Preliminary studies on the indium slide immunoassay for estimation of human chorionic gonadotropin and antihuman chorionic gonadotropin antibody

Human chorionic gonadotropin (hCG) is synthesized and secreted as early as 170 hr after fertilization and has been used as an index for pregnancy. Neutralization of hCG with a beta-subunit hCG vaccine(s) has been proposed as a contraceptive technique. To monitor the duration of effectiveness of the vaccine, it will be necessary to monitor the anti-hCG antibodies, especially those responsible for inhibiting the hCG bioactivity. We report a simple, rapid technique using an indium slide immunoassay for the qualitative estimation of hCG and to monitor a bioeffective anti-hCG antibody. The sensitivity of the indium slide assay to measure hCG ranged from 1 microgram/ml to 1 ng/ml, depending on the format of the assay. The indium slide assay also detected anti-hCG antibodies generated against a specific determinant on hCG recognized by a neutralizing monoclonal antibody (P3W80) in women immunized with a contraceptive vaccine.     

Use of Medroxyprogesterone Acetate as a Contraceptive in conjunction with Early Postpartum Rubella Vaccination

During a 12-month period 170 women received early postpartum rubella vaccination. An injectable “depot” progestogen was given to each of these patients for contraceptive purposes at the same time as the vaccine was administered. Subsequent observations showed that the progestogen was effective as a contraceptive in this context and that it did not appear to affect the immune response of the patients to the vaccine.     

Immunocontraception in Wild Horses: One Inoculation Provides Two Years of Infertility

ABSTRACT ABSTRACT Previous studies reported one year of contraception associated with a 1-injection porcine zona pellucida (PZP) vaccine. We have subsequently determined contraceptive effectiveness of a presumptive 1-injection, 2-year-duration PZP vaccine in free-roaming wild horses (Equus caballus) in Nevada, USA. In January 2000, we captured, freeze-branded, treated, and subsequently released 96 adult females that received 1) a primary dose of vaccine emulsion consisting of aqueous PZP and Freund's Complete Adjuvant, and 2) booster doses of PZP and adjuvant in controlled-release polymer pellets. We determined PZP release characteristics of pellets in vitro, prior to field use. We determined reproductive success in treated and untreated females through October 2004 via measurement of estrone sulfate and progesterone metabolites in fresh feces collected from the ground and by twice-annual foal counts. Among treated females, annual reproductive success from 2001 though 2004 sequentially was 5.9%, 14.0%, 32.0%, and 47.5%. Untreated females showed average reproductive success of 53.8 ± 1.3% across this period. This study revealed that: 1) PZP acted as an effective contraceptive for 2 years posttreatment; 2) some residual contraceptive effect remained in year 3; and 3) fertility returned to control levels by year 4 posttreatment. It appears that controlled-release technology can replace both the second(1-month) and annual booster injection of PZP vaccine, thereby decreasing cost and increasing efficiency of use of this vaccine in wild horse management.     

Immunocontraception par la prévention de l’interaction gamétique

The paper summarize the main data relevant to the obtention of contraceptive vaccines based on spermatozoa as well as zona pellucida antigens. The development of novel forms of contraception is one way in which this global population problems can be tackled. The sperm as well as the oocyte antigens are studied as possible contraceptive vaccine candidates are the subject of this review.     

Immunocontraception of captive exotic species

The biological efficacy of porcine zona pellucida (PZP) immunocontraception and the timing of booster inoculations were determined in 24 species of ungulates and five species of non‐ungulates across 10 years of treatment and for which no technical problems were identified. The collective contraceptive efficacy for 265 ungulates, 25 bears, and 11 sea lions, across 517 contraceptive intervals was 93.3%, and contraceptive efficacy ranged from a low of 60% in nyala (Taurotragus angasi) to 100% in 16 other species. The timing of annual booster inoculations was adjusted, between 6 months and 12 months, depending on the length of the breeding season and the species‐specific immune responses. The high degree of efficacy in bears and sea lions suggests that the PZP vaccine has some application in certain non‐ungulate species. Technical problems in the timing and delivery of the vaccine can cause non‐biological failures and were identified in an additional 20 animals, not included above, and included inoculating pregnant animals, the use of needles too short for effective intramuscular injections, failure to complete the initial inoculation series, and failure to give booster inoculations at the prescribed time. Zoo Biol 0:1–10, 2005. © 2005 Wiley‐Liss, Inc.     

