Vaccination against <i>Rhipicephalusmicroplus</i>: an alternative to chemical control?

Silva, Lucas Andre Dedavid e; Ali, Abid; Termignoni, Carlos; Vaz Júnior, Itabajara da Silva

doi:10.1590/0103-8478cr20230161

ABSTRACT:

Rhipicephalus (Boophilus) microplus is a hard tick endemic in livestock-growing regions and causes economic losses in the largest beef-producing countries, including Brazil, Mexico, Argentina, Australia and Uruguay. The use of chemical acaricides is still the main strategy to control R. microplusinfestations. Nevertheless, immunological control of R. microplus with an anti-tick vaccine is a suitable alternative and has manifold advantages because it can avoid drug-resistance and the presence of acaricide residues in milk, beef and in the environment. Indeed, vaccines based on the Bm86 antigen have had relative commercial and technical success to control R. microplus in some regions. Although, the efficacy of such vaccines varies among tick populations and is insufficient to provide an acceptable level of protection. Therefore, the need to search for better antigens is impelling. This review focused on the restrictions imposed on the use of acaricides in Brazil and in the European Union, as well as on the impacts of Bm86-based vaccines on R. microplus control. The efficacy of experimental anti-tick vaccines (based on subolesin, glutathione S-transferase, ferritin 2; voltage-dependent anion channel; aquaporin, 60 S acidic ribosomal protein, metalloprotease and trypsin) that can elicit an immune response against the physiological functions of various ticks is discussed.

Key words:
Rhipicephalus microplus; vaccine; acaricides; Brazil; food contamination

RESUMO:

O Rhipicephalus (Boophilus) microplus é um carrapato duro que é endêmico de regiões de pecuária e causa perdas econômicas nos maiores países produtores de carne bovina, incluindo Brasil, México, Argentina, Austrália e Uruguai. O uso de acaricidas ainda é a principal estratégia para controlar infestações por R. microplus. No entanto, o controle imunológico do R. microplus com uma vacina contra carrapatos é uma alternativa adequada e possui diversas vantagens, por evitar a seleção de populações de carrapato resistentes a drogas, evitar a presença de resíduos de acaricidas no leite, na carne e no ambiente. As vacinas baseadas no antígeno Bm86 tiveram relativo sucesso comercial e técnico no controle do R. microplus em diversas regiões. No entanto, a eficácia dessas vacinas varia entre as populações de carrapatos e é insuficiente para fornecer um nível aceitável de proteção. Portanto, há uma necessidade de procurar novos antígenos. Esta revisão foca nas restrições impostas ao uso de acaricidas no Brasil e na União Europeia, bem como nos impactos das vacinas baseadas em Bm86 no controle do R. microplus. Também é discutida a eficácia de vacinas anti-carrapatos experimentais (baseadas em subolesina, glutationa S-transferase, ferritina 2; canal aniônico dependente de voltagem; aquaporina, proteína ribossômica ácida 60S, metaloprotease, tripsina) que podem elicitar uma resposta imune contra as funções fisiológicas de vários carrapatos.

Palavras-chave:
Rhipicephalus microplus; vacina; acaricida; Brasil; contaminação de alimentos

INTRODUCTION:

Ticks are responsible for considerable morbidity and mortality (unless controlled), and economic losses, both directly through blood sucking and indirectly as vector of pathogens (JONGEJAN & UILENBERG, 2004JONGEJAN, F., UILENBERG, G. The global importance of ticks. Parasitology, v.129, p.S3-S14, 2004. Available from: <Available from: https://doi.org/10.1017/S0031182004005967 >. Accessed: Mar. 13, 2023. doi: 10.1017/S0031182004005967.
https://doi.org/10.1017/S003118200400596... ). Ticks constitute a threat to public and animal health, with major effects on livestock (DE LA FUENTE et al., 2016DE LA FUENTE, J. et al. Strategies for new and improved vaccines against ticks and tick-borne diseases. Parasite Immunology, v.38, p.754-769, 2016. Available from: <Available from: https://doi.org/10.1111/pim.12339 >. Accessed: Mar. 13, 2023. doi: 10.1111/pim.12339.
https://doi.org/10.1111/pim.12339... ). It is estimated that approximately 80% of the world’s cattle population is exposed to tick infestation (SNELSON, 1975, cited by MCCOSKER, 1979MCCOSKER, P. J. Global aspects of the management and control of ticks of veterinary importance. In: RODRIGUEZ, J. G. Recent Advances in Acarology, Academic Press, Inc., 1979. p.45-53 Available from: <Available from: https://doi.org/10.1016/B978-0-12-592202-9.50012-4 >. Accessed: Mar. 13, 2023. doi: 10.1016/B978-0-12-592202-9.50012-4.
https://doi.org/10.1016/B978-0-12-592202... ). The cattle tick Rhipicephalus (Boophilus) microplus is responsible for economic losses in the livestock industry, due to decreased production of milk and meat, as well as impairing leather quality. These effects are not only caused by the tick infestation itself but also by the pathogens transmitted to bovines, mainly protozoa (e.g., Babesiabovis and Babesiabigemina) and bacteria (Anaplasmamarginale). These parasites are responsible for high bovine mortality (DU PLESSIS et al., 1994DU PLESSIS, J. L. et al. A survey of the incidence and importance of the tick-borne diseases heartwater, redwater and anaplasmosis in the heartwater-endemic regions of South Africa. The Onderstepoort Journal of Veterinary Research, v.61, p.295-301, 1994.; MOLOSSI et al., 2021MOLOSSI, F. A. et al. Causes of death in beef cattle in southern Brazil. Journal of Veterinary Diagnostic Investigation, v.33, p.677-683, 2021. Available from: <Available from: https://doi.org/10.1177/10406387211007952 >. Accessed: Mar. 13, 2023. doi: 10.1177/10406387211007952.
https://doi.org/10.1177/1040638721100795... ). In addition, treatment with chemical acaricides is costly and increasingly less effective. In Brazil, it is estimated that the annual costs associated with R. microplus infestation are around US$ 3.2 billion (GRISI et al., 2014GRISI, L. et al. Reassessment of the potential economic impact of cattle parasites in Brazil. Revista Brasileira de Parasitologia Veterinária, v.23, p.150-156, 2014. Available from: <Available from: https://doi.org/10.1590/S1984-29612014042 >. Accessed: Mar. 13, 2023. doi: 10.1590/S1984-29612014042.
https://doi.org/10.1590/S1984-2961201404... ). In Brangus cattle breed, the cost of R. microplus infestation in Brazil has been estimated to be US$ 34.61 per animal in the backgrounding phase (from weaning to feedlot placement) and US$ 7.97 per animal in the finishing phase (when cattle are fed until they reach market weight). Even in Nellore cattle, a pure Bosindicus breed that is relatively resistant to R. microplus, infestation costs in Brazil have been estimated at US$ 4.66 and US$ 1.18 per animal in the backgrounding and finishing phases, respectively (CALVANO et al., 2019CALVANO, M. et al. Economic efficiency of Rhipicephalusmicroplus control and effect on beef cattle performance in the Brazilian Cerrado.Experimental and Applied Acarology, v.79, p.459-471, 2019. Available from: <Available from: https://doi.org/10.1007/s10493-019-00446-5 >. Accessed: Mar. 13, 2023. doi: 10.1007/s10493-019-00446-5.
https://doi.org/10.1007/s10493-019-00446... ).Significant annual losses due to R. microplus infestation have been reported for other countries, such as US$ 573.61 million in Mexico (RODRÍGUEZ-VIVAS et al., 2017RODRÍGUEZ-VIVAS, R. I. et al. Potential economic impact assessment for cattle parasites in Mexico. Revista Mexicana de Ciencias Pecuarias, v.8, p.61-74, 2017. Available from: <Available from: https://doi.org/10.22319/rmcp.v8i1.4305 >. Accessed: Mar. 13, 2023. doi: 10.22319/rmcp.v8i1.4305.
https://doi.org/10.22319/rmcp.v8i1.4305... ) and US$ 128 - 146 million in Australia (MEAT & LIVESTOCK AUSTRALIA, 2005MEAT & LIVESTOCK AUSTRALIA. Review of research needs for cattle tick control - Phases I and II. 2005. Available from: <Available from: https://www.mla.com.au/research-and-development/reports/2005/review-of-research-needs-for-cattle-tick-control---phases-i-and-ii/ >. Accessed: Mar. 13, 2023.
https://www.mla.com.au/research-and-deve... ).

Various strategies to control this tick have been used, such as acaricides (the main control method), pasture management, vaccine, nutritional management, and selection of resistant hosts (RODRÍGUEZ-VIVAS et al., 2018RODRÍGUEZ-VIVAS, R. I. et al. Strategies for the control of Rhipicephalusmicroplusticks in a world of conventional acaricide and macrocyclic lactone resistance. Parasitology Research, v.117, p.3-29, 2018. Available from: <Available from: https://doi.org/10.1007/s00436-017-5677-6 >. Accessed: Mar. 13, 2023. doi: 10.1007/s00436-017-5677-6.
https://doi.org/10.1007/s00436-017-5677-... ). The major classes of acaricides currently in use are amidines, organophosphates, organochlorines, synthetic pyrethroids, insect growth regulators, phenylpyrazoles, and macrocyclic lactones (RODRÍGUEZ-VIVAS et al., 2018RODRÍGUEZ-VIVAS, R. I. et al. Strategies for the control of Rhipicephalusmicroplusticks in a world of conventional acaricide and macrocyclic lactone resistance. Parasitology Research, v.117, p.3-29, 2018. Available from: <Available from: https://doi.org/10.1007/s00436-017-5677-6 >. Accessed: Mar. 13, 2023. doi: 10.1007/s00436-017-5677-6.
https://doi.org/10.1007/s00436-017-5677-... ). However, all these acaricides have major drawbacks due to the increasing level of acaricide resistance among tick populations (CUTULLE et al., 2013CUTULLE, C. et al. In vitro diagnosis of the first case of amitraz resistance in Rhipicephalusmicroplus in Santo Tome (Corrientes), Argentina. Veterinary Parasitology, v.192, p.296-300, 2013. Available from: <Available from: https://doi.org/10.1016/j.vetpar.2012.10.014 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vetpar.2012.10.014.
https://doi.org/10.1016/j.vetpar.2012.10... ; KLAFKE et al., 2017KLAFKE, G. et al. Multiple resistance to acaricides in field populations of Rhipicephalusmicroplus from Rio Grande do Sul state, Southern Brazil. Ticks and Tick-borne Diseases, v.8, p.73-80, 2017. Available from: <Available from: https://doi.org/10.1016/j.ttbdis.2016.09.019 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.ttbdis.2016.09.019.
https://doi.org/10.1016/j.ttbdis.2016.09... ; LOVIS et al., 2013LOVIS, L. et al. Determination of acaricide resistance in Rhipicephalus (Boophilus) microplus (Acari: Ixodidae) field populations of Argentina, South Africa, and Australia with the Larval Tarsal Test. Journal of Medical Entomology, v.50: p.326-335, 2013. Available from: <Available from: https://doi.org/10.1603/me12127 >. Accessed: Mar. 13, 2023. doi: 10.1603/me12127.
https://doi.org/10.1603/me12127... ; RECK et al., 2014RECK, J. et al. First report of fluazuron resistance in Rhipicephalusmicroplus: a field tick population resistant to six classes of acaricides. Veterinary Parasitology, v.201, p.128-136, 2014. Available from: <Available from: https://doi.org/10.1016/j.vetpar.2014.01.012 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vetpar.2014.01.012.
https://doi.org/10.1016/j.vetpar.2014.01... ).

