[Immunological aspects of the development of contraceptive vaccines].
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The prospect of an immunological approach to contraception that would disrupt the process of fertilisation itself has resulted in a considerable interest into research in this area. It has been known for some time that antibodies raised against the zona pellucida (ZP) can suppress fertility very effectively. However, the initial optimism of this approach has been marred by the appearance of an ovarian pathology characterised by disruption of folliculogenesis and depletion of the primordial follicle pool. Adverse auto-immune reactions have been observed in the ovaries of mice after the induction of immunity with mouse ZP3 epitopes. However, this was associated with lymphocytic infiltration of the ovarian stroma, which could be circumvented by careful selection of B-cell epitopes to induce reversible infertility. In order to identify similar epitopes on primate ZP3, epitope-mapping studies were performed and incorporated into chimeric vaccines that included a promiscuous T-helper cell epitope. Both single and triple peptide vaccines have been evaluated in vivo and no detrimental effects on ovarian function were observed. The resulting high titre antibodies bound exclusively to the ZP of marmoset and human ovarian sections and could suppress in vitro human sperm-egg binding by approximately 60%, but did not prevent pregnancy in actively immunised female marmosets. Thus, considerable research is still required to identify a combination of ZP3 epitopes that will induce infertility free of any unwanted side effects.
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Testosterone undecanoate (TU) is under phase III clinical trial as a hormonal male contraceptive in China. Sex hormones can modulate the immune system. Female hormonal contraceptives may affect SIV/HIV-1 transmission. To evaluate the safety of TU and to understand whether long-term use of TU for a male contraceptive affects users' immunological features, adult male rats were treated for a 32-week TU-treated phase at the dose of 20 mg TU/kg body weight and a 24-week recovery phase. The reproductive and immunological parameters of 4-6 rats in each subgroup were examined at the stated time point. The mean sperm count and viability in the treated rats were significantly suppressed (p < 0.01). In the TU-treated group: the mean blood leukocyte and lymphocyte counts; the proliferation indexes of T cells from peripheral blood mononuclear cells (PBMC) and spleen; and, of B cells from spleen, as well as the mean counts of blood T, NK, and B cells decreased in comparison with those of control group. These decreases were not significant (p > 0.01). Similarly, the mean serum IgM, IgG, and IgA levels and complement activity in TU-treated rats were lower than those in control group (p > 0.01), and the changes in the antibody levels of the examined genital secretions were not significant (p > 0.01). The changes in the thickness of urethra epithelium, and in secretory component (SC) expression in genitals were not observed in the treated group. These results demonstrated that long-term supraphysiological TU injection did not obviously affect the examined rat immunological parameters.
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The basic principle of a contraceptive (or anti-fertility) vaccine is to use the body's own immune defence mechanisms to provide protection against an unplanned pregnancy. Factors such as: economic production, convenience of use, relatively long-lasting but reversible action, low failure rate, and the avoidance of mechanical devices or exogenous hormones make this approach a potentially attractive option for family planning programmes in both developing and developed countries. The major efforts in research and development have involved the prospect of active immunization against specific antigens of sperm, ovum, zygote and early embryo, and the pregnancy hormone hCG. Several anti-hCG vaccines have entered clinical trials and show promising results. These vaccines operate by preventing or interrupting pregnancy at the peri-implantation stage probably by neutralizing the luteotrophic action of hCG. The most refined vaccine is one directed against the unique C-terminal peptide on the beta-subunit of hCG. This vaccine provokes antibodies that are specific for hCG and do not cross react with hLH. Future research efforts aim to optimize the anti hCG approach, utilize new vaccine delivery systems, and broaden the spectrum of target antigens of potential utility for contraceptive vaccines.
A reversible, inexpensive birth control vaccine for men and women may come from an unlikely source--genetically altered salmonella bacteria. The bacteria cause food poisoning, typhoid and diarrhea. But with some genes removed and others spliced in, an altered form produces proteins that make the immune system reject sperm and does not cause disease, says Dr. Roy Curtiss, a biology professor at Washington University in St. Louis, Missouri, US. The approach was announced in November at a US meeting of the Council for the Advancement of Science Writing. "Salmonella act as the factory, making specific antigens. It is a slow-release system," he says. The altered bacteria produce sperm antigens, and both male and female immune systems make antibodies against them. To sustain immunity, a booster vaccine might be necessary every 6 to 12 months. Numerous concerns, however, have been raised over the use of such live vaccines. A live vaccine, for example, could accidentally immunize people through fecal contamination of water or food. Researchers are testing the vaccine approach in mice and are scheduled to begin experiments soon with macaque monkeys and baboons. Experiments among humans are not yet scheduled and would not begin until ethical and health issues are resolved. The contraceptive vaccine could be inexpensive to produce and would require no refrigeration, making it easy to store. It would probably be administered orally, eliminating costs and risks associated with injections, Dr. Curtiss says.
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Recent advances in antigen definition and production have made the development of a contraceptive vaccine more attainable. Such a vaccine must evoke an immune response that blocks an indispensable step in the reproductive process. Vaccine research involves many approaches to fertility prevention. Vaccines are being developed that could interrupt fertility by inhibition of gonadotrophin release, the function of follicle-stimulating hormone or the effects of human chorionic gonadotrophin (hCG); alternatively, they may prevent fertilization by interfering with the transport of spermatozoa or with sperm-zona pellucida binding. The most advanced prototype is a vaccine based on antibodies to beta hCG. Such vaccines are being studied for clinical efficacy. Many hurdles remain in contraceptive vaccine development. Since the antigens are peptides or small proteins, the resultant immune response is usually moderate, and better adjuvants and delivery systems must be developed to enhance and maintain the immune response. Improvement of the mucosal immune response may be necessary for vaccines incorporating sperm antigens. Research on vaccines that control fertility has resulted in a fascinating base of scientific knowledge that, it is hoped, can be converted into products that will allow another option for individuals who wish to control their fertility.
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