Human sperm-specific peptide vaccine that causes long-term reversible contraception

A novel dodecamer peptide sequence, YLP(12), was identified on human sperm that is involved in oocyte binding. We investigated its immunocontraceptive effects in a murine model. A vaccine was prepared by conjugating the synthetic YLP(12) peptide with the binding subunit of recombinant cholera toxin. Vaccination of female mice by i.m. or intranasal routes without any additional adjuvant induced a sperm-specific immune response in serum and the vaginal tract that caused a long-term contraceptive state. Fertility was fully regained when antibody reactivity diminished at 305-322 days. The contraceptive effect was also completely reversed voluntarily by intravaginal administration of the peptide. Antibodies affected fertility at the prefertilization stage by inhibiting sperm capacitation and the acrosome reaction, and sperm-oocyte binding. The peptide sequence is an epitope of a 50 +/- 5-kDa membrane protein localized on the acrosome and tail of spermatozoa. Thus, the sperm-specific YLP(12) is an attractive candidate for contraceptive vaccine.     

Birth control vaccine targeting leukemia inhibitory factor

The population explosion and unintended pregnancies resulting in elective abortions continue to impose major public health issues. This calls for a better method of contraception. Immunocontraception has been proposed as a valuable alternative that can fulfill most, if not all, of the properties of an ideal contraceptive. There are several targets that are being explored for contraceptive vaccine development. Leukemia inhibitory factor (LIF), a member of interleukin‐6 family, is required for embryo development and successful blastocyst implantation in several mammalian species. The present study was conducted to examine if LIF can be a target for the development of a birth control vaccine. Three sequences from LIF and two sequences from LIF‐receptor (LIF‐R) that span the regions involved in ligand‐receptor binding were delineated, and peptides were synthesized based upon these sequences. Antibodies raised against these five peptides reduced LIF bioactivity in an in vitro culture assay using BA/F3 mLIF‐R‐mpg130 cells. Vaccines were prepared by conjugating these peptides to various carrier proteins. Immunization of female mice with these peptide vaccines induced a long‐lasting, circulating as well as local antibody response in various parts of the genital tract, and resulted in a significant (P ≤ 0.05) inhibition in fertility in all the three trials; the LIF‐R peptide vaccines proved to be a better vaccine target. The data indicate that LIF/LIF‐R is an excellent target for the development of a birth control vaccine. This is the first study, to our knowledge, that examined LIF/LIF‐R as a target for immunocontraception. The findings of this study can be easily translated to humans since LIF/LIF‐R is also important for implantation and pregnancy in women. Mol. Reprod. Dev. 79:97–106, 2012. © 2011 Wiley Periodicals, Inc.     

Immunocontraception and increased longevity in equids

Intensive population management by means of fertility control has been shown to change the age profile of a wild horse herd. The primary change has been an increase in the number and percent of older animals, as expected, but also the appearance of new and older age classes. An examination of direct effects of fertility control on two groups of treated animals shows a significant increase in longevity over non‐treated animals that is associated with contraceptive treatment. The mean age at death (MAD) was calculated for 128 wild horses for which precise birth and death dates were known, including 56 stallions, 42 untreated mares, 11 mares treated with a porcine zona pellucida contraceptive vaccine for 1–2 years, and 19 mares treated with the same vaccine for ≥3 years. The MAD for stallions (10.3±0.84 [SEM] years), and mares treated for 1–2 years (10.2±0.56), was significantly greater (P<0.05) than for untreated mares (6.4±0.85), and significantly <19.9±1.66 for mares treated ≥3 years (19.9±1.66). Zoo Biol 26:237–244, 2007. © 2006 Wiley‐Liss, Inc.     

The impact of demand factors, quality of care and access to facilities on contraceptive use in Tanzania

The low contraceptive prevalence rate and the existence of unmet demand for family planning services present a challenge for parties involved in family planning research in Tanzania. The observed situation has been explained by the demand-side variables such as socioeconomic characteristics and cultural values that maintain the demand for large families. A small, but growing body of research is examining the effect of supply-side factors such as quality of care of family planning services on the demand for contraceptives. This paper analyses the demand and supply factors determining contraceptive use in Tanzania using the Tanzania Service Availability Survey (1996) and the Tanzania Demographic and Health Survey (1996) data sets. The results show that access to family planning services and quality of care of services are important determinants of contraceptive use in Tanzania even after controlling for demand-side factors.     

Immunoinhibition of human fertilization in vitro by antibodies to the cumulus oophorus intercellular matrix

Rabbit polyvalent antiserum raised against the solubilized cumulus matrix was a powerful inhibitor of human fertilization in vitro, affecting sperm-zona pellucida interaction. Both sperm binding to, and penetration of, the zona pellucida were severely impaired by the anti-cumulus matrix antiserum, whereas no effects of this antiserum on cumulus matrix solubilization or penetration of zona-free human eggs were evident. Moreover, the anti-cumulus antiserum partly neutralized the acrosome reaction-inducing activity of the cumulus matrix. These results warrant further research into the functional specificity of different cumulus matrix components and into the effects of the respective antibodies on reproductive function as a possible lead to a new approach to contraceptive vaccine development.     