Immunization to control tick populations is an interesting alternative because it avoids or reduces the use of acaricides. This may lead to decreased food and environmental contamination with pesticide residues, and to a reduced selection-pressure for acaricide-resistance. (GUERRERO et al., 2012aGUERRERO, F. D. et al. Acaricide resistance mechanisms in Rhipicephalus (Boophilus) microplus. Revista Brasileira de Parasitologia Veterinária, v.21, p.1-6, 2012a. Available from: <Available from: https://doi.org/10.1590/s1984-29612012000100002 >. Accessed: Mar. 13, 2023. doi: 10.1590/s1984-29612012000100002.
https://doi.org/10.1590/s1984-2961201200... ). Among the advantages of using immunological control are the absence of a resting period after the use of chemical acaricides, safety in the application of vaccines, and avoiding even the possibility of the presence of acaricide residues in animal products intended for human consumption (CANALES et al., 2010CANALES, M. et al. Bioprocess design and economics of recombinant BM86/BM95 antigen production for anti-tick vaccines. Biochemical Engineering Journal, v.52, p.79-90, 2010. Available from: <Available from: https://doi.org/10.1016/j.bej.2010.07.008 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.bej.2010.07.008.
https://doi.org/10.1016/j.bej.2010.07.00... ; DE LA FUENTE, 2016DE LA FUENTE, J. et al. Strategies for new and improved vaccines against ticks and tick-borne diseases. Parasite Immunology, v.38, p.754-769, 2016. Available from: <Available from: https://doi.org/10.1111/pim.12339 >. Accessed: Mar. 13, 2023. doi: 10.1111/pim.12339.
https://doi.org/10.1111/pim.12339... ; DE LA FUENTE & CONTERAS, 2015DE LA FUENTE, J.; CONTRERAS, M. Tick vaccines: current status and future directions. ExpertReview of Vaccines, v.14, p.1367-1376, 2015. Available from: <Available from: https://doi.org/10.1586/14760584.2015.1076339 >. Accessed: Mar. 13, 2023. doi: 10.1586/14760584.2015.1076339.
https://doi.org/10.1586/14760584.2015.10... ).

Acaricide control of R. microplus and food contamination concerns

According to the United Nations Food and Agriculture Organization (FAO, 2012FOOD AND AGRICULTURE ORGANIZATION (FAO). International Code of Conduct on the Distribution and Use of Pesticides. Guidelines on Prevention and Management of Pesticide Resistance. 2012. Available from: <Available from: https://www.fao.org/documents/card/en/c/8dcf273c-c907-4e71-b5e5-8753a861de87/ >. Accessed: Mar. 13, 2023.
https://www.fao.org/documents/card/en/c/... ), insecticide resistance is defined as “a heritable change in the sensitivity of a pest population that is reflected in the repeated failure (more than one instance) of a product to achieve the expected level of control when used according to the label recommendation for that pest species”. The difficulties in cattle tick control due to drug resistance come from the increasing number of tick populations that are unaffected by acaricides in subsequent generations (FAO, 2012FOOD AND AGRICULTURE ORGANIZATION (FAO). International Code of Conduct on the Distribution and Use of Pesticides. Guidelines on Prevention and Management of Pesticide Resistance. 2012. Available from: <Available from: https://www.fao.org/documents/card/en/c/8dcf273c-c907-4e71-b5e5-8753a861de87/ >. Accessed: Mar. 13, 2023.
https://www.fao.org/documents/card/en/c/... ). Since 1936, it has been known that there are acaricide-resistant R. microplus populations of (GEORGE et al., 2008GEORGE, J. et al. Acaricides for controlling ticks on cattle and the problem of acaricide resistance. In: BOWMAN, A., NUTTALL, P. Ticks: Biology, disease and control. Cambridge: Cambridge University Press. p.408-423, 2008. Available from: <Available from: https://doi.org/10.1017/CBO9780511551802.019 >. Accessed: Mar. 13, 2023. doi: 10.1017/CBO9780511551802.019.
https://doi.org/10.1017/CBO9780511551802... ). Nowadays, there are cattle tick acaricide-resistant populations in Africa, Asia, Central America, South America, and Oceania (reviewed by DZEMO et al., 2022DZEMO, W. D. et al. Development of acaricide resistance in tick populations of cattle: A systematic review and meta-analysis. Heliyon, v.8, p.e08718, 2022. Available from: <Available from: https://doi.org/10.1016/j.heliyon.2022.e08718 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.heliyon.2022.e08718.
https://doi.org/10.1016/j.heliyon.2022.e... ). In addition, the need to discard milk and not to slaughter the animal during the resting period after the application of acaricides increases the costs of tick control (DALLEGRAVE et al., 2016DALLEGRAVE, A. et al. Methodology for trace analysis of 17 pyrethroids and chlorpyrifos in foodstuff by gas chromatography-tandem mass spectrometry. Analytical and Bioanalytical Chemistry, v.408, p.7689-7697, 2016. Available from: <Available from: https://doi.org/10.1007/s00216-016-9865-5 >. Accessed: Mar. 13, 2023. doi: 10.1007/s00216-016-9865-5.
https://doi.org/10.1007/s00216-016-9865-... ; DALLEGRAVE et al., 2018DALLEGRAVE, A. et al. Residue of insecticides in foodstuff and dietary exposure assessment of Brazilian citizens. Food and Chemical Toxicology, v.115, p.329-335, 2018. Available from: <Available from: https://doi.org/10.1016/j.fct.2018.03.028 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.fct.2018.03.028.
https://doi.org/10.1016/j.fct.2018.03.02... ; DE MENEGHI et al., 2016DE MENEGHI, D. et al. Experiences in tick control by acaricide in the traditional cattle sector in Zambia and Burkina Faso: possible environmental and public health implications. Frontiers in Public Health, v.9, p.239, 2016. Available from: <Available from: https://doi.org/10.3389/fpubh.2016.00239 >. Accessed: Mar. 13, 2023.doi: 10.3389/fpubh.2016.00239.
https://doi.org/10.3389/fpubh.2016.00239... ). These practices are essential, given acaricides and/or its metabolites accumulate in animal fat and could be hazardous to human health.

Due to their highly lipophilic nature, residues of ivermectin (a macrocyclic lactone) persist in milk and dairy products, the use of ivermectin in lactating animals must; therefore, be avoided (ESCRIBANO et al., 2012ESCRIBANO, M. et al. Ivermectin residue depletion in food producing species and its presence in animal foodstuffs with a view to human safety. Current Pharmaceutical Biotechnology, v.13, p.987-998, 2012. Available from: <Available from: https://doi.org/10.2174/138920112800399121 >. Accessed: Mar. 13, 2023. doi: 10.2174/138920112800399121.
https://doi.org/10.2174/1389201128003991... ). Although, ivermectin residues are less persistent during cheese production processes, it has been reported that 65% of the drug remains in the raw milk used to produce cheese (CERKVENIK et al., 2004CERKVENIK, V. et al. Fate of ivermectin residues in ewes’ milk and derived products. Journal of Dairy Science,v.71, p.39-45, 2004. Available from: <Available from: https://doi.org/10.1017/s0022029903006381 >. Accessed: Mar. 13, 2023. doi: 10.1017/s0022029903006381.
https://doi.org/10.1017/s002202990300638... ). In Brazil, a study conducted under the auspices of the Official Program for Analysis of Residues of Veterinary Drugs in Foods of Animal Origin detected ivermectin residues in samples of dairy products - in 42% of ultra-high temperature milk samples, in 11% of pasteurized milk samples, and in 59% of powdered milk samples; - although, the maximum residue limit (MRL) was not exceeded in any of the samples it is motive of concern (NOVAES et al., 2017NOVAES, S. F. et al. Residues of veterinary drugs in milk in Brazil. Ciência Rural, v.47, p.8, 2017. Available from: <Available from: https://doi.org/10.1590/0103-8478cr20170215 >. Accessed: Mar. 13, 2023. doi: 10.1590/0103-8478cr20170215.
https://doi.org/10.1590/0103-8478cr20170... ). Despite the fact that the use of ivermectin during lactation is not recommended, it is reported to be common in some regions of Brazil (NOVAES et al., 2017NOVAES, S. F. et al. Residues of veterinary drugs in milk in Brazil. Ciência Rural, v.47, p.8, 2017. Available from: <Available from: https://doi.org/10.1590/0103-8478cr20170215 >. Accessed: Mar. 13, 2023. doi: 10.1590/0103-8478cr20170215.
https://doi.org/10.1590/0103-8478cr20170... ).

Cypermethrin, a synthetic pyrethroid, is another acaricide that is widely used for control of R. microplus in livestock in Brazil (KLAFKE et al., 2017KLAFKE, G. et al. Multiple resistance to acaricides in field populations of Rhipicephalusmicroplus from Rio Grande do Sul state, Southern Brazil. Ticks and Tick-borne Diseases, v.8, p.73-80, 2017. Available from: <Available from: https://doi.org/10.1016/j.ttbdis.2016.09.019 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.ttbdis.2016.09.019.
https://doi.org/10.1016/j.ttbdis.2016.09... ; PICININ et al., 2017PICININ, L. C. A. et al. Survey of pyrethroid, macrocyclic lactone and antibacterial residues in bulk milk tank from Minas Gerais State, Brazil. Pesquisa Veterinária Brasileira, v.37, p.97-104, 2017. Available from: <Available from: https://doi.org/10.1590/S0100-736X2017000200001 >. Accessed: Mar. 13, 2023. doi: 10.1590/S0100-736X2017000200001.
https://doi.org/10.1590/S0100-736X201700... ). Pyrethroids are also fat-soluble pesticides and contamination of meat and milk by these chemicals has also been reported (DALLEGRAVE et al., 2016DALLEGRAVE, A. et al. Methodology for trace analysis of 17 pyrethroids and chlorpyrifos in foodstuff by gas chromatography-tandem mass spectrometry. Analytical and Bioanalytical Chemistry, v.408, p.7689-7697, 2016. Available from: <Available from: https://doi.org/10.1007/s00216-016-9865-5 >. Accessed: Mar. 13, 2023. doi: 10.1007/s00216-016-9865-5.
https://doi.org/10.1007/s00216-016-9865-... ). The resting period must be at least 14 days in lactating cows (BASTOS et al., 2011BASTOS, L. H. P. et al. Possible contamination sources of milk by agrotoxics and studies on monitoring their residues: a Brazilian national review. Cadernos Saúde Coletiva, v.19, p.51-60, 2011. Available from: <Available from: https://pesquisa.bvsalud.org/portal/resource/pt/lil-593699 >. Accessed: Mar. 13, 2023.
https://pesquisa.bvsalud.org/portal/reso... ; HERNANDES et al., 2009HERNANDES, T. et al. Sanitary Management of milk producing cows and insecticide pyrethroids residue in cow milk produced on Chapada dos Guimarães, Brazil. Acta Scientiae Veterinariae, v.37, p.171-176, 2009. Available from: <Available from: https://doi.org/10.22456/1679-9216.16246 >. Accessed: Mar. 13, 2023.doi: 10.22456/1679-9216.16246.
https://doi.org/10.22456/1679-9216.16246... ). However, that guideline is not always followed in Brazil, where 15% of milk producers are reportedly unaware of a resting period for any acaricide (NASCIMENTO et al., 2021NASCIMENTO, A. F. D. et al. Use of anti-tick drugs in dairy farms in the microregion of Alfenas, Minas Gerais, Brazil. Revista Brasileira de Parasitologia Veterinária, v.30, p.e020620, 2021. Available from: <Available from: https://doi.org/10.1590/s1984-29612021016 >. Accessed: Mar. 13, 2023. doi: 10.1590/s1984-29612021016.
https://doi.org/10.1590/s1984-2961202101... ). Residue levels of pyrethroid and other acaricides have been detected in up to 15.1% of milk samples, with some samples (until 6.8%) exceeding the legal limit (PICININ et al., 2016PICININ, L. C. A. et al. Milk quality parameters associated with the occurrence of veterinary drug residues in bulk tank milk. Scientia Agricola, v.74, p.195-202, 2016. Available from: <Available from: https://doi.org/10.1590/1678-992X-2016-0120 >. Accessed: May, 03, 2023.doi: 10.1590/1678-992X-2016-0120.
https://doi.org/10.1590/1678-992X-2016-0... ; PICININ et al., 2017PICININ, L. C. A. et al. Survey of pyrethroid, macrocyclic lactone and antibacterial residues in bulk milk tank from Minas Gerais State, Brazil. Pesquisa Veterinária Brasileira, v.37, p.97-104, 2017. Available from: <Available from: https://doi.org/10.1590/S0100-736X2017000200001 >. Accessed: Mar. 13, 2023. doi: 10.1590/S0100-736X2017000200001.
https://doi.org/10.1590/S0100-736X201700... ; CISCATO et al., 2002CISCATO, C. H. P. et al. Pesticide residues in cow milk consumed in São Paulo city (Brazil), Journal of Environmental Science and Health, Part B, v.37, p.323-330, 2002. Available from: <Available from: https://doi.org/10.1081/PFC-120004473 >. Accessed: May, 03, 2023. doi: 10.1081/PFC-120004473.
https://doi.org/10.1081/PFC-120004473... ; OLIVEIRA et al., 2023OLIVEIRA, M. et al. Pesticides in different environmental compartments in Brazil: a review. Ciência e Natura, v.45, p.e2., 2023. Available from: <Available from: https://doi.org/10.5902/2179460X70715 >. Accessed: May, 03, 2023. doi: 10.5902/2179460X70715.
https://doi.org/10.5902/2179460X70715... ).

