Ecology and prevention of Lyme borreliosis

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10. P ublic-private partnership enabled use of anti-tick vaccine for integrated cattle fever tick eradication in the USA Adalberto A. Pérez de León1*, Suman Mahan2, Matthew Messenger3, Dee Ellis4, Kevin Varner5, Andy Schwartz6, Dan Baca5, Renato Andreotti7, Manuel Rodríguez Valle8, Rodrigo Rosario Cruz9, Delia Inés Domínguez García9, Myrna Comas Pagan10, Carmen Oliver Canabal10, Jose Urdaz11, Francisco Collazo Mattei12, Fred Soltero13, Felix Guerrero1 and Robert J. Miller14 1United States Department of Agriculture-Agricultural Research Service, Knipling-Bushland United States Livestock Insects Research Laboratory, and Veterinary Pest Genomics Center, 2700 Fredericksburg Rd., Kerrville, TX 78028, USA; 2Zoetis, Veterinary Medicine Research and Development, 333 Portage Street, KZO-300-329.4SW, Kalamazoo, MI 49007, USA; 3United States Department of Agriculture-Animal and Plant Health Inspection Service, Plant Protection and Quarantine, 4700 River Road, Unit 140, Riverdale, MD 20737, USA; 4Institute for Infectious Animal Diseases, Texas A&M University System, 1500 Research Parkway, Suite B270, College Station, TX 77843-2129, USA; 5United States Department of AgricultureAnimal and Plant Health Inspection Service, Veterinary Services, San Jacinto Blvd., Austin, TX 78701, USA; 6Texas Animal Health Commission, 2105 Kramer Lane, Austin TX 78758-4013, USA; 7Embrapa Gado de Corte, Av. Rádio Maia, No. 830, Zona Rural, CEP 79106-550 Campo Grande, MS, Brazil; 8The University of Queensland, Queensland Alliance for Agriculture and Food Innovation, 306 Carmody Rd., Bldg. 80, Level 3; St. Lucia, Qld 4072, Australia; 9Laboratorio de Investigación en Biotecnología, Salud y Ambiente de la Unidad Académica de Ciencias Naturales de la Universidad Autonoma de Guerrero. Campus el Shalako, Petaquillas, Guerrero, C.P. 39105, Mexico; 10Department of Agriculture of Puerto Rico, P.O. Box 10163, San Juan 00908-1163, Puerto Rico; 11United States Department of Agriculture-Animal and Plant Health Inspection Service, Veterinary Services, 2150 Centre Ave. Bldg. B, MS-3E13, Ft. Collins, CO 80526, USA; 12United States Department of Agriculture-Animal and Plant Health Inspection Service, Veterinary Services, 8100 NW 15th Place Gainesville, FL 32606, USA; 13United States Department of AgricultureAnimal and Plant Health Inspection Service, Veterinary Services, 654 Munoz Rivera Ave. Plaza Bldg. Suite 700 San Juan 00918, Puerto Rico; 14United States Department of Agriculture-Agricultural Research Service, Cattle Fever Tick Research Laboratory, 22675 North Moorefield Rd. MAB 6419, Edinburg, TX 78541, USA; [email protected]

Abstract Rhipicephalus (Boophilus) microplus and Rhipicephalus annulatus are invasive tick species and vectors of microbes causing bovine babesiosis and anaplasmosis that were declared eradicated from the USA in 1943 through efforts of the Cattle Fever Tick Eradication Program. These tick disease vectors remain established and affect livestock health and production in other countries located in tropical and subtropical parts of the world. R. microplus is considered the most economically important external parasite of livestock where it is established. Synthetic acaricides are used intensely to kill R. microplus and R. annulatus, but this leads eventually to the problem of acaricide resistance and other associated undesired effects. Novel and safer technologies that can be integrated with existing control methods are required to manage R. microplus and R. annulatus populations and associated diseases sustainably. In the case of the USA, the need for a systems approach was identified to keep the national cattle herd free of bovine babesiosis through the integrated use of technologies, including anti-tick vaccines, to eliminate outbreaks of R. microplus and R. annulatus. Anti-tick vaccines containing the recombinant antigen Bm86 are veterinary biologics used together with veterinary pharmaceuticals such as acaricides to enhance livestock protection where populations of R. microplus and R. annulatus are established. But, access to Gavac™, the only anti-tick vaccine commercially available and used to control R. microplus and R. Claire Garros, Jérémy Bouyer, Willem Takken and Renate C. Smallegange (eds.) Pests andvector-borne vector-borne diseases in the livestock industry Pests and diseases in the livestock industry – Ecology and control of vector-borne diseases Volume 5 DOI 10.3920/978-90-8686-863-6_10, © Wageningen Academic Publishers 2018

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annulatus, is limited to certain national veterinary products markets, excluding the USA. Efforts of a public-private partnership that developed, and obtained an experimental use permit issued to the animal health company Zoetis for a novel Bm86-based vaccine formulation to be integrated as part of operations by the Cattle Fever Tick Eradication Program are described here. Statutes more than 100 years old governing operations of the Cattle Fever Tick Eradication Program were adapted to eliminate R. microplus and R. annulatus infestations in cattle and mitigate the risk of future tick outbreaks in the Permanent Quarantine Zone in south Texas on the border with Mexico by adding immunization with the Bm86-based vaccine as part of the operational protocol. This achievement enabled the experimental use of the Zoetis Bm-86 based vaccine to immunize beef and dairy cattle as part of the research project for integrated control of the southern cattle fever tick in Puerto Rico. Our collective work documenting anti-cattle tick vaccine discovery research is described to illustrate how international cooperation supported research on integrated management for the Cattle Fever Tick Eradication Program. Public-private partnerships may be a way to develop novel anti-tick vaccines in other parts of the world for use as part of integrated R. microplus management strategies. Keywords: cattle ticks, cattle, ectoparasite, disease vector, immunization

