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Immunocontraception As a Tool for Controlling Reproduction in Coyotes

Immunocontraception As a Tool for Controlling Reproduction in Coyotes

University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln

Symposium Proceedings—Coyotes in the Southwest: A Compendium of Our Knowledge Wildlife Damage Management, Internet Center (1995) for

March 1995

IMMUNOCONTRACEPTION AS A TOOL FOR CONTROLLING REPRODUCTION IN COYOTES

Lowell A. Miller U. S. Department of Agriculture, National Wildlife Research Center

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Miller, Lowell A., "IMMUNOCONTRACEPTION AS A TOOL FOR CONTROLLING REPRODUCTION IN COYOTES" (1995). Symposium Proceedings—Coyotes in the Southwest: A Compendium of Our Knowledge (1995). 20. https://digitalcommons.unl.edu/coyotesw/20

This Article is brought to you for free and open access by the Wildlife Damage Management, Internet Center for at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Symposium Proceedings—Coyotes in the Southwest: A Compendium of Our Knowledge (1995) by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. IMMUNOCONTRACEPTION AS A TOOL FOR CONTROLLING REPRODUCTION IN COYOTES

LOWELL A MILLER, U. S. Dcpatment of Agriculture, National Wildlife Research Center, 17 16 Heath Parkway, Fott Collins. CO 80524

Abstract: The development of imrnunocontraception as a tool for population management of coyotes (Canis la~.ans)and reduction of coyote predation may provide an environmentally safer alternative to pesticides. Because they are , ~mmunocontraceptivevaccines do not persist in the environment or bioaccumulate in the food chain. The National Wildlife Research Center (NWRC) will examine the effects (immunological, holmonal and behavioral) of treating penned coyotes with 2 imrnunocontraceptive : porcine (PZP) and gonadotropin releas~nghoimone (GnRH). Initial studies will be conducted using traditional subcutaneous injections; howeva-, the goal IS to develop an orally-deliverable immunocontraceptive as an alternative tool for coyote populat~onmanagement

Livestock predation by coyotes is a chronic predation problems conern of many and goat ranchers. A 1990 survey estimated that, of the nearly 6 million lambs Immunocontraception has been suggested as 1 born in the 16 westeln states, 549,000 lambs died nonlethal technique with application for reducing from all causes (Connolly 1992). Nearly 60% of coyote numbers In areas where they are causing the losses were a I-esultof predators. Coyotes were depredat~onlosses, or for managing the predatory the main culprit, accounting for 70% of the behavior of tell-~tol-ialpairs (Knowlton 1989). predator-caused mot-talltles The econonlic impact However, private industry has had little economic on producers and consumers 11.1 1990 was approxi- incentive to develop new materials for this use mately $1 1 4 million Desp~teintensive historical because of the small quant~t~esof materials that control effol-1s in production areas, and would be used in predation control This situation despite spoil hunting and trapping for fur, coyotes with mlmunoconkaception vaccines parallels that for cont~nueto thrivc and expand their range, occu11-ing toxicants and other coyote predation control prod- w~delyacross North and Central America ucts (Linhai-t et al 1992).

