Contraceptive Vaccines: Success, Status, and Future Perspective (2011)

The contraceptive choices available to women at this time include steroid contraceptives, intrauterine devices, barrier methods, spermicidal compounds, natural family planning, male and female sterilization, and recently available emergency contraceptives. Contraception has come a long way from when the first oral contraceptive pill was approved for use by the FDA in 1960. Despite all of the advances in contraceptive technology, the world population is increasing at a tremendous rate, affecting growth and development in every sector. It has exceeded 6.891 billion and is increasing by one billion every 12 years.1 In the first year AD, the world population was 250 million, which increased to 1 billion by 1830. It took the next 100 years for the population to increase by 1 billion and presently it is increasing by ∼270,000 every day. Ninety-five percent of this growth is in the developing nations. Also, apart from this population growth, unintended pregnancies resulting in elective abortions continue to be a major public health issue. An estimated 80 million women have unintended/unwanted pregnancies worldwide annually, and 45 million of these end in abortion.2 In the United States, each year, half of all pregnancies are unintended, which results in over 1 million elective abortions.3 In over half of these unintended pregnancies, the women were using some type of contraceptive. This calls for a better method of contraception that is acceptable, effective, and available both in the developed and developing nations. It should be non-steroidal, non-barrier, non-surgical, intercourse independent, and reversible. Contraceptive vaccines (CV) have been proposed as valuable alternatives that can fulfill most, if not all, of the properties of an ideal contraceptive. Because of their high target specificity, long-term action, low cost, and without any side-effect, the development of CV is indeed an advancement in the field of contraception. As the developed and most of the developing nations have an infrastructure for mass immunization, constructing vaccines for contraception is an exciting proposition. Besides the emerging contraceptive needs for humans, there is an urgent need for novel contraceptive methods for fertility regulation of domestic animals, wildlife (wild horses, deer, elephants), stray dogs and cats, zoo animals, and cattle. A non-surgical humane method that is less expensive and long-lasting is required for controlling farm, feral, stray, and domestic animal populations. Immunological approach to block fertility in these species has been found to be most suitable modality and drawn considerable attention lately. Wildlife contraception has its own set of unique challenges, not required for human contraception. The history of immunocontraception started with the ‘sperm’, as the first target. It started in 1899 when Nobel Prize recipient Karl Landsteiner4 from Austria and Serge Metchnikoff5 from Russia working at the Pasteur Institute independently demonstrated that injection of sperm from heterospecies can produce antibody response. Following this, there are reports published in early 1900 that injection of sperm can produce a period of sterility/infertility in the injected animals. In 1929, Morris J. Baskin,6 a Denver-based surgeon and the clinical director of the Denver Maternal Hygiene Committee, used human sperm to produce reversible sterilization in fertile women. A US patent was issued for this spermatoxic vaccine in 1937 (US patent number 2103240). Subsequently, there are few preliminary reports that used bull sperm instead of human sperm to induce antibodies in women for contraception. Between 1950 and 1970, the sperm immunization studies regained impetus for fertility regulation. The recent Nobel Prize winner of Physiology and Medicine in 2010, Dr. Robert Edwards, was also very interested in immunocontraception.7 When he started the new journal, Human Reproduction Update, that is now the most prestigious journal in reproductive biology with the highest impact factor (>7.04), he asked me to write a review on the CV. That review was published as the first article in the first volume and first issue, starting with the first page.8 During 1970s, the scientists began investigating various other targets besides sperm that can be used for contraceptive vaccine development. The various molecules that are being explored for CV development at the present time are summarized in Fig. 1. They can be broadly divided into three categories: vaccines targeting gamete production [gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH)], gamete function [sperm antigens and oocyte zona pellucida (ZP)], and gamete outcome [human chorionic gonadotropin (hCG)]. Their success, limitations, and current status are summarized in Table I. The vaccines targeting gamete production, namely the GnRH vaccines, have demonstrated a high degree of success in several wildlife species, including cats, in both the male and female sexes. They affect sex steroids because they block LH/FSH secretion. The GnRH vaccines have been developed by several pharmaceutical companies as substitutes for castration of domestic pets, farm, and wild animals. These vaccines can also be used in humans, especially for non-contraceptive purposes, such as decreasing androgens in prostatic hypertrophy and carcinoma in men. They can also be used in women that require decreasing sex steroids, such as in uterine fibroids, polycystic ovary syndrome, endometriosis, and precocious puberty. CV targeting molecules involved in gamete function, such as sperm antigens and ZP proteins, are exciting choices. Sperm constitute the most promising and exciting target for CV. Several sperm-specific antigens have been delineated in various laboratories and are being actively explored for CV development. Studies are focused on delineating appropriate sperm-specific epitopes and increasing the immunogenicity (specifically in the local genital tract) and efficacy on the vaccines. Anti-sperm antibody (ASA)-mediated immunoinfertility provides a naturally occurring model to indicate how a vaccine might work in humans. Vaccines based on ZP proteins are quite efficacious in producing contraceptive effects, but may induce oophoritis, affecting sex steroids in some species. They have been successful in controlling feral populations of deer, horses, and elephants, populations of several species of zoo animals, and female dogs. The current research for human applicability is focused on delineating infertility-related epitopes (B-cell epitopes) from oophoritis-inducing epitopes (T-cell epitopes). Vaccines targeting gamete outcome primarily focus on the hCG molecule. The hCG vaccine is the first vaccine to under Phase I and II clinical trials in humans. Both efficacy and lack of immunopathology have been well demonstrated for this vaccine. At the present time, studies are focused on increasing the immunogenicity and efficacy of the birth control vaccine and examining its clinical applications in various hCG-producing cancers. Schematic model indicating various targets that are being explored for the contraceptive vaccine development. These include targeting gamete production [gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH)], gamete function [zona pellucida (ZP) proteins of the oocytes and sperm antigens], and gamete outcome (human chorionic gonadotropin [hCG]). This special issue has six articles written by well-established investigators who are pioneers and have extensively published in the field of immunocontraception. These articles review the success, status, and future perspective of CV targeting various molecules. The article by: Rajesh K. Naz focuses on vaccines targeting sperm antigens, Angela R. Lemons and Rajesh K. Naz on vaccines targeting molecules involved in pregnancy establishment and maintenance, G.P. Talwar et al. on hCG vaccine, Jay Kirkpatrick et al. on PZP vaccine, Satish K. Gupta et al. on zona vaccine, and Julie R. Levy on GnRH vaccine. This special issue is a unique and comprehensive treatise offering up-to-date information on immunocontraception. Each author has presented the data in a dynamic manner, including updated and vital scientific information. After reading these articles, one can come to the conclusion that immunological approach to contraception is indeed a viable and exciting proposition which has become a reality in several species. The field of immunocontraception has come a long way during the last decade. PZP and GnRH vaccines have been highly successful in controlling wildlife population, domestic pets, and several species of zoo animals. The hCG vaccine has shown potential success in human clinical trials in women. Additional impetus and funding from federal, pharmaceutical, and other sources are urgently needed to move this exciting field forward and translate this successful proposition to clinical utility in humans and animals.