughing, he put it off for a week. The calves were medicated and evaluated, and vaccination was put off for another week. "When do you pull the plug?" Hardesty asks. "These calves needed to be vaccinated or they would be breaking over the next three months. So you vaccinate, and that can be enough of a stressor that you have to medicate a lot more of them. It's always a challenge and it's always related to environment and nutrition. I don't necessarily think it's the products we use."
Chris Chase, DVM, PhD, South Dakota State University, adds that vaccination problems he has seen, particularly at weaning time, involve the presence of persistently infected BVDV animals. Hardesty agrees and says typically there is a problem pen with a PI BVDV animal, Salmonella or both.
Some calf raisers are vaccinating newborn calves weekly to get ahead of the disease problem, but the immunologists aren't sure that's the best thing to do. "There's a maturation process involved with the immune system," says Chase. "You vaccinate and then you revaccinate and everything is in disarray."
Another thing that can happen with frequent young-calf vaccination, says Chase, is the animal can be tolerized because it's exposed over and over. "Now the response is worse because the calf's immune system doesn't recognize vaccine antigens as foreign," he explains. "There's no way you can get a good response with vaccine every week. Cells grow and proliferate, but they also go through apoptosis. The system has to mature, so it gets to a point where it shuts itself off and doesn't get a chance to mature. When you use the same antigen, particularly if it's viral, it just doesn't make any sense to keep going over and over it again."
Ellis isn't sure that frequent vac-cination of a young calf will necessarily cause harm, but "you're certainly wasting money, at the minimum."
When the immune system responds to vaccination or disease, it causes a caloric drain. "The energy for that has to come from somewhere else, so we're looking at less milk or less beef," says Chase. He published a paper where he was able to mimic subclinical acidosis, which subsequently put the immune system into a nose dive.
"That's one of the things I always worry about in a freshening cow," says Chase. "Her metabolic systems are already on overload, and then we come along and vaccinate her." Chase believes that a high percentage of cows have subclinical acidosis after freshening. "And it's the same when you vac-cinate and vaccinate calves. That's something taken away from their growth and development."
So, what we're looking for is a balance to overcome and prevent disease, but at the same time we don't want to give so many vaccinations that it will affect the growth and development of that animal. "We still have a lot of work to do with that freshening cow," Chase says. "If we vaccinate her in 30 days, what does that do long term?"
Clostridial vaccines can cause adverse effects in cattle, but Chase says they've improved. "They were not necessarily a good thing to give in combination. Some research shows that IBR with leukotoxin reduces antibody response because IBR is immunosuppressive. Gram-negatives and clostridials given with other vaccines seem to cause more depression. Anaphylaxis is an acute allergic reaction. There are some animals that may react to antigens, but we now see less of that. Companies have done a good job of working their formulation. Typically, the anaphylaxis was due to something else that was in the vaccine -- something that was in a carrier, something you didn't know you paid for. My gut still says the Gram-negatives and the clostridials are the most problematic."
Ellis says that obviating adverse effects has to do with the efficiency of the antigen-presenting cells in the skin, the Langerhans cells. "Quite a bit of work has been done looking at reduced doses given transdermally or intradermally, down to 100 microliters or even less," he explains. "If you have something with a lot of toxins in it, like a clostridium or a Gram-negative, the obvious thing would be to use that delivery method as opposed to giving 10 times as much via a traditional route. It's simply a numbers game. Then some of these concerns about giving the vaccines together would go away."
|If you get enough pro-inflammatory cytokines induced by by vaccination, they can result in a reduced appetite and cause fever, depression and lethargy.|
WHAT IS A VACCINE SWEAT?
For some people, making vaccine decisions depends on the number of antigens put together at one time. Breck Hunsaker, DVM, PhD, has done several safety studies where feedlot cattle were vaccinated so they could look for lumps and bumps and systemic reactions. "We've found surprisingly few," says Hunsaker. "I think, in general, manufacturers are cleaning up those vaccines. They know that's a criterion for testing and approval through USDA. That becomes less of an issue as vaccines are distinguished and selected."
What is an issue, Hunsaker says, is this phenomenon called a vaccine sweat. "We see these animals back off feed," he explains. "We see them go through this post-vaccination syndrome where they seem to drop in feed intake and so on. Among practitioners and feedyard managers, there's a perception that some vaccines sweat cattle more than others. But if you go across the road, it's a different vaccine that causes the sweat than it is on your side. I'm pretty sure it's driven by perception and we don't have data that clarifies this syndrome. I'd like to see some post-vaccination-effect work done comparing some of these vaccines because I think that would be a distinguishing feature in the decision as to which vaccine to use based on the perception of sweat."
Why the sweat occurs
Vaccines have to induce pro-inflammatory cytokines in order to induce an immune response. The pro-inflammatory cytokines decrease appetite if there's a high enough concentration. They have to be produced at the site of injection and the local lymph node, or the vaccine doesn't work. But if you get enough of those cytokines produced that they start circulating in the blood and go to the brain, they reduce appetite and cause fever, depression and lethargy.
"When you have a fever, you feel lethargic and you're not hungry; that's due to pro-inflammatory cytokines," says Jim Roth, DVM, PhD. "The vaccines induce low levels of those. If you're using just one vaccine and it's been safety tested, it should be pretty minor. But if you use four or five vaccines, every one of them induces some of these cytokines."
Endotoxin induces the exact same cytokines, so if you have endotoxin in your vaccine, you're going to get more. And if the cattle already have a low-grade infection and they have some cytokines being produced, if you vaccinate and you get more cytokines, you start seeing the sweat. "So you have to consider what's happening to those animals to begin with, and what you've added and how much you've added," notes Roth.
Hunsaker agrees and believes it's a threshold situation. "That's always been my suspicion because I have not been successful in reproducing the clinical sweat in a research setting. We bring these animals in and we acclimate them for 14 days, then we vaccinate them with vaccine A. Clinically, looking across the fence, we don't see what we would call a sweat until we add all the risk factors for a sweat that Dr. Roth mentioned. You can see it in a few animals, or typically the pen looks like they've all been beaten up."
Vaccine handling contributes
As noted previously, a variety of factors are at play. Vaccine handling is one of them. Gram-negative bacterins have whole dead bacteria in them, and dead bacteria are coated with endotoxin. As long as the endotoxin stays in the bacterial membrane, it's not toxic. It's the free endotoxin that is capable of causing the sweat.
"When the manufacturer releases the vaccine, it's going to have low free endotoxin," says Roth. "But over the one-year shelf life of that vaccine, as those bacteria start breaking down, they release endotoxin. So the amount of free endotoxin when it's manufactured could be much lower than a year later, especially if it got frozen and thawed or shaken up or sat in the hot sun. The free endotoxin is a dynamic. It can increase over time and can change with the life history of that bottle of vaccine."
"The industry needs to define this perception of sweat because a lot of decisions are based on the assumption that X vaccine causes a sweat and Y doesn't, yet across the street the perception is just the opposite," says Hunsaker. "We get in fist fights over this issue."