Introduction Ticks and tick-borne diseases affect animal health and the productivity of livestock (Brites-Neto et al. 2015; De la Fuente et al. 2008). The ticks Rhipicephalus (Boophilus) microplus (Canestrini) and Rhipicephalus annulatus (Say) affect livestock health and production (Brake and Pérez de León 2012; Reck et al. 2009), and are vectors of microbes that cause bovine babesiosis and anaplasmosis in countries where they are established, which are located in tropical and subtropical parts of the world (Aubry and Geale 2011; Pérez de León et al. 2014a). R. microplus is more invasive than R. annulatus, and it is considered the most economically important external parasite of livestock wherever it is established (Jongejan and Uilenberg 2004; Sonenshine and Roe 2014). It has been estimated that in Brazil, which is the country with the largest commercial cattle herd including around 219 million head in 2016 (USDA 2016b), R. microplus causes annual losses totaling around USD 3 billion (Grisi et al. 2014). Producers in Mexico, which has the 8th largest national bovine herd in the world with 16 million head (USDA 2016b), suffer annual losses estimated at USD 573 million due to the effects of R. microplus parasitism on livestock (Rodriguez-Vivas et al. 2017). Bovine babesiosis, caused principally by Babesia bovis (Babes) or Babesia bigemina (Smith and Kilborne), is the most financially important arthropod-borne disease of cattle worldwide (Bock et al. 2008). Chemicals synthetized by humans that kill ticks, commonly known as acaricides, are used predominantly for tick control, and in particular to manage R. microplus populations (Graf et al. 2004; Kiss et al. 2012), and to mitigate the health and economic burden of bovine babesiosis (Drummond 1983). However, intense use selects for acaricide resistance (Dominguez García et al. 2010; Guerrero et al. 2014a; Higa Lde et al. 2016). Of concern is the increased frequency of R. microplus populations reported to be resistant to multiple classes of acaricides (Abbas et al. 2014; Klafke et al. 2017; Miller et al. 2013; Rosario-Cruz et al. 2009). In the case of endectocides, that is molecules with endo- and ectoparasiticidal activities, the frequency to treat primarily gastrointestinal infections in cattle and other livestock may be selecting for resistance in R. microplus against molecules like ivermectin (Alegría-López et al. 2015; Rodriguez-Vivas et al. 2014a,b). This situation highlights the urgency to innovate technologies that can be used together to overcome the problem with resistance to synthetic acaricides, and the undesired effects of acaricide overuse (Hlatshwayo and Mbati 2005; Lopez-Arias et al. 2015).

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10. Public-private partnership enabled use of anti-tick vaccine in the USA

Tick control and the management of tick-borne diseases is a complex issue (De Meneghi et al. 2016). Integrated tick management approaches have been proposed, and some have been applied recently to R. microplus in several countries (Barnard et al. 1988; Jonsson 2004; Mondal et al. 2013; Pérez de León 2014b; Rodríguez-Vivas et al. 2016; Suarez et al. 2016). The history of integrated R. microplus management includes efforts that ranged from combining acaricide use with alternative methods to control tick numbers relative to an injury level threshold, to approaches that resulted in tick eradication (Angus 1996; Bram and Gray 1983; FAO 1989). In addition to a sound understanding of the ecological processes that regulate tick populations (Schmidtmann 1994), control or eradication efforts must consider economic and social aspects to be successful (De la Fuente 2015; Pegram et al. 2000; Walker 2011). Models have also been used to anticipate the effects of different management interventions, or to document the benefits of integrated approaches (Elder and Morris 1986; Hernandez et al. 2000; Norton et al. 1983; Popham and Garris 1991; Wang et al. 2016).

Anti-tick vaccine for integrated cattle fever tick eradication in USA The challenge to manage the populations of tick disease vectors affecting cattle like R. microplus and R. annulatus can be viewed as a continuum of options that can range from doing nothing about it to establishing national eradication programs as it was attempted in several countries before (Pegram et al. 2000). Table 1 lists some characteristics of parameters related to control or eradication as intervention strategies to mitigate the impact of tick infestations in cattle. Aspects related to global change complicate efforts to keep national areas or countries encompassing suitable habitat free of R. microplus invasion or re-invasion in the long term (Benavides Ortiz et al. 2016; George 2008; Giles et al. 2014; White et al. 2003). However, even the strategy to maintain the USA free of the invasive cattle fever ticks requires adaptation to be able to deal with an evolving world (Esteve-Gassent et al. 2014; Pérez de León et al. 2012). The elimination of bovine babesiosis was the main driver to establish the Cattle Fever Tick Eradication Program in the USA, which started operations in 1907 (Graham and Hourrigan 1977). As a result, the USA was declared free of R. microplus and R. annulatus in 1943 with the exception of a Permanent Quarantine Zone, also known as the Systematic Area, in south Texas along the border with Mexico (Bram et al. 2002). This Permanent Quarantine Zone starts in Del Rio, extends Table 1. Suggested parameters to consider for spectrum of strategies, using control and eradication as examples, to manage populations of the southern cattle fever tick, Rhipicephalus microplus, which can mitigate the burden of bovine babesiosis and anaplasmosis on cattle herds. Parameter

Control

Eradication1

Tolerance for infestation Surveillance Quarantine Treatment Cost

economic threshold optional, or reactive no optional variable

Duration

seasonal

zero constant obligatory; sanctioned by laws obligatory although initial inputs can be considerable, the return on investment long-term is high requires continuous commitment

