Immunocontraception
Immunocontraception is the use of an animal's immune system to prevent it from fertilizing offspring. Contraceptives of this type are not currently approved for human use.
Typically immunocontraception involves the administration of a
Thus far immunocontraception has focused on
- Gamete production
- Organisms that undergo sexual reproduction must first produce
- Gamete function
- After gametes are produced in sexual reproduction, two gametes must combine during fertilization to form a zygote, which again has the full typical number of chromosomes of the species. Methods that target gamete function prevent this fertilization from occurring and are true contraceptives.
- Gamete outcome
- Shortly after fertilization a zygote develops into a multicellular
Medical use
Immunocontraception in not currently available but is under study.[8]
Obstacles
Variability of immunogenicity
In order for an immunocontraceptive to be palatable for human use, it would need to meet or exceed the efficacy rates of currently popular forms of contraception.[9] Currently the maximum reduction of fertility due to sperm vaccines in laboratory experiments with mice is ~75%.[8] The lack of efficacy is due to variability of immunogenicity from one animal to another. Even when exposed to the exact same vaccine, some animals will produce abundant antibody titers to the vaccine's antigen, while others produce relatively low antibody titers. In the Eppin trial that attained 100% infertility, a small sample size (only 9 monkeys) was used, and even among this small sample 2 monkeys were dropped from the study because they failed to produce sufficiently high antibody titers.[10]
This trend—high efficacy when antibody titers are above a threshold coupled with variability in how many animals reach such a threshold—is seen throughout immunocontraception and immune-based birth control research. A long-term study of PZP vaccination in deer that spanned 6 years found that infertility was directly related to antibody titers to PZP.[11] The phase II clinical trial of hCG vaccines was quite successful among women who had antibody titers above 50 ng/mL, but quite poor among those with antibody titers below this threshold.[12]
Lack of mucosal immunity
Adverse effects
Whenever an immune response is provoked, there is some risk of autoimmunity. Therefore, immunocontraception trials typically check for signs of autoimmune disease.[14] One concern with zona pellucida vaccination, in particular, is that in certain cases it appears to be correlated with ovarian pathogenesis.[2] However, ovarian disease has not been observed in every trial of zona pellucida vaccination, and when observed, has not always been irreversible.[15]
Gamete production
Gonadotropin-releasing hormone
The production of gametes is induced in both male and female mammals by the same two hormones:
While GnRH immunity has been known to have contraceptive effects for some time,[4] only in the 2000s has it been used to develop several commercial vaccines. Equity® Oestrus Control is a GnRH vaccine marketed for use in non-breeding domestic horses. Repro-Bloc is GnRH vaccine marketed for use in domestic animals in general.[4] Improvac® is a GnRH vaccine marketed for use in pigs not as a contraceptive, but as an alternative to physical castration for the control of boar taint.[5] Unlike the other products which are marketed for use in domestic animals, GonaCon™ is a GnRH vaccine being developed as a United States Department of Agriculture initiative for use for control of wildlife, specifically deer.[17] GonaCon has also been used on a trial basis to control kangaroos in Australia.[18]
Gamete function
The form of sexual reproduction practiced by most placental mammals is
Zona pellucida
The zona pellucida is a
Early research
Work begun by researchers at the University of Tennessee in the 1970s into immunity against zonae pellucidae resulted in its identification as a target antigen for immunocontraception. The zona pellucida's suitability is a result of it being necessary for fertilization and containing at least one antigen that is tissue-specific and not species-specific. The tissue-specificity implies that immunity against zonae pellucidae will not also affect other tissues in the immunized animal's body. The lack of species-specificity implies that zonae pellucidae harvested from animals of one species will induce an immune response in those of another, which makes zona pellucida antigens readily available, since zonae pellucidae can be harvested from farm animals.[20]
Zonagen
In 1987, a pharmaceutical company called Zonagen (later renamed
Application to wildlife population control
Also in the late 1980s, research began into the use of vaccines based around zonae pellucidae harvested from pigs for the purpose of wildlife control. Such porcine zona pellucida (PZP) vaccines were tested in captive and domestic horses in 1986 with encouraging results.[22] This led to the first successful field trial of contraceptive vaccines with free-ranging wildlife, which examined PZP vaccines used upon wild horses of Assateague Island National Seashore in 1988.[23] The successful results of the field trial were maintained by annual booster inoculations.[24]
Following the success of trials with horses, initial trials using captive animals showed promise for the use of PZP vaccines with
As a result of these successes, PZP vaccination has become the most popular form of immunocontraception for wildlife. As of 2011, thousands of animals are treated with PZP vaccination every year, including 6 different species of free-ranging wildlife in 52 different locations and 76 captive exotic species in 67 different zoological gardens.[1]
Bio Farma
In 2012, researchers from
Viral and microbial vectors
While contraceptive vaccines can be delivered remotely, they still require administration to each individual animal that is to be made infertile. Thus contraceptive vaccines have been used to control only relatively small populations of wildlife. Australia and New Zealand have large populations of European invasive species for which such approach will not scale. Research in these countries has therefore focused on genetically modifying viruses or microorganisms that infect the unwanted invasive species to contain immunocontraceptive antigens.[30]
Such research has included targeting the