Scientists at the Nat~onal Wildlife Research Center and its prcdeccssor laboratories have con- Basics of immunocontraception ducted research for over 50 years on the problem of livestock pl-edation by coyotes, and on developing The neonatal veltebl-ate devel- methods to min~mizepredation losses Available ops a recogn~tionof "self' proteins, carbohydrates, techniques include husband~ypractices, shooting, and holmones. This self recognition is essential, trapping, frightening devices, livestock guarding since the production of against pathogenic dogs and tos~cants(Fall 1990). None of these bacteria and viluses is necessary for survival. control methods is completely practical or effective However, the foimation of antibodies against "self' in all of the diverse situat~onsin which coyote can be an abnolmal destructive process, e.g., dis- predation on l~vestockoccurs. Also, as the costs of eases like multiple sclerosis and arthritis. labor-intens~veskills and appl-oaches continue to increase, new techn~quesare needed. Further, The entire immune system is in constant surveil- coyotes are viewed increasingly by the public as a lance to detelmine "self' vs "foreign" proteins. For desirable w~ldl~fespeclcs Accordingly, efl'ective example, in the digestive ti-act, particles and organ- nonlethal methods are being sought for resolution of isms are examined and either tolerated or attacked by antibodies The respiratory and intestinal muco- sal surfaces contain various white blood cells (lym- surrounding the egg or oocyte. It is located phocytes and macrophages) that are responsible for on the outer surface of the egg between the oocyte generating specific immune responses. In the small and the granulosa cells. Antibodies to this glyco- intestine, groups of lymphoid cells known as Peyer's protein layer result in infertility by 1 or both of these patches (PP) sample bits of food proteins and micro- actions: (a) blocking from binding to the ZP organisms as they pass through to determine if an layer, and (b) interfering with oocyte maturat~on. will be directed against the incom- For a sperm to fertilize the egg, it must first bind to ing organism or food particle. a receptor on the ZP. An enzyme in the sperm breaks down the ZP and allows the sperm passage Anti-fertility vaccines are directed against "self' Into the ovum. Ant~bodiesto the ZP also prevent reproductive (holmones or proteins) to fertilization by interfering with oocyte-granulosa which the recipient normally is immunologically communication, resulting in the death of the devel- tolerant. These antigens are made "non-self' or oping oocyte (Dunbar and Schwoebel 1988). "foreign" by coupling them to a protein that is recognized as fore~gnto the animal. As the animal' Smce protein in the ' head normally bind immune system exanlines the conjugated self-fore~gn to the ZP receptor on the oocyte, antibodies to these protein, antibodies are produced to its own repro- sperm prote~nscan be produced, by vaccination in ductive proterns and holmones This Induced the female that are available to bind to sperm In the immune response agalnst "self' is the key to . This prevents sperm fiom binding to the ZP immunocontracept~on The mfer-tility lasts as long as receptor Sperm protein immunocontraception IS there are suflic~entantrbod~es to intelfere wrth the belng investrgated for contraception of the red fox biological activ~tyof the targeted hormone or repro- and the rabbit In (Morel1 1993, Tyndale- ductive protein, usually 1-2 years. B~scoe199 1) A ZP protein has not been identified in avian species, nor has the cross-reactivity of PZP been tested in avian species. Reproductive hormones and proteins involved in immunocontraception Chorionic gonadotropin (CG) holmone, which is produced by the Implanting in some Immunocontraceptive vaccines can control species, induces the to continue reproduction at various stages They can interrupt production of which is required for the the reproductrve activrty of both sexes by (a) inter- maintenance of pregnancy. Ant~bodiesto CG reduce ferrng with the biological act~vrtyof hornlones, (b) blood levels of this holmone and thereby prevent block~ngspelni penetration of an ovulated egg, or ~mplantationof the fertilized egg. (c) preventing implantat~onand development of a fertilized egg The riboflav~nrequirement of the developing emblyo is sat~sfiedby active transport of this water- Gonadotropin releasing holmone (GnRH) 1s soluble v~taminacross the placenta. This transport produced in the bra~nby the and is provided by a gestatronal-specific carrier protern controls release of the pituitaly reproductive hor- called riboflavin carrier protein (RCP). RCP plays mones follrcle stimulating holmone (FSH) and a pivotal role in emb~yodevelopment in avian and (LH). These ho~monesin turn mammalian specles. Antibodies formed agalnst control the hormonal hncrions of the (ova- RCP interfere w~thplacental transfer of riboflavin, ries and testes) Antibodies to the hypothalamic thereby preventing development of the early embryo. hormone will reduce the crrculating level of This technology probably would result in the least biologically-active GnIUI, thereby reducing the change in social behav~orof the target species of any release of subsequent reproductive hormones. The of the proposed vaccines (Natraj et al. 1987, 1988). reduction or absence of these hormones leads to atrophy of the gonads, resulting in infertil~tyin both Reproduction can be blocked at many sites in sexes. Both avran and mammalian fo~msof GnRH the reproductive process; the above examples are the have been Identified. sites where most investigative work has been done. Behavioral and social changes in target animals The zona pellucida (ZP) is an acellular glyco- result~ngfrom specific vaccines may dictate the vaccine of choice in each s~tuation(Jones 1982, surviving intact through the stomach, it must have Griffin 1992). adhesive properties which allow it to adhere to and colonize the intestinal wall, resulting in an infection. Bacteria without adhesive properties will be carried Methods of adrr~inisteringvaccincs out of the gut w~ththe waste material.