1 Known operations of the U.S. Cattle Fever Tick Eradication Program exemplify eradication parameters.


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southeast for 700 km to Brownsville varying in width between 0.4 to 16 km, and serves as a buffer zone under constant surveillance by state and federal inspectors to prevent dispersal into the Free Area of R. microplus and R. annulatus from parts of Mexico where they are endemic (Miller et al. 2007). Tick-infested cattle in the Permanent Quarantine Zone undergo systematic acaricide treatment and the premises are quarantined for 6-9 months until the outbreak is eliminated (Davey et al. 2012; Miller et al. 2005). Outbreaks of R. microplus and R. annulatus have been detected in the USA outside the Permanent Quarantine Zone since 1968 (Graham and Hourrigan 1977). This situation is managed through Temporary Preventative Quarantine Areas created to eliminate tick outbreaks detected in the Free Area (see maps in Lohmeyer et al. 2011 and Pérez de León 2012 for details). Alternative approaches were taken recently in other parts of the world to deal with cattle ticks and associated diseases. In New Caledonia, the approach to eradicate bovine babesiosis was chemosterilization of the infections through the use of the babesiocidal drug imidocarb without having to totally eliminate populations of what was then considered to be R. microplus, and now reclassified to be Rhipicephalus australis (Fuller) (Barré et al. 2011; Estrada Peña et al. 2012). A regionalization approach was taken in Australia to deal with populations of what is now considered to be R. australis whereby biosecurity zones are established in Queensland to manage the risk associated with cattle tick infestation (Barker et al. 2014; State of Queensland 2016a). Queensland State Regulations require that the person, who is the owner or occupier of infested land, takes action to eradicate R. australis and to comply with the stated way or procedure for eradication (State of Queensland 2016b). Technologies considered as alternatives for use with acaricides include essential oils, biocontrol agents, anti-tick vaccines, ecological measures (pasture vacation whereby cattle are removed from grazing land to starve host-seeking tick larvae, brush cleaning in the pasture, induction of engorged female detachment in unfavourable environment to reduce pasture infestation), and the use of cattle breeds and crosses resistant to tick infestation (Biegelmeyer et al. 2015; Costa-Junior et al. 2016; Fernandes et al. 2012; Goolsby et al. 2016; Mapholi et al. 2016; Martinez-Velazquez et al. 2011; Redondo et al. 1999; Rodriguez Valle et al. 2004). Regulatory and commercial intricacies influence the availability of those technologies across national and regional veterinary medicines markets. Essential oil-based acaricidal products remain to be widely available commercially for practical use (Andreotti et al. 2013). Biocontrol products based on acaropathogenic fungi are emerging in certain markets (Bharadwaj and Stafford 2010; Camargo et al. 2016). Access to the only commercially available anti-R. microplus vaccine worldwide is limited to certain national animal health markets (De la Fuente et al. 2007). Investment decisions based on economic principles determine research, development, and marketing of an anti-tick vaccine by an animal health company in a particular national market (Guerrero et al. 2012). The benefit of integrating the use of some of these technologies has been documented (Bautista-Garfias and Martínez-Ibañez 2012; Rodriguez Valle et al. 2004; Suarez et al. 2016; Webster et al. 2015). Our collaboration on anti-tick vaccine discovery research involving international partners was established after a public workshop convened in April 2009 by the United States Department of Agriculture – Agricultural Research Service and the Center for Ecoepidemiology, Yale University School of Medicine in McAllen, Texas where the One Health concept, that is the collaborative effort of multiple disciplines to attain optimal health for people, animals and our environment, was applied to identify research gaps regarding bovine and human babesioses in the USA (Androetti et al. 2012; Guerrero et al. 2014b; Pérez de León et al. 2010). Integrated approaches for sustainable cattle fever tick eradication in the USA, and the overarching theme of anti-tick vaccine use in the

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context of bovine and human babesioses were among the topics of focused discussions during the workshop. We developed the concept of sustainable tick eradication to reflect the need for a systems approach in agricultural research whereby the principle of precision agriculture was adapted to integrate technologies, including anti-tick vaccines, which translate into resilient management practices to keep the USA free of R. microplus and R. annulatus in the context of shifting ecological, economical, and societal paradigms (Miller et al. 2012; Pérez de León et al. 2012; Pound et al. 2010). Dialogue among diverse stakeholder groups at the workshop generated discussion on the possibility to address those challenges through public-private partnerships to promote innovation in agricultural research on ticks and tick-borne diseases. Public-private partnerships involve an agreement between a public agency (federal, state or local) and a private sector entity to join forces to deliver science-based solutions to agricultural problems addressing unmet societal technological needs (Chatelain and Don 2009; USDA 2016a). Adaptation of the public-private partnership business model for product development was identified as a strategy that could achieve technological solutions for the Cattle Fever Eradication Program. Regarding anti-tick vaccines, one of the research gaps identified was the need to conduct studies to determine whether the treatment of cattle with Gavac™ (Heber Biotec, Habana, Cuba), another Bm86-based vaccine formulation, or a vaccine formulation containing novel antigen(s) could be used safely in the Permanent Quarantine Zone together with other technologies to manage outbreaks by invasive populations of R. microplus and R. annulatus according to requirements established by state and federal regulatory agencies. Bm86-based products represent the first generation of anti-tick vaccines to be commercialized (Rodriguez et al. 1995b; Willadsen et al. 1995). The opportunity to research existing and emerging anti-tick vaccine technology according to the One Health perspective to deal with ticks and tick-borne diseases of public health and veterinary importance was a factor that facilitated the public-private partnership delivering a new Bm86-based vaccine formulation for experimental use in cattle in the USA and Puerto Rico (Évora et al. 2017; Rodríguez-Mallon et al. 2013). This is another example of how the One Health approach has expanded to try to overcome barriers for the development and commercialization of novel global health vaccines, and public-private partnerships have been identified as a mechanism to achieve that goal (Benfield 2016; King et al. 2004; Monath 2013).

