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Results for “Contraception, Immunologic”

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PubMed2002

Two-dimensional electrophoretic analysis of sperm antigens recognized by sperm immobilizing antibodies detected in infertile women.

In this study, high resolution two-dimensional (2-D) gel electrophoresis was used to identify human sperm antigens recognized by the sera from infertile women having sperm immobilizing (SI) antibodies. Two-D gel electrophoresis was employed to separate Percoll purified human sperm proteins using isoelectric focusing (IEF), followed by polyacrylamide gel electrophoresis (PAGE). Sperm proteins were transferred to the nitrocellulose membranes and immunoblotted with seven sera from infertile women with high titers of SI antibodies and 6 sera from those without SI antibodies. The blots were compared to the 2-D composite image of human sperm proteins [Sperm Protein Encyclopedia] and sperm surface index and the sperm surface proteins recognized by infertile sera were identified. Fifty-two human sperm surface proteins reacted with sera containing SI antibodies, while 35 of these were reactive with the SI-negative control sera. The average numbers of protein spots reacted with test and control sera were 24.6 and 15.0 respectively. A subset of sperm surface proteins which were unique to the SI antibodies were identified by the following criteria; the sperm protein spots which were highly reactive with the infertile sera containing SI antibodies but not reactive with any of the SI-negative infertile sera. The coordinates of 4 prominent immunoreactive sperm proteins were considered as possibly relevant to antibody mediated female infertility.

Antigens, Surface↗

PubMed2002

The contraceptive potential of ZP3 and ZP3 peptides in a primate model.

It has been known for some time that antibodies raised against ZP3, the major component of the glycoprotein shell that surrounds all mammalian oocytes, can successfully inhibit sperm-egg interaction in vitro. In our own studies using the non-human primate Callithrix jacchus, active immunisation was successfully achieved when homologous or heterologous ZP3 was used as an immunogen. However this long-term suppression of fertility was at the expense of ovarian function. An ovarian pathology was observed which was characterised by a disruption of folliculogenesis and depletion of the primordial follicle pool. Adverse auto-immune reactions have also been observed in mice following induction of immunity to mouse ZP3. Following careful selection of B-cell epitopes on mouse ZP3, peptide vaccines were formulated which could circumvent these adverse side effects and induce reversible infertility in actively immunised mice. To identify similar epitopes on primate ZP3, epitope mapping studies were performed and several candidate regions of the molecule were identified. These were incorporated into chimeric peptide vaccines and administered as single or triple peptide vaccines. Active immunisation successfully induced antibodies that bound exclusively to the zona pellucida of marmoset and human ovarian sections. These antibodies were able to suppress human sperm-egg binding by up to 60% in vitro. Encouragingly, no adverse side effects on ovarian function were observed following long-term immunisation however, no loss of fertility was consistently observed in vivo. Thus considerable research is still required to identify a combination of ZP epitopes that will induce reversible infertility in the absence of any ovarian dysfunction.

Animals↗

PubMedDate not supplied

Native zona pellucida reactivity and in-vitro effect on human sperm-egg binding with antisera against bonnet monkey ZP1 and ZP3 synthetic peptides.

In mammals, zona pellucida glycoprotein-3 (ZP3) is the putative ligand for primary sperm binding and induces the acrosome reaction. Recent evidence suggests that zona pellucida glycoprotein-1 (ZP1) also play an important role, in some species, during fertilization. In order to identify synthetic peptide immunogens capable of inducing antibodies reactive with native zona and inhibiting sperm-oocyte interaction, peptide encompassing the amino acid (aa) residues 334-343 of bonnet monkey ZP3 (bmZP3) was synthesized co-linearly with a 'promiscuous' T-cell epitope of circumsporozoite protein (CSP, 378-398 aa) of Plasmodium falciparum. In addition, four peptides corresponding to bonnet monkey ZP1 (bmZP1((58-79 aa)), bmZP1((136-153 aa)), bmZP1((212-228 aa)) and bmZP1((251-273 aa))) were synthesized. The synthetic peptides corresponding to bmZP1 were conjugated with diphtheria toxoid. Immunization of female BALB/cJ mice with the above conjugates and CSP-bmZP3((334-343 aa)) peptide led to the generation of an adequate antibody response against the respective zona peptide. Antibodies against bmZP1((251-273 aa)) and CSP-bmZP3((334-343 aa)) recognized bonnet monkey and human zona pellucida in an indirect immunofluorescence assay. Further, these antibodies when tested independently or in combination also significantly inhibited the binding of human spermatozoa to zona pellucida in a hemizona assay. These studies will further help in the design of synthetic peptide immunogens comprising of multiple B cell epitope from different zona proteins for better immunocontraceptive efficacy.