Subcutaneous or intramuscular (I M.) injection Liposomes are spherical, artificial biological are the traditional fo~msof vaccine delivery. In membranes made up of phospholipids and choles- order to accomplish I M injections in free-roaming terol that can be used to protect oral vaccines from an~mals,the vaccine must be del~veredby a dart or digestive tract degradation. Since the liposome a "bio-bullet" (Kirkpatrick et al. 1990, Tu~nerand membrane contains lipids, which are stable in the Kirkpatrick 199 1, Gall-ot et al. 1992, Tu~neret al. gastrointestinal tract, an placed inside during 199 1, .I 992). Whlle these methods may be effective liposome synthesis is protected from gastrointestinal in certain confined locations, they are impractical degradation. Cholesterol in the membrane adds when dealing with mobile wildl~fepopulations in stability and makes it attractive to macrophages in large open areas . the PP where the liposome is taken up rap~dly because of the membrane's lipophilic nature. This Except for the oral polio vacclne introduced by character~sticof the membrane causes the liposome Dr. Sabul in the 1950s, oral vaccinat~onhas received to simulate a microb~alcell when presented to the little attention fbr humans bccause it requires larger immune system The liposome acts as an antigen quantities of vacclne and 1s less predictable than micl-ocanicrcapable of targeting the antigen directly subcutaneous or I M. routes In marnnials, oral to the PP. immunization takes place in the pha~yngealinlmune follicles (e.g., the tonsils) and in the small intestine. I-Iowever, before a hposome can be taken up by Thcre are thousands of immune foll~clesthroughout the mas-ophages, it must bind to the mucosal sutface tlie small intest~nc,wlth a h~gherconcentration in the of the ~ntestine;othe~wise it will be swept out with distal portion in most specles Vaccines, being the waste material. This mucosal adhesive property protern m nature, arc digested rap~dlyIn the stomach increases the mucosal uptake efficiency, thus requir- when given orally, hence, ~mniunizationmust occur ing a smaller oral vacclne dose The most com- e~therin thc pharyngeal arca 01-the vaccine needs a monly used liposome adhesive is a nontoxlc form of protective capsule to sur\ll\re passage through the the bacterial lectin, cholera toxln (CT), a member of stomach then be released In the small intestine a family of enterotoxlns produced by several strains (McGhee et al. 1992) of enteropathogen~c bacteria (Holmgren et al. 1992). Lectins have multiple binding sites and can The safest way to deliver the antlgen orally is to bind to receptors on the liposome as well as to protect it until it is taken up by the PP and del~vered intestinal receptors. to macrophages A combination of 2 approaches could lead to effective antlgen uptake and potentla- Recent advancements in molecular b~ologyand tion of mucosal immune response. (a) entel-ic immunology have provided us with new tools such coat~ngof the ant~genresult~ng In delive~yvehicles as "live vectors" as delive~yvehicles. The most that prevent degradation in the stomach but allow pmminent use ofthls technology In w~ldlifemanage- absorption in the intestlnc, and (b) des~gningthe ment is the use of the live vacclnla vi~usto deliver vaccine to have enhanced attraction to the immune rabies vaccine orally to raccoons (Procyon lotor-) follicles In the small ~ntestine and foxes (Vull~esvulpes). The attenuated , a member of the pox vlruses, was used as a Recent underst:~nding of the n~echanisn~sby vaccine agalnst smallpox m humans for over 20 wh~chpathogenic \Illuses and bacteria colonize and years. Using recombinant genetic engineer~ng,the Infect the intestinal tract has provided new insights gene responsible for encoding of the rabies vlrus for developing successful and safe attenuated l~veor was insetted into the vaccinia virus by killed, oral vaccines. For example, a bacteria must sclent~stsat the Wistar Institute This recombinant sul-vlve the stomach's acid and proteolytic enzymes pox vi~us,when given orally, was able to vaccinate to successh~llyinfect the small intestine. After the target animal against rabies. The tonsil lymphoid tissue is thought to initiate the immune response in testinal environment and can induce a 500-fold these target animals (USDA-APHIS 1991). greater oral immune response as compared to free antigens We plan to develop liposomes with a Live viral vectors potentially can be used to cholera-toxin-B subunit on their surface to mimic the deliver a contraceptive vaccine. This delivery adhesive properties of intestinal pathogens and system is currently being tested in Australia ensure optimal host immune response. (Tyndale-Biscoe 1991). Finally, prior to field use, U. S Food and Drug Adrrunistiation approval of the safety and efficacy of Potential of immunocontraccption in coyote this new vaccine will be needed Extensive labora- management tory, field and product testing will be required before this or other materials are available for use in man- Immunocontraception as a technology is avail- agement programs. able today, but only for use in a laboratory setting and pen studies. Immunocontraceptive vaccines are being produced in limited quantities and animals Literature Cited injected with these vaccines become infertile for 1 -3 years. Connolly, G. 1992. Sheep and goat losses to predators in the United States. Proc East. The development of a practical, cost-effective Wildl. Damage Control Conf. 5:75-82. immunocontraceptive vaccine for coyotes is a multi- year, multi-task project. The first task the NWRC Dunbar, B. S. and E Schwoebel. 1988. Fertility will undertake will be to determine the immune, studies for the benefit of animals and human hormonal and behavioral responses to non-species- beings. Development of improved sterilization specific PZP and GnRH immunocontraceptive and contraceptive methods J Am Vet. Med vaccines. Using from known lmmuno- Assoc. 193.1165-1170. sterilized and fertile coyotes from the above study, a new mimotope assay will be used to determine Fall, M. W. 1990. Control of coyote predation on portions of the PZP active in sterilizing the coyote. livestock — progress in research and develop- This new test may hold promise for finding a PZP ment Proc Vertebr Pest Conf. 14:386-392. specific to coyotes These species-specific could then be used to develop a species- Ganott,R A, D. B Siniff, J. R. Tester, T C. Eagle, specific ZP vaccine GnRH will continue to be and E D Plotka 1992. A comparison of studied where species specificity is not critical contraceptive technologies for feral management. Wildl. Soc. Bull. 20:318-326 Some important behavioral questions related to the effects of contraception on pair formation, pair Griffin, P D. 1992. Options for immuno- bond maintenance, breeding behavior and territorial contraception and issues to be addressed in the defense need to be addressed. The answers may development of vaccines. Scand. dictate in pail the choice of vaccines to be developed J. Immunol 36:111-117. for immunocontraception in coyotes Holmgren, J., C Czerkinsky, N Lycke, and A. Practical use of immunocontraception for Svennerholm. 1992 Mucosal immunity: controlling fi-ee-rangingcoyot e populations will have Implication of vaccine development. to involve oral delivery of the vaccine The technol- Immunobiol 184:157-179. ogy for developing oral vaccines is in its infancy However, because of a worldwide need for oral Jones, W R. 1982 Immunological fertility vaccines against cholera and the HIV vims, rapid regulation Blackwell Scientific Publications. progress is being made in this area. Oral immuniza- London. 273pp. tion using liposome or bacterial vectors will be the goal of the NWRC Vaccines encapsulated in liposomes will provide protection from the gastroin-