Past experiences developing Bm86-based vaccines Pioneer work on the possibility to control tick infestations in livestock through immunization led a group of Australian scientists to discover that the recombinant version of a midgut glycoprotein called Bm86, from the tick species now recognized as R. australis, elicited an immune response that reduced tick infestations on cattle, which opened the way for the development of a vaccine that was commercially released as TickGard® (Intervet, Bendigo East, Victoria, Australia) in 1994 (Allen and Humphreys 1979; Trager 1939; Willadsen et al. 1995). Similar efforts undertaken in Cuba after the patent with the Bm86 gene sequence was published around 1988 resulted in the commercialization in 1993 of another Bm86-based vaccine marketed as Gavac™ (Rodriguez Valle et al. 1994, 1995b; Willadsen 2008a), which was registered in Colombia, Dominican Republic, Brazil, and Mexico (Canales et al. 1997; Rodriguez Valle et al. 1995a). TickGard® disappeared from the market about a decade after its commercial release for reasons described by Playford (2005) and De la Fuente et al. (2007). It must be noted that in the case of Bm86-based vaccines, the knock down effect against R. microplus is observed over time after continued vaccine usage in the entire herd, which requires enforcement of product use compliance through education of producers and animal health personnel. This is discussed below in the context of our research efforts involving the integrated use of an anti-tick vaccine for R. microplus and R. annulatus eradication in the USA.


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Vaccine development is an arduous process that requires resources (Chambers et al. 2016; Giese 2013). Vaccines for use in domestic animals and wildlife are developed and approved by regulatory agencies for sale by animal health companies (Heldens et al. 2008; Marshall 2014). National agencies ensure that veterinary vaccines meet purity, safety, and efficacy regulations required for market authorization (Banks 2014; Henderson and Lewis 2014). Because economic context drives corporate investment in their commercialization (BBSRC 2015; Benfield 2016), the protection of intellectual property for vaccine-based innovations through patents ensuring freedom to operate is an important consideration to make in the decision making process to develop vaccines (Durell 2016; Farmer and Grund 2014; Krol et al. 2016). Several publications have outlined the stages in the development of Bm86-based vaccines commercialized before (Canales et al. 1997; De la Fuente et al. 1999; De la Fuente et al. 1998; Jittapalapong et al. 2006; Rodriguez-Mallon 2016; Willadsen 2008b; Willadsen et al. 1992, 1995). In the case of TickGard®, it took 14 years and testing in thousands of cattle to complete demonstration of feasibility, documentation of efficacy in field trials, completion of product registration, and post-marketing product surveillance to complete the commercialization process (Willadsen 2008b; Willadsen et al. 1995). In addition to access to the R. microplus genome (Barrero et al. 2017; Bellgard et al. 2012), the advent of next-generation sequencing platforms enabled strategies that analyse genomic data through bioinformatics such as immunogenomics, reverse vaccinology, and vaccinomics to accelerate the identification of potentially immunoprotective R. microplus polypeptides, which helped prioritize the production of recombinant tick proteins for in vivo testing (De la Fuente and Merino 2013; Guerrero et al. 2012; Lew-Tabor and Rodriguez Valle 2016; Santos et al. 2004). Beyond the identification of a highly efficacious antigen through discovery research and the selection of an adjuvant that improves the immunological response (Guerrero et al. 2014b; Petermann et al. 2017; Rodriguez-Mallon et al. 2015; Shah et al. 2017), economic considerations related to cost-effective production bioprocesses, estimation of the potential market, and pricing of the vaccine product relative to acaricides significantly influence the decision to develop a novel anti-R. microplus vaccine formulation for commercial use (Canales et al. 2010). An incentive for animal health companies to partner with academic institutions and public agencies is having access to technological platforms that can be developed into a product, including vaccines, rapidly (Rippke 2105; Yarbrough 2016). Despite the testing in cattle of several recombinant proteins regarded as candidate antigens since the commercialization of TickGard® and Gavac™ (Almazan et al. 2010; De la Fuente et al. 2016; Fang and Pung 2011; Lew-Tabor and Rodriguez Valle 2016; Olds et al. 2013), it appears that a gap between basic research and translation to novel therapeutics, also known as the ‘valley of death’, may have occurred in the anti-tick vaccine scientific field (Collins et al. 2016; Guerrero et al. 2012; Plotkin et al. 2015). For example, the antigen pP0 was reported to afford 96% efficacy against R. microplus infesting cattle (Rodriguez-Mallon et al. 2015), but we were unaware of a commercial vaccine based on that technology as of this writing. However, the future looks promising because consortia have been established to overcome the challenge to obtain regulatory and marketing approval for novel vaccines to protect livestock against cattle ticks (Schetters et al. 2016), and diverse host species from tick vectors of zoonotic diseases (Sprong et al. 2014).

