immunocontraception immunocontraception immunocontraception is the use of an animal's immune system to prevent it from fertilizing offspring. contraceptives of this type are not currently approved for human use. typically immunocontraception involves the administration of a vaccine that induces an adaptive immune response which causes an animal to become temporarily infertile. contraceptive vaccines have been used in numerous settings for the control of wildlife populations. however, experts in the field believe that major innovations are required before immunocontraception can become a practical form of contraception for human beings. thus far immunocontraception has focused on mammals exclusively. there are several targets in mammalian sexual reproduction for immune inhibition. they can be organized into three categories. gamete productionorganisms that undergo sexual reproduction must first produce gametes, cells which have half the typical number of chromosomes of the species. often immunity that prevents gamete production also inhibits secondary sexual characteristics and so has effects similar to castration. gamete functionafter gametes are produced in sexual reproduction, two gametes must combine during fertilization to form a zygote, which again has the full typical number of chromosomes of the species. methods that target gamete function prevent this fertilization from occurring and are true contraceptives. gamete outcomeshortly after fertilization a zygote develops into a multicellular embryo that in turn develops into a larger organism. in placental mammals this process of gestation occurs inside the reproductive system of the mother of the embryo. immunity that targets gamete outcome induces abortion of an embryo while it is within its mother's reproductive system. medical use immunocontraception in not currently available but is under study. variability of immunogenicity in order for an immunocontraceptive to be palatable for human use, it would need to meet or exceed the efficacy rates of currently popular forms of contraception. currently the maximum reduction of fertility due to sperm vaccines in laboratory experiments with mice is ~75%. the lack of efficacy is due to variability of immunogenicity from one animal to another. even when exposed to the exact same vaccine, some animals will produce abundant antibody titers to the vaccine's antigen, while others produce relatively low antibody titers. in the eppin trial that attained 100% infertility, a small sample size (only 9 monkeys) was used, and even among this small sample 2 monkeys were dropped from the study because they failed to produce sufficiently high antibody titers. this trend—high efficacy when antibody titers are above a threshold coupled with variability in how many animals reach such a threshold—is seen throughout immunocontraception and immune-based birth control research. a long-term study of pzp vaccination in deer that spanned 6 years found that infertility was directly related to antibody titers to pzp. the phase ii clinical trial of hcg vaccines was quite successful among women who had antibody titers above 50 ng/ml, but quite poor among those with antibody titers below this threshold. lack of mucosal immunity mucosal immunity, which includes immune function in the female reproductive tract, is not as well understood as humoral immunity. this may be an issue for certain contraceptive vaccines. for instance, in the second ldh-c4 primate trial that had negative results, all of the immunized macaque monkeys developed high antibody titers against ldh-c4 in serum, but antibodies against ldh-c4 were not found in the monkeys' vaginal fluids. if antibodies against ldh-c4 do indeed inhibit fertilization, then this result highlights how the difference in the functioning of mucosal immunity from humoral immunity may be critical to the efficacy of contraceptive vaccines. adverse effects whenever an immune response is provoked, there is some risk of autoimmunity. therefore, immunocontraception trials typically check for signs of autoimmune disease. one concern with zona pellucida vaccination, in particular, is that in certain cases it appears to be correlated with ovarian pathogenesis. however, ovarian disease has not been observed in every trial of zona pellucida vaccination, and when observed, has not always been irreversible. gamete production gonadotropin-releasing hormone the production of gametes is induced in both male and female mammals by the same two hormones: follicle-stimulating hormone (fsh) and luteinizing hormone (lh). the production of these in turn is induced by a single releasing hormone, gonadotropin-releasing hormone (gnrh), which has been the focus of most of the research into immunocontraception against gamete production. gnrh is secreted by the hypothalamus in pulses and travels to the anterior pituitary gland through a portal venous system. there it stimulates the production of fsh and lh. fsh and lh travel through the general circulatory system and stimulate the functioning of the gonads, including the production of gametes and the secretion of sex steroid hormones. immunity against gnrh thus lessens fsh and lh production which in turn attenuates gamete production and secondary sexual characteristics. while gnrh immunity has been known to have contraceptive effects for some time, only in the 2000s has it been used to develop several commercial vaccines. equity® oestrus control is a gnrh vaccine marketed for use in non-breeding domestic horses. repro-bloc is gnrh vaccine marketed for use in domestic animals in general. improvac® is a gnrh vaccine marketed for use in pigs not as a contraceptive, but as an alternative to physical castration for the control of boar taint. unlike the other products which are marketed for use in domestic animals, gonacon™ is a gnrh vaccine being developed as a united states department of agriculture initiative for use for control of wildlife, specifically deer. gonacon has also been used on a trial basis to control kangaroos in australia. gamete function the form of sexual reproduction practiced by most placental mammals is anisogamous, requiring two kinds of dissimilar gametes, and allogamous, such that each individual only produces one of the two kinds of gametes. the smaller gamete is the sperm cell and is produced by males of the species. the larger gamete is the ovum and is produced by females of the species. under this scheme, fertilization requires two gametes, one from an individual of each sex, in order to occur. immunocontraception targeting the female gamete has focused on the zona pellucida. immunocontraception targeting the male gamete has involved many different antigens associated with sperm function. zona pellucida the zona pellucida is a glycoprotein membrane surrounding the plasma