By Bonnie Urquhart, R.N.
Native Wild Horses in Utah (Photo © Cynthia Smalley, all rights reserved)
Feral mares grazing on Assateague, a barrier island off the Maryland coast, benefit from a contraceptive strategy that would leave many women envious. Their fertility is curbed by a method that employs neither hormones nor devices, but instead convinces the immune system to target reproductive components and render them inactive. Derived from the ova of pigs, the porcine zona pellucida (PZP) vaccine has been administered annually via dart gun to regulate the fertility of these fast-breeding animals since 1988.
An immunized mare comes into come into heat and mates as usual, but as soon as she ovulates, her immune system considers her endogenous zona pellucida foreign and spackles it with antibodies, blocking fertilization with an effectiveness rate of 90-100 percent (Kirkpatrick, Turner, Liu, Fayrer-Hosken, & Rutberg, 1997). Immunocontraception does not alter the normal reproductive behavior of these horses, is usually reversible if used for less than seven years, and does not appear to harm unborn foals if the mother is accidentally injected while pregnant. Until this approach was developed, feral horse overpopulation was a chronic headache for wildlife biologists determined to keep the large animals from outstripping their food supply and outcompeting native wildlife.
Vaccination against pregnancy is itself a unique concept. Traditional vaccines are derived from foreign proteins that sensitize the body to fight off microbial invaders. Immunocontraceptives reprogram the body to attack part of itself by attaching it to a foreign, non-tolerated molecule (Sprenger, 1995) (Schrater, 1995). By focusing on different target molecules, researchers can prime the immune system to thwart the production and transport of gametes, disturb the interaction of the gametes that leads to fertilization, or interfere with implantation. Zona pellucida vaccines focus on what may be the ideal target-the translucent glycoprotein extracellular matrix, surrounding all mammalian ova, that sperm must penetrate to achieve fertilization.
Nearly 100 species have been successfully contracepted with PZP vaccines, including rabbits, dogs, deer, elephants, gray seals, and non-human primates, as well as amphibians and fish. “Its application to wildlife…has been spectacular. We are fourteen years down the road with wildlife and it comes close to being the perfect agent,” says Dr. Jay Kirkpatrick, reproductive physiologist and developer of the PZP vaccine used today for wildlife management (personal communication, October 23, 2001).
Zona pellucida vaccines were being for considered for human contraceptive use long before Kirkpatrick’s research group adapted it for wildlife. Around the time it gained favor with wildlife biologists, researchers seeking human application were becoming quite discouraged. Native pig protein was not suitable for human use, and researchers were unable to develop an effective recombinant or synthetic form of human ZP (Kirkpatrick, 2001). Molecular biologists could synthesize the protein backbone of the molecule, but not the carbohydrate components. Without the carbohydrates, the vaccine would trigger immune response, but could not block fertilization.
Another problem is the vaccine’s tendency to become irreversible over time. Immature eggs within the ovaries are also surrounded by zona pellucida. An agent that sensitizes the woman against zona pellucida not only would cause her body to attack its mature ova at ovulation, but could also provoke an immune attack on her immature egg cells and inflammatory destruction of the ovary itself, causing permanent infertility (Feng, Sandlow, Sparks, & Sandra 1999) (Richter, 1996).
Adverse autoimmune reactions resulting in disruption of folliculogenesis and depletion in the primordial follicle pool have been observed in the ovaries of mice (Patterson, Jennings, van Duin, & Aitkin, 2000). Mares, rabbits, and dogs maintained on long-term PZP have sometimes shown abnormal hormonal profiles and altered estrus cycles. A wild mare vaccinated for three years might take between one and six years to regain fertility. After seven years, she may become permanently infertile. Women who desire a reversible method would find this effect unacceptable, but clinicians might someday find zona pellucida vaccines an attractive option for women who have finished childbearing.
Human immunocontraceptive research is not new. At least twelve studies in the 1920s and 1930s evaluated immunocontraception in the human female, but the trials were not successful and “unspecified ethical restrictions” ended the research (Richter, 1996). Better understanding of immune function and molecular biology has revived interest in immunocontraceptive research over the past two decades.
The most suitable candidates for contraceptive vaccine development are molecules on the surface of the gametes or on the fertilized ovum and early embryo and the hormones hCG and GnRH. Anti-gamete vaccines are the most attractive option because they do not disrupt an embryo after fertilization or alter the hormonal balance, but researchers have so far been unable to reliably block fertilization without introducing cross-reactions with other tissues (Schrater, 1995).
Bringing a product from the laboratory to the pharmacy is a long and expensive process, and funding sources are limited (Klitsch, 1995). After selecting a target molecule for study, biologists must isolate, characterize, and synthesize effective molecules from sperm or ova; understand mechanisms by which the immune system blocks fertility; develop an effective, benign adjuvant; create reliable, inexpensive tests to monitor fertility status in immunized individuals; and carefully evaluate the product for immunological and other side-effects (O’Rand & Lea, 1997) To market an effective immunocontraceptive, developers must progress from creating the vaccine in the laboratory to preclinical studies to clinical trials (Feng, Sandlow, Sparks, & Sandra 1999).