175 Kirkpatrick, J. F., I. K. M. Liu, and J. W. Turner. ., S. Geol-ge, and M. S. Kadam. 1988. 1 990. Remotely-del~veredimmunocontra- Characterization of antibodies to chicken ception in feral . Wildl. Soc. Bull. riboflavin canier protein. Biochem. J. 254:287- 18:326-330. 292.

Knowlton, F. F. 1989. PI-edator biology and Turner, J. W. and J. F. Kirkpatrick. 1991. New livestock depredation management. Pages 504- developments in feral horse contraception and 509 In Proc. Weste~nSect., Am. Soc. Anim. their potential application to wildlife. Wildl Sci. Soc. Bull. 19,350-359.

L~nhart,S B , G J Dasch, R. R. Johnson, J. D. ., I. Liu, and J. F. Kirkpatrick. 1992. Robelis, and C. J Packham. 1992 Electsonic Remotely delivered ~mmunocontraceptionin fi-ightening devices for reducing coyote preda- captive wh~te-taileddeer. J. Wildl. Manage. tion on domest~csheep: Efiicacy under range 56: 154- 1 57. conditions and operational use. Proc. Vel-tebr. Pest Conf 15:386-392 Tyndale-Biscoc, C. H. 1991. Fertility control in wildlifc. Repsod. Fe~til.Dev. 3:339-343. McGhee, J R , J Mcstechy, M T. DCI-tzbaugh,J. H. Eldridge, M. Hirasawa, and 1-1 Kiyono 1992. USDA-APHIS. 199 1. Proposed field trial of live The mucosal immune system. From fundanien- esperimental vacc~nia vector recombinant tal concepts to vacclnc development. Vaccine rabies vaccine for raccoons. Unpubl. Environ 10:75-88 mental assessment and finding of no significant impact. Pages 1-8 1. MOI-ell,V 1993 Austral~anpest contl-ol by vil-us causes concern Science 26 1 :683-684.

Natraj, U., R. Asok Kumar, and P. Kadam. 1987. Te~minationof pregnancy in mice with anti- selum to chicken ribotlavin-carrier prote~n. Biol of Repro 36:677-685

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