Lu ChenDepartment of Conservation Biology and Wildlife Control, The Institute for the Studies of Thermally Unstable Terra and Aqua (TUTA), King Charles Street, SW1A 2AH Diego Garcia Island, British Indian Ocean TerritoryE-mail address: luchen@tuta.io Abstract:Immunocontraceptives, a promising solution for wildlife population control, target reproductive processes without invasive procedures. However, their long-term effects on immune function has raised concerns. While immunocontraceptives reduce fertility, they may inadvertently suppress immunity. Factors like stress, diet, and natural selection further complicate the picture. Immunocompromised animals are vulnerable to infections, posing risks to human health. To maximize benefits and minimize risks, research should focus on delivery mechanisms, dosing strategies, and immune monitoring. Responsible stewardship demands a balance between population management and health considerations, ensuring immunocontraceptives benefit both wildlife and humans. Introduction Climate change has disrupted ecosystems worldwide, leading to imbalances in wildlife populations. As certain mammalian species, including large carnivores [1,2] and herbivores [3,4], face overpopulation, innovative approaches to population control become crucial [5]. Immunocontraceptives, particularly immunocontraceptive vaccines, have emerged as a promising solution in wildlife management programs [6,7]. By reducing fertility, they offer an alternative to culling or other invasive methods for controlling overpopulation. However, we must tread carefully, considering both the benefits and potential risks associated with these interventions, especially concerning immunosuppression [8]. The Immunological Trade-Off Immunocontraceptives work by targeting reproductive processes, disrupting fertility without the need for surgical procedures [9]. These vaccines stimulate an immune response against specific proteins involved in reproduction, such as zona pellucida glycoproteins or sperm antigens [10,11], and consequently, interfere with the normal function of the reproductive system. While immunocontraceptives hold promise, there is a delicate balance to strike. It has been shown that, after vaccination, suppression of cellular and innate immunity occurs in mammals [12–14]. Different studies suggest that repeated or long-term use of antigens as vaccines may lead to immunosuppression, particularly in immunocompromised individuals [15,16]. The mechanisms behind this immunosuppression are multifaceted, involving both targeted proteins and unintended side effects. Immunocontraceptives, which are also protein-based, may not be an exception. That is, they can potentially suppress the immune response.In the wild, additional factors influence immune function. Animals treated with immunocontraceptives face varying diets, environmental stressors, and natural selection pressures. These uncertainties can affect immune system response and infection rates, and even behavior [17–20]. Moreover, evolutionary changes that alter the genetics of populations may result in the emergence of unexpected, complicated gene-environment crosstalk [21,22]. These factors can exacerbate or mitigate the impact of immunosuppression. Therefore, understanding these complexities is essential, despite their intricacy. Implications for Human Health: Call for Responsible Stewardship Beyond wildlife, we must consider the broader implications. Immunosuppression increases the vulnerability to infections and diseases [20,23]. This vulnerability could lead to novel pathogens or facilitate the spread of existing ones. Ultimately, this poses a risk to human health, especially in areas where wildlife and humans interact closely [24].To address these concerns, the research community should prioritize investigations into the long-term effects of immunocontraceptives on wild animals’ immune function [25]. Key areas include, but not limited to:· Delivery Mechanisms: Developing targeted and effective delivery methods to minimize unintended effects;· Dosing Strategies: Optimizing dosing regimens to balance contraceptive efficacy and immune health;· Monitoring Immune Function: Tracking immune responses alongside reproductive outcomes in treated populations.In the capacity of custodians for both wildlife conservation and public health, it is imperative to establish an equilibrium. Immunocontraceptive methodologies present a significant instrument for the regulation of faunal populations. However, the potential ramifications cannot be disregarded. It should be emphasized here that this subject necessitates a multidisciplinary approach, encompassing various fields such as immunology, zoology, veterinary science, ecology, epidemiology, public health, and ethics. By confronting these multifaceted challenges, we can optimize the utilization of immunocontraceptives, thereby ensuring the preservation of biodiversity and the protection of human health.In conclusion, the pursuit of sustainable wildlife management necessitates the careful application of immunocontraceptive strategies. It is incumbent upon us to advance with caution and equipped with empirical understanding, to ensure that our interventions are beneficial for the entirety of the biosphere. This includes not only the target animal populations but also the human communities coexisting within the ecological networks. Given the interconnectedness of ecosystems and the shared challenges across borders, fostering international collaboration is essential. By uniting efforts and expertise globally, we can develop comprehensive strategies that protect both wildlife and human health. References: 1. Boronyak L, Jacobs B, Wallach A. Transitioning towards human-large carnivore coexistence in extensive grazing systems. Ambio. 