Non-cross-reactivity of antibodies to murine LDH-C4 with LDH-A4 and LDH-B4

The induction of infertility by immunization with the sperm-specific lactate dehydrogenase, LDH-C4, suggests its use in a contraceptive vaccine. Development of an immunological contraceptive for human use, however, requires that there be no cross-reactions with somatic tissues. We have demonstrated, using enzyme-linked immunoabsorbence, solid-phase radioimmunoassay, and competitive inhibition radioimmunoassay, that antisera to LDH-C4 is specific and does not cross-react with the somatic isozymes, LDH-A4 and LDH-B4.     

Contraception épididymaire: état des recherches et perspectives

The development of new contraceptive strategies is a major economic challenge. The epididymis, the site of post-testicular maturation of spermatozoa, has recently become the subject of research as a target organ for the development of new contraceptive approaches in mammals. The epididymis, which transports and stores spermatozoa (in most mammals), is a key organ, due to its various funtions, in the acquisition of the fertilizing property of male gametes. Although the complex phenomena of secretion and reabsorption leading to remodelling of spermatozoa and acquisition of their capacity to recognize and fertilize the ovum are far from being fully elucidated, major progress has been made concerning the physiology of the mammalian epididymis. After a brief review of the activities of epididymal epithelium, the authors discuss the main lines of research for the development of future post-testicular contraceptive strategies with particular emphasis on the cases of infertility encountered in recent generations of various models of transgenic mice.     

Contraceptive implants: long acting and provider dependent contraception raises concerns about freedom of choice.

David Bromham''s editorial on contraceptive implants ignores the wider issues to voice concern that trial by media could limit contraceptive choice by jeopardising research into new methods. However, it is more beneficial to the public for points of conflict to be debated openly. Furthermore, the impetus for research into new contraceptive technology is driven by profit and political motives and is only marginally affected by the media. Implanted contraceptives may increase the choice of contraceptive methods, but they put control of fertility increasingly into the hands of the medical profession. Herein lies their greatest problem: their potential to increase providers'' control over clients'' choice. There is the danger that certain groups of women may be targeted for their use: in the United States the coercive use of Norplant for mothers receiving welfare benefit has been suggested. Long acting contraceptives are a contraceptive of choice only when they are available without pressure, as part of a wider menu; when instant removal on request is guaranteed; and when there is an open and free flow of information and opinions between users, health professionals, and special interest groups.     

Enhanced contraceptive response by co-immunization of DNA and protein vaccines encoding the mouse zona pellucida 3 with minimal oophoritis in mouse ovary

Zona pellucida 3 (ZP3) acts as the primary sperm receptor, induces autoantibody that can prevent oocyte fertilization and has been proposed as a vaccine candidate for contraception in humans. Due to the elicited autoreactive T cell inflammation that causes ovarian destruction, ZP3-based vaccine with removed T epitopes from the ZP3 is considered as a preferred approach. We present here a new strategy to eliminate the T cell inflammation while retaining a high level of antibody by co-immunization of mZP3 DNA and protein vaccines, which resulted in a higher reduction rate of fertility in this group. Histological analysis showed that there were normal follicular developments of infertile mice in the co-immunized group; while other vaccine groups of the most infertile mice lacked mature follicles. There was a significant correlation between normal follicular development and the inhibition of T cell response in co-immunized mice. At the same time, co-immunization reduced the production of inflammatory cytokine, IFN-gamma, and increased the productions of IL-10 and FoxP3 in CD4 T cells, suggesting the anti-inflammation may be via a T regulatory function. The results indicate that co-immunization of mZP3 DNA- and protein-based vaccines can reduce fertility without interfering with the normal follicular development and present a novel strategy to develop a contraceptive vaccine in humans.     

Vaccines for control of fertility.