Fluazuron is a benzoylphenyl urea derivative that impairs chitin synthesis in ticks, affecting their ecdysis and oviposition (JUNQUERA et al., 2019JUNQUERA, P. et al. Benzoylphenylureas as veterinary antiparasitics. An overview and outlook with emphasis on efficacy, usage and resistance. Parasite, v.26, p.26, 2019. Available from: <Available from: https://doi.org/10.1051/parasite/2019026 >. Accessed: Mar. 13, 2023.doi: 10.1051/parasite/2019026.
https://doi.org/10.1051/parasite/2019026... ). Recently, it was reported that nursing calves had higher plasma levels than did their lactating dams that had been treated with fluazuron, indicating that the compound is passed through milk and accumulates in calves due to the continuous intake (EMA, 2018EUROPEAN MEDICINE AGENCY (EMA). Committee for Medicinal Products for Veterinary Use EMA/CVMP/456716/201725 Fluazuron. 2018. Available from: <Available from: https://www.ema.europa.eu/documents/mrl-opinion/opinion-cvmp-establishment-maximum-residue-limits-fluazuron_en.pdf >. Accessed: Mar. 13, 2023.
https://www.ema.europa.eu/documents/mrl-... ; SUAREZ et al., 2021SUAREZ, G. et al. Is the suckling period and application pattern relevant for fluazuron against tick infestation in cows and their suckling calves? BMC Veterinary Research, v.7, p.375, 2021. Available from: <Available from: https://doi.org/10.1186/s12917-021-03090-7 >. Accessed: Mar. 13, 2023. doi: 10.1186/s12917-021-03090-7.
https://doi.org/10.1186/s12917-021-03090... ).

The organophosphate diazinon is used to control cattle ticks in various regions. Organophosphate residues have been detected in raw milk (FAGNANI et al., 2011FAGNANI, R. et al. Organophosphorus and carbamates residues in milk and feedstuff supplied to dairy cattle. Pesquisa Veterinária Brasileira, v.31, p.598-602, 2011. Available from: <Available from: https://doi.org/10.1590/S0100-736X2011000700009 >. Accessed: Mar. 13, 2023. doi: 10.1590/S0100-736X2011000700009.
https://doi.org/10.1590/S0100-736X201100... ; JARDIM et al., 2018JARDIM, A. et al. Dietary cumulative acute risk assessment of organophosphorus, carbamates and pyrethroids insecticides for the Brazilian population.Food and Chemical Toxicology, v.112, p.108-117, 2018. Available from: <Available from: https://doi.org/10.1016/j.fct.2017.12.010 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.fct.2017.12.010.
https://doi.org/10.1016/j.fct.2017.12.01... ; NERO et al., 2007NERO, L. A. et al. Organophosphates and carbamates in milk produced in four milk producing regions from Brazil: occurrence and activity against Listeria monocytogenes and Salmonella spp. Food Science and Technology,v.27, p.201-204, 2007. Available from: <Available from: https://doi.org/10.1590/S0101-20612007000100035 >. Accessed: Mar. 13, 2023. doi: 10.1590/S0101-20612007000100035.
https://doi.org/10.1590/S0101-2061200700... ; SILVA et al., 2014SILVA, L. C. C. et al. Milk contamination by organophosphorus and carbamate residues present in water and animal feedstuff. Semina: Ciências Agrárias, v.35, p.2485-2494, 2014. Available from: <Available from: https://doi.org/10.5433/1679-0359.2014v35n5p2485 >. Accessed: Mar. 13, 2023. doi: 10.5433/1679-0359.2014v35n5p2485.
https://doi.org/10.5433/1679-0359.2014v3... ). Organophosphate residues detected in raw milk are similar to those detected in animal feed (FAGNANI et al., 2011FAGNANI, R. et al. Organophosphorus and carbamates residues in milk and feedstuff supplied to dairy cattle. Pesquisa Veterinária Brasileira, v.31, p.598-602, 2011. Available from: <Available from: https://doi.org/10.1590/S0100-736X2011000700009 >. Accessed: Mar. 13, 2023. doi: 10.1590/S0100-736X2011000700009.
https://doi.org/10.1590/S0100-736X201100... ; SILVA et al., 2014SILVA, L. C. C. et al. Milk contamination by organophosphorus and carbamate residues present in water and animal feedstuff. Semina: Ciências Agrárias, v.35, p.2485-2494, 2014. Available from: <Available from: https://doi.org/10.5433/1679-0359.2014v35n5p2485 >. Accessed: Mar. 13, 2023. doi: 10.5433/1679-0359.2014v35n5p2485.
https://doi.org/10.5433/1679-0359.2014v3... ). It has been suggested that the levels of organophosphate contamination of milk can be explained by the animal feed, in which organophosphates are present, since they are widely used in crops used to produce animal feed (FAGNANI et al., 2011FAGNANI, R. et al. Organophosphorus and carbamates residues in milk and feedstuff supplied to dairy cattle. Pesquisa Veterinária Brasileira, v.31, p.598-602, 2011. Available from: <Available from: https://doi.org/10.1590/S0100-736X2011000700009 >. Accessed: Mar. 13, 2023. doi: 10.1590/S0100-736X2011000700009.
https://doi.org/10.1590/S0100-736X201100... ).

In October 2017, European Union regulations prohibited the use of fipronil in farm animals to control tick infestations (EU, 2017EUROPEAN UNION (EU). Official Journal of the European Union, v.60, p.L 277, 2017. Available from: <Available from: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=OJ:L:2019:277:TOC >. Accessed: Mar. 13, 2023.
https://eur-lex.europa.eu/legal-content/... ). However, in Brazil, the use of fipronil is allowed for crop protection against some pests (ANVISA, 2020AGÊNCIA NACIONAL DE VIGILÂNCIA SANITÁRIA (ANVISA). Índice monográfico. Fipronil F43. 2020. Available from: <Available from: https://www.gov.br/anvisa/pt-br/setorregulado/regularizacao/agrotoxicos/monografias/monografias-autorizadas/f/4351json-file-1 >. Accessed: Mar. 13, 2023.
https://www.gov.br/anvisa/pt-br/setorreg... ) and for tick control (KLAFKE et al., 2017KLAFKE, G. et al. Multiple resistance to acaricides in field populations of Rhipicephalusmicroplus from Rio Grande do Sul state, Southern Brazil. Ticks and Tick-borne Diseases, v.8, p.73-80, 2017. Available from: <Available from: https://doi.org/10.1016/j.ttbdis.2016.09.019 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.ttbdis.2016.09.019.
https://doi.org/10.1016/j.ttbdis.2016.09... ; NASCIMENTO et al., 2021NASCIMENTO, A. F. D. et al. Use of anti-tick drugs in dairy farms in the microregion of Alfenas, Minas Gerais, Brazil. Revista Brasileira de Parasitologia Veterinária, v.30, p.e020620, 2021. Available from: <Available from: https://doi.org/10.1590/s1984-29612021016 >. Accessed: Mar. 13, 2023. doi: 10.1590/s1984-29612021016.
https://doi.org/10.1590/s1984-2961202101... ; RECK et al. 2014RECK, J. et al. First report of fluazuron resistance in Rhipicephalusmicroplus: a field tick population resistant to six classes of acaricides. Veterinary Parasitology, v.201, p.128-136, 2014. Available from: <Available from: https://doi.org/10.1016/j.vetpar.2014.01.012 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vetpar.2014.01.012.
https://doi.org/10.1016/j.vetpar.2014.01... ). This is an issue of major concern because European Union (a very important market for Brazilian beef) could ban beef and milk from countries when the use of this drug is allowed. Pesticide residues are transferred from feed to cow milk (FAOUDER et al., 2007FAOUDER, J. L. et al. Transfer assessment of fipronil residues from feed to cow milk. Talanta, v.73, p.710-717, 2007. Available from: <Available from: https://doi.org/10.1016/j.talanta.2007.04.061 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.talanta.2007.04.061.
https://doi.org/10.1016/j.talanta.2007.0... ), and it is possible that milk can be contaminated indirectly from feed or directly from the acaricide used in the herd. In fact, contamination of raw milk with fipronil has been reported in Brazil (OLIVEIRA, 2016).

Legislation regulating the use of acaricides in Brazil and in the European Union

In a society increasingly concerned with human and animal health issues, the contamination of animal products with acaricides presents a serious obstacle for cattle farming. Recently, the Brazilian Health Regulatory Agency (ANVISA) issued Resolution No. 328 and Normative Instruction No. 51 (ANVISA, 2019aAGÊNCIA NACIONAL DE VIGILÂNCIA SANITÁRIA (ANVISA). Resolução - RDC Nº 328. Diário Oficial da União, Nº 249, p.82-89. 2019a. Available from: <Available from: https://www.in.gov.br/web/dou/-/resolucao-rdc-n-328-de-19-de-dezembro-de-2019-235414702 >. Accessed: Mar. 13, 2023.
https://www.in.gov.br/web/dou/-/resoluca... ; ANVISA, 2019bAGÊNCIA NACIONAL DE VIGILÂNCIA SANITÁRIA (ANVISA). Instrução normativa N° 51. Diário Oficial da União, Nº 249, p.98-124. 2019b. Available from: <Available from: https://www.in.gov.br/web/dou/-/instrucao-normativa-n-51-de-19-de-dezembro-de-2019-235414514 >. Accessed: Mar. 13, 2023.
https://www.in.gov.br/web/dou/-/instruca... ). Those documents define the maximum residue limits (MRLs) in foods of livestock origin and the acceptable daily intakes (ADIs) of acaricides (Table 1). Legislation in Brazil and the European Union is similar regarding the MRLs and ADIs for amitraz, fluazuron, flumethrin, and ivermectin (Table 1). However, the legislation is more restrictive in the European Union than in Brazil. The MRLs and ADIs for cypermethrin and ivermectin are lower in the European Union than in Brazil. Besides fipronil, the European Union has also banned the use of fluazuron and ivermectin in dairy cattle (Table 1), which effectively blocks the exportation of dairy products from Brazil to the European Union.

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Table 1
Acaricides approved for use in Brazil and in the European Union, together with their acceptable daily intakes, marker residues in tissues, and maximum residue limits.

Immunological control of R. microplus with Bm86- and Bm95-based vaccines

In a breakthrough research, ALLEN & HUMPHREYS (1979ALLEN, J. R., HUMPHREYS, S. J. Immunisation of guinea pigs and cattle against ticks. Nature, v.280, p.491-493, 1979. Available from: <Available from: https://doi.org/10.1038/280491a0 >. Accessed: Mar. 13, 2023. doi: 10.1038/280491a0.
https://doi.org/10.1038/280491a0... ) showed that immunization of hosts using tick proteins induces an immune response which confers high levels of protection against tick infestation (ALMAZÁN, 2022ALMAZÁN, C. Impact of the paper by Allen and Humphreys (1979) on anti-tick vaccine research. Pathogens, v.11, p.1253, 2022. Available from: <Available from: https://doi.org/10.3390/pathogens11111253 >. Accessed: Mar. 13, 2023. doi: 10.3390/pathogens11111253.
https://doi.org/10.3390/pathogens1111125... ). This historic achievement is the basis of all subsequent landscape in anti-tick vaccine development. Indeed, first commercial vaccine against any ectoparasite was an anti-tick vaccine based on Bm86 protein (Bm86), an R. microplus gut glycoprotein. This vaccine was pivotal because it established the concept of a concealed antigen. A concealed antigen is defined as an antigen that is not encountered by the host immune system under natural infestation and; consequently, the host cannot mount an immune response but when a parasite-derived molecule is injected, the host produces antibodies against it. Actually, functional antibodies present in the blood meal reach the midgut and also other tissues of the parasite (VAZ et al, 1996VAZ JÚNIOR, I. S. et al. Functional bovine immunoglobulins in Boophilusmicroplus hemolymph. Veterinary Parasitology, v.62, p.155-160, 1996. Available from: <Available from: https://10.1016/0304-4017(95)00851-9 >. Accessed: May, 03, 2023. doi: 10.1016/0304-4017(95)00851-9.
https://10.1016/0304-4017(95)00851-9... ). Although, this type of vaccine does not avoid host infestation, because the effect comes after the blood meal, it does reduce the size of the next tick generation and the parasite propagation is inhibited along the time (WILLADSEN & KEMP, 1988WILLADSEN, P.; KEMP, D. H. Vaccination with ‘concealed’ antigens for tick control. Parasitology Today, v.4, p.196-198, 1988. Available from: <Available from: https://doi.org/10.1016/0169-4758(88)90084-1 >. Accessed: Mar. 13, 2023. doi: 10.1016/0169-4758(88)90084-1.
https://doi.org/10.1016/0169-4758(88)900... ).