Amino Acid Sequence↗

PubMed1997

Induction of native protein reactive antibodies by immunization with peptides containing linear B-cell epitopes defined by anti-porcine ZP3 beta monoclonal antibodies.

To identify pertinent target epitopes for contraceptive vaccine development, rabbit polyclonal antibodies were raised against four peptides synthesized from the deduced amino acid (aa) sequence of porcine zona pellucida macromolecule ZP3 beta and coupled to diphtheria toxoid (DT). Synthetic peptides consisted of: P1, 23-37 aa; P2, 164-179 aa with an additional C-terminal cysteine; P3, 246-263 aa with an extra C-terminal cysteine; and P4, 310-321 aa residues corresponding to pZP3 beta precursor protein. Selected sequences were based upon B cell epitopes identified previously by monoclonal antibodies. Immune sera reacted with their respective peptides and DT in an ELISA, and also recognized porcine SIZP and pZP3 beta both in ELISA and Western blot and zona pellucida of porcine oocytes in an indirect immunofluorescence assay. None of the four anti-peptide sera recognized pZP3 alpha in Western blot, emphasizing the specificity of these antibodies to pZP3 beta. The anti-peptide sera, individually, failed to inhibit in vitro attachment of boar sperm to antibody treated zona encased porcine oocytes. However, combinations of immune sera against peptides such as P1 + P4, P2 + P4 and P1 + P2 + P4, did significantly inhibit porcine sperm-oocyte interaction. These results identify combinations of peptides that could potentially be used in the design of an immunocontraceptive vaccine based upon synthetic peptides corresponding to pZP3 beta or its homologues in other species.

Amino Acid Sequence↗

PubMed1997

Evidence for a long-lasting single administration contraceptive vaccine in wild grey seals.

A single-administration birth control vaccine based on liposome delivery of porcine zona pellucida antigens reduced pup production in grey seals (Halichoerus grypus) by about 90%. Anti-porcine zona pellucida titers of individual seals with two or more recaptures were variable but without a diminishing trend during the 5 year post-immunization period. Seals that produced at least one or more pups during the 2-5 year post-immunization period when the vaccine is fully effective, had an average anti-porcine zona pellucida titer of 5% of the reference serum. In contrast, the subset of seals that did not reproduce but were recaptured during the breeding season had an average titer of 31% of the reference serum. As measured by antibody titers and pup production, there were no differences in efficacy of the vaccine in 14-, 20- and 21-year-old female grey seals.

Age Factors↗

PubMed1999

The potential use of sperm antigens as targets for immunocontraception; past, present and future.

Immunocontraception, and in particular the targeting of antibodies to gamete-specific antigens implicated in sperm egg binding and fertilisation, offers an attractive approach to the growing global problem of overpopulation. Such an idea is not new; indeed several immunocontraception trials, using animal model systems, have been reported in recent years and a number are reviewed here. However, the results of these studies have been largely disappointing. We believe that two fundamental flaws attribute to the poor success of most of these preliminary immunocontraceptive trials. Firstly, loss of fertility has invariably been used as the assay. This presupposes that immuno-neutralisation of a single, gamete-specific antigen will be sufficient to cause a significant reduction in fertility; however, recent data suggests that such a premise may not be well-founded for a number of reasons. Secondly, and arguably the most important flaw, is the almost universal, but largely inappropriate, use of systemic immunisation as the sole route of antigen delivery. Whilst systemic immunisation regimes may lead to high serum IgG levels, these levels do not correlate with specific antibody levels in the reproductive tract or with contraceptive efficacy. Hence, an alternative antigen delivery approach is required which will induce an effective local immune response in the reproductive tract. Here we discuss the ways in which this might be achieved.

Animals↗

PubMed2000

Possible mechanisms of mammalian immunocontraception.

Ecological and conservation programs in ecosystems around the world have experienced varied success in population management. One of the greatest problems is that human expansion has led to the shrinking of wildlife habitat and, as a result, the overpopulation of many different species has occurred. The pressures exerted by the increased number of animals has caused environmental damage. The humane and practical control of these populations has solicited the scientific community to arrive at a safe, effective, and cost-efficient means of population control. Immunocontraception using zona pellucida antigens, specifically porcine zona pellucida (pZP), has become one of the most promising population control tools in the world today, with notable successes in horses and elephants. A conundrum has risen where pZP, a single vaccine, successfully induces an immunocontraceptive effect in multiple species of mammals. This review describes the most current data pertaining to the mammalian zona pellucida and immunocontraception, and from these studies, we suggest several potential mechanisms of immunocontraception.

