Comparative efficacy of two immunocontraceptive vaccines

doi:10.1016/S0264-410X(97)00141-2

Vaccine

Volume 15, Issues 17–18, December 1997, Pages 1858-1862

https://doi.org/10.1016/S0264-410X(97)00141-2 Get rights and content

Abstract

As part of our research program to develop immunocontraception as a wildlife management tool, we compared the physiological responses of wild Norway rats (Rattus norvegicus) to two immunocontraceptive vaccines; one involved mouse zona pellucida peptide (MZPP); the other involved gonadotropin releasing hormone (GnRH). Efficacy was monitored by immune, hormonal, and natality responses. Both vaccines were effective, but GnRH was much more effective (100% sterility of both sexes vs. 50% sterility of MZPP-treated females). Breeding success of control rats was 88% with litters of 5–9 pups; breeding success of MZPP rats was 50% with litters of 2–8; GnRH rats produced no young. In GnRH-treated male rats monitored for up to 17 months, testosterone was nondetectable and testes were atrophied to about 10% of their original volume for 10–13 months. There were no notable differences in nortality or body weights among groups, and, with the exception of testicular regression, there were no changes in general appearance. The GnRH vaccine is potentially a good rat reproductive control agent that may be effective over the normal lifespan of a rat under natural conditions in the wild.