Indeed, further in silico analysis suggested that Bm86 has characteristics of both exposed and concealed antigens, since its localization and presence of a signal peptide do not fit perfectly as a truly concealed antigen (TRIMNELL et al., 2002TRIMNELL, A. R. et al. Dual action ectoparasite vaccine targeting ‘exposed’ and ‘concealed’ antigens. Vaccine, v.20, p.3560-3568, 2002. Available from: <Available from: https://doi.org/10.1016/s0264-410x(02)00334-1 >. Accessed: Mar. 13, 2023. doi: 10.1016/s0264-410x(02)00334-1.
https://doi.org/10.1016/s0264-410x(02)00... ; NUTTALL et al., 2006NUTTALL, P. A. et al. Exposed and concealed antigens as vaccine targets for controlling ticks and tick-borne diseases. Parasite Immunology, v.28, p.155-163, 2006. Available from: <Available from: https://doi.org/10.1111/j.1365-3024.2006.00806.x >. Accessed: Mar. 13, 2023. doi: 10.1111/j.1365-3024.2006.00806.x.
https://doi.org/10.1111/j.1365-3024.2006... ; TABOR, 2018TABOR, A. E. The enigma of identifying new cattle tick vaccine antigens. In: ABUBAKAR M. Ticks and Tick-Borne Pathogens. Interchopen, 2018. Available from: <Available from: https://doi.org/10.5772/intechopen.81145 >. Accessed: Mar. 13, 2023.doi: 10.5772/intechopen.81145.
https://doi.org/10.5772/intechopen.81145... ). In the case of rBm86-based vaccines, bovine antibodies are ingested by ticks in the blood meal, encounter Bm86 on the apical surface of R. microplus gut cells, and disturbs gut function, thus impairing the parasite fitness (RAND et al., 1989RAND, K. N. et al. Cloning and expression of a protective antigen from the cattle tick Boophilusmicroplus. Proceedings of the National Academy of Sciences, v.86, p.9657-9661, 1989. Available from: <Available from: https://doi.org/10.1073%2Fpnas.86.24.9657 >. Accessed: Mar. 13, 2023. doi: 10.1073%2Fpnas.86.24.9657.
https://doi.org/10.1073%2Fpnas.86.24.965... ; WILLADSEN & KEMP, 1988WILLADSEN, P.; KEMP, D. H. Vaccination with ‘concealed’ antigens for tick control. Parasitology Today, v.4, p.196-198, 1988. Available from: <Available from: https://doi.org/10.1016/0169-4758(88)90084-1 >. Accessed: Mar. 13, 2023. doi: 10.1016/0169-4758(88)90084-1.
https://doi.org/10.1016/0169-4758(88)900... ).

The antithesis of the concept of concealed antigens is that of exposed antigens. Exposed antigens are secreted in tick saliva during attachment and feeding. Vaccines based on exposed antigens induce an immune response which can be enhanced by subsequent natural infestations (NUTTALL et al., 2006NUTTALL, P. A. et al. Exposed and concealed antigens as vaccine targets for controlling ticks and tick-borne diseases. Parasite Immunology, v.28, p.155-163, 2006. Available from: <Available from: https://doi.org/10.1111/j.1365-3024.2006.00806.x >. Accessed: Mar. 13, 2023. doi: 10.1111/j.1365-3024.2006.00806.x.
https://doi.org/10.1111/j.1365-3024.2006... ). The host immune response against tick-derived exposed antigens is subject to host immune-evasion strategies develop along the co-evolution of the parasite and the host (reviewed by ALI et al., 2022ALI, A. et al. Host immune responses to salivary components - a critical facet of tick-host interactions. Frontiers in Cellular and Infection Microbiology, v.12, p.809052. 2022. Available from: <Available from: https://doi.org/10.3389/fcimb.2022.809052 >. Accessed: Mar. 13, 2023. doi: 10.3389/fcimb.2022.809052.
https://doi.org/10.3389/fcimb.2022.80905... ; WILLADSEN & KEMP, 1988WILLADSEN, P.; KEMP, D. H. Vaccination with ‘concealed’ antigens for tick control. Parasitology Today, v.4, p.196-198, 1988. Available from: <Available from: https://doi.org/10.1016/0169-4758(88)90084-1 >. Accessed: Mar. 13, 2023. doi: 10.1016/0169-4758(88)90084-1.
https://doi.org/10.1016/0169-4758(88)900... ). So, antibodies induced by salivary proteins could be less effective in impairing tick physiology. In addition, variations in the composition and expression of proteins during tick feeding have been observed and are thought to be a strategy to evade host immunity (KIM et al., 2020KIM, T. K. et al. Time-resolved proteomic profile of Amblyommaamericanum tick saliva during feeding. PLOS Neglected Tropical Diseases, v.14, p.e0007758, 2020. Available from: <Available from: https://doi.org/10.1371/journal.pntd.0007758 >. Accessed: Mar. 13, 2023. doi: 10.1371/journal.pntd.0007758.
https://doi.org/10.1371/journal.pntd.000... ; TIRLONI et al., 2014TIRLONI, L. et al. Proteomic analysis of cattle tickRhipicephalus (Boophilus) microplus saliva: a comparison between partially and fully engorged females. PLOS ONE, v.9, p.e94831, 2014. Available from: <Available from: https://doi.org/10.1371/journal.pone.0094831 >. Accessed: Mar. 13, 2023. doi: 10.1371/journal.pone.0094831.
https://doi.org/10.1371/journal.pone.009... ; TIRLONI et al., 2015TIRLONI, L. et al. Saliva from nymph and adult females of Haemaphysalislongicornis: a proteomic study. Parasites & Vectors, v.8, p.338, 2015. Available from: <Available from: https://doi.org/10.1186/s13071-015-0918-y >. Accessed: Mar. 13, 2023. doi: 10.1186/s13071-015-0918-y.
https://doi.org/10.1186/s13071-015-0918-... ). However, various anti-tick vaccination experiments have shown that exposed and concealed antigens can induce some degree of protective immune response against ticks (PEREIRA et al., 2022PEREIRA, D. F. S. et al. Rhipicephalusmicroplus: An overview of vaccine antigens against the cattle tick. Ticks and Tick-borne Diseases, v.13, p.101828, 2022. Available from: <Available from: https://doi.org/10.1016/j.ttbdis.2021.101828 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.ttbdis.2021.101828.
https://doi.org/10.1016/j.ttbdis.2021.10... ; SEIXAS et al., 2012SEIXAS, A. et al. Rhipicephalus (Boophilus) microplus embryo proteins as target for tick vaccine. Veterinary Immunology and Immunopathology, v.148, p.149-156, 2012. Available from: <Available from: https://doi.org/10.1016/j.vetimm.2011.05.011 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vetimm.2011.05.011.
https://doi.org/10.1016/j.vetimm.2011.05... ; TRENTELMAN et al., 2019TRENTELMAN, J. J. A. et al. A combination of antibodies against Bm86 and Subolesin inhibits engorgement of Rhipicephalusaustralis (formerly Rhipicephalusmicroplus) larvae in vitro. Parasites & Vectors, v.12, p.362, 2019. Available from: <Available from: https://doi.org/10.1186/s13071-019-3616-3 >. Accessed: Mar. 13, 2023. doi: 10.1186/s13071-019-3616-3.
https://doi.org/10.1186/s13071-019-3616-... ). The first rBm86-based vaccine became available in 1994 and was marketed in Australia as TickGARD (WILLADSEN et al., 1995WILLADSEN, P. et al. Commercialisation of a recombinant vaccine againstBoophilusmicroplus. Parasitology, v.110 Suppl, p.S43-50, 1995. Available from: <Available from: https://doi.org/10.1017/s0031182000001487 >. Accessed: Mar. 13, 2023. doi: 10.1017/s0031182000001487.
https://doi.org/10.1017/s003118200000148... ). That vaccine was taken off the market for several reasons, including its low efficacy in some R. microplus populations and the fact that it did not exert the knockdown effects exhibited by chemical acaricides (TRENTELMAN et al., 2019TRENTELMAN, J. J. A. et al. A combination of antibodies against Bm86 and Subolesin inhibits engorgement of Rhipicephalusaustralis (formerly Rhipicephalusmicroplus) larvae in vitro. Parasites & Vectors, v.12, p.362, 2019. Available from: <Available from: https://doi.org/10.1186/s13071-019-3616-3 >. Accessed: Mar. 13, 2023. doi: 10.1186/s13071-019-3616-3.
https://doi.org/10.1186/s13071-019-3616-... ). Additionally, 3-4 vaccinations per year are necessary and this is impractical and even incompatible within extensive beef cattle production farms (TABOR, 2021TABOR, A. E. A review of Australian tick vaccine research. Vaccines (Basel), v.9, p.1030, 2021. Available from: <Available from: https://doi.org/10.3390/vaccines9091030 >. Accessed: Mar. 13, 2023. doi: 10.3390/vaccines9091030.
https://doi.org/10.3390/vaccines9091030... ). Another rBm86-based vaccine, marketed under the name Gavac, has been shown to have a positive economic impact on the cattle industry in several countries (CANALES et al., 1997CANALES, M. et al. Large-scale production in Pichia pastoris of the recombinant vaccine Gavac against cattle tick. Vaccine,v.15, p.414-422, 1997. Available from: <Available from: https://doi.org/10.1016/s0264-410x(96)00192-2 >. Accessed: Mar. 13, 2023. doi: 10.1016/s0264-410x(96)00192-2.
https://doi.org/10.1016/s0264-410x(96)00... ; DE LA FUENTE et al., 1998DE LA FUENTE, J. et al. Field studies and cost-effectiveness analysis of vaccination with Gavac against the cattle tick Boophilusmicroplus. Vaccine, v.16, p.366-373, 1998. Available from: <Available from: https://doi.org/10.1016/s0264-410x(97)00208-9 >. Accessed: Mar. 13, 2023. doi: 10.1016/s0264-410x(97)00208-9.
https://doi.org/10.1016/s0264-410x(97)00... ). More recently, a rBm86-based vaccine BovimuneIxovac was launched in Mexico (LAPISA, 2018LAPISA. BovimuneIxovac, 2018. Available from: <Available from: http://lapisa.com/eng/bovimune-ixovac%C2%AE.html >. Accessed: Mar. 13, 2023.
http://lapisa.com/eng/bovimune-ixovac%C2... ). The effectiveness of rBm86-based vaccines is highly variable among tick populations, it ranges from 51% to 91% (DE LA FUENTE et al., 2000DE LA FUENTE, J. et al. Immunological control of ticks through vaccination with Boophilusmicroplus gut antigens. Annals of the New York Academy of Sciences, v.916, p.617-621, 2000. Available from: <Available from: https://doi.org/10.1111/j.1749-6632.2000.tb05347.x >. Accessed: Mar. 13, 2023. doi: 10.1111/j.1749-6632.2000.tb05347.x.
https://doi.org/10.1111/j.1749-6632.2000... ; DE LA FUENTE et al., 1999DE LA FUENTE, J. et al. Vaccination against ticks (Boophilusspp.): the experience with the Bm86-based vaccine Gavac. Genetic Analysis: Biomolecular Engineering, v.15, p.143-148, 1999. Available from: <Available from: https://doi.org/10.1016/s1050-3862(99)00018-2 >. Accessed: Mar. 13, 2023. doi: 10.1016/s1050-3862(99)00018-2.
https://doi.org/10.1016/s1050-3862(99)00... ; HUE et al., 2017HUE, T. et al. Experimental efficacy of a vaccine against Rhipicephalusaustralis. Experimental and Applied Acarology, v.73, p.245-256, 2017. Available from: <Available from: https://doi.org/10.1007/s10493-017-0184-0 >. Accessed: Mar. 13, 2023. doi: 10.1007/s10493-017-0184-0.
https://doi.org/10.1007/s10493-017-0184-... ; PATARROYO et al., 2002PATARROYO, J. H. et al. Immunization of cattle with synthetic peptides derived from the Boophilusmicroplus gut protein (Bm86). Veterinary Immunology and Immunopathology,v.88, p.163-172, 2002. Available from: <Available from: https://doi.org/10.1016/s0165-2427(02)00154-x >. Accessed: Mar. 13, 2023. doi: 10.1016/s0165-2427(02)00154-x.
https://doi.org/10.1016/s0165-2427(02)00... ; RODRIGUEZ et al., 1995RODRIGUEZ, M. et al. Effect of vaccination with a recombinant Bm86 antigen preparation on natural infestations of Boophilusmicroplus in grazing dairy and beef pure and cross-bred cattle in Brazil. Vaccine,v.13, p.1804-1808, 1995. Available from: <Available from: https://doi.org/10.1016/0264-410x(95)00119-l >. Accessed: Mar. 13, 2023. doi: 10.1016/0264-410x(95)00119-l.
https://doi.org/10.1016/0264-410x(95)001... ; WILLADSEN & KEMP, 1988WILLADSEN, P.; KEMP, D. H. Vaccination with ‘concealed’ antigens for tick control. Parasitology Today, v.4, p.196-198, 1988. Available from: <Available from: https://doi.org/10.1016/0169-4758(88)90084-1 >. Accessed: Mar. 13, 2023. doi: 10.1016/0169-4758(88)90084-1.
https://doi.org/10.1016/0169-4758(88)900... ).