Animals↗

PubMed1999

Vaccines for fertility regulation of wild and domestic species.

The application of fertility control technologies for the management of animal populations is still a relatively new concept and remains to be proven on a large scale. While there have been demonstrations of its utility using crude antigenic preparations of porcine zona pellucida, refined, cheap and easily delivered vaccines are still in the early phases of development, especially those required for remote delivery to free-ranging wild animal populations. The relative slow emergence of such technologies for practical application clearly reflects the complexity of the science and the requirement for a multidisciplinary research approach when attempting to develop such technologies for wild animal management. In many cases, one of the areas where further information is required is the immunobiology of such target species. Effective immunocontraceptive vaccines will also be critically dependent upon the design of the delivery systems. These will be unique to each species under study. A major challenge for free-ranging species will be to ensure that the vaccine can induce a long-lasting immune response to a high percentage of the target population, thus reducing the frequency and, hence, the cost of vaccine application. Many of the delivery systems being considered will utilise recombinant organisms. Hence, considerations on the use of such organisms needs to take into account the political, ethical and safety constraints prior to any environmental release. Also of prime importance is the issue of species specificity. In some instances, this will be a major challenge and careful thought will need to be given to ensure that specificity can be built into the vaccine at several levels. These might include the target antigen or epitopes, the microbial or other delivery vector, and, where applicable, the bait matrix and any target-specific attractive properties it may require. If these caveats can be satisfied and the public is able to accept the use of such vaccines, the potential for their application to manage animal populations and their impact is most certainly assured.

Animals↗

PubMed2002

Analysis of recombinant mouse zona pellucida protein 2 (ZP2) constructs for immunocontraception.

In this study we have examined the potential of recombinant mouse zona pellucida glycoprotein 2 (ZP2) as a target for immunocontraception. Immunogenicity studies and fertility trials were performed in outbred Swiss-Webster mice using four ZP2 constructs: Val(35)-Gly(200) (ZP2(V35-G200)), Val(35)-Leu(331) (ZP2(V35-L331)), Pro(325)-Ala(637) (ZP2(P325-A637)), and Val(35)-Ala(637) (ZP2(V35-A637)). A significant antibody response occurred to three of the four immunogens, however antibodies capable of recognizing native ZP occurred only after immunization with ZP2(V35-A637) and ZP2(P325-A637). Only immunization with ZP2(V35-A637) correlated with a reduction in fertility. Examination of the physiological basis for infertility revealed that: (1) passive transfer of ZP2 antiserum induced infertility in non-immune mice; (2) ovaries of infertile mice appeared histologically normal; (3) infertile mice produced normal numbers of eggs and (4) ZP of ovulated eggs from infertile mice demonstrated a significant reduction in the number of sperm bound compared to eggs from adjuvant controls. Infertility can be caused entirely by ZP2 antibodies without the incidence of significant ovarian pathology. This study also demonstrated that immunization with the bioactive (sperm binding) region of ZP2, recombinant ZP2(V35-G200), did not result in a significant immune response that recognized native ZP or inhibited fertility. Consequently we designed a ZP2-sperm antigen construct, replacing the C-terminal region of ZP2 with Sp17. This construct proved to be immunogenic and reduce fertility while directing the immune response to the Val(35)-Gly(200) region of ZP2.

Animals↗

PubMed2002

Elimination of luteinizing hormone cross-reactive epitopes from human chorionic gonadotropin.

The beta-chain of human chorionic gonadotropin (hCG) has been shown to have efficacy in clinical trials when used as a contraceptive vaccine. This hormone is a heterodimer, the alpha-chain being shared with the other members of the glycoprotein hormone family but the beta-chain being unique to hCG. Nevertheless, there is sequence homology between the hCG beta-chain and the beta-chain of human luteinizing hormone (hLH) which results in cross-reactive antibodies being produced following immunization with wild-type hCGbeta. To reduce or eliminate such cross-reactions we generated a number of mutants of the hCGbeta-chain. One mutant (hCGbeta(R68E)), containing an arginine to glutamic acid replacement at position 68, has been expressed as a recombinant protein in High Five insect cells. The recombinant BAChCGbeta(R68E) form of this molecule was used to immunize rabbits and the antibody response compared to the response following immunization with the recombinant wild-type protein BAChCGbeta and with the native hCGalphabeta heterodimer isolated from pregnancy urine. The mutant elicited the production of antibodies which avidly recognize native hCG. Compared to immunization with wild-type hCG, the response showed very little cross reactivity with hLH. This is demonstrated to be due to a radically altered epitope usage in the response to the mutant, which now focuses mainly upon the C-terminal region of the beta-chain.

