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Immunocontraception of white-tailed deer with GnRH vaccine.

PROBLEM: Reduction of excess numbers of white-tailed deer (Odocoileus virginianus) is an example of a potential use for immunocontraception as a means of wildlife population management. METHOD OF STUDY: A 4 year multifaceted study was conducted to determine the long term effects of gonadotropin releasing hormone (GnRH) contraceptive vaccine on the fertility and behavior of female and male white-tailed deer. Deer were monitored for breeding behavior, hormone levels, pregnancy, fawning and GnRH specific antibody levels. RESULTS: Treatment lead to reduced fawning rates, altered estrus behavior, reduced concentrations of progesterone, contraception and failure to maintain pregnancy following conception. GnRH immunized does bred to untreated bucks had an 88% reduction in fawning caused by either immunocontraception or immunocontragestion. The vaccine effect is reversible, directly related to the antibody titer. Infertility lasted up to two years without boosting. GnRH immunized bucks demonstrated no interest in sexual activity when paired with control females. Depending on the immunization schedule, antlers either dropped early or remained in velvet. CONCLUSIONS: The results of this study demonstrate that GnRH vaccine is effective in inducing a reversible infertility in white-tailed deer, the infertility lasting up to two years without boosting.

Animals↗

Birth control vaccines and immunological approaches to the therapy of noninfectious diseases.

Vaccination usually means the immunization of persons or animals against foreign infectious organisms for disease prevention. However, it has now been demonstrated that immunization against certain self substances to which tolerance normally exists can elicit beneficial effects to humans and other animals without inducing autoimmune disease. Clinical trials in women have been conducted with vaccines against reproductive antigens for the prevention of pregnancy and research is under way to develop more advanced formulations. Other self antigens have been described that might be used for developing methods of immunological therapy for such diseases as cancer, ulcers, and complications of diabetes. Emphasis is placed on the need for careful studies in appropriate animal models before any clinical application of such procedures is suggested.

Abortion, Habitual↗

An improved immunogen for anti-human chorionic gonadotropin vaccine eliciting antibodies reactive with a conformation native to the hormone without cross-reaction with human follicle stimulating hormone and human thyroid stimulating hormone.

Beta-subunit of human chorionic gonadotropin (hCG) was associated with alpha-subunit of ovine luteinizing hormone (OLH) to create a heterospecies dimer (HSD) which has a higher steroidogenic potency than the homologous dimer of alpha hCG and beta hCG in the mouse Leydig cell bioassay. The properties and merits of the antibodies induced by this HSD and beta hCG linked to carrier(s) were investigated in rodents and in a subhuman primate species. The antisera had, in both cases, high affinity for binding with hCG (K alpha = 10(9)-10(10) M-1). The mean (+/- S.E.M.) bioneutralization capacity as a percentage of immunoreactivity (determined by radioimmunoassay (RIA)) of the antibodies generated by the HSD-carrier in rats and bonnet monkeys was higher in comparison with those induced by beta hCG linked to carrier (80 +/- 2.3% vs. 63 +/- 1.5% in rats, and 65 +/- 1.9% for HSD vs. 44 +/- 3.7% in monkeys). None of the sera gave any evidence of cross-reactivity with human follicle stimulating hormone (hFSH) and human thyroid stimulating hormone (hTSH).

Animals↗

Peptide vaccines in immunocontraception.

Vaccines have been used successfully to treat and eradicate infectious diseases; this has encouraged a major drive towards development of contraceptive vaccines (immunocontraception) as an additional method against rising human and animal populations. Despite three decades worth of research in this field, there are no licensed human contraceptive vaccines and less than ten for use in animals. The development of peptide antifertility vaccines has had a substantial impact on improving safety and specificity of immunogens, but has resulted in efficacy problems. Innovative strategies have been developed to overcome these problems.

Animals↗

Contraceptive vaccines.

Three major approaches to contraceptive vaccine development are being pursued at the present time. The most advanced approach, which has already reached the stage of phase 2 clinical trials, involves the induction of immunity against human chorionic gonadotrophin (hCG). Vaccines are being engineered based on conjugates incorporating tetanus or diphtheria toxoid linked to a variety of hCG-based peptides centred on the beta-subunit of this molecule. Clinical trials have revealed that such preparations are capable of stimulating the production of anti-hCG antibodies. However, the long term consequences of such immunity in terms of safety or efficacy are, as yet, unknown. The alternative approaches to contraceptive vaccine development involve the induction of immunity against gamete-specific antigens found on the surface of the human spermatozoon or the zona pellucida. There is an abundance of experimental and clinical data to suggest that this approach is feasible although the biochemical characterization and synthesis of candidate antigens is still incomplete.