In some R. microplus populations, the low efficacy of rBm86-based vaccines was overcome by using the Bm95 protein as the vaccinal antigen. In a study conducted in Argentina, Bm95 was identified in a population of R. microplus and was shown to have 91.4% amino acid similarity with Bm86 (GARCIA-GARCIA et al., 1999GARCIA-GARCIA, J. C. et al. Sequence variations in the Boophilusmicroplus Bm86 locus and implications for immunoprotection in cattle vaccinated with this antigen. Experimental and Applied Acarology, v.23, p.883-895, 1999. Available from: <Available from: https://doi.org/10.1023/a:1006270615158 >. Accessed: Mar. 13, 2023. doi: 10.1023/a:1006270615158.
https://doi.org/10.1023/a:1006270615158... ). Recombinant Bm95 was found to protect cattle from tick infestation in Argentina and Cuba, demonstrating its efficacy against some tick populations refractory to immunization with rBm86 (GARCIA-GARCIA et al., 1999GARCIA-GARCIA, J. C. et al. Sequence variations in the Boophilusmicroplus Bm86 locus and implications for immunoprotection in cattle vaccinated with this antigen. Experimental and Applied Acarology, v.23, p.883-895, 1999. Available from: <Available from: https://doi.org/10.1023/a:1006270615158 >. Accessed: Mar. 13, 2023. doi: 10.1023/a:1006270615158.
https://doi.org/10.1023/a:1006270615158... ). An inverse correlation was observed between vaccine efficacy and variation in the Bm86/Bm95 locus, suggesting that an amino acid sequence variation greater than 2.8% is enough to diminish the efficacy (GARCIA-GARCIA et al., 1999GARCIA-GARCIA, J. C. et al. Sequence variations in the Boophilusmicroplus Bm86 locus and implications for immunoprotection in cattle vaccinated with this antigen. Experimental and Applied Acarology, v.23, p.883-895, 1999. Available from: <Available from: https://doi.org/10.1023/a:1006270615158 >. Accessed: Mar. 13, 2023. doi: 10.1023/a:1006270615158.
https://doi.org/10.1023/a:1006270615158... ).

Integrated control of R. microplus with Gavac and acaricides

Integrated pest control management is defined as using a combination of common-sense practices to take advantage of environmental factors and the population dynamics of a pest species in order to control that species. Information about the life cycles of ticks and their interaction with the environment, as well as climatologic data and vector control methods (including the use of pesticides), are critical to designing effective strategies to reduce tick infestations (RODRÍGUEZ-VIVAS et al., 2018RODRÍGUEZ-VIVAS, R. I. et al. Strategies for the control of Rhipicephalusmicroplusticks in a world of conventional acaricide and macrocyclic lactone resistance. Parasitology Research, v.117, p.3-29, 2018. Available from: <Available from: https://doi.org/10.1007/s00436-017-5677-6 >. Accessed: Mar. 13, 2023. doi: 10.1007/s00436-017-5677-6.
https://doi.org/10.1007/s00436-017-5677-... ).

Effectively, vaccines are an additional tool in the tick-control arsenal. In a study conducted in Cuba (RODRIGUEZ-VALLE et al., 2004RODRIGUEZ-VALLE, M. et al. Integrated control of Boophilusmicroplus ticks in Cuba based on vaccination with the anti-tick vaccine Gavac. Experimental and Applied Acarology, v.34, p.375-382, 2004. Available from: <Available from: https://doi.org/10.1007/s10493-004-1389-6 >. Accessed: Mar. 13, 2023. doi: 10.1007/s10493-004-1389-6.
https://doi.org/10.1007/s10493-004-1389-... ), this approach was taken with the Gavac vaccine, and the use of such vaccine resulted in an increase in the interval between acaricide treatments in Bostaurus and an 87% decrease in the total number of acaricide treatments required. Similar results were obtained in B. indicus, in which there was also an increase in the interval between acaricide treatments, together with a 68% decrease in the total number of acaricide treatments required (RODRIGUEZ-VALLE et al., 2004RODRIGUEZ-VALLE, M. et al. Integrated control of Boophilusmicroplus ticks in Cuba based on vaccination with the anti-tick vaccine Gavac. Experimental and Applied Acarology, v.34, p.375-382, 2004. Available from: <Available from: https://doi.org/10.1007/s10493-004-1389-6 >. Accessed: Mar. 13, 2023. doi: 10.1007/s10493-004-1389-6.
https://doi.org/10.1007/s10493-004-1389-... ). In another study, conducted in Mexico, Gavac vaccine was used in combination with an amidine for the controlof R. microplus, resulting in a lower number of acaricide treatments in cattle that had received the anti-tick vaccine (REDONDO et al., 1999REDONDO, M. et al. Integrated control of acaricide-resistant Boophilusmicroplus populations on grazing cattle in Mexico using vaccination with Gavac and amidine treatments. Experimental and Applied Acarology, v.23, p.841-849, 1999. Available from: <Available from: https://doi.org/10.1023/A:1015925616490 >. Accessed: Mar. 13, 2023. doi: 10.1023/A:1015925616490.
https://doi.org/10.1023/A:1015925616490... ). Over a 9-year period, cattle on a ranch in Mexico were immunized with Gavac, and the annual number of acaricide treatments decreased from 24 in 1997 to 7-8 in 2006, the number of ticks per animal decreased from 100 to < 20 over the same period (DE LA FUENTE et al., 2007DE LA FUENTE, J. et al. A ten-year review of commercial vaccine performance for control of tick infestations on cattle. Animal Health Research Reviews, v.8, p.23-28, 2007. Available from: <Available from: https://doi.org/10.1017/s1466252307001193 >. Accessed: Mar. 13, 2023. doi: 10.1017/s1466252307001193.
https://doi.org/10.1017/s146625230700119... ).

In Venezuela, 1.9 million cattle on nearly 40,000 ranches were vaccinated with Gavac via the national integrated program for bovine tick control, as reported by SUAREZ et al. (2016SUAREZ, M. et al. High impact and effectiveness of Gavac™ vaccine in the national program for control of bovine ticks Rhipicephalusmicroplus in Venezuela. Livestock Science,v.187, p.48-52, 2016. Available from: <Available from: https://doi.org/10.1016/j.livsci.2016.02.005 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.livsci.2016.02.005.
https://doi.org/10.1016/j.livsci.2016.02... ). The authors found that, by the end of the second year, the use of chemical acaricides had been reduced by 83.7%, corresponding to a reduction of more than 260 tons, and that there had been an 81.5% reduction in the economic costs (i.e., savings in acaricide purchases). These data indicate that the success of an anti-tick vaccine relies on its integration into a tick control management strategy that includes acaricide treatments and other measures. Undoubtedly, vaccines constitute a useful tool to prolong the useful lifespan of a given acaricide, given that they delay the selection of acaricide-resistant tick populations. The use of vaccines can decrease the amount of chemicals applied, thus reducing the risk of food and environmental contamination.

Although, Bm86-based vaccines were developed some time ago, they are still in use in less extensively grazed herds in some regions such as Cuba (WILLADSEN, 2006WILLADSEN, P.Tick control: thoughts on a research agenda. Veterinary Parasitology, v.138, p.161-168, 2006. Available from: <Available from: https://doi.org/10.1016/j.vetpar.2006.01.050 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vetpar.2006.01.050.
https://doi.org/10.1016/j.vetpar.2006.01... ; VARGAS-HERNÁNDEZ et al., 2018VARGAS-HERNÁNDEZ, M. et al. Stability, safety and protective immunity of Gavac® vaccine subjected to heat stress. Biotecnologia Aplicada, v.35: p.1222-1227. 2018. Available from: <Available from: https://www.medigraphic.com/cgi-bin/new/resumenI.cgi?IDARTICULO=86508 >. Accessed: Mar. 13, 2023.
https://www.medigraphic.com/cgi-bin/new/... ). In addition, because the global market for acaricides and tick repellents is huge and more profitable than anti-tick vaccines, there has been limited investment and interest to developed novel ectoparasite vaccines, even those that have proven effective (DE LA FUENTE & ESTRADA-PENA, 2019DE LA FUENTE, J.; ESTRADA-PENA, A. Why new vaccines for the control of ectoparasite vectors have not been registered and commercialized? Vaccines,v.7, p.75, 2019. Available from: <Available from: https://doi.org/10.3390/vaccines7030075 >. Accessed: Mar. 13, 2023. doi: 10.3390/vaccines7030075.
https://doi.org/10.3390/vaccines7030075... ). Antiparasitic treatment is the usual method to control ticks and other parasites in cattle, so alternative control strategies, including vaccination, remain largely unknown and many livestock farmers do not have a good understanding of the efficacy of vaccines to control parasites. Furthermore, vaccines do not control ticks as effectively as acaricides, and it is essential to educate livestock producers on the fundamentals of correct use of antiparasitic vaccines. Despite the technical and marketing problems related to the Bm86-based anti-tick vaccine against R.microplus, vaccines still remain as a promising alternative because the widespread use of acaricides leads to the selection of acaricide-resistant tick populations and because consumer concerns impel legislation to be more and more restrictive in relation to the presence chemical residues in food. In fact, anti-tick vaccines could make possible not just to reduce hazardous residues in meat and dairy products but also to produce those products by processes that eliminate even the risk of contamination by acaricides and their residues. Therefore, it is imperative to identify and validate better antigens. In addition to looking for antigens with greater efficacy against different populations of R. microplus, it is also useful to identify those able to cross react and be able to induce protection against more than one tick species (ALMAZAN et al., 2018ALMAZAN, C. et al. Immunological control of ticks and tick-borne diseases that impact cattle health and production. Frontiers in Bioscience,v.23, p.1535-1551, 2018. Available from: <Available from: https://doi.org/10.2741/4659 >. Accessed: Mar. 13, 2023. doi: 10.2741/4659.
https://doi.org/10.2741/4659... ; GUERRERO et al., 2012bGUERRERO, F. D. et al. Cattle tick vaccines: many candidate antigens, but will a commercially viable product emerge? International Journal for Parasitology, v.42, p.421-427, 2012b. Available from: <Available from: https://doi.org/10.1016/j.ijpara.2012.04.003 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.ijpara.2012.04.003.
https://doi.org/10.1016/j.ijpara.2012.04... ).

Potential antigens for the control of R. microplus

More than two dozen tick proteins have been tested as antigens for anti-tick vaccines. However, only a few have shown potential as promising viable candidates (Table 2). Several comprehensive reviews focusing on different aspects of tick vaccine development have recently been published (RODRIGUEZ-VIVAS et al., 2018RODRÍGUEZ-VIVAS, R. I. et al. Strategies for the control of Rhipicephalusmicroplusticks in a world of conventional acaricide and macrocyclic lactone resistance. Parasitology Research, v.117, p.3-29, 2018. Available from: <Available from: https://doi.org/10.1007/s00436-017-5677-6 >. Accessed: Mar. 13, 2023. doi: 10.1007/s00436-017-5677-6.
https://doi.org/10.1007/s00436-017-5677-... , LEAL et al., 2021FERREIRA LEAL, B. et al. Ticks and antibodies: May parasite density and tick evasion influence the outcomes following immunization protocols? Veterinary Parasitology, 2021 v.300, p.109610. Available from: <Available from: https://doi.org/10.1016/j.vetpar.2021.109610 >. Accessed: May, 03, 2023. doi: 10.1016/j.vetpar.2021.109610.
https://doi.org/10.1016/j.vetpar.2021.10... ; PEREIRA et al., 2022PEREIRA, D. F. S. et al. Rhipicephalusmicroplus: An overview of vaccine antigens against the cattle tick. Ticks and Tick-borne Diseases, v.13, p.101828, 2022. Available from: <Available from: https://doi.org/10.1016/j.ttbdis.2021.101828 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.ttbdis.2021.101828.
https://doi.org/10.1016/j.ttbdis.2021.10... ; ABBAS et al., 2023ABBAS, M. N. et al. Recent advances in tick antigen discovery and anti-tick vaccine development. International Journal of Molecular Sciences, v.24, p.4969, 2023. Available from: <Available from: https://doi.org/10.3390/ijms24054969 >. Accessed: May, 03, 2023. doi: 10.3390/ijms24054969.
https://doi.org/10.3390/ijms24054969... ). Here, the intent is to present a brief overview of the processes of antigen discovery and characterization and development of anti-tick vaccines considering the discovery and characterization of new antigens which can elicit an immune response that impairs tick physiological functions.

