Making sure newborn calves get colostrum and passive transfer of immunity from their dams has become somewhat of a “duh” moment -- we all know that’s the first, best way to protect a calf from disease. But what has still been unclear is just how that passive immunity relates to early and later disease challenge, and how those maternal antibodies react to early vaccine exposure.
Cytokines are key
We all know that good-quality colostrum is rich in antibodies, but advances in humoral and cell-mediated immunity (CMI) research has further shown the importance of other factors. “Research has shown on the order of 105 per mL of immunologically important cells are in colostrum,” says Breck Hunsaker, DVM, PhD, Horton Research, Wellington, Colo. “Those are comprised of both non-specific macrophages and neutrophils that would provide some protection initially. There are also some antigen-specific cells there that probably are more important in seeding than in providing actual protection, but that has not been explored enough. We focus on antibody because we have the ability to do so and it’s relatively simple compared to looking at cellular mechanisms and the assays that assess those mechanisms.”
Another important factor in colostrum are cytokines such as interleukin 1 & 6, interferon and tumor necrosis factor. Cytokines regulate the duration and intensity of the immune response, are responsible for cell-to-cell communication, and boost T-cell activity and the production of immunoglobulins.
“Some cytokines activate innate immune cells, such as phagocytes and natural killer cells, and stimulate their participation in inflammatory processes, whereas others suppress or resolve inflammation,” says Jim Roth, DVM, PhD, Iowa State University. “Several promote the activation of antibody production by B-cells, as well as antibody class switching of B-cells. Certain cytokines have effects further upstream in the ontogeny of cells, in that they direct the maturation and mobilization of distinct classes of cells.”
Cytokines in colostrum are crucial. “Very high levels of various cytokines have been demonstrated in the colostrum as compared to the levels in milk, so getting that colostrum into the calf has more benefit than just antibody,” adds Roth.
Christopher Chase, DVM, PhD, South Dakota State University, says there are some data indicating a surface stimulus that is important in colostrum. “The data shows the organization of lymphoid tissues, particularly on the mucosal surfaces,” he says. “It helps the immune system become more
organized and helps those cells to differentiate so that the calf will be ready to respond to antigen.”
So why don’t we just create products that will increase the amount of cytokines in colostrum? Roth thinks a better avenue would be to just avoid destroying what’s already there. “I think the cow has evolved to deliver the optimal amount already, and putting in more cytokines could have side effects,” he explains. “The thing we can avoid doing is destroying the cytokines already available. If the calf suckles from its mother when it’s supposed to, it’s going to get a good charge of cytokines.”
Roth notes that freezing colostrum doesn’t hurt antibody titers, but he’s not sure what it does to cytokines. “Freezing probably preserves the cytokines; thawing it out in a microwave probably cooks them. We have to be careful how we handle that colostrum because it isn’t just antibodies we are concerned with.”
Treat them like puppies?
The models of immunity in older animals aren’t so difficult to comprehend -- introduce an antigen and the immune system responds with antibodies and cell-mediated immunity. But introduce those same antigens to young calves, and a complex interaction with maternal antibodies may be taking place that we don’t fully understand.
The transition from colostral immunity to active immunity in the calf is extremely important. “Colostral immunity is very important to protect the neonate, but it also inhibits vaccination response, especially antibody production,” says Roth. “What do veterinarians recommend for puppies and kittens? They recommend vaccination at 6 weeks of age and then every three weeks until they are 12 to 15 weeks old, ensuring a smooth transition from maternal immunity to active immunity.” That way, whenever that titer is low enough, the vaccine will kick in.
“But what do we do in food animals?” Roth continues. “We vaccinate the young animals whenever it’s convenient and we can get a hold of them. We vaccinate them once and expect them to be protected. I think there are conditions where we should vaccinate calves and foals and pigs like we do puppies and kittens. Maybe that’s every three weeks, starting at 6 or 8 weeks of age, to get good, solid immunity. This could be especially useful in veal calves if you are not getting adequate protection from a single dose of vaccine.” However, Roth adds, in the cow-calf world if you suggest producers round up animals every three weeks, they’ll just laugh. “But it’s the same immune system that cats and dogs have. The biology is the same, and veterinarians give two different recommendations. It’s our management schemes that don’t allow it.”