Animals↗

Immunologic studies of male infertility.

The immunological basis of male sterility, as previously described, is related to alterations of spermatogenesis or impairment of seminal plasma formation. Both may be developed independently or may be related. Acute or subacute lesions of the genital tract or gonads may be more closely related to the presence of autosensitization than are chronic inflammatory processes or endocrine diseases of the testis. Oligo- or azoospermia may reflect the destruction of cells or halting of spermatogenesis. Immobilization and agglutination of sperm cells would depend predominantly on an allergic reaction that originates in the adnexal glands. Antibodies against testis do not affect adnexal glands but may immobilize epididymal spermatozoa, whereas antiseminal plasma antibodies react only with adnexal glands and seminal spermatozoa, but not with testicular cells. The pathogenic role of detectable antispermatic antibodies in sterile male or female patients are not sufficiently clarified. Their presence apparently correlate with unexplained cases of infertility, but this does not necessarily mean that they are specifically responsible for this abnormality; furthermore, they might be only an epiphenomenon of the immunological process involved.

Animals↗

Immunocontraception in companion animals.

There is real need worldwide to control the population growth of companion animals. Throughout the world and particularly in the United States, overpopulation of unwanted dogs and cats is a concern for many reasons. Feral populations pose risk to native species by spread of disease and predation. That unwanted animals are humanely eradicated is of concern to many persons. The need to control population growth has led to various approaches to contraception, including immunocontraception. Concerns regarding efficacy, duration of action, harm to the individual, and species specificity are among the issues being addressed. As new technologies emerge, ethical, political, and safety issues evoke differing opinions. It is hoped that in the near future, different strategies will be developed to solve this disturbing problem.

Animals↗

Contraception of bison by GnRH vaccine: a possible means of decreasing transmission of brucellosis in bison.

Preventing pregnancy in brucellosis-infected bison (Bison bison) provides a potential means of preventing transmission of disease. To determine whether a gonadotropin-releasing hormone (GnRH) vaccine was effective in reducing pregnancy in bison and to study the safety of injecting GnRH in pregnant bison, a study was conducted at the Idaho Fish and Game Wildlife Health Laboratory in Caldwell, Idaho (USA). Four pregnant and two nonpregnant female bison were given a single injection of GnRH vaccine, and five pregnant adult females were given a sham injection that contained only adjuvant. Three of the GnRH-vaccinated bison that were pregnant at the time of vaccination delivered healthy calves. One treated bison had dystocia that resulted in a dead calf. All control bison delivered healthy calves. After calving, females of both groups were exposed to two bulls. Treated bison were palpated 6 wk after exposure to the bulls, and blood was drawn for pregnancy-specific protein B analysis. The six treated bison were not pregnant. The sham-treated bison became pregnant and delivered viable calves. This study demonstrates that a single dose of GnRH vaccine is effective in preventing pregnancy in female bison for at least 1 yr.

Abortion, Veterinary↗

Immunologic hazards associated with vaccination of humans.

Universal vaccination remains the most effective measure for preventing the spread of many infectious diseases. Since vaccination is one of the few medical interventions applied to healthy individuals, its safety must be as absolute as human efforts can make it. Questions have been raised recently about the possibility that particular vaccines can trigger or promote autoimmune disease, although controlled, population-based studies have not supported this notion. In collaboration with the World Health Organization, we investigated a subunit vaccine of human chorionic gonadotropin, and found evidence of benign, but not pathologic, autoimmunity. We propose an algorithm for systematic study of possible immunologic hazards of vaccines in animals and human subjects.

Animals↗

Influence of active immunization against GnRH on VIP- and NPY-positive innervation of the porcine testis.

The influence of an anti-GnRH vaccine on VIP- and NPY-positive innervation of testes was studied in the pig. The immunization prevented the occurrence of changes in the pattern of VIP- and NPY-positive testicular innervation associated with the sexual maturation: it maintained the density of innervation at the high level characteristic for sexually immature animals. The effect was dependent on the method of immunization: the application of two doses of the vaccine was more efficient than application of only one dose, and vaccination with adjuvant was more efficient than vaccination with the plain vaccine. The studies on VIP and NPY concentration in the testicular tissue with radioimmunoassay (RIA) revealed immunization-dependent changes in the peptide concentration, however, some discrepancies between morphological changes and peptide levels were observed.