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Table 2
Efficacy of antigens used in immunizing cattle against Rhipicephalusmicroplus.

In general, such antigens should encounter immunoglobulins entering the hemolymph (or gut) and are associated with some crucial function for the tick survival or fitness (NUTTALL et al., 2006NUTTALL, P. A. et al. Exposed and concealed antigens as vaccine targets for controlling ticks and tick-borne diseases. Parasite Immunology, v.28, p.155-163, 2006. Available from: <Available from: https://doi.org/10.1111/j.1365-3024.2006.00806.x >. Accessed: Mar. 13, 2023. doi: 10.1111/j.1365-3024.2006.00806.x.
https://doi.org/10.1111/j.1365-3024.2006... ). Their efficacy must be evaluated in anti-tick vaccine trials. In such trials, it is necessary to calculate the overall efficacy, that is, considering the overall effect on the size of the next tick generation. It is important to standardize the results and compare the efficacy showed by different research groups with different antigens. In general, the efficacy is calculated as a percentage considering the difference between an immunized group and an unvaccinated control group in terms of the number of fully engorged ticks, their egg laying capacity, and egg fertility, in other words, an indication of the overall impact in the next tick generation. (CUNHA et al., 2013CUNHA, R. C. et al. Calculation of the efficacy of vaccines against tick infestations on cattle. Revista Brasileira de Parasitologia Veterinária, v.22, p.571-578, 2013. Available from: <Available from: https://doi.org/10.1590/S1984-29612013000400019 >. Accessed: Mar. 13, 2023. doi: 10.1590/S1984-29612013000400019.
https://doi.org/10.1590/S1984-2961201300... ).

Subolesin (SUB) is an intracellular regulatory protein involved in signal transduction that affects multiple cellular processes in ticks, such as the innate immune response, feeding, reproduction, and development (NARANJO et al., 2013NARANJO, V. et al. Reciprocal regulation of NF-kB (Relish) and Subolesin in the tick vector, Ixodesscapularis. PLOS ONE, v.8, p.e65915, 2013. Available from: <Available from: https://doi.org/10.1371/journal.pone.0065915 >. Accessed: Mar. 13, 2023. doi: 10.1371/journal.pone.0065915.
https://doi.org/10.1371/journal.pone.006... ). Knockdown of SUB by RNA interference (RNAi) has been shown to lead to a more than 90% reduction in oviposition and progeny in five tick species (DE LA FUENTE et al., 2006DE LA FUENTE, J. et al. The tick protective antigen, 4D8, is a conserved protein involved in modulation of tick blood ingestion and reproduction. Vaccine, v.24, p.4082-4095, 2006. Available from: <Available from: https://doi.org/10.1016/j.vaccine.2006.02.046 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vaccine.2006.02.046.
https://doi.org/10.1016/j.vaccine.2006.0... ), evidence of physiological importance of this protein and its usefulness for the development of an anti-tick vaccine. Also, cattle immunized with the recombinant protein and challenged with R. microplus showed a 47% decrease in the number of engorged females, and the overall efficacy of the vaccine was 60% (ALMAZAN et al., 2010ALMAZAN, C. et al. Identification and characterization of Rhipicephalus (Boophilus) microplus candidate protective antigens for the control of cattle tick infestations. Parasitology Research, v.106, p.471-479, 2010. Available from: <Available from: https://doi.org/10.1007/s00436-009-1689-1 >. Accessed: Mar. 13, 2023. doi: 10.1007/s00436-009-1689-1.
https://doi.org/10.1007/s00436-009-1689-... ; MERINO et al., 2013MERINO, O. et al. Vaccination with proteins involved in tick-pathogen interactions reduces vector infestations and pathogen infection. Vaccine, v.31, p.5889-5896, 2013. Available from: <Available from: https://doi.org/10.1016/j.vaccine.2013.09.037 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vaccine.2013.09.037.
https://doi.org/10.1016/j.vaccine.2013.0... ). In another study, quantitative PCR was used in order to measure the presence of B. bigemina and A. marginale DNA in ticks feeding on SUB-vaccinated and control cattle (MERINO et al., 2013MERINO, O. et al. Vaccination with proteins involved in tick-pathogen interactions reduces vector infestations and pathogen infection. Vaccine, v.31, p.5889-5896, 2013. Available from: <Available from: https://doi.org/10.1016/j.vaccine.2013.09.037 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vaccine.2013.09.037.
https://doi.org/10.1016/j.vaccine.2013.0... ). The authors found that SUB was capable of controlling tick infestation and tick-borne pathogens in cattle. In crossbred B. taurus-B. indicus cattle, the efficacy of the SUB vaccine was reported to be 44 % and 37% after the first and second challenges, respectively (SHAKYA et al., 2014SHAKYA, M. et al. Subolesin: a candidate vaccine antigen for the control of cattle tick infestations in Indian situation. Vaccine, v.32, p.3488-3494, 2014. Available from: <Available from: https://doi.org/10.1016/j.vaccine.2014.04.053 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vaccine.2014.04.053.
https://doi.org/10.1016/j.vaccine.2014.0... ).

Ferritin 2 (FER2) has been confirmed as the primary transporter of nonheme iron between the tick gut and the peripheral tissues in Ixodesricinus, a vector of tick-borne encephalitis and Lyme borreliosis. In RNAi experiments, HAJDUSEK et al. (2009HAJDUSEK, O. et al. Knockdown of proteins involved in iron metabolism limits tick reproduction and development. Proceedings of the National Academy of Sciences, v.106, p.1033-1038, 2009. Available from: <Available from: https://doi.org/10.1073/pnas.0807961106 >. Accessed: Mar. 13, 2023. doi: 10.1073/pnas.0807961106.
https://doi.org/10.1073/pnas.0807961106... ) demonstrated the relevance of FER2 in iron metabolism, showing that it is involved tick development and reproduction. In that study, the authors immunized cattle with the recombinant R. microplus FER2 homologue (RmFER2), expressed in E. coli. Results indicated that RmFER2 is a protective antigen with an efficacy of 64% (Table 2). Artificial feeding with cattle blood containing antibodies against recombinant I. persulcatus FER2 has been shown to decrease the weight and engorgement of R. microplus females (XAVIER et al., 2021XAVIER, M. A. et al. Cross-species reactivity of antibodies against Ixodespersulcatus ferritin 2 to Rhipicephalusmicroplus. The Japanese Journal of Veterinary Research, v.69, p.57-65, 2021. Available from: <Available from: https://doi.org/10.14943/jjvr.69.1.57 >. Accessed: Mar. 13, 2023. doi: 10.14943/jjvr.69.1.57.
https://doi.org/10.14943/jjvr.69.1.57... ).

Glutathione S-transferase (GST) is widely distributed among organisms and plays a role in the detoxification of endogenous substances and xenobiotics (PAVLIDI et al., 2018PAVLIDI, N. et al. The role of glutathione S-transferases (GSTs) in insecticide resistance in crop pests and disease vectors. Current Opinion in Insect Science, v.27, p.97-102, 2018. Available from: <Available from: https://doi.org/10.1016/j.cois.2018.04.007 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.cois.2018.04.007.
https://doi.org/10.1016/j.cois.2018.04.0... ). In arthropods, GST plays a pivotal role in one of the mechanisms of pesticide detoxification. It has been demonstrated that GST metabolizes insecticides by facilitating a reductive dehydrochlorination or by conjugating them with reduced glutathione, as well as contributing to the removal of toxic free radical oxygen species produced through the action of pesticides (ENAYATI et al., 2005ENAYATI, A. A. et al. Insect glutathione transferases and insecticide resistance. Insect Molecular Biology, v.14, p.3-8, 2005. Available from: <Available from: https://doi.org/10.1111/j.1365-2583.2004.00529.x >. Accessed: Mar. 13, 2023. doi: 10.1111/j.1365-2583.2004.00529.x.
https://doi.org/10.1111/j.1365-2583.2004... ). Reports on GST over expression in pesticide-resistant strains have shown that elevated pesticide metabolism is not the only effect of such over expression. Increased GST expression can attenuate oxidative stress or sequester the pesticide rather than metabolizing it (FEYEREISEN et al., 2015FEYEREISEN, R. et al. Genotype to phenotype, the molecular and physiological dimensions of resistance in arthropods. Pesticide Biochemistry and Physiology, v.121, p.61-77, 2015. Available from: <Available from: https://doi.org/10.1016/j.pestbp.2015.01.004 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.pestbp.2015.01.004.
https://doi.org/10.1016/j.pestbp.2015.01... ).

Several acaricides are substrates for R. microplus GST, suggesting that this enzyme plays a role in pesticide detoxification (DA SILVA VAZ et al., 2004aDA SILVA VAZ JR, I. et al. Effect of acaricides on the activity of a Boophilusmicroplus glutathione S-transferase. Veterinary Parasitology, v.119, p.237-245, 2004a. Available from: <Available from: https://doi.org/10.1016/j.vetpar.2003.11.004 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vetpar.2003.11.004.
https://doi.org/10.1016/j.vetpar.2003.11... ). In addition, serum from rabbits immunized with recombinant GST from Haemaphysalislongicornis(rGST-Hl) has been shown to recognize recombinant R. microplusGST, confirming cross immunization (DA SILVA VAZ et al., 2004bDA SILVA VAZ JR, I. et al. Cloning, expression and partial characterization of a Haemaphysalislongicornis and a Rhipicephalusappendiculatus glutathione S-transferase. Insect Molecular Biology, v.13, p.329-335, 2004b. Available from: <Available from: https://doi.org/10.1111/j.0962-1075.2004.00493.x >. Accessed: Mar. 13, 2023. doi: 10.1111/j.0962-1075.2004.00493.x.
https://doi.org/10.1111/j.0962-1075.2004... ). In fact, rGST-Hl has been shown to induce a protective response against R. microplus in cattle, with an efficacy of 57% (PARIZI et al., 2011PARIZI, L. F. et al. Cross immunity withHaemaphysalislongicornis glutathione S-transferase reduces an experimental Rhipicephalus (Boophilus) microplus infestation. Experimental Parasitology, v.127: 113-118, 2011. Available from: <Available from: https://doi.org/10.1016/j.exppara.2010.07.001 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.exppara.2010.07.001.
https://doi.org/10.1016/j.exppara.2010.0... ). In one of the few field trials for tick vaccines, rGST-Hl was used in combination with other antigens and that the number of semi-engorged female ticks was significantly lower among the vaccinated cattle. Surprisingly, cattle weight gain in the vaccinated group was 56% bigger in comparison with the unvaccinated cattle (body weight gain was 39% and 25% in 127 days, respectively) ). Among the various antigens tested in that trial, rGST-Hl elicited the most persistent humoral response (PARIZI et al., 2012aPARIZI, L. F. et al. The quest for a universal vaccine against ticks: cross-immunity insights. The Veterinary Journal, v.194, p.158-165, 2012a. Available from: <Available from: https://doi.org/10.1016/j.tvjl.2012.05.023 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.tvjl.2012.05.023.
https://doi.org/10.1016/j.tvjl.2012.05.0... ; PARIZI et al., 2012bPARIZI, L. F. et al. Multi-antigenic vaccine against the cattle tick Rhipicephalus (Boophilus) microplus: a field evaluation. Vaccine, v.30, p.6912-6917, 2012b. Available from: <Available from: https://doi.org/10.1016/j.exppara.2010.07.001 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.exppara.2010.07.001.
https://doi.org/10.1016/j.exppara.2010.0... ). Immunization with rGST-Hl has also been shown to provide cross protection against other hard tick species (NDAWULA et al., 2019NDAWULA, C. et al. Constituting a glutathione S-transferase-cocktail vaccine against tick infestation. Vaccine, v.37, p.1918-1927, 2019. Available from: <Available from: https://doi.org/10.1016/j.vaccine.2019.02.039 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vaccine.2019.02.039.
https://doi.org/10.1016/j.vaccine.2019.0... ; SABADIN et al., 2017SABADIN, G. A. et al. Effect of recombinant glutathione S-transferase as vaccine antigen against Rhipicephalusappendiculatus and Rhipicephalussanguineus infestation. Vaccine, v.35, p.6649-6656, 2017. Available from: <Available from: https://doi.org/10.1016/j.vaccine.2017.10.026 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vaccine.2017.10.026.
https://doi.org/10.1016/j.vaccine.2017.1... ). A cocktail of recombinant GST from Rhipicephalusdecoloratus and A. variegatumhas been shown to induce a protective response in rabbits and to reduce the number of Rhipicephalussanguineus adult females by 35.3% (NDAWULA et al., 2019NDAWULA, C. et al. Constituting a glutathione S-transferase-cocktail vaccine against tick infestation. Vaccine, v.37, p.1918-1927, 2019. Available from: <Available from: https://doi.org/10.1016/j.vaccine.2019.02.039 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vaccine.2019.02.039.
https://doi.org/10.1016/j.vaccine.2019.0... ). Since R. decoloratus and A. variegatum are also cattle parasites a broad-spectrum universal anti-tick vaccine could be prepared based on GST as the major antigen.