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USA experience developing Bm86-based vaccine through public-private partnership Regulatory requirements for veterinary biologics in the USA made impractical the importation of Gavac™ manufactured in Cuba for use by the Cattle Fever Tick Eradication Program. We sought international collaboration with more experienced research groups as a way to accelerate our anti-tick vaccine discovery research efforts initiated in 2009. Research outcomes are described here to illustrate how international cooperation resulted in the experimental use of a new Bm86based vaccine formulation in beef cattle in the USA, and in beef and dairy cattle in Puerto Rico. We experienced some of the vicissitudes associated with the development and adoption of anti-tick vaccine technology based on the Bm86 recombinant antigen in the 1990s to be able to understand aspects of the critical path that animal health companies take into consideration to decide if financial investment (Woodcock 2014), and the commitment of other corporate resources is warranted to seek regulatory approval of a novel anti-R. microplus vaccine. Regulatory aspects influencing attempts to develop a public-private partnership that could enable the translation of our anti-tick vaccine discovery research findings are described below. The research and development program between public agencies and Zoetis that delivered a novel experimental Bm86-based vaccine in the USA provides another case study of how public-private partnerships can create value for society and corporations, among other ways, by enhancing the sustainability of animal agriculture (Black 2012; Hendriks et al. 2013). Resource constraints in vaccine development require the identification of rational approaches that are likely to succeed in prioritizing molecules, like those discovered in ticks, for testing as antigens (Giersing et al. 2016; Guerrero et al. 2012). Following examples of landscape analyses applied to vaccines (Geels et al. 2015; Stephens 2014), notable publications in the scientific literature are cited here in the context of key considerations that influenced decisions by the public-private partnership established to obtain approval by the USA agency regulating veterinary biologics for experimental use of an anti-tick vaccine in cattle. It is elemental to reach consensus on a mutually acceptable Research and Development to License Approval (R&D2LA) plan as soon as the proper agreement(s) covering the interaction between an academic or public anti-tick vaccine discovery research group and a team from an animal health company are in place. The R&D2LA plan should outline activities and milestones for each step in the Research and Development phases to be able to inform go or no-go decisions on the project. It has been argued that ‘failing early’ in vaccine studies allows more effective use of limited resources (Benfield 2016). Sources on strategy and requirements to develop a safe and effective vaccine to protect animals against tick infestation, which can help structure a R&D2LA include the publications by Willadsen et al. (1995), Willadsen (2008a), Rodríguez-Mallon (2016), and the guidelines by the International Cooperation on Harmonization of Technical Requirements for Registration of Biological Veterinary Medicinal Products (VICH 2016). It is productive to select as early as possible an expression system for the recombinant version of the candidate antigen that maximizes immunogenicity and is scalable for industrial production. Research on expression systems keeps advancing the science of heterologous protein production for veterinary immunotherapeutics and prophylactics (Drugmand et al. 2012; Legastelois et al. 2016; MacDonald 2015). For example, redesign of the bioprocess to produce the recombinant Bm86 antigen in the yeast Pichia pastoris (Phaff ) resulted in cost savings (Canales 2010). Other biotechnological advances are optimizing further the use of the P. pastoris expression system (Liu et al. 2016; Shen et al. 2016). It is important for health companies to determine sooner than later, among other things, if the recombinant antigen production cost will be profitable and


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whether the sale price for the vaccine product is competitive (Lee and McGlone 2010; Schwartz and Mahmoud 2016). Adjuvant selection is an important aspect of the vaccine formulation process because adjuvants are substances that can enhance, accelerate, prolong, or modulate the immune response to an antigen (Olafsdottir et al. 2016; Petermann et al. 2017; Shah et al. 2017). A new formulation of the TickGARD Plus product (Intervet) that included a different adjuvant was introduced in 2002 in the Australian animal health market and was reported to decrease R. australis, counts by 70% when used according to label instructions (Hunter 2002; Willadsen 2008a). Further development work, including adjuvant formulation, resulted in the launch of GavacPlus containing the oilbased adjuvant Montanide 888 (Rodriguez Valle et al. 2001; Vargas et al. 2010). Other oil-based adjuvants have been developed that can stimulate humoral- and cell-mediated immune responses in ruminants, which can be used to formulate parasite antigens (Kalyanasundaram et al. 2015; Khorasani 2016). A way anti-tick vaccine researchers in academic institutions and public agencies can benefit from partnering with industry is through confidential access to corporate knowledge of adjuvants approved as safe by the regulatory agencies that can maximize the efficacy of a development candidate antigen (Boué et al. 1999; Guerrero et al. 2012; Shah et al. 2017). Commercial and non-commercial forces influence the perception of the attributes that would differentiate a new vaccine developed for sale in markets encompassing tropical and subtropical regions of the world to protect cattle under field conditions against the direct and indirect health and productivity effects caused by R. microplus (Guerrero et al. 2012; Playford 2005; Willadsen 2008a). Reaching consensus on an acceptable level of efficacy to make a go/no-go decision in the development process of an anti-R. microplus vaccine may require significant discussion among the parties involved in a public-private partnership. The current paradigm to assess the efficacy of a vaccine against R. microplus in pen trials, controlled field trials, and subsequently under field conditions is based on the experience to commercialize TickGard and Gavac™ (De la Fuente et al. 1999, 2007; Willadsen 2008b; Wong and Opdebeeck et al. 1989). Efficacy assessment depends on the capacity to evaluate the host immune response, and the ability to quantitate host protection afforded by a vaccine formulation against the development of ticks during the parasitic phase of their life cycle. In vitro tick feeding techniques provide a way to begin assessing protective effects by testing blood or serum from cattle immunized with a candidate vaccine formulation (Antunes et al. 2014; De la Vega 2004; Inokuma and Kemp 1998; Lew-Tabor et al. 2014). Host systems other than cattle can be used to begin screening candidate antigens in vivo (Galay et al. 2016). The influence of the genetic background on bovine to bovine variation in response to vaccination with a particular tick antigen should be considered as soon as possible (Acosta-Rodriguez et al. 2005; Jonsson et al. 2014; Piper et al. 2016; Sitte et al. 2002). Tick vaccine efficacy can also have implications on the transmission of tick-borne diseases, including bovine babesiosis in the case of R. microplus and R. annulatus (De la Fuente et al. 1998, 2007; Merino et al. 2013). Procedures to calculate the efficacy of candidate antigens to develop vaccines against one- and three-host ticks were reviewed recently (Aguirre Ade et al. 2015; Cunha 2013; Rodríguez-Mallon 2016). Having a plan helps the working team make informed science-based decisions, which will help maximize the chances of fulfilling the R&D2LA. One way this can be achieved is by elaborating a Target Product Profile (Lee and Burke 2010; Pramod 2016). A ‘wish-list’ of optimistic, realistic, and minimal goals for the anti-tick vaccine development project we embarked on was presented to

