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RESEARCH CONTINUES ON CASTRATION BY VACCINATION

by: Heather Smith Thomas

No risk castration of bull calves (and suppression of estrus in heifers) may soon be available to livestock producers as an injection. Thomas E. Adams, PhD (a professor at U.C. Davis) has been researching "castration vaccination" for a number of years.

A vaccine has been developed that stimulates the animal's body to develop immunity to one of its own hormones a reproductive hormone called GnRH. Immunological castration prevents GnRH from triggering other hormones that lead to production of testosterone and sperm in the males' testes and estrogen production in females. The vaccine can thus suppress testicular function and masculinity in bulls, and halt ovarian activity in heifers. Using a vaccine is less invasive (with less risk to the animal) than surgical castration or spaying, and it also provides some improvement in feed efficiency and carcass quality.

In Canada, a vaccine produced by Biostar, Inc. (Saskatoon, SK) was tested in several studies at the      Lethbridge Research Centre in Alberta. In the U.S. another vaccine was developed at U.C. Davis. Dr. Adams says, “Our procedure is similar to the Canadian procedure except that they are using a protein that is, synthesized in bacteria recombinant (new combination) protein and we use a naturally occurring protein for our vaccine."     

Basically, this involves vaccinating animals against the critical hormone that controls reproductive function, he says. "If the vaccine is successful, the animal generates antibodies against GnRH. The antibodies neutralize the GnRH and interrupt the hormone that controls testosterone production and testicular growth. Gonadal tissue (testes or ovaries) doesn't develop and is not active. There is no production of sperm in males, no ovulation (no estrogen or progesterone production) in females,” he says.

"We've done a number of studies in males and in females where we've demonstrated effectiveness of the immunization procedure. It is very effective in several species much more effective in pigs and sheep than in cattle, primarily because the immune system of cattle seems to be more resistant to the vaccine. It's difficult to get an antibody level high enough to completely shutdown bovine reproductive function. The vaccine we've produced at U.C. Davis seems to be the most effective because of the unique method of production that we use," says Adams.     

"In sheep and pigs we just use one injection of vaccine. In cattle we use two injections a primary immunization and a booster. In our studies we had the greatest success when we vaccinated at about three months of age with the primary immunization and gave a booster at feedlot entry, at about one year of age. We get a good response with this program," he says. The vaccine (2 cc.) is administered subcutaneously in the top area of the upper part of the neck, split into two different sites.     

With a primary vaccination and a booster several months later, testosterone levels stay low from feedlot entry until slaughter, assuming the cattle are slaughtered at 18 months of age or earlier. "After that age, you might see a gradual increase in testosterone. If you keep animals longer than 18 months, it might be necessary to give them a second booster. But the one booster has seemed adequate for the cattle raised here in California," says Adams.

"We did a study with heifers where the objective was not to permanently eliminate reproductive function, but to delay puberty so the heifers would not become pregnant at an early age – becoming pregnant when they were more mature and able to carry a pregnancy. In that study we gave only a primary immunization. It did delay puberty, but, the animals eventually began to cycle and ovulate, and did become pregnant. So it was effective in blocking reproductive function but not completely eliminating it," he explains.

Adams is fairly confident that the vaccine will be produced commercially at some point in the future for cattlemen to use. "Biostar is actively pursuing commercialization of it, and there is already a commercial product available in Australia. I am not sure if it is available for cattle yet, but it is certainly being used in Australia for sheep and pigs," he says.     

"There's a lot of interest in the U.S. not only from cattlemen but from people interested in controlling reproduction in wild animals like deer, for population control. We've had a number of people inquire about it for controlling wildlife in areas where other means of control are not effective or possible, such as in parks where they don't allow hunting. So the vaccine would have a lot of application, not only in livestock but in dogs, cats and wild animals," he points out.

"The problem with our system is that it's not a patentable process. Vaccine companies are not interested in marketing it since they can't have an exclusive right to it. I think the work that Biostar is doing will lead to a marketable product, because they are adding a different twist to it that might make it patentable. They may be able to get a patent, to make it feasible for a manufacturer to produce it," says Adams.

"The problem with their system and the other recombinant proteins is that they are not as immunogenic as the naturally occuring proteins we use. Theirs have not been quite as effective in suppressing testicular or ovarian function as we have been with our conjugate. Our conjugate probably will not be commercialized, however, because it is not a patentable process."

The process of immunization involves injecting an antigen such as a foreign protein into the body. "But we face a problem with GnRH because it's not foreign. It's a naturally occurring hormone." The body won't develop an immunity to its own protein.