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The carrier virus used to deliver immunocontraceptive agent should be species specific [11–22]. At best, it should not cause a severe disease to the natural host [13,23,24]. For instance, rat cytomegalovirus is very common, endemic and only infecting rat species.
The common physical and chemical methods for controlling rat pest are less than satisfactory and inhumane. Immunocontraception approach has been considered more humane and it can be accomplished by inducing the relevant host immune response that block further development of reproductive gametes. ZP3 proteins are known to play very important role during sperm-ovum fertilization. It is a self-antigen and only localized in female ovaries. Therefore, an immunization with ZP3 protein elsewhere will induce a generalize host immune response against ZP3 protein. This study employed rat ZP3 (rZP3) gene prepared from its cDNA of Rattus rattus diardii. It was delivered and expressed in vivo by naked plamid DNA (DrZP3) or recombinant ZP3-Adenovirus (Ad-rZP3). Expression studies in vitro with DrZP3 or Ad-ZP3 showed rZP3 proteins were successfully expressed in Vero cells. Hyperimmune serum against rZP3 that were prepared by immunizing several rats with purified rZP3-pichia yeast fusion protein showed it blocked sperms from binding DrZP3-transfected Vero cells. Female Sprague Dawley rats immunized with DrZP3 demonstrated a long-term effect for significant reduction of fertility up to 92.6%. Ovaries from rats immunized with DrZP3 were severely atrophied with disappearance of primordial follicles from ovarian cortex with an increased in the amount of oocyte-free cell clusters. Female rats immunized with Ad-rZP3 demonstrated 27% reduction of fertility. The infertility induced by Ad-rZP3 is comparatively low and ineffective. This could be due to a strong host immune response that suppresses the recombinant virus itself resulted in minimum rZP3 protein presentation to the host immune system. As a result, low antibody titers produced against rZP3 is insufficient to block oocytes from maturity and fertilization. Therefore, immunization with DrZP3 for immunocontraception is more effective than Ad-rZP3 recombinant adenovirus. It is proposed to explore further on the use of adenovirus or other alternative viruses to deliver ZP3 protein and for the development of enhanced expression of rZP3 in target host.
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GonaCon™, and a previous formulation of this vaccine, also did not alter blood chemistry in treated white-tailed deer [5,6]. Although GonaCon™ vaccine formulations have been tested in California ground squirrels (Spermophilus beecheyi) and Norway rats (Rattus norvegicus), these studies did not examine blood chemistry [7,8]. However, no overt adverse effects were noted in these species.
Management of prairie dogs in the past has included poisoning, fumigants, barriers, and relocation. Because of the diverse attitudes related to prairie dog management, nonlethal methods that allow the existence of prairie dogs but help minimize damage related to population growth need to be developed. GonaCon™ is an immunocontraceptive vaccine that elicits antibodies to native GnRH; this prevents the secretion of reproductive hormones necessary for sperm and oocyte production. Prairie dogs were vaccinated with 0.1, 0.2, or 0.4 mL of the GonaCon™ emulsion intramuscularly in the upper thigh containing 100, 200, or 400 μg GnRH conjugate, respectively. Control animals were vaccinated with 0.4 mL saline emulsion in the upper thigh. Blood samples (≤1 mL) were taken from the femoral vein once pretreatment and at 1, 2, 3, 4, 6, and 15 months post-vaccination. Age (adult or juvenile) did not affect immune response to GonaCon™. Antibody titers were higher in the 200 and 400 μL GonaCon™ groups than in the 100 μL group, and there was no difference between the 200 and 400 μL GonaCon™ groups. No adverse effects of GonaCon™ were noted on weight or blood chemistry parameters during the study. GonaCon™ will likely contracept prairie dogs for ≥1 year in the field using either 200 or 400 μg conjugate. GonaCon™ could be incorporated into management plans to help maintain prairie dog populations while reducing habitat degradation due to overpopulation.
MHC haplotypes and response to immunocontraceptive vaccines in the brushtail possum
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However, trials on captured wild possums have revealed considerable individual variation in response to any given immunocontraceptive vaccine (Duckworth et al., 2007; Cui and Duckworth, 2005). Similarly, tests of immunocontraceptive vaccines in a wide range of species have shown a proportion of the immunised animals remain fertile (Magiafoglou et al., 2003; Miller et al., 1999, 1997; Kirkpatrick et al., 1996; Liu et al., 1989; Turner et al., 1996; Garrott et al., 1998; Fayrer-Hosken et al., 1999; Goldberg et al., 1981; Bradley et al., 1997). If a vaccine was applied to a wild population this variability could result in selection for individuals that remain fertile because of low or no response to the vaccine (Magiafoglou et al., 2003).
The possum is a major invasive pest in New Zealand. One option for its control is the use of immunocontraceptive vaccines. Initial trials of vaccines have shown individual variation in response. The use of vaccines on wild populations could result in the evolution of a resistant population through selection for possums that remain fertile because of low or no response. Understanding the basis of this variation is therefore important. The major histocompatibility complex (MHC) is an important influence on the nature of immune responses. This study has investigated the relationship between MHC alleles and individual immune responses to immunocontraceptive vaccines comprising zona pellucida peptides. We identified MHC alleles and putative haplotypes, and compared these between individuals with measured responses to immunocontraceptive vaccines. Two haplotypes were found to associate significantly with differences in vaccine response. Possums that carried haplotype 6 showed reduced responsiveness to one vaccine, while possums that carried haplotype 9 showed increased responsiveness to a separate vaccine. The identification of MHC haplotypes associated with different responses to immunocontraceptive vaccines offers the opportunity to understand what factors trigger non-response and the persistence of fertility in some individuals, and may allow vaccines to be optimised to minimise non-responsiveness.
Update on Neuroendocrine Regulation and Medical Intervention of Reproduction in Birds
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In order to provoke an immunologic response and the production of antibodies, GnRH has to be conjugated with an antigenetic determinant or carrier to mobilize T-helper cells [126,127]. Long-term contraception is possible and GnRH vaccines have been used successfully in humans and mammals [126–137]. A commercial GnRH vaccine (Improvac; CSL Animal Health) is available in some countries for use in mares.
In avian species, reproductive disorders and undesirable behaviors commonly reflect abnormalities in the neuroendocrine regulation of the reproductive system. Current treatment options are often disappointing, show no long-lasting effect, or have significant side effects. A possible reason for our lack of success is a dearth of knowledge of the underlying neuroendocrine, behavioral, and autonomous physiology of the reproductive processes. Tremendous progress has been made in the last few years in our understanding of the neuroendocrine control of reproduction in birds. Advantage should be taken of these experimentally derived data to develop appropriate and safe treatment protocols for avian patients suffering from reproductive disorders.
The C-terminal pentapeptide of LHRH is a dominant B cell epitope with antigenic and biological function
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Luteinizing hormone releasing hormone (LHRH) has been intensively studied as a target for the control of fertility and hormone dependent cancers. In most studies a decapeptide, EHWSYGLRPG, which is identical to the native LHRH sequence, has been used. In this study we investigated whether short sequences of LHRH could retain immunogenic and antigenic properties and be employed in a vaccine preparation. Our results show that the C-terminal five-residue peptide (LHRH^6–10) of LHRH was able to inhibit the binding of anti-LHRH^1–10 antisera to LHRH^1–10 in an inhibition ELISA. A totally synthetic peptide vaccine incorporating LHRH^6–10 also elicited a strong anti-LHRH antibody response and prevented mice from becoming pregnant in fertility trials. The primary immune response elicited by a peptide vaccine based on LHRH^1–10 could be boosted with LHRH^6–10. Finally, an antigen system comprising of biotinylated LHRH^6–10 bound to streptavidin-coated plates was capable of discriminating between anti-LHRH antibodies present in fertile and non-fertile mice. This study demonstrates that LHRH^6–10 retains immunogenic and antigenic properties and also discerns antibody specificities associated with reproductive competence.
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As our knowledge of molecular reproduction grows, more members of the functional molecules, which participate in the fertilization, development or transportation of gametes, have been assessed as potential candidates for the development of antifertility vaccines. In this regard, most of the studies thus far have focused on the immunoresponse of reproductive protein hormones [17,18] and gamete-specific antigens [19,20]. However, serious side effects, such as hormone imbalance, orchiditis or ovaritis, may develop [21].
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PaperComparative efficacy of two immunocontraceptive vaccines

Abstract

J. Steroid Biochem.

Vaccine

J. Reprod. Immun.

Potential role of sterilization for suppressing rat populations, a theoretical appraisal

Influence of sterile males on fecundity of a rat colony

J. Wildl. Manage.

Antifertility effects of SC-20775 in Norway and Polynesian rats

J. Wildl. Manage.

Important role of the carrier in the induction of antibody response without Freund's complete adjuvant against a ‘self’ peptide luteinizing hormone-releasing hormone (LHRH)

Am. J. Reprod. Immunol.

Paper
Comparative efficacy of two immunocontraceptive vaccines