Animals↗

PubMed2002

Evaluation of the immunocontraceptive potential of Escherichia coli expressed recombinant non-human primate zona pellucida glycoproteins in homologous animal model.

In order to evaluate the immunocontraceptive potential of zona pellucida (ZP) glycoproteins, recombinant bonnet monkey (Macaca radiata) zona pellucida glycoprotein-1 (r-bmZP1) and -2 (r-bmZP2) were expressed as polyhistidine fusion proteins in Escherichia coli. Female bonnet monkeys were immunized with the purified r-bmZP1 (n=5) and r-bmZP2 (n=4) conjugated to diphtheria toxoid (DT). Immunization led to generation of antibodies against r-bmZP1, r-bmZP2 and DT as determined by enzyme linked immunosorbent assay. The immunized animals exhibited normal menstrual cyclicity and progesterone profile, except during the summer amenorrhoea. Immunized animals, when mated with males of proven fertility, showed protection from conceiving for cumulative 45 ovulatory cycles in r-bmZP1-DT immunized group and 32 ovulatory cycles in r-bmZP2-DT immunized group. Ovarian histopathology of both the immunized groups revealed the presence of atretic follicles with degenerated oocytes, which may have been the principle cause for the failure of immunized animals to conceive in spite of the decline in either anti-r-bmZP1 or anti-r-bmZP2 antibody titres to background levels. These studies demonstrate, for the first time, that the block of fertility subsequent to immunization with r-bmZP1 and r-bmZP2, in a homologous non-human primate model, may be mediated due to ovarian dysfunction.

Animals↗

PubMed1997

Colinear synthesis of an antigen-specific B-cell epitope with a 'promiscuous' tetanus toxin T-cell epitope: a synthetic peptide immunocontraceptive.

Carrier conjugation is commonly used to provide T-cell help for small, linear peptides containing antigen-specific B-cell epitopes. However, carrier conjugation is expensive, variable and often results in adverse side effects if the conjugate is administered repeatedly. To eliminate the need for carrier conjugation, we examined two synthetic peptides for their ability to elicit sustained antibody titres in female rabbits and baboons. One peptide (hC1-20) was based on the sequence of the sperm-specific isozyme of human lactate dehydrogenase (LDH-C4). This peptide stimulates helper T-cell responses. The other peptide (bC5-19:TT) was a chimera between an LDH-C4 B-cell epitope and a 'promiscuous' T-cell epitope from tetanus toxin which has been shown to bind to and stimulate many different major histocompatibility complex alleles. Both peptides were immunogenic in rabbits and baboons. The chimera elicited consistently high antibody titres and was immunogenic in 19/19 wild-caught female baboons. When 14 bC5-19:TT immunized baboons were mated, their fertility was reduced by 62% compared with controls (P < 0.02). This carrier-free construct can be incorporated into biodegradable microspheres which may provide long-term protection from pregnancy with a single dose.

Amino Acid Sequence↗

PubMed1997

Comparative efficacy of two immunocontraceptive vaccines.

As part of our research program to develop immunocontraception as a wildlife management tool, we compared the physiological responses of wild Norway rats (Rattus norvegicus) to two immunocontraceptive vaccines; one involved mouse zona pellucida peptide (MZPP); the other involved gonadotropin releasing hormone (GnRH). Efficacy was monitored by immune, hormonal, and natality responses. Both vaccines were effective, but GnRH was much more effective (100% sterility of both sexes vs. 50% sterility of MZPP-treated females). Breeding success of control rats was 88% with litters of 5-9 pups; breeding success of MZPP rats was 50% with litters of 2-8; GnRH rats produced no young. In GnRH-treated male rats monitored for up to 17 months, testosterone was nondetectable and testes were atrophied to about 10% of their original volume for 10-13 months. There were no notable differences in mortality or body weights among groups, and, with the exception of testicular regression, there were no changes in general appearance. The GnRH vaccine is potentially a good rat reproductive control agent that may be effective over the normal lifespan of a rat under natural conditions in the wild.