In addition to rabbits and mice, this approach has been explored for other animals. Researchers have attempted to replicate similar results when targeting the
Sperm
In placental mammals, fertilization typically occurs inside the female in the
Spermatozoa are protected from the male's immune system by the
Early research
In 1899, the discovery of the existence of antibodies against sperm was made independently both by Serge Metchnikoff[38] of the Pasteur Institute and by Nobel prize laureate Karl Landsteiner.[39]
In 1929, the first recorded attempt at immunocontraception was made by Morris Baskin, clinical director of the Denver Maternal Hygiene Committee. In this trial 20 women who were known to have at least 1 prior pregnancy were injected with their husband's semen, and no conception was recorded in 1 year of observation of these couples.[40] A United States patent (number 2103240) was issued in 1937 for this approach as a contraceptive, but no product for widespread consumption ever came from this approach.[8]
Renewed interest
Throughout the 1990s, there was a resurgence of research in immunocontraception targeting sperm with the hope of developing a contraceptive vaccine for human use. Unlike earlier research which explored the contraceptive effect of immune responses to whole sperm cells, contemporary research has focused on searching for specific molecular antigens that are involved with sperm function.
Antigens that have been identified as potential targets for immunocontraception include the sperm-specific
Early primate trials had mixed results. One study examined the sperm-specific
Since then, a study examining vaccination based on an epididymal protease inhibitor (Eppin) in male macaque monkeys demonstrated that vaccination against sperm antigens could be an effective, reversible contraceptive in male primates. While 4 of 6 control monkeys impregnated females during the trial, none of the 7 monkeys included in the trial that were vaccinated against Eppin impregnated females, and 4 of these 7 vaccinated monkeys recovered their fertility within a year and a half of observation after the trial.[10]
This illustrated that not only could sperm immunocontraception be effective, but it could have several advantages over zona pellucida vaccines. For instance, sperm vaccines could be used by males, in addition to females.[10]
Additionally, while there are relatively few glycoproteins in the zona pellucida and thus relatively few target antigens for zona pellucida vaccines, more than a dozen prospective target antigens for the inhibition of sperm function have been identified. This relative abundance of prospective target antigens makes the prospects of a multivalent vaccine better for sperm vaccines. A study which examined the use of one such multivalent vaccine in female macaque monkeys found that the monkeys produced antibodies against all antigens included in the vaccine, suggesting the efficacy of the multivalent approach.[60]
Finally, while there has been autoimmune ovarian pathogenesis found in some trials using zona pellucida vaccines,[2] anti-sperm antibodies are not likely to have adverse health effects, since anti-sperm antibodies are produced by up to 70% of men who have had vasectomies, and there has been much investigation into possible adverse health side-effects of the vasectomy procedure.[61]
Passive immunity
A vaccine induces active immunity when antigens are injected into an animal that cause it to produce desired antibodies itself. In
Gamete outcome
Human chorionic gonadotropin
Most of the research into immunity that inhibits gamete outcome has focused on human chorionic gonadotropin (hCG). hCG is not necessary for fertilization, but is secreted by embryos shortly thereafter.[66][67] Therefore, immunity against hCG does not prevent fertilization. However, it was found that anti-hCG antibodies prevent marmoset embryos from implanting in the endometrium of their mother's uterus.[6]
The main function of hCG is to sustain the ovarian corpus luteum during pregnancy past the time it would normally decay as part of the regular menstrual cycle. For the first 7–9 weeks in humans, the corpus luteum secretes the progesterone necessary to maintain the viability of the endometrium for pregnancy.[68] Therefore, immunity against hCG during this time frame would function as an abortifacient, as confirmed by experiments in baboons.[7] In the scientific literature the more inclusive term "birth control vaccine" rather than "contraceptive vaccine" is used to refer to hCG vaccines.[3]
Clinical trials
Research begun in the 1970s led to clinical trials in humans of a hCG birth control vaccine. A phase I (safety) clinical trial examined 15 women from clinics in
This was followed by another phase I trial in 1977-1978 examining previously sterilized women at 5 institutions in
This more potent version of the vaccine was used in a phase II (efficacy) trial during 1991-1993 conducted at 3 locations: the
Application to cancer therapy
Following these clinical trails of hCG vaccination as a birth control method, hCG was discovered to be expressed in certain kinds of
Ongoing research
The vaccine tested in the phase II clinical trial in India did not proceed further because it produced antibody titers of 50 ng/mL for at least 3 months duration in only 60% of women in the trial. Ongoing research in hCG birth control vaccines has focused on improving immunogenicity. A vaccine in which the beta subunit of hCG is fused to the B subunit of
Wildlife control
Immunocontraception is one of the few alternatives to lethal methods for the direct control of wildlife populations. While there was research into the use of
One concern about the use of hormonal contraceptives in general, but especially in wildlife, is that the sex steroid hormones that are used are easily passed, often via the food chain, from animal to animal. This can lead to unintended ecological consequences. For instance, fish exposed to treated human sewage effluents were found to have concentrations of the synthetic hormone levonorgestrel in blood plasma higher than those found in humans taking hormonal contraceptives.[86] Because the antigens used in contraceptive vaccines are protein, not steroids, they are not easily passed from animal to animal without loss of function.[23]
References
- ^ S2CID 3890080.