Previous studies on Drosophila melanogaster (FROLOV & BIRCHLER, 1998FROLOV, M. V.; BIRCHLER, J. A. Mutation in P0, a dual function ribosomal protein/apurinic/apyrimidinic endonuclease, modifies gene expression and position effect variegation in Drosophila. Genetics, v.150, p.1487-1495, 1998. Available from: <Available from: https://doi.org/10.1093/genetics/150.4.1487 >. Accessed: Mar. 13, 2023. doi: 10.1093/genetics/150.4.1487.
https://doi.org/10.1093/genetics/150.4.1... ) and Aedesalbopictus (JAYACHANDRAN & FALLON, 2003JAYACHANDRAN, G.; FALLON, A. M. Ribosomal protein P0 from Aedesalbopictus mosquito cells: cDNA cloning and analysis of expression. Genetica, v.119, p.1-10, 2003. Available from: <Available from: https://doi.org/10.1023/a:1024426411780 >. Accessed: Mar. 13, 2023. doi: 10.1023/a:1024426411780.
https://doi.org/10.1023/a:1024426411780... ) have demonstrated the crucial role of a 60S ribosomal proteins (P0) in regulating gene expression in arthropods, as evidenced by gene disruption experiments. In a subsequent study, an immunogenic region in Rhipicephalus sp. P0 was identified and a 20 amino acid synthetic peptide corresponding to host-non homologous region was inoculated in rabbits (RODRIGUEZ-MALLON et al., 2012RODRIGUEZ-MALLON, A. et al. A novel tick antigen shows high vaccine efficacy against the dog tick, Rhipicephalussanguineus. Vaccine, v.30, p.1782-1789, 2012. Available from: <Available from: https://doi.org/10.1016/j.vaccine.2012.01.011 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vaccine.2012.01.011.
https://doi.org/10.1016/j.vaccine.2012.0... ). After a challenge with R. sanguineus, the protective efficacy of this peptide was found to be 90%. A subsequent vaccine trial demonstrated that the same peptide is protective against R. microplus in cattle, with an efficacy of 96% (RODRIGUEZ-MALLON et al., 2015RODRIGUEZ-MALLON, A. et al. High efficacy of a 20 amino acid peptide of the acidic ribosomal protein P0 against the cattle tick, Rhipicephalusmicroplus. Ticks and Tick-borne Diseases, v.6, p.530-537, 2015. Available from: <Available from: https://doi.org/10.1016/j.ttbdis.2015.04.007 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.ttbdis.2015.04.007.
https://doi.org/10.1016/j.ttbdis.2015.04... ). Another successful approach with P0 was obtained by chemically conjugating the peptide to Bm86. The use of such a pP0-Bm86 construct in cattle resulted in 84% reduction of R. microplus (RODRÍGUEZ MALLÓN et al., 2020).

Immunization with a R. microplus metalloprotease has been shown to be 60% efficacious against that same tick (ALI et al., 2015aALI, A. et al. Immunoprotective potential of a Rhipicephalus (Boophilus) microplus metalloprotease. Veterinary Parasitology, v.207, p.107-114, 2015a. Available from: <Available from: https://doi.org/10.1016/j.vetpar.2014.11.007 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vetpar.2014.11.007.
https://doi.org/10.1016/j.vetpar.2014.11... ). Metalloproteases have been shown to be essential for diverse biological functions in organisms, including modulation of host innate immune responses, as well as inhibiting host angiogenesis and blood coagulation (ALI et al., 2015bALI, A. et al. Probing the functional role of tick metalloproteases. Physiology Entomololgy, v.40, p.177-188, 2015b. Available from: <Available from: https://doi.org/10.1111/phen.12104 >. Accessed: Mar. 13, 2023. doi: 10.1111/phen.12104.
https://doi.org/10.1111/phen.12104... ; SIMO et al., 2017SIMO, L. et al. The essential role of tick salivary glands and saliva in tick feeding and pathogen transmission. Frontiers in Cellular and Infection Microbiology, v.7, p.281, 2017. Available from: <Available from: https://doi.org/10.3389/fcimb.2017.00281 >. Accessed: Mar. 13, 2023.doi: 10.3389/fcimb.2017.00281.
https://doi.org/10.3389/fcimb.2017.00281... ).

Peptidase inhibitors play a pivotal role in tick parasitism because they interfere with several systems and also in defense-related host peptidases, thus facilitating blood feeding (PARIZI et al., 2018PARIZI, L. F. et al. Peptidase inhibitors in tick physiology. Medical and Veterinary Entomology, v.32, p.129-144, 2018. Available from: <Available from: https://doi.org/10.1111/mve.12276 >. Accessed: Mar. 13, 2023. doi: 10.1111/mve.12276.
https://doi.org/10.1111/mve.12276... ). Some peptidase inhibitors, such as several serpins and cystatins, have been identified in cattle tick saliva (FENG et al., 2019FENG, L. L. et al. Proteomic analysis of saliva from partially and fully engorged adult female Rhipicephalusmicroplus (Acari: Ixodidae). Experimental and Applied Acarology, v.78, p.443-460, 2019. Available from: <Available from: https://doi.org/10.1007/s10493-019-00390-4 >. Accessed: Mar. 13, 2023. doi: 10.1007/s10493-019-00390-4.
https://doi.org/10.1007/s10493-019-00390... ; TIRLONI et al., 2014TIRLONI, L. et al. Proteomic analysis of cattle tickRhipicephalus (Boophilus) microplus saliva: a comparison between partially and fully engorged females. PLOS ONE, v.9, p.e94831, 2014. Available from: <Available from: https://doi.org/10.1371/journal.pone.0094831 >. Accessed: Mar. 13, 2023. doi: 10.1371/journal.pone.0094831.
https://doi.org/10.1371/journal.pone.009... ). The immunogenic properties of these inhibitors and their potential as multispecies anti-tick vaccines have been described (PARIZI et al., 2020PARIZI, L. F. et al. Rhipicephalusmicroplus cystatin as a potential cross-protective tick vaccine against Rhipicephalusappendiculatus. Ticks and Tick-borne Diseases, v.11, p.101378, 2020. Available from: <Available from: https://doi.org/10.1016/j.ttbdis.2020.101378 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.ttbdis.2020.101378.
https://doi.org/10.1016/j.ttbdis.2020.10... ; TIRLONI et al., 2016TIRLONI, L. et al. The putative role of Rhipicephalusmicroplus salivary serpins in the tick-host relationship. Insect Biochemistry and Molecular Biology, v.71, p.12-28, 2016. Available from: <Available from: https://doi.org/10.1016%2Fj.ibmb.2016.01.004 >. Accessed: Mar. 13, 2023. doi: 10.1016%2Fj.ibmb.2016.01.004.
https://doi.org/10.1016%2Fj.ibmb.2016.01... ). In one study, trypsin inhibitors were used as vaccines against R. microplus. Effectively, they confer partial protection in the immunized cattle (ANDREOTTI et al., 2002ANDREOTTI, R. et al. BmTI antigens induce a bovine protective immune response against Boophilusmicroplus tick. International Immunopharmacology,v.2, p.557-563, 2002.Available from: <Available from: https://doi.org/10.1016/s1567-5769(01)00203-x >. Accessed: Mar. 13, 2023. doi: 10.1016/s1567-5769(01)00203-x.
https://doi.org/10.1016/s1567-5769(01)00... ). In a subsequent study (ANDREOTTI et al., 2012ANDREOTTI, R. et al. Protective immunity against tick infestation in cattle vaccinated with recombinant trypsin inhibitor of Rhipicephalusmicroplus. Vaccine,v.30, p.6678-6685, 2012. Available from: <Available from: https://doi.org/10.1016/j.vaccine.2012.08.066 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vaccine.2012.08.066.
https://doi.org/10.1016/j.vaccine.2012.0... ), a tick-derived recombinant trypsin inhibitor was found to have an efficacy of 32% against R. microplus infestation in cattle (Table 2).

A flagelliform silk protein has been identified in R. microplus, Dermacentorandersoni (ALARCON-CHAIDEZ et al., 2007ALARCON-CHAIDEZ, F. J. et al. Transcriptome analysis of the salivary glands of Dermacentorandersoni Stiles (Acari: Ixodidae). Insect Molecular Biology, v.37, p.48-71, 2007. Available from: <Available from: https://doi.org/10.1016/j.ibmb.2006.10.002 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.ibmb.2006.10.002.
https://doi.org/10.1016/j.ibmb.2006.10.0... ; SANTOS et al., 2004SANTOS, I. K. et al. Gene discovery in Boophilusmicroplus, the cattle tick: the transcriptomes of ovaries, salivary glands, and hemocytes. Annals of the New York Academy of Sciences, v.1026, p.242-246, 2004. Available from: <Available from: https://doi.org/10.1196/annals.1307.037 >. Accessed: Mar. 13, 2023. doi: 10.1196/annals.1307.037.
https://doi.org/10.1196/annals.1307.037... ), and R. appendiculatus (MULENGA et al., 2007MULENGA, A. et al. The molecular basis of the Amblyommaamericanum tick attachment phase. Experimental and Applied Acarology, v.41, p.267-287, 2007. Available from: <Available from: https://doi.org/10.1007/s10493-007-9064-3 >. Accessed: Mar. 13, 2023. doi: 10.1007/s10493-007-9064-3.
https://doi.org/10.1007/s10493-007-9064-... ). Also, the recombinant silk protein induced a partial protection against R. microplus (MERINO et al., 2013MERINO, O. et al. Vaccination with proteins involved in tick-pathogen interactions reduces vector infestations and pathogen infection. Vaccine, v.31, p.5889-5896, 2013. Available from: <Available from: https://doi.org/10.1016/j.vaccine.2013.09.037 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vaccine.2013.09.037.
https://doi.org/10.1016/j.vaccine.2013.0... ) and a reduction in A. marginale DNA levels, suggesting that immunization with the silk protein confers some protection against this bacterium.

Aquaporins are channel pore-forming membrane proteins that are able to transport water across the cell membrane. Hereafter, in one transcriptomics study (GUERRERO et al., 2014GUERRERO, F. D. et al. Rhipicephalus (Boophilus) microplus aquaporin as an effective vaccine antigen to protect against cattle tick infestations. Parasite & Vectors, v.12, p.475, 2014. Available from: <Available from: https://doi.org/10.1186/s13071-014-0475-9 >. Accessed: Mar. 13, 2023. doi: 10.1186/s13071-014-0475-9.
https://doi.org/10.1186/s13071-014-0475-... ), a sequence encoding an aquaporin from R. microplus was identified and cloned in an expression vector. In that study, the recombinant protein was expressed in P. pastoris and it was found to have an efficacy of 75% and 68% in two independent cattle pen trials (GUERRERO et al., 2014GUERRERO, F. D. et al. Rhipicephalus (Boophilus) microplus aquaporin as an effective vaccine antigen to protect against cattle tick infestations. Parasite & Vectors, v.12, p.475, 2014. Available from: <Available from: https://doi.org/10.1186/s13071-014-0475-9 >. Accessed: Mar. 13, 2023. doi: 10.1186/s13071-014-0475-9.
https://doi.org/10.1186/s13071-014-0475-... ), as shown in table 2. Recently, synthetic peptides corresponding to predicted extracellular domains from another aquaporin of R. microplus led to an overall reduction of tick-numbers on cattle by 25% (SCOLES et al., 2022SCOLES, G. A. et al. Vaccination of cattle with synthetic peptides corresponding to predicted extracellular domains of Rhipicephalus (Boophilus) microplus aquaporin 2 reduced the number of ticks feeding to repletion. Parasites & Vectors, v.15, p.22, 2022. Available from: <Available from: https://doi.org/10.1186/s13071-022-05166-1 >. Accessed: Mar. 13, 2023. doi: 10.1186/s13071-022-05166-1.
https://doi.org/10.1186/s13071-022-05166... ). Another channel protein identified in R. microplus is a mitochondrial voltage-dependent anion channel, designated BmVDAC (RODRIGUEZ-HERNANDEZ, 2012RODRIGUEZ-HERNANDEZ, E. et al. The identification of a VDAC-like protein involved in the interaction of Babesiabigemina sexual stages with Rhipicephalusmicroplus midgut cells. Veterinary Parasitology, v.187, p.538-541, 2012. Available from: <Available from: https://doi.org/10.1016/j.vetpar.2012.01.028 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vetpar.2012.01.028.
https://doi.org/10.1016/j.vetpar.2012.01... ). Among cattle immunized with recombinant BmVDAC, the efficacy against R. microplus was found to be 82%. Interestingly, when ticks were infected with B. bigemina, the reported efficacy of recombinant BmVDAC decreased to 34% (ORTEGA-SANCHEZ et al., 2020ORTEGA-SANCHEZ, R. et al. Vaccine efficacy of recombinant BmVDAC on Rhipicephalusmicroplus fed on Babesiabigemina-infected and uninfected cattle. Vaccine,v.38, p.3618-3625, 2020. Available from: <Available from: https://doi.org/10.1016/j.vaccine.2019.12.040 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vaccine.2019.12.040.
https://doi.org/10.1016/j.vaccine.2019.1... ).