Animals↗

PubMed1999

Prior immunity to a carrier enhances antibody responses to hCG in recipients of an hCG-carrier conjugate vaccine.

Pre-sensitization with carrier often leads to epitopic suppression of subsequent anti-hapten antibody responses. To ascertain whether epitopic suppression occurs in humans, we examined the effect of pre-existing anti-carrier immunity on antibody responses to hCG in volunteers of a clinical trial of an hCG-based conjugate birth-control vaccine. When we studied the correlation between pre-vaccination anti-carrier immunity and post-vaccination anti-hCG responses, we found that prior immunity to the carriers did not lead to epitopic suppression of anti-hCG responses. On the contrary, it was found that prior immunity to TT, one of the two carriers used in this vaccine, led to enhancement of anti-hCG responses. Our data indicates that prior immunity to the carriers may not be detrimental to the performance of conjugate vaccines, and may actually be beneficial in some cases.

Adult↗

PubMed1999

Long-term effects of PZP immunization on reproduction in white-tailed deer.

A 6-year study was conducted to determine the long-term effects of porcine zona pellucida (PZP) vaccine on the immune and hormonal responses, and reproduction of the white-tailed deer. The first 2 years of active immunization resulted in an 89% reduction in fawning. Vaccination with PZP produced reversible infertility lasting 1-4 years. Infertility was directly related to immune titers to PZP. Doe fertility was restored when the antibody titer dropped to minimal levels, but following re-immunization, infertility was reestablished. Reduction in fawning throughout the 6-year study was 76%. It was also observed that immune responses among deer were variable, especially in the first year of treatment. Variability was also observed among deer for the duration of infertility following the initial vaccination.

Animals↗

PubMed1999

The antigenic and immunogenic properties of synthetic peptide immunocontraceptive vaccine candidates based on gamete antigens.

In this study we have investigated the immunogenicity and antigenicity of synthetic immunocontraceptive vaccine candidates containing T- and B-cell epitopes arranged in different geometries. Two epitopes were selected, a B-cell epitope from fox sperm lactate dehydrogenase C(4) and a B-cell epitope from murine zona pellucida protein 3. Both were immunogenic in BALB/c mice when coupled to defined T helper cell determinants, eliciting antibodies which bound to the corresponding B-cell epitope and also to the recombinant protein. Because each of these proteins represent important components in the fertilisation process the results encourage further investigation of synthetic immunocontraceptive vaccines.

Amino Acid Sequence↗

PubMed2000

Reversible protection of disulfide bonds followed by oxidative folding render recombinant hCGbeta highly immunogenic.

Active immunization of women against human chorionic gonadotropin (hCG) has been considered as a promising option for contraception. However, prototype hCG vaccines based on natural sources of antigen are expected to be costlier for use by common people. In the present report, a functionally active, cost-effective antigen of bacterial origin has been described. Sulfonation of thiol groups of the protein, anion-exchange purification, refolding with concomitant formation of disulfide bonds in the presence of cysteamine-cystamine redox buffer, and slow removal of denaturant resulted in 95% homogeneous, monomeric form of the antigen. The recombinant processed antigen [CGbeta(p)] obtained this way was highly immunopotent. Cellular DNA and endotoxin contaminants were appreciably low in the final product. The immunogenic response was drastically reduced with the unprocessed antigen. This finding envisages better prospect of a cost-effective hCG vaccine for birth control.

Animals↗

PubMed2000

Immunocontraception of white-tailed deer using native and recombinant zona pellucida vaccines.

We conducted a 2-year feasibility study with native porcine zona pellucida (PZP) vaccine and three recombinant rabbit zona pellucida vaccines (RC55, RC75a and a combination of RC55, RC75a and RC75b) as an initial phase of developing a recombinant immunocontraceptive vaccine to control reproduction in overpopulated herds of white-tailed deer (Odocoileus virginianus). Forty captive white-tailed does were divided into five groups (one sham and four treated), of eight each and injected with a 500microg prime dose of vaccine. Each prime dose was followed by a 300microg booster dose at 3-7 weeks post prime. The frequency and number of months of observed breeding were higher in PZP immunized does than in sham controls. Although the antibody titers of the three recombinant groups were 1000 or less, as compared with the PZP group with titers often over 128,000, the fawning rates of the two recombinants were significantly lower than that of the control group. The combined antigen group did not have a significantly lower fawning rate.

Animals↗