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stakeholders in 2012 to communicate the framework of our strategy and to manage expectations regarding the potential end results of our efforts (Figure 1). Successful commercialization of a an anti-tick vaccine will depend upon the demand for the product, the size of the market that needs the product to make it a profitable venture, and continued regulatory compliance. Ultimately, the goal would be to produce the vaccine cheaply so that the end user is able to afford it. With the understanding that biologics like anti-tick vaccines and pharmaceuticals such as acaricides are dissimilar classes of veterinary products, a nice-to-have attribute that would contribute to the commercial success of a new vaccine targeting R. microplus would be a strong knock-down effect. One way to achieve that could be through a polyvalent vaccine including ‘concealed’ and ‘exposed’ tick antigens that alter larval development or the blood feeding process, which could be perceived as a faster effect controlling ticks infesting cattle (Nuttall et al. 2006; Parizi et al. 2012; Riding et al. 1994). The combination with standard acaricide applications during initial use of a Bm86-based vaccine helps potentiate its long-term effect because over time acaricide treatments decrease due to the reduced tick population caused by the protective effect of the vaccine at the cattle herd level (Canales et al. 1997; Floyd et al. 1995; Lodos et al. 2000; Suarez et al. 2016). Acaricidal products and anti-R. microplus vaccines should have their attributes differentiated in marketing materials highlighting their distinct nature as pharmaceuticals and biologics, respectively, to ensure consumers understand how they must be used to protect cattle against tick infestation and the risk of bovine babesiosis and anaplasmosis transmission.

Anti-tick vaccine for integrated R. microplus and R. annulatus eradication in the USA Because the anti-tick vaccine technology would have to be registered in the USA before a company could distribute, or might sell it for administration to cattle, it was determined early on in the process that outlining a critical path for registration and the need for production domestically

The Vision Strategic Evaluation Framework for Use of Tick Vaccine by CFTEP Attribute

Have to have

Nice to have

Indication

Cattle

Cattle & deer

Efficacy

R. annulatus: >95% R. microplus: ≥50% Bm86 + novel adjuvant

R. annulatus: 99% R. microplus: >95% Polyvalent + nanoadjuvant

0, 4, 7 weeks, then boost every 6 months Injection

0, 6 months, then boost annually Needleless

Composition Immunization schedule Delivery system

Walking the critical path to cross the valley of death

Figure 1. Framework for Target Product Profile concept applied to meet the need of USA stakeholders to use antitick vaccine in the Cattle Fever Tick Eradication Program that was presented at the 58th Texas A&M University Beef Cattle Short Course.


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would need to be considered if a Bm86-based, or any other anti-tick vaccine showed potential as a tool for integrated tick eradication (Pérez de León et al. 2010, 2012). Additionally, it was anticipated that assessing this potential would require the conduct of trials in the USA before an anti-tick vaccine were to be licensed for use as an aid in the prevention of R. microplus infestation among cattle in the Permanent Quarantine Zone. The fruitful public-private partnership described here enabled stall tests with Gavac™ against strains of R. microplus and R. annulatus causing outbreaks in the Permanent Quarantine Zone, which had been colonized at the USDA-ARS Cattle Fever Tick Research Laboratory (Miller et al. 2012). Because we didn’t have access to TickGardPlus (Vargas et al. 2010), we adhered to instructions in the product label to vaccinate cattle with Gavac™, which required an initial injection followed by two booster immunizations at 5 and 7 weeks thereafter. Subsequently, instructions in the Gavac™ label recommended revaccination every 6 months to maintain effective antibody titres. The paradigm to assess anti-tick vaccine efficacy against one-host ticks like R. microplus and R. annulatus is founded on the experience with commercial Bm86-based vaccines evaluated in stall tests where an algorithm is applied to assess the effect of vaccination on the ability of females infesting immunized cattle to complete the parasitic phase of their life cycle on the host, their fecundity, i.e. the amount of eggs laid by engorged females that dropped off the host, and fertility, i.e. the amount of larvae hatching from a subsample of the eggs laid, relative to the same parameters evaluated in a control group of non-vaccinated animals infested similarly (Cunha et al. 2013; Rodríguez-Mallon 2016). For the R. annulatus study, an initial tick infestation in cattle was established 2 weeks after the second booster injection. To get a sense of duration of immunity, cattle were infested again 5 months after the second booster injection. Gavac™ was highly efficacious against the R. annulatus Texas outbreak strain with a vaccine efficacy of 99.9 and 91.4%, two weeks and 5.5 months after the second booster, respectively (Miller et al. 2012). These findings confirmed previous reports of the high efficacy of Bm-86 based vaccines against R. annulatus (Fragoso et al. 1998; Pipano et al. 2003). Lower efficacy was documented with Gavac™ against the R. microplus Texas outbreak strain. In this experiment, cattle were infested with ticks 2 weeks after the second booster injection as it was done for R. annulatus. However, 6 months after the second boost vaccination, cattle received a third injection and were infested again 2 weeks thereafter. The efficacy of Gavac™ against the R. microplus Texas outbreak strain was 27 and 23% after the second and third booster injections, respectively (R.J. Miller et al. unpublished data). Differences in protein degradation machinery involved in blood meal digestion correlate with the higher efficacy of Bm-86 vaccines against R. annulatus as compared to R. microplus (Popara et al. 2013). Our work with Gavac™ prompted adaptation of the Estrada-Peña and Venzal (2006) model in a way that allowed us to run simulations based on measurement of tick habitat suitability taking into account tick development under various abiotic conditions, vegetation, weather, and host animal density for the Permanent Quarantine Zone. In this simulation model a prediction of the tick population expected under different levels of control achieved by vaccination was estimated based on an initial input of 100 engorged females into a tick-free environment (Miller et al. 2012). Simulations were completed for 10 years, 100 times each. The model estimated that with control greater than 40%, eradication would be maintained for R. annulatus in the northern part of the Permanent Quarantine Zone (Figure 2), where this species is the predominant cause of outbreaks (Lohmeyer et al. 2011). For R. microplus, however, 80% control would be required using an antitick vaccine alone to maintain eradication whereas 40% control would reduce the tick burden by over 50% (Figure 3; R.J. Miller et al. unpublished data). Researchers are developing and testing models for the combined effect of treatments including acaricides plus vaccination in cattle that also contemplate the effect of integrated interventions to mitigate the risk of tick infestation in