"Another problem with GnRH is that it is a very small peptide; it is composed of only 10 amino acids. Generally, proteins have to be much larger than that in order to activate the immune system. One way to get around that is to covalently link that peptide (GnRH) to a larger carrier protein," he explains. This linking up is a process called conjugation.

"The body can recognize the conjugated (combined) product as foreign and will develop antibodies against it. So one of the steps in generating a vaccine for GnRH is to take a carrier protein and couple it to GnRH. We do that chemically, linking GnRH to a protein called keyhole limpet hemocyanin (KLH) that we obtain from a marine snail. That's what we inject into cattle, sheep or pigs. Because we can chemically couple GnRH to this protein we can control or regulate the number of GnRH molecules that are attached to that protein. Generally, the more the better; the more GnRH molecules associated with each molecule KLH, the more immunogenic the conjugate is. So that's one of the advantages of our process; we can take a carrier protein that has known immunogenicity and couple GnRH to it at high levels and that makes a very effective conjugate," he says.

"In the Biostar system, what they are doing is generating a protein using molecular, biological techniques. They use the gene for a carrier protein (such as human or bovine albumin). They take the gene that codes for serum albumin and modify it. They insert several copies of GnRH into that gene and then express that gene in bacteria. The bacteria then take the modified gene and produce protein based on the nuclear sequence in that gene. The result is serum albumin that incorporates a few copies of GnRH into the sequence. That's their twist that makes their system possibly patentable, whereas ours is not," says Adams.      

"The problem with their process is that serum albumin is not nearly as antigenic as the protein we get from the snails. The other problem is that they can only incorporate a couple copies of GnRH into the structure whereas we can incorporate 20 or 30 into the structure of the KLH. So there are some problems associated with the Biostar vaccine, but those problems will likely be overcome by a company looking at it for commercialization in cattle. I think eventually there will be patentable products that can be used by cattlemen," he says.

The vaccine is more effective for suppressing estrus in heifers than is use of MGA, and less risky than spaying. In males, cattlemen may eventually have to reconsider traditional methods of castration, with animal rights and animal welfare groups demanding more humane techniques. "The primary impetus for our work was the animal rights/animal welfare issue. We wanted to give cattlemen an alternative that would not affect production, growth or carcass quality. Our work, although it is not patentable, has demonstrated that vaccination is an effective procedure; we are just waiting for a company to come along that can generate a patentable vaccine that is as effective as the chemically synthesized vaccine," says Adams.

"It maybe 5 years or so, but I think that something will soon be available. Every time we give a talk, there's a lot of interest in it. I carry jars of bull testes with me and show the changes in size with vaccination; this is very dramatic in terms of suppressing testicular size," he says.

Trials with Steers and Bulls

The researchers at U. C. Davis have done several trials with feedlot cattle using vaccine to immunize against GnRH to test the immune response to the vaccine, and to measure feedlot performance. Steers were compared with bulls (vaccinated and unvaccinated), and groups of bulls and steers receiving anabolic steroid implants were compared with groups that did not receive the implants (Synovex S; 200 mg of progesterone and 20 mg of estradiol benzoate).

Feedlot performance of young bulls was significantly affected (lowered) by castration but not by immunization against GnRH. Though weight at feedlot entry was the same in each group, the animals castrated at feedlot entry had lower final live weight and lower daily gain than the intact controls or the bulls that were vaccinated against GnRH. In order to compensate for castration, the steers needed implants containing steroids. Using vaccination instead of castration reduces the need for use of implants. There are residual levels of testosterone secretion in immunized bulls that may have anabolic effects.

A number of trials were also done to determine the most effective age for immunization. Vaccination given when bull calves are young (before they reach 4 to 7 months of age) seems to be the most effective. A significant change in testicular function begins to occur at 4 to 7 months as the calf makes a transition from the infantile to prepubertal state; there is a progressive increase in the size of the testicles. Immunization before this transitional period of development is likely to be more effective in suppressing testicular function (and the effects of immunization last much longer) than a vaccination given later.

Bull calves that were vaccinated at 3 to 4 months of age all developed significant titer against GnRH by weaning time and the titer remained high until slaughter. In calves given a booster vaccination at feedlot entry, titer was greatly increased four weeks later, but returned to pre booster levels within 12 weeks of the secondary immunization. Best results seem to be obtained by giving a primary vaccination at a young age, and a booster at feedlot entry. If calves are to be given only one vaccination however, it seems to work best to give it at about seven months of age. This showed greater suppression of testicular function than in the calves immunized at a younger age, with no booster.