Because research and development are costly and regulatory obstacles to new drugs are forbidding, any pharmaceutical company that puts an immunocontraceptive on the market is likely to emphasize its effectiveness, play down adverse findings, and energetically court clinicians with free samples and gadgets. Artfully crafted advertisements will spark public excitement over this innovative contraceptive method, and as a result patients will request the medication without understanding much about its action. The CNM will serve as intermediary between hyperbole and hope, keeping clients grounded in reality as they discuss benefits and possible adverse outcomes.
Vaccines targeting human chorionic gonadotropin (hCG) show a higher likelihood of success than many other immunocontraceptive projects. Produced by the embryo to sustain progesterone production, hCG allows the pregnancy to establish and maintain itself. If antibodies disable the hCG molecule, progesterone drops and uterine endometrium sheds, preventing implantation. Because the result is loss of an early pregnancy, anti-abortionists strongly oppose developing an effective hCG vaccine and block U.S. government grants that would speed research (Klitsch, 1995). By 1995, three prototype hCG vaccines had undergone limited clinical trials in women (Schrater, 1995). The initial three injections lasted about 6 months, and did not affect menstrual cycles.
Unfortunately, the chemical similarity of hCG to luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH) apparently induces cross-reactions elsewhere in the hormonal system. Blocking some hormones and interfering with feedback mechanisms could conceivably wreak endocrine havoc, perhaps irreparably damaging the thyroid and the pituitary glands (Feng, Sandlow, Sparks, & Sandra 1999) (Richter,1996). The vaccinated woman would produce and then attack reproductive hormones, continuously creating immune complexes that could cause tissue damage. Or perhaps this reaction would prove to be benign; in short-term clinical trials of the hCG vaccine, all subjects developed cross-reactive antibodies to LH, and all continued to cycle normally. Female rhesus monkeys immunized repeatedly for seven years with ovine (sheep) LH became infertile but continued to ovulate, had regular menstrual cycles, and maintained normal pituitary function (Schrater, 1995).
Higher on the hypothalamic-pituitary-ovarian axis is gonadotropin- releasing hormone (GnRH), the hormone that spearheads the production of sex steroids in both men and women. The National Institute of Immunology and the Population Control Council have tested a GnRH vaccine on human subjects, including breastfeeding women (Schrater, 1995). The result is effective-but dramatic. The GnRH vaccine essentially effects non-surgical castration, halting testosterone production in men (with accompanying impotence and loss of body hair) and effecting menopause in women (Richter,1996). Hormonal supplements could remedy the deficit, but consumers are unlikely to find this approach acceptable. This technology would be more applicable to veterinary medicine, making possible non-traumatic spaying and castration and in wildlife biology the reduction of, say, deer herds in suburban neighborhoods where hunting is not feasible. Trials of GnRH vaccines on Norway rats resulted in 100 percent sterility in both sexes (Miller, 1997).
Potentially promising are experimental vaccines that target male FSH receptor proteins, inducing men to produce low-quality sperm incapable of fertilization but sparing them the need for exogenous testosterone supplementation. Other biologists have targeted prostaglandinF2, oxytocin, and structural placental antigens (Feng, Sandlow, Sparks, & Sandra 1999). It is the advanced practice nurse who must serve as the intermediary between technology and the client, translating technical information and exploring treatment options while considering the safety of the product.
Vaccines triggering an immune response against sperm could be used by either men or women. Laboratories have experimented with structural and functional antigens on the sperm itself, and with spermatic enzymes. Target specificity is the stumbling block-an immune response that incapacitates sperm also tends to induce the immune system to attack other organs and tissues as well.
With immunocontraceptives, there is often a reciprocal relationship between specificity and effectiveness. If a vaccine is very specific to one small antigen, there is little danger that the immune system will attack similar targets, but contraceptive action is ineffective. An agent that targets several components is much more effective, but the immune response is likely to involve other tissues. The immune system is intimately connected to every part of the body. The potential for an untoward autoimmune response is great, and tissue injury may be difficult to prevent. But perhaps this damage is purely theoretical: anti-sperm antibodies frequently occur in vasectomized men and some women spontaneously become immune to sperm with no identifiable systemic damage (Schrater, 1995) (Diekman & Herr, 1997). Women sometimes develop immune responses against their own zona pellucida as well, and seem to suffer no other ill effects (Schrater, 1995).
Kirkpatrick reports that Assateague mares, freed from the stress of pregnancy and lactation, have enjoyed improved health since the vaccine program started (Barber &Frayer-Hosken, 2000). Studies in horses and dogs show that although ovarian damage occurs, the PZP antibodies in a vaccinated animal do not cross-react with major organ systems such as the brain, heart, and urinary tract (Barber & Frayer-Hosken, 2000). Research with horses and other animals indicates that offspring born to previously contracepted mares, and even mares who were accidentally vaccinated while pregnant, appear normal and go on to produce normal foals themselves. Damage to human fetuses might be more subtle, perhaps manifesting in a chronically overstimulated or sluggish immune system or in hormonal anomalies that might not appear until puberty. We just do not know.