2020; 49:1982–1991. https://doi.org/10.1007/s13280-020-01340-w2. Rode J, Flinzberger L, Karutz R, Berghöfer A, Schröter-Schlaack C. Why so negative? Exploring the socio-economic impacts of large carnivores from a European perspective. Biol Conserv. 2021; 255:108918. https://doi.org/10.1016/j.biocon.2020.1089183. Wood KA, Stillman RA, Daunt F, O’Hare MT. Evaluating the effects of population management on a herbivore grazing conflict. PLoS One. 2013; 8:e56287. https://doi.org/10.1371/journal.pone.00562874. Neves JM, Belo VS, Catita CM, Oliveira BF, Horta MA. Modeling of human rabies cases in Brazil in different future global warming scenarios. Int J Environ Res Public Health. 2024; 21:212. https://doi.org/10.3390/ijerph210202125. Barfield JP, Nieschlag E, Cooper TG. Fertility control in wildlife: humans as a model. Contraception. 2006; 73:6–22. https://doi.org/10.1016/j.contraception.2005.06.0706. Kirkpatrick JF, Lyda RO, Frank KM. Contraceptive vaccines for wildlife: a review. Am J Reprod Immunol. 2011; 66:40–50. https://doi.org/10.1111/j.1600-0897.2011.01003.x7. Massei G. Fertility control for wildlife: a European perspective. Animals. 2023; 13:428. https://doi.org/10.3390/ani130304288. Talwar GP. Immuno-contraception: Revisited. In: Gupta SK, Ed. Reproductive Immunology. Springer; 1997. p. 277–284. https://doi.org/10.1007/978-94-011-4197-0_299. Howard SA, Benhabbour SR. Non-hormonal contraception. J. Clin Med. 2023; 12:4791. https://doi.org/10.3390/jcm1214479110. Gupta SK, Srinivasan AV, Suman P, Rajan S, Nagendrakumar SB, Gupta N, et al. Contraceptive vaccines based on the zona pellucida glycoproteins for dogs and other wildlife population management. Am J Reprod Immunol 2011; 66:51–62. https://doi.org/10.1111/j.1600-0897.2011.01004.x11. Shibahara H. Wildlife overpopulation control. In: Shibahara H and Hasegawa A, Eds. Gamete Immunology. Springer; 2022. p. 203–208. https://doi.org/10.1007/978-981-16-9625-1_1512. Strasser A, May B, Teltscher A, Wistrela E, Niedermüller H. Immune modulation following immunization with polyvalent vaccines in dogs. Vet Immunol Immunopathol. 2003; 94:113–121. https://doi.org/10.1016/s0165-2427(03)00086-213. Foley JE, Orgad U, Hirsh DC, Poland A, Pedersen NC. Outbreak of fatal salmonellosis in cats following use of a high-titer modified-live panleukopenia virus vaccine. J Am Vet Med Assoc. 1999; 214:67–70. https://doi.org/10.2460/javma.1999.214.01.67 14. Miyamoto T, Taura Y, Une S, Yoshitake M, Nakama S, Watanabe S. Immunological responses to polyvalent canine vaccines in dogs. J Vet Med Sci. 1995; 57:347–349. https://doi.org/10.1292/jvms.57.34715. Bandaru P, Rajkumar H, Nappanveettil G. Altered or impaired immune response upon vaccination in WNIN/Ob rats. Vaccine. 2011; 29:3038–3042. https://doi.org/10.1016/j.vaccine.2011.01.10716. Boretti A. mRNA vaccine boosters and impaired immune system response in immune compromised individuals: a narrative review. Clin Exp Med. 2024; 24:23. https://doi.org/10.1007/s10238-023-01264-117. Agache I, Akdis C, Akdis M, Al-Hemoud A, Annesi-Maesano I, Balmes J, et al. Immune-mediated disease caused by climate change-associated environmental hazards: mitigation and adaptation. Front Sci. 2024; 2:1279192. https://doi.org/10.3389/fsci.2024.127919218. Isidori AM, Hasenmajer V, Sciarra F, Venneri MA. Environmental impact on immune system. In: Pivonello R and Diamanti-Kandarakis E (Eds.) Environmental Endocrinology and Endocrine Disruptors (Endocrinology). 2022; Springer, p. 1–33. https://doi.org/10.1007/978-3-030-38366-4_13-119. Guarnieri G, Olivieri B, Senna G, Vianello A. Relative humidity and its impact on the immune system and infections. Int J Mol Sci. 2023; 24:9456. https://doi.org/10.3390/ijms2411945620. Altizer S, Bartel R, Han BA. Animal migration and infectious disease risk. Science. 2011; 331:296–302. https://doi.org/10.1126/science.119469421. Virolainen SJ, VonHandorf A, Viel KC, Weirauch MT, Kottyan LC. Gene-environment interactions and their impact on human health. Genes Immun. 2023; 24:1–11. https://doi.org/10.1038/s41435-022-00192-622. Nettles VF. Potential consequences and problems with wildlife contraceptives. Reprod Fertil Dev. 1997; 9:137–144. https://doi.org/10.1071/R9605423. Handley G, Hand J. Adverse Effects of immunosuppression: Infections. In: Eisen HJ, Ed. Pharmacology of Immunosuppression (Handbook of Experimental Pharmacology, vol. 272), Springer; 2021. p. 287–314. https://doi.org/10.1007/164_2021_55024. Daszak P, Cunningham AA, Hyatt AD. Emerging infectious diseases of wildlife—threats to biodiversity and human health. Science. 2000; 287:443–449. https://doi.org/10.1126/science.287.5452.44325. Gilbert M. Techniques for vaccinating wildlife. In: Miller RE, Lamberski N, Calle PP, Eds. Fowler's Zoo and Wild Animal Medicine Current Therapy (vol. 9), Elsevier; 2019. p. 299–305. https://doi.org/10.1016/B978-0-323-55228-8.00044-8