- ^ S2CID 30055375.
- ^ PMID 21645164.
- ^ a b c "Repro-Bloc Vaccine Technology". Amplicon Vaccine, LLC. Archived from the original on 2012-10-18. Retrieved 2 June 2012.
- ^ a b "Improvac® A better way forward". Pfizer Animal Health. Archived from the original on 29 April 2012. Retrieved 2 June 2012.
- ^ PMID 3142993.
- ^ PMID 6456132.
- ^ PMID 21481057.
- ^ S2CID 45802473.
- ^ S2CID 34816491.
- PMID 10519948.
- ^ PMID 8078917.
- ^ S2CID 20222814.
- PMID 1518006.
- PMID 3580465.
- ^ ISBN 978-0-9657648-3-4.
- ^ "Development of Injectable and Oral Contraceptive Technologies and Their Assessment for Wildlife Population and Disease Management". National Wildlife Research Center. Archived from the original on 3 July 2012. Retrieved 2 June 2012.
- ^ Long, Claudia (8 February 2017). "Roo contraceptive trial continues". Canberra Times. Retrieved 1 July 2017.
- PMID 6708012.
- PMID 6168990.
- ^ Wallstin, Brian (20 August 1998). "Biological Disaster". Houston Press. Retrieved 11 April 2012.
- PMID 2915353.
- ^ a b Kirkpatrick, JF; IKM Liu; JW Turner (1990). "Remotely delivered immunocontraception in feral horses". Wildl Soc Bull. 18: 326–330.
- ^ Kirkpatrick, JF; IKM Liu; JW Turner; M Bernoco (1991). "Antigen recognition in mares previously immunized with porcine zona pellucida". J Reprod Fertil. 44: 321–325.
- JSTOR 3808803.
- PMID 10735124.
- JSTOR 3802615.
- S2CID 2561700.
- ^ Aminudin, Muhammad. "Peneliti Unibraw Ciptakan Kontrasepsi Berbahan Baku Vaksin". detikSurabaya. Archived from the original on 27 January 2012. Retrieved 11 April 2012.
- PMID 11999324.
- PMID 16306421.
- doi:10.1071/wr06167.
- PMID 9472936.
- PMID 18667753.
- doi:10.1071/wr07041.
- doi:10.1071/wr07007.
- doi:10.1071/wr07174.
- ^ Metchnikoff, E (1899). "Etudes sur la resorption de cellule". Annales de l'Institut Pasteur. 13: 737–779.
- ^ Landsteiner, K (1899). "Zur Kenntis der spezifisch auf blutkörperchen wirkenden sera". Zentralblatt für Bakteriologie. 25: 546–549.
- .
- PMID 3793758.
- PMID 2203052.
- PMID 2337631.
- PMID 2371290.
- PMID 7513024.
- PMID 7884740.
- PMID 9022615.
- PMID 9239740.
- PMID 9716550.
- S2CID 39942080.
- PMID 10642568.
- PMID 11404006.
- PMID 16036917.
- PMID 17344468.
- S2CID 4402928.
- PMID 16061308.
- PMID 18514978.
- PMID 19219058.
- PMID 9364680.
- PMID 17643494.
- ^ Liskin, L; JM Pile; WF Quillan (1983). "Vasectomy safe and simple". Popul Rep. 4: 61–100.
- PMID 1172943.
- PMID 90147.
- PMID 15353298.
- PMID 18372255.
- PMID 984142.
- PMID 6546453.
- PMID 5017636.
- PMID 7418885.
- PMID 2182290.
- PMID 1708276.
- PMID 1282101.
- PMID 8655711.
- PMID 9099973.
- PMID 9563788.
- PMID 9505891.
- PMID 9930074.
- PMID 10921029.
- PMID 10502732.
- PMID 10987258.
- PMID 12237895.
- PMID 15041707.
- JSTOR 1309816.
- ^ Kirkpatrick, JF; JW Turner (1991). "Reversible fertility control in nondomestic animals". J Zoo Wildl Med. 22: 392–408.
- ^ Seal, US (1991). "Fertility control as a tool for regulating captive and free-ranging wildlife populations". J Zoo Wildl Med. 22: 1–5.
- PMID 20222725.