Potential lawsuits make domestic pharmaceutical companies reluctant to engage in immunocontraceptive research, but several companies around the world are optimistic. Canadian biotech firm Immucon has a patent for a male immunocontraceptive vaccine that neutralizes sperm fertilizing capacity by targeting a crucial zona pellucida sperm-binding protein at the level of the epididymus. The company expects to market the vaccine between 2005 and 2007. Immucon believes that reversible male immunocontraceptives will be an $850 million-a-year industry worldwide, and female immunocontraceptives will be worth $990 million a year (Immucon, 2001). Liability reform may encourage the pharmaceutical industry to conduct more contraceptive research (Klitsch, 1995).
Researchers are also exploring injectable agents that could render a man or woman permanently sterile. This could eliminate the pain and expense of tubal ligation or vasectomy while effectively ending childbearing.
Four out of every ten pregnancies in the world are unplanned-80 million a year (AGI,1997). The World Health Organization estimates that between eight million and 30 million unplanned pregnancies are the result of inconsistent or incorrect use of contraceptive methods or from method-related failure, and 120 to 150 million married women want to limit or space their pregnancies but lack the information and services to do so. Worldwide, 55,000 unsafe abortions take place every day, 95 percent of them in developing countries. Every day, more than 200 women die from these procedures (http://www.who.int/archives/whday/en/pages1998/whd98_10.html.). Optimally spaced and planned pregnancies benefit the health of both mothers and children. World population is expected to reach 10 billion by the year 2050, and overpopulation can lead to poverty, famine, disease, depletion of resources, and environmental degradation (Feng, Sandlow, Sparks, & Sandra 1999).
A safe, reliable immunocontraceptive agent could be the family planning strategy of choice for women in developing countries. Proper implementation, however, could strain resources. Clinicians must perform pregnancy tests before immunization and periodically screen recipients to verify that the vaccine is still effective.
If the perfect immunocontraceptive is developed, there would be tremendous potential for misuse and coercion by population-control programs to reduce the birth rate of the poor, non-whites, and people in Third World countries (Richter,1996). (Schrater, 1995). Judith Richter writes in The Ecologist “within this conceptual framework, birth control is regarded as a weapon of war against the ‘teeming multitudes,’ a war in which people are treated as mere numbers or statistics to be controlled, manipulated reduced and dispensed with” (Richter,1996, page 58). The reproductive rights of individuals could become secondary to the perceived need of the population as a whole.
There have been many documented cases of IUD insertion and sterilization procedures carried out without a woman’s knowledge or consent. Immunocontraception would make it much easier to surreptitiously render a woman infertile. Clinics could administer long-acting contraceptive vaccines to uninformed, unaware patients who think the injection is for protection against disease. Some immunocontraceptive agents, such as anti-sperm vaccines, could sensitize a woman for life, and it is likely she would never know that her inability to conceive was artificially induced. (Richter,1996).
Population-control programs usually focus on women because they are the ones who become pregnant. The subordinate status of women in much of the world makes them less likely to resist coercive fertility regulation policies. Conversely, state-imposed vasectomy programs in China and India led to social unrest and the downfall of a government (Schrater, 1995).
Immunocontraceptive clinical trails show great variability in effectiveness although research subjects are healthy, well-nourished individuals in supervised health-care settings. How effective will these vaccines be when used on anemic, malnourished people with little access to care? Immune response varies greatly between individuals and even within an individual, and the duration of protection from pregnancy may be difficult to predict. Individuals with the tendency towards allergies and autoimmune disease could experience an exaggerated reaction that might render them permanently infertile (Richter,1996). Diseases that suppress immunity might reduce the effectiveness of the vaccine.
Researchers talk of developing a finger-stick kit that could be used in the home so that vaccine recipients could monitor their own fertility status and use additional protection if titers are low. It is unclear how feasible these kits would be in Third World counties with few health care supplies.
The ideal immunocontraceptive would be a highly effective, fully reversible vaccine effective for a predictable period. Today’s immunocontraceptives are prototypes in need of improved formulation that will give longer acting, reliable responses with little chance of cross reaction, and offer a high level of protection against pregnancy. Our knowledge of molecular biology grows daily. New vaccine technology may soon isolate target antigens that are much different from the substances synthesized now, creating a safe, effective product that will change the lives of millions. The leadership of nurse midwives will help clients process information and make informed decisions about contraceptive vaccines when they begin to reach the market.
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Diekman, Herr, J. (1997). Sperm antigens and their use in the development of an immunocontraceptive. American Journal of Reproductive Immunology 37(1): 111-117.
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