membrane of an ovum. the zona pellucida's main function in reproduction is to bind sperm. immunity against zonae pellucidae causes an animal to produce antibodies that themselves are bound by a zona pellucida. thus when a sperm encounters an ovum in an animal immunized against zonae pellucidae, the sperm cannot bind to the ovum because its zona pellucida has already been occupied by antibodies. therefore, fertilization does not occur. early research work begun by researchers at the university of tennessee in the 1970s into immunity against zonae pellucidae resulted in its identification as a target antigen for immunocontraception. the zona pellucida's suitability is a result of it being necessary for fertilization and containing at least one antigen that is tissue-specific and not species-specific. the tissue-specificity implies that immunity against zonae pellucidae will not also affect other tissues in the immunized animal's body. the lack of species-specificity implies that zonae pellucidae harvested from animals of one species will induce an immune response in those of another, which makes zona pellucida antigens readily available, since zonae pellucidae can be harvested from farm animals. zonagen in 1987, a pharmaceutical company called zonagen (later renamed repros therapeutics) was started with the goal of developing zona pellucida vaccines as an alternative to the surgical sterilization of companion animals and eventually as a contraceptive for human use. the products would be based on research being done at the baylor college of medicine by bonnie s. dunbar that was funded by zonagen. however, the relationship between zonagen and bonnie dunbar ended acrimoniously in 1993. despite claims later that year that development of a contraceptive vaccine was imminent and an agreement with schering ag for funding for joint development of a contraceptive vaccine for human use, no vaccine was made commercially available and the agreement with schering was terminated after primate studies were disappointing. the company would go on to pursue other projects and be renamed. application to wildlife population control also in the late 1980s, research began into the use of vaccines based around zonae pellucidae harvested from pigs for the purpose of wildlife control. such porcine zona pellucida (pzp) vaccines were tested in captive and domestic horses in 1986 with encouraging results. this led to the first successful field trial of contraceptive vaccines with free-ranging wildlife, which examined pzp vaccines used upon wild horses of assateague island national seashore in 1988. the successful results of the field trial were maintained by annual booster inoculations. following the success of trials with horses, initial trials using captive animals showed promise for the use of pzp vaccines with white-tailed deer and with african elephants. this led to successful field trials of pzp vaccines in white-tailed deer at the smithsonian conservation biology institute in front royal, va from september 1992 to september 1994 and in african elephants of kruger national park in south africa in 1996. as a result of these successes, pzp vaccination has become the most popular form of immunocontraception for wildlife. as of 2011, thousands of animals are treated with pzp vaccination every year, including 6 different species of free-ranging wildlife in 52 different locations and 76 captive exotic species in 67 different zoological gardens. bio farma in 2012, researchers from brawijaya university in conjunction with pharmaceutical company bio farma received a grant from the indonesian government to develop a zona pellucida contraceptive vaccine for human use. instead of pigs, the zonae pellucidae for the program are harvested from cows. the program hopes to mass-produce a contraceptive vaccine in indonesia in 2013 at the earliest. viral and microbial vectors while contraceptive vaccines can be delivered remotely, they still require administration to each individual animal that is to be made infertile. thus contraceptive vaccines have been used to control only relatively small populations of wildlife. australia and new zealand have large populations of european invasive species for which such approach will not scale. research in these countries has therefore focused on genetically modifying viruses or microorganisms that infect the unwanted invasive species to contain immunocontraceptive antigens. such research has included targeting the european rabbit (oryctolagus cuniculus) in australia by engineering rabbit zona pellucida glycoproteins into a recombinant myxoma virus. this approach has induced marginal reduction of fertility in laboratory rabbits with some of the glycoproteins. further improvement of efficacy is necessary before such an approach is ready for field trials. research has also targeted the house mouse (mus domesticus) in australia by engineering murine zona pellucida antigens into a recombinant ectromelia virus and a recombinant cytomegalovirus. the latter approach has induced permanent infertility when injected into laboratory mice. however, there is some attenuation of efficacy when it is actually transmitted virally. in addition to rabbits and mice, this approach has been explored for other animals. researchers have attempted to replicate similar results when targeting the red fox (vulpes vulpes) in australia using such vectors as salmonella typhimurium, vaccinia, and canine herpesvirus, but no reduction in fertility has been achieved thus far for a variety of reasons. initial exploration into the control of the common brushtail possum (trichosurus vulpecula) in new zealand using the nematode parastrongyloides trichosuri has identified it as a possible immunocontraceptive vector. sperm in placental mammals, fertilization typically occurs inside the female in the oviducts. the oviducts are positioned near the ovaries where ova are produced. an ovum therefore needs only to travel a short distance to the oviducts for fertilization. in contrast sperm cells must be highly motile, since they are deposited into the female reproductive tract during copulation and must travel through the cervix (in some species) as well as the uterus and the oviduct (in all species) to reach an ovum. sperm cells that are motile are spermatozoa. spermatozoa are protected from the male's immune system by the blood-testis barrier. however, spermatozoa are deposited into the female in semen, which is mostly the secretions of the seminal vesicles, prostate gland, and bulbourethral glands. in this way antibodies generated by the male are deposited into the female along with spermatozoa. because of this and the extensive travel in the female reproductive tract, spermatozoa are susceptible to anti-sperm antibodies generated by the male in addition to waiting anti-sperm