Major developments in birth control vaccines are on the horizon. The human chorionic gonadotropin (hCG) vaccine has entered phase II clinical trials after successful completion of phase I studies at 5 centers in India and 4 centers abroad. It is the most advanced vaccine of its type in the world. The trials are being conducted on women of proven fertility who are sexually active. The available results indicate the efficiency of the vaccine to prevent pregnancy in women at or above titres of 50 ng/ml. A vaccine inducing antibodies against gonadotropin releasing hormone (GnRH) has been approved in India for trials in postpartum women, to determine whether immunization can help prolong lactational amenorrhea. The GnRH vaccine is also in clinical trial in prostate cancer patients at 2 centers in India and in Austria and the Dominican Republic. The follicle stimulating hormone (FSH) vaccine is about to enter phase I clinical trial after completing experimental and toxicological studies. A vaccine against FSH has been developed for human males employing ovine FSH (oFSH) as an immunogen. oFSH adsorbed on alum induces antibodies reactive with human FSH in bonnet monkeys. Immunization leads to oligospermia with resultant impairment of fertilization potential. No reduction in testosterone levels has been reported. Research is in progress to identify antigens on spermatozoa, which could serve as vaccine candidates. PH-20, a protein located on the inner acrosomal membrane of capacitated sperms, has been reported to have 100% contraceptive efficacy in both sexes of guinea pigs in active immunization studies. cDNA probes of PH-20 cross-react with genomic DNAs of mouse, rat, hamster, and human. The sperm antigen, lactate dehydrogenase C4 (LDH-C4), is a glycolytic enzyme. Active immunization with LDH-C4 suppressed fertility in mice, rabbits, and baboons. SP-10, which is a testis-specific human sperm protein, is also a promising candidate.     

Strategies for successful designing of immunocontraceptive vaccines and recent updates in vaccine development against sexually transmitted infections - A review

BackgroundThe world population is continuously growing. It has been estimated that half of the world’s population is from the Asian continent, mainly from China and India. Overpopulation may lead to many societal problems as well as to changes in the habitat. Birth control measures are thus needed to control this growth. However, for the last 50–60 years, there have not been any improvements in the field of contraception. Nevertheless, the immunocontraceptive vaccine is an emerging field, and it might be the only replacement for the existing mode of contraception for the next millennium. Sexually transmitted infections (STIs) are frequent, and their transmission rate increases yearly. As antibiotics are the prevailing treatment for this kind of infections, resistance in humans has increased; therefore, having effective antibiotic treatments for STIs is now a concern. Vaccines against STIs are now needed. It is thought that the improvements in the fields of proteomics, immunomics, metabolomics, and other omics will help in the successful development of vaccines.ObjectiveTo collect and review the literature about recent advancements in immunocontraception and vaccines against sexually transmitted diseases/infections.MethodsReliable scientific databases, such as PubMed Central, PubMed, Scopus, Science Direct, and Goggle Scholar, were consulted. Publications bearing important information on targeted antigens/immunogens for contraceptive vaccine design and advancements in vaccine development for STIs were gathered and tabulated, and details were analyzed as per the theme of each study.ResultsImportant antigens that have a specific role in fertility have been studied extensively for their contraceptive nature. Additionally, the advancements in the screening for the best antigens, according to their antigenic nature and how they elicit immune responses for an extended period were also studied. Herd immunity for STIs and advancements in the development of vaccines for syphilis, gonorrhea, and herpes simplex virus were also studied and tabulated in this review. An extensive knowledge on STIs vaccines was gained.ConclusionThis extensive review is aimed to provide insights for active researchers in vaccinology, immunology, and reproductive biology. Advancements in the development of vaccines for different STIs can be gathered as a wholesome report.     

Delivering non-hormonal contraceptives to men: advances and obstacles

There have been major advances in male contraceptive research during the past two decades. However, for a contraceptive to be used by men, its safety requires more stringent scrutiny than therapeutic compounds for treatment of illnesses because the contraceptives will be used by healthy individuals for an extended period of time, perhaps decades. A wide margin is therefore required between the effective dose range and doses that cause toxicity. It might be preferable that a male contraceptive, in particular a non-hormone-based compound, is delivered specifically and/or directly to the testis and has a rapid metabolic clearance rate, reducing the length of exposure in the liver and kidney. In this article, we highlight the latest developments regarding contraceptive delivery to men and with the aim of providing useful information for investigators in future studies.     

AIDS猕猴模型在HIV疫苗研究中的应用

对HIV疫苗的研究一直是国际上艾滋病方面研究的热点和难点。动物模型则为疫苗研究必不可缺少的重要工具,缺乏合适的动物模型很大程度上制约了AIDS疫苗的研究。目前在国际上SIV或SHIV感染的猕猴模型为最常用的AIDS研究模型,受猕猴背景及病毒特性等多种因素的影响,使得以上两种模型在HIV疫苗研究中仍存在一定的局限性。为了更好地发挥猕猴模型在HIV疫苗研究中的巨大潜力,开发理想的AIDS猕猴模型已成为目前HIV疫苗研究的首要任务。本文简要介绍了AIDS疫苗的研发策略、研发概况以及SIV/SHIV猕猴模型在HIV疫苗中的应用,并对其中存在的问题及其应用前景进行了探讨。