CONCLUSION AND PERSPECTIVES:

As an anti-tick vaccine, Bm86 is far from being a complete technical and economic success. However, it has proven that an anti-tick vaccine is feasible and can be a valuable tool for the control of R. microplus, which constitutes a huge problem for livestock production. A number of antigens conferring a considerable degree of protection against R. microplus have been identified. Also, some of these antigens confer cross protection against other tick species besides the species from which they were obtained. Thus, the identification of new proteins with potential use in vaccines, a deeper characterization of proteins already identified, as well as the study of the multi-antigen vaccines, are necessary to increase the protection already reached. This approach also requests to discover and characterize analogous proteins in different tick species in order to develop a vaccine efficient against various tick species simultaneously.

Studies to develop a commercially acceptable vaccine against ticks is still in progress. Traditional vaccine design processes, which involve identifying putative antigens through costly and time-consuming in vivo tests, have limitations. In contrast, the development of reverse vaccinology methodologies that utilize bioinformatics approaches has led to the discovery of new vaccine candidates and can short the time to achieve a vaccine that fulfil all the requirements to have a spread use. Indeed, several recent studies have successfully identified new tick antigens using this strategy (DE LA FUENTE & MERINO, 2013DE LA FUENTE, J.; MERINO, O. Vaccinomics, the new road to tick vaccines. Vaccine, v.31, p.5923-5929, 2013. Available from: <Available from: https://doi.org/10.1016/j.vaccine.2013.10.049 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vaccine.2013.10.049.
https://doi.org/10.1016/j.vaccine.2013.1... ; MARUYAMA et al., 2017MARUYAMA, S. R. et al. Mining a differential sialotranscriptome of Rhipicephalusmicroplus guides antigen discovery to formulate a vaccine that reduces tick infestations. Parasites & Vectors, v.10, p.206, 2017. Available from: <Available from: https://doi.org/10.1186%2Fs13071-017-2136-2 >. Accessed: Mar. 13, 2023. doi: 10.1186%2Fs13071-017-2136-2.
https://doi.org/10.1186%2Fs13071-017-213... ; PÉREZ-SÁNCHEZ et al., 2019PÉREZ-SÁNCHEZ, R. et al. In silico selection of functionally important proteins from the mialome of Ornithodoroserraticus ticks and assessment of their protective efficacy as vaccine targets. Parasites Vectors, v.12, p.508, 2019. Available from: <Available from: https://doi.org/10.1186/s13071-019-3768-1 >. Accessed: May, 03, 2023. doi: 10.1186/s13071-019-3768-1.
https://doi.org/10.1186/s13071-019-3768-... ; NDAWULA et al., 2020NDAWULA, C. et al. Prediction, mapping and validation of tick glutathione S-transferase B-cell epitopes. Ticks and Tick-borne Disease, v.11, p.101445, 2020. Available from: <Available from: https://doi.org/10.1016/j.ttbdis.2020.101445 >. Accessed: May, 03, 2023. doi: 10.1016/j.ttbdis.2020.101445.
https://doi.org/10.1016/j.ttbdis.2020.10... ; TIRLONI et al., 2020TIRLONI, L. et al. A physiologic overview of the organ-specific transcriptome of the cattle tick Rhipicephalusmicroplus. Scientific Reports, v.10, p.18296, 2020. Available from: <Available from: https://doi.org/10.1038/s41598-020-75341-w >. Accessed: Mar. 13, 2023. doi: 10.1038/s41598-020-75341-w.
https://doi.org/10.1038/s41598-020-75341... ; TRENTELMAN et al., 2020TRENTELMAN, J. J. A. et al. A combined transcriptomic approach to identify candidates for an anti-tick vaccine blocking B. afzelii transmission. Scientific Reports, v.10, p.20061, 2020. Available from: <Available from: https://doi.org/10.1038/s41598-020-76268-y >. Accessed: May, 03, 2023. doi: 10.1038/s41598-020-76268-y.
https://doi.org/10.1038/s41598-020-76268... ; ALI et al., 2021ALI, A. et al. Prediction of novel drug targets and vaccine candidates against human lice (insecta), acari (arachnida), and their associated pathogens. Vaccines. v.10, p.8, 2021. Available from: <Available from: https://doi.org/10.3390/vaccines10010008 >. Accessed: May, 03, 2023. doi: 10.3390/vaccines10010008.
https://doi.org/10.3390/vaccines10010008... ; COUTO et al., 2021COUTO, J. et al. Probing the Rhipicephalus bursa sialomes in potential anti-tick vaccine candidates: a reverse vaccinology approach. Biomedicines, v.9, p.363, 2021. Available from: <Available from: https://doi.org/10.3390/biomedicines9040363 >. Accessed: May, 03, 2023. doi: 10.3390/biomedicines9040363.
https://doi.org/10.3390/biomedicines9040... ; PÉREZ-SÁNCHEZ et al., 2022PÉREZ-SÁNCHEZ, R. et al. A proteomics informed by transcriptomics insight into the proteome of Ornithodoroserraticus adult tick saliva. Parasites Vectors, v.15, p.1, 2022. Available from: <Available from: https://doi.org/10.1186/s13071-021-05118-1 >. Accessed: May, 03, 2023. doi: 10.1186/s13071-021-05118-1.
https://doi.org/10.1186/s13071-021-05118... ). In addition, a multi-antigen tick vaccine will be useful to control multiple tick species, particularly in areas where animals are parasitized by more than one tick species.

ACKNOWLEDGEMENTS

This research was supported by grants from the Instituto Nacional de Ciência e Tecnologia em Entomologia Molecular of the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development; grant no. 465678/2014-9), the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Coordination for the Improvement of Higher Education Personnel; grant no. 88881.068421/2014-01 and Finance code 001), the Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ, Carlos Chagas Filho Foundation for the Support of Research in the State of Rio de Janeiro; grant no. E-26/210.012/2018), and the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS, Foundation for the Support of Research in the State of Rio Grande do Sul; grant no. 21/2551-0002221-3).

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CR-2023-0161.R2

BIOETHICS AND BIOSSECURITY COMMITTEE APPROVAL

The research was conducted in accordance with the Norms for Animal Experimentation Ethics Committee of Universidade Federal do Rio Grande do Sul.

Edited by

Editor: Rudi Weiblen (0000-0002-1737-9817)

Publication Dates

Publication in this collection
21 Aug 2023
Date of issue
2024

History

Received
16 Mar 2023
Accepted
14 June 2023
Reviewed
14 July 2023

This is an open-access article distributed under the terms of the Creative Commons Attribution License

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	---------------ADI--------------				-----------MRL-----------
Acaricide	Brazil	EU	Marker residue	Tissue	Brazil^a,b	EU
	(µg/kg BW)	(µg/kg BW)			(µg/kg BW)	(µg/kg BW)
Amitraz (amidine)	0-0^a	0-3^c	Sum of amitraz and all of its metabolites containing the 2,4-DMA fraction	Muscle	NN	NN^c
				Liver	200	200^c
				Kidney	200	200^c
				Fat	200	200^c
				Milk	10	10^c
Cypermethrin (synthetic pyrethroid)	0-20^a	0-15^d	Total cypermethrin residues	Muscle	50	20^d
				Liver	50	20^d
				Kidney	50	20^d
				Fat	1000	200^d
				Milk	100	20^d
Flumethrin (synthetic pyrethroid)	0-1.8^a	0-1.8^e	Flumethrin (sum of trans-Z isomers)	Muscle	20	10^e
				Liver	20	20^e
				Kidney	10	10^e
				Fat	150	150^e
				Milk	30	30^e
Diazinon (organophosphate)	0-2^a	0-0.2^f	Diazinon	Muscle	20	20^f
				Liver	20	30^f
				Kidney	20	30^f
				Fat	700	70^f
				Milk	20	20^f
Fluazuron (insect growth regulator)	0-40^a	0-43^g	Fluazuron	Muscle	200	200^g
				Liver	500	500^g
				Kidney	500	500^g
				Fat	7000	7000^g
				Milk	200	N/A^g,*
Ivermectin (macrocyclic lactone)	0-10^a	0-10^h	22,23-Dihydro-avermectin B1a	Muscle	30	30^h
				Liver	800	100^h
				Kidney	100	30^h
				Fat	400	100^h
				Milk	10	N/A^h,*
Fipronil (phenylpyrazole)	0.2^j	N/A^i,†	Fipronil (sum of fipronil and sulfone metabolites)	Muscle	ND	5^i,‡
				Liver	ND
				Kidney	ND
				Fat	ND
				Milk	ND

Antigen	Efficacy (%)	Formula to calculate vaccine efficacy(%)	Reference
Subolesin	60	=100 [l - (CRT ^* CR0 ^* CRF)]	(ALMAZAN et al., 2010)
	44.0 and 37.2^*	=100 [l - (CRT ^* CR0 ^* CRF)]	(SHAKYA et al., 2014)
	54	= 100 [l - (CRT ^* CR0)]	(KUMAR et al., 2017KUMAR, B. et al. Functional characterization of candidate antigens of Hyalommaanatolicum and evaluation of its cross-protective efficacy against Rhipicephalusmicroplus. Vaccine, v.35, p.5682-5692, 2017. Available from: <Available from: https://doi.org/10.1016/j.vaccine.2017.08.049 >. Accessed: Mar. 13, 2023. doi: 10.1016/j.vaccine.2017.08.049. https://doi.org/10.1016/j.vaccine.2017.0... )
Glutathione S-transferase	57	=100 [1 - (NFE ^* WE ^* WL)]	(PARIZI et al., 2011)
Voltage-dependent anion channel	82	=100 [l - (CRT ^* CR0 ^* CRF)]	(ORTEGA-SANCHEZ et al., 2020)
Metalloprotease	60	=100 [1 - (NFE ^* WE ^* WL)]	(ALI et al., 2015a)
Trypsin inhibitors	72.8	=100 [l - (NET ^* EW ^* EF)]	(ANDREOTTI et al., 2002)
Low trypsin inhibitor	32	=100 [l - (CRT ^* CR0 ^* CRF)]	(ANDREOTTI et al., 2012)
Aquaporin 1	68 and 75†	=100 [1- (NET ^* EWPF ^* H)].	(GUERRERO et al., 2014)
60 S acidic ribosomal protein (P0)	96	=100 [1- (RA ^* PA ^VA ^ OA ^* FE)]	(RODRIGUEZ-MALLON et al., 2015)
Ferritin 2	64	=100[l − (CRT ^* CR0 ^* CRF)]	(HAJDUSEK et al., 2010HAJDUSEK, O. et al. Characterization of ferritin 2 for the control of tick infestations. Vaccine, v.28, p.2993-2998, 2010. Available from: <Available from: https://doi.org/10.1016/j.vaccine.2010.02.008 >. Accessed: May, 03, 2023. doi: 10.1016/j.vaccine.2010.02.008. https://doi.org/10.1016/j.vaccine.2010.0... )
Flagelliform silk protein	62	= 100 [l - (CRT ^* CR0)]	(MERINO et al., 2013)

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