In all trials, feedlot performance (final live weight and rate of gain) of immunized bulls was comparable to intact bulls, but the immunized bulls had the advantage of improved carcass quality and less aggressive behavior. In immunized animals, aggressive and masculine behavior is greatly reduced. Immunized bulls' behavior was similar to that of castrated (and non implanted) steers and less aggressive than that of steers given Synovex C and S implants.

Carcass quality grade from steers and immunized bulls was significantly better than the grade assigned to carcasses from control bulls. Degree of masculinity (sex class score) of carcasses from steers and immunized bulls were similar. Muscle mass was similar in carcasses of implanted steers and immunized bulls; by contrast, muscle mass and dressing percentage was significantly smaller in nonimplanted steers. Marbling was comparable in all steers and immunized bulls; the animals with the least marbling were the intact control bulls.

Traditionally, bull calves have been castrated (in spite of higher rates of gain and muscle mass in intact bulls) to improve their behavioral traits during the feeding period and to improve marbling and carcass quality. Steers receiving implants (to counter some of the effects of castration) increase aggressive behavior ten fold over steers that do not receive implants. All of these factors would point to immunization being an effective noninvasive and desirable alternative to castration.

Trials with Heifers

Several trials were conducted at U.C. Davis to evaluate reproductive function and feedlot performance in beef heifers immunized against GnRH. In one trial, heifers were divided into two groups one group vaccinated and the other group non-vaccinated. Vaccinated heifers developed titers against GnRH and their serum concentrations of progesterone decreased. Weight of ovarian and uterine tissues in the vaccinated heifers was less than that of unvaccinated heifers, as was their total weight gain.

In the second trial, unvaccinated heifers and vaccinated heifers were compared with non immunized heifers that were treated with MGA (melengestrol acetate). Serum concentrations of progesterone were low in both the vaccinated and MGA fed groups, but only the vaccinated heifers had lower ovarian and uterine weights. Total weight gains (and gain during the final four weeks of confinement) were similar in the heifers (both vaccinated and unvaccinated) that received steroid implants. This suggests that vaccination against GnRH effectively suppresses reproductive activity and that the lower weight gain that goes hand in hand with this suppression can be reversed by use of implants containing anabolic steroids.

Spaying of heifers has been a means to prevent reproductive activity (riding during estrus, unwanted pregnancies in the feedlot), but always carries some risk along with reducing growth rate. Gonadal steroids play a big role in animal growth and development. Spayed heifers generally must be implanted in order to make gains similar to intact heifers. Immunization, against GnRH can be a non surgical alternative to spaying, especially since the use of implants can counter the subsequent reductions in growth and feed efficiency. In the U.C. Davis trials, feed efficiency and weight gain during the final four weeks of confinement were slightly improved in the vaccinated heifers and the MGA fed heifers, compared to the heifers in the control groups.     

Another management advantage to use of vaccination in heifers in contrast to spaying is that vaccination can be used as a temporary measure to keep young heifers from becoming pregnant if desired, allowing them to become pregnant later. Heifers destined for the feedlot or for the beef herd are sometimes accidentally exposed to bulls at a young age. If heifers are vaccinated against GnRH, the economic liability associated with pregnancy in feedlot heifers is greatly reduced, and the risk of having a herd replacement heifer bred too young is also reduced.

In the U.C. Davis trial, 145 commercial crossbred yearling heifers were put into three groups. One group was immunized against GnRH and the other two groups were not. Sixteen weeks after the primary immunization, fertile bulls were put into the pens with the immunized group and one of the other groups, and kept with the heifers for two months. The third group was not intentionally exposed to bulls. At the end of the breeding period, all heifers received Synovex H implants and entered a commercial feedlot, and were slaughtered after 116 days of feedlot confinement.

In the 48 heifers that were exposed to bulls but not vaccinated against GnRH, 40 were pregnant (83.3 percent). By contrast only 4 of the 48 heifers in the vaccinated group were pregnant at slaughter. Feedlot gain did not differ much between the three groups, but dressing percentage and muscle mass were reduced (and marbling and quality grade increased) in the pregnant heifers. Heifers immunized against GnRH had carcass characteristics that were intermediate between those of the pregnant and non pregnant controls. Vaccination may ultimately be a viable management tool (along with implants) in heifers destined for the feedlot, and may also be useful in situations where producers do not want the risk of young replacement heifers being bred too early in life.

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