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Figure 2. Simulation of the effect of anti-tick vaccine at different levels of efficacy against Rhipicephalus annulatus outbreak populations in the Permanent Quarantine Zone in south Texas (adapted from Miller et al. 2012). Simulation results are shown for 100 engorged R. annulatus invading the northwestern half of the Permanent Quarantine Zone where the ticks had been eradicated. The results are an average of 100 simulations over 10 years at various levels of control achieved by vaccination. The first year shows an increasing population with stabilization over years 2 and 3. A similar seasonal population trend occurs from year 3 until year 10, which are not shown. The model predicted that efficacy greater than 40% achieved with an anti-tick vaccine prevented the establishment of R. annulatus populations for the entire simulation period mainly due to the climate in the northwestern half of the Permanent Quarantine Zone assuming initial tick-free status (see map in Lohmeyer et al. 2011).

white-tailed deer, which is an abundant wildlife species in the Permanent Quarantine Zone that complicates eradication efforts in the USA (Estrada Peña et al. 2014; Wang et al. 2016). The experience testing Gavac™ in the USA was a breakthrough that enabled the partnership with Zoetis to test a novel Bm86-based vaccine in efforts to meet the needs of the Cattle Fever Tick Eradication Program for technologies that could be integrated to existing operational protocols described above. Following stall tests documenting efficacy equivalent to Gavac™, we were able to conduct a field safety test that involved around 200 beef cattle in two ranches located in the Permanent Quarantine Zone. No adverse reactions associated with vaccination were observed in cattle. Evaluation of the efficacy and safety data by the USDA Center for Veterinary Biologics resulted in the issuance of an experimental use permit for the Zoetis Bm86-based vaccine. The data generated indicated that a booster immunization could be applied 28 days after the initial vaccination, and subsequent injections administered every 6 months thereafter. In 2015, the Texas Animal Health Commission had initiated the process to facilitate the use of the novel Bm86-based vaccine in the Cattle Fever Tick Eradication Program. Efficacy of the Zoetis Bm86-based vaccine in stalls tests conducted at the USDA-ARS Cattle Fever Tick Research Laboratory was 98 and 40% versus R. annulatus and R. microplus, respectively (R.J. Miller et al.


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Figure 3. Simulation of the effect of anti-tick vaccine at different levels of efficacy against Rhipicephalus microplus outbreak populations in the Permanent Quarantine Zone in south Texas (adapted from Miller et al. 2012). Simulation results are shown for 100 engorged R. microplus invading the southeastern half of the Permanent Quarantine Zone where the ticks had been eradicated. The results are an average of 100 simulations over 10 years at various levels of control achieved by vaccination. The first year shows an increasing population with stabilization over years 2 and 3. A similar seasonal population trend occurs from year 3 until year 10, which are not shown. The model predicted that efficacy greater than 80% maintained eradication, whereas 40% control would reduce the tick burden 50%, for the entire simulation period mainly due to the climate in the southeastern half of the Permanent Quarantine Zone assuming initial tick-free status (see map in Lohmeyer et al. 2011).

unpublished data). During its 395th Meeting on 24 May 2016, the Texas Animal Health Commission adopted rules calling for the administration of the vaccine to beef cattle residing in the Permanent Quarantine Zone (http://tinyurl.com/ybhza59t). This was a significant event in the history of the Cattle Fever Tick Eradication Program because statutes more than 100 years old were adapted to integrate the use of an anti-tick vaccine as part of its operations. The first doses of the Zoetis Bm86-based vaccine arrived in Texas by June 2016. At the same time, plans were formalized to train Program personnel on the use of the anti-tick vaccine as part of an integrated eradication strategy. Public hearings in south Texas were conducted in September 2016 to educate cattle producers on how the anti-tick vaccine technology would be used, and the purpose of adapting official protocols to realize the full potential of this technology to promote raising cattle in the Permanent Quarantine Zone.

Puerto Rico experience meeting the challenge for integrated R. microplus control using anti-tick vaccine in dairy cattle operations Livestock in Puerto Rico was re-infested with R. microplus after eradication efforts in the island were terminated before every tick in the entire island was eliminated (Cortés et al. 2005; UrdazRodriguez et al. 2012). Morbidity and mortality due to bovine babesiosis and anaplasmosis in