Animals↗

Field applications of immunocontraception in African elephants (Loxodonta africana).

The primary aim of the Makalali elephant immunocontraception programme is to test the efficacy of porcine zona pellucida (PZP) vaccine for practical population control of elephants in small, enclosed reserves, with the goal of stabilizing the current growth rate and reducing it to the 5-10% per annum displayed currently in the Kruger National Park. A secondary aim is to test the hypothesis that PZP treatment does not affect patterns of elephant social behaviour. Eighteen sexually mature cows (age > 12 years) were vaccinated in May 2000 using remote darts. Behavioural observations before, during and after vaccination included noting the activity of individual animals every minute for 15 min. No changes in general behaviour patterns have been noted to date although the animals' spatial use of the reserve was erratic during the period of vaccination, indicating irregular or disturbed patterns associated with vaccination. Normality was resumed on completion of the vaccinations. No aggressive or indifferent behaviour related to nursing, calf proximity or bull-cow interactions have been noted. Ten of the females were in various stages of pregnancy when treated. Subsequently, seven of them gave birth to healthy calves and the other three females are expected to calve shortly. It is too early in the study to draw conclusions about stabilization of growth rates.

Animals↗

Functional and immunological relevance of the COOH-terminal extension of human chorionic gonadotropin beta: implications for the WHO birth control vaccine.

The World Health Organisation (WHO) Task Force on Birth Control Vaccines has selected the pregnancy hormone human chorionic gonadotropin (hCG) as a target molecule for a contraceptive vaccine. A synthetic peptide antigen corresponding to the amino acid sequence 109-145 of the carboxyl-terminal portion of the hCG beta-subunit (hCG beta CTP), which is supposed to elicit hCG-immunoneutralizing antibodies, has been submitted to clinical trials. Recent findings suggest that hCG beta CTP does not play a role in the biological activity of hCG. This raises the question concerning the assumed mechanism of action of the hCG beta CTP-based birth control vaccine. We therefore investigated the immunoneutralizing capacity of antibodies directed against hCG beta CTP. Although it is possible to generate specific monoclonal and polyclonal antibodies for hCG by using hCG beta CTP as an immunogen, it appeared that the biological response to hCG was not affected by such antibodies. The reason for this is that the hCG-antibody-complex is still able to bind to target cell receptors and therefore the intended contraceptive effect should not occur. In addition there is a risk of hazardous possible side effects such as an autoimmune reaction against the ovary because we found that at least one epitope is still accessible for antibody binding on receptor-bound hCG. We conclude from our results that both the efficacy and safety of the WHO vaccine are not yet ensured.

Animals↗

Effect of antibodies to sperm-specific recombinant contraceptive vaccinogen (rCV) on murine fertilization: search for an animal model to examine its contraceptive potential.

Recently, we cloned and sequenced a sperm-specific antigen, designated as Contraceptive Vaccinogen (rCV), from human testis (Naz et al., 2001). The present study was conducted to examine its proteomic homologue and function in murine sperm, in order to find out whether or not the mouse can provide a suitable model for examining its immunocontraceptive effects. This was examined by using purified antibodies (Ab) raised against the recombinant (r) human CV antigen of approximately 44 kD. In the Western blot procedure, rCV antibodies recognized a specific protein band of approximately 64 +/- 5 kD in murine testis and murine sperm extracts, the band similar to that found in human testis and human sperm. In the immunoprecipitation procedure, rCV Ab immunoprecipitated a protein band of similar size from murine sperm and murine testis extracts. The immunocytochemical (ICT), immunoscanning electronmicroscopic (ISEM) and the immunobead binding technique (IBT) revealed the subcellular localization of CV antigen on the surface of acrosome and tail regions of the noncapacitated and capacitated murine sperm cell. In functional bioassays, rCV Ab inhibited the acrosome reaction as well as sperm-egg binding in vitro. These data indicate that the CV antigen is expressed in murine sperm and has a biological role in sperm function and sperm-egg binding. In vitro inhibition of capacitation/acrosome reaction and sperm-zona binding suggest that the mouse can provide a suitable model to examine the immunocontraceptive effects of CV antigen in actively-immunized animals.

Animals↗