John Ellis, DVM, PhD, University of Saskatchewan, thinks it’s a two-part process. One part would be to make sure we have good passive immunity by vaccinating dams. “Look at the way nature has designed the system,” he says. “Most of the infections in human and veterinary medicine are endemic at some level; they haven’t gone away. So young animals are protected passively and then they’re exposed at a very young age and they’re primed very effectively.”
Ellis has seen this happen in BRSV trials. “If an animal is primed mucosally while it has maternal antibodies, it might be seronegative three or four months down the line. You can’t make them sick because they’ve had such effective priming. It’s amazing to me that we haven’t stepped back and looked at nature’s plan rather than upping the antigen load for young animals. We’re fighting against maternal antibodies rather than working with them.”
Calf vaccination strategies
The idea of vaccinating at branding time is perceived by many producers to be futile, says Hunsaker. It doesn’t get done because it is thought that maternal immunity will just neutralize the vaccine. “But while a disease such as BRSV suppresses antibody response, it does not suppress memory response,” he notes. “Those animals are still protected as they’re challenged later in life. Surveys by Wittum and Perino estimated 25% failure of passive transfer in beef cattle herds. It’s probably higher than that in the dairy industry. Those animals would benefit from active immunity. That’s a different viewpoint from what we’ve seen in the past.”
There are still some unknowns about how vaccines work in the face of maternal antibody. “We know that natural exposure can break through and stimulate cell-mediated immunity without antibody production,” says Roth. “But the vaccines are attenuated. Virulent virus can probably break through a relatively high titer, and the modified-live viruses can probably break through a lower titer. At what age do calves reach the point where a modified-live virus will break through maternal antibody? We don’t know, because it will be highly variable between animals depending on their titer.”
Chase believes once calves are past 17 days of age, they should respond to whatever you give them, other than maternal interference.
Ellis thinks it’s a matter of maturity and amount of response rather than if response occurs or not. “One thing that does happen, particularly in ruminants, is they have this high proportion of gamma-delta T-cells. We don’t really know what they do. There are very high levels in young calves, so that could contribute to the young calf not responding well to acquired immunity -- because he has such a high level of these T-cells that don’t behave the way the other T-cells behave. That changes as the animal ages.”
In any population of calves, there will be a bell-shaped curve of passive transfer. “Animals are going to be all over the place in terms of passive immunity, and at times, you’re not going to get the optimal onset of immunity because of that,” states Ellis. “If you started vaccinating at 2 or 3 weeks of age and continued at every two or three weeks, then you’d be hitting certain animals within the population.”
Knowing what to vaccinate for at an early age is also important. “Are we seeing bacterial pneumonias or is it something viral?” says Chase. “It’s very unusual to see IBR or respiratory BVD in young calves. So even if you didn’t have passive transfer, it doesn’t make sense to come back with those four-way virals. I’d rather wait and give it to them a little bit later when they can handle it better. Sometimes, clostridial disease might be what you’re really dealing with. In younger calves, we’re more likely to see GI problems than respiratory problems.”
Chase recommends choosing the pathogen that is giving the calves the most trouble at that time for that age group. “You know that virus is immuno-suppressive just because of its nature, so that’s something I’d want to vaccinate for early. You figure out your problems and try to sequence the administration of your vaccines to attack the specific problems.”
Portions of this article were from a CMI roundtable sponsored by Intervet
CMI: WHAT HAVE WE LEARNED IN 10 YEARS?
Since Bovine Veterinarian last wrote about cell-mediated immunity over 10 years ago, there have been some advances in our understanding of CMI.
Jim Roth, DVM, PhD, Iowa State University, shares some of the more recent things we’ve learned:
Appreciation of the role of T-helper-1 and T-helper-2 responses for different types of infections.
Appreciation of the role of gamma-delta T-cells in protection from disease.
Appreciation of the role of dendritic cells as important cells for presenting antigen to T-cells.
Improved ability to detect activation of antigen-specific T-cell subsets (T-helper-1, T-helper-2, T-cytotoxic and gamma-delta T-cells) after vaccination or infection.
Availability of more mono-clonal antibodies for bovine cytokines and cell surface molecules.
Availability of gene sequence information for bovine cytokines and other important immune system molecules. This allows synthesis of probes for gene expression and synthesis of important proteins.
Demonstration that calves with high maternal antibody are capable of developing effective T- cell-mediated immunity and memory B-cells in response to antigen even though they don’t produce antibody. These calves can potentially be protected from disease after they have lost their maternal antibody and are seronegative.
New information helps explain passive immunity’s role with cell-mediated immunity.