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the dairy cattle herd of Puerto Rico became such a problem that livestock producers requested technical assistance from state and federal agencies to address the situation (Urdaz-Rodriguez et al. 2009a, 2009b). Members of our partnership were invited to visit Puerto Rico in 2012 to evaluate the problem with R. microplus and associated diseases in the island, and discuss the burden of tick and tick-borne diseases on animal health in the Caribbean. The possibility to conduct research and generate science-based information that could serve as the basis for integrated tick management was identified as an opportunity to control R. microplus in a progressive manner. With the support of the livestock industry of Puerto Rico and USDA-Animal and Plant Health Inspection Service-Veterinary Services, an agreement was established in 2014 between the Puerto Rico Department of Agriculture and the USDA-Agricultural Research Service to conduct the research project for integrated control of the southern cattle fever tick in Puerto Rico. The objective of this project was to create science-based knowledge to integrate technologies for sustainable control of R. microplus infestations (for details see page 4 in: http://tinyurl.com/y7nr8j96). Originally, four commercial farms were selected to represent the main dairy farming areas of Puerto Rico. An additional research site was a commercial beef cattle ranch in the southwest quadrant of the island. Our approach addressed food safety and environmental health concerns with the ecological impact, and residue levels of synthetic acaricides in dairy cattle products. The project implemented good acaricide management practices through the acknowledgement of parasite economic thresholds prior to treatment and the use of novel pesticide formulations containing natural products, which were labelled to treat lactating cows and their environment. Dairy and beef cattle producers in Puerto Rico had the opportunity to explore the use of the Zoetis Bm86based vaccine and safer acaricides as part of an experimental integrated tick control protocol as it was done before with other Bm86-based vaccines in lactating dairy cows (Jonsson et al. 2000; Rodríguez-Valle et al. 2004). Participating producers were able to mitigate the economic impact of R. microplus in their cattle operations as a result of concerted efforts taking place between the animal health industry, and federal and state regulatory agencies. No adverse reactions were observed in association with the experimental use in Puerto Rico of the Zoetis Bm86-based vaccine in beef cattle (R.J. Miller et al. unpublished data). A study was completed documenting the safe use of the vaccine in dairy cattle under field conditions (R.J. Miller et al. unpublished data).

Brief update of anti-R. microplus vaccine discovery research efforts in Brazil and Mexico International collaboration contributed to our ability to deliver an anti-tick vaccine for the Cattle Fever Tick Eradication Program. In this section we describe briefly anti-tick vaccine discovery research by our international collaborators with emphasis on recent efforts in Mexico and Brazil. The only known test comparing the efficacy of TickGard® and Gavac™ in a pen trial was done in Brazil where efficacy of 46 and 49%, respectively, was documented with the two vaccine products against R. microplus infesting cattle (Andreotti 2006). The hypothesis that recombinant Bm86 from a local strain would enhance protection against R. microplus infesting cattle in the same area was tested in a pen trial (Cunha et al. 2012). However, aspects involving vaccine formulation or host factor polymorphisms may have caused the lesser than expected efficacy obtained in cattle immunized with the recombinant version of the Bm86 antigen based on partial genetic information from the local R. microplus strain. Novel protective antigens that could be used alone or formulated together have been discovered and they offer the opportunity to develop a highly efficacious vaccine against R. microplus (Andreotti et al. 2012; Parizi et al. 2012; Prudencio et al. 2010). Reverse vaccinology approaches have shown positive results using a peptide derived from the ATAQ protein against R. microplus (Aguirre Ade et al. 2016). Transcriptomics translational


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research helped advance the project to the early development stage. The apparent genetic diversity of R. microplus populations in Brazil should be addressed in terms of efficacy when developing a new vaccine for an animal health market that involves the largest commercial cattle herd in the world (Csordas et al. 2016). The use of Gavac™ and its contribution as a tool in integrated cattle fever tick management was documented in Mexico (Bautista-Garfias and Martínez-Ibañez 2012; Domínguez García et al. 2016; Redondo et al. 1999). Anti-cattle fever tick vaccine research and development efforts have increased in Mexico in part due to issues regarding the availability of Gavac™ in the national veterinary products market. Alternative recombinant proteins potentially useful for development to control infestations caused by R. microplus have been identified (Almazan et al. 2012; Ramirez Rodriguez et al. 2016). The economic impact of multiple acaricide resistance in Mexico highlights the need for an anti-R. microplus vaccine that is commercially available (Dominguez García et al. 2010; Rosario-Cruz et al. 2009). An experimental vaccine decreased the local R. microplus population for 7 months when tested in Mexico under field conditions where 90% of the cattle herd was immunized; however, the identity of the antigen tested was not revealed by the investigators publishing their research results (Palacios-Bautista 2014). Applying the subunit vaccine approach (Willadsen 1990), a recombinant peptide derived from the subolesin gene sequence showed 79% reduction on tick numbers in immunized cattle with the effect observed on knock-down because no significant reduction was detected on female tick weight and individual egg mass (Almazán et al. 2010; Dominguez García et al. 2015). The opportunity exists to adapt what was learned from our experience to try to incorporate the latest science and technology to develop an anti- R. microplus vaccine through public-private partnerships for the Brazilian and Mexican animal health markets. Mexico and Brazil are working to establish enabling environments for public-private partnerships that enhance sustainable animal production (Bassi et al. 2015; Hopper et al. 2012). International collaborations help the United States Department of Agriculture – Agricultural Research Service contribute to global food security.

Acknowledgements We thank those that had the audacity to challenge us to conduct anti-tick vaccine discovery research at the USDA-ARS Knipling-Bushland USA Livestock Insects Research Laboratory and the Cattle Fever Tick Research Laboratory in support of the U.S. Cattle Fever Tick Eradication Program. The support and collaboration of industry colleagues, initially with Pfizer Animal Health, and then Zoetis is greatly appreciated. Now we understand when efforts have to stay on the critical path for development, and focused to be pragmatic and meet mutual interests of the public-private partnership. All vaccine discovery research with cattle at the USDA-ARS Cattle Fever Tick Research Laboratory was conducted according to protocols reviewed and approved by the Institutional Animal Care and Use Committee. We are deeply grateful to all the staff at the USDA-ARS KniplingBushland U.S. Livestock Insects Research Laboratory and the Cattle Fever Tick Research Laboratory, APHIS-VS, TAHC, and Zoetis that assisted with the research and development of the novel Bm86based vaccine. This would have never been possible without the support of livestock producers in the USA and Puerto Rico.

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