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CYTED Network to develop an immunogen compatible with integrated

management strategies for tick control in cattle

Article  in  Vaccine · October 2018

DOI: 10.1016/j.vaccine.2018.09.064

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Contents lists available at ScienceDirect

Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Conference report

CYTED Network to develop an immunogen compatible with integrated

management strategies for tick control in cattle
Alina Rodríguez-Mallon a,⇑, Jose Luis Cenis Anadón b, Antonio Abel Lozano Pérez b, Gervasio H. Bechara c,
Rosangela Zacarias Machado d, Ricardo Lleonart Cruz e, Ana Domingos f, Alma R. Tamayo Sosa g
a
Animal Biotechnology Department, Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
b
Instituto Murciano de Investigación y Desarrollo Agrario y Alimentario (IMIDA), Murcia, Spain
c
Escola de Ciências da Vida, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba, Brazil
d
Faculdade de Ciências Agrárias e Veterinárias, Universidade Estadual Paulista (FCAV-UNESP), Jaboticabal, Brazil
e
Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Panama
f
Instituto de Higiene e Medicina Tropical – Universidade Nova de Lisboa (IHMT-UNL), Lisboa, Portugal
g
Instituto de Investigaciones en Ciencias Veterinarias, Universidad Autónoma de Baja California (IICV-UABC), Mexico

a r t i c l e i n f o a b s t r a c t

Article history: INCOGARR is a thematic network recently approved to be financially supported by the Ibero-American
Received 31 May 2018 Program of Science and Technology for Development (CYTED). The objectives of this Network are the
Received in revised form 23 September design and evaluation of an efficient and feasible anti-tick vaccine candidate from the technical and eco-
2018
nomical points of view and also sharing experiences in the immunological control of ticks as part of an
Accepted 26 September 2018
Available online xxxx
Integrated Control Program. The Network consists of seven laboratories and one company from six coun-
tries. The first meeting of the Network took place with the representation of each laboratory involved. In
the meeting, general and specific objectives and activities of the Network were discussed and it was a
Keywords:
CYTED
very nice example of international collaboration to address an unsolved worldwide topic on tick control
Tick control in which laboratories with different competencies and expertise join their efforts in a common goal.
Anti-tick vaccine
P0 peptide
Silk nanoparticles

1. Tick control: A worldwide unsolved problem efficacy, environmental safety and economic sustainability. In
addition, it is applicable to all genotypes of acaricide-resistant
The most important concern about ticks is their capacity to ticks. Therefore, the challenge for the scientific community is to
transmit a wide variety of infectious agents that cause diseases develop immunogens with high efficacy against ticks taking into
in humans and animals [1,2]. Losses in livestock caused by ticks account that a vaccine against ectoparasites will not work as a clas-
in tropical and subtropical areas are millionaire [3,4]. Additionally, sical vaccine and will not show a ‘‘knock down” effect like that of
climate change has had an adverse effect on the distribution of the chemicals [2,7].
ticks and tick-borne diseases, worsening the problem worldwide Ticks carry out part of their life cycle outside the parasitized
[5]. organisms, meaning that the effects of the immunological response
Currently, the fight against ticks and ectoparasites in general against tick antigens generated by the vaccination take place only
continues to be addressed with the application, in many cases after the blood ingestion. Hence, the immunological control of ticks
indiscriminately, of chemical substances that contaminate foods starts with ticks feeding on a vaccinated animal, and ingesting
and environment and whose intensive use selects multi resistant blood containing immunological mediators (antibodies, comple-
tick strains to these chemicals [6]. The immunological control of ment molecules, etc.) which will impair the subsequent steps of
ticks is considered a promising alternative due to its potential their life cycle, mimicking an increased host resistance to the para-
site. This impairment may be detected as a reduction in tick viabil-
ity and a reduction in its reproductive potential (less eggs laid by
⇑ Corresponding author: Animal Biotechnology Department, Center for Genetic
each female, less larvae hatching) and consequently a progressive
Engineering and Biotechnology, 31th Avenue and 190, P.O. Box 6162, Havana
10600, Cuba. reduction of the tick populations in the areas of vaccinated herds
E-mail address: [email protected] (A. Rodríguez-Mallon). [8].

https://doi.org/10.1016/j.vaccine.2018.09.064
0264-410X/

Please cite this article in press as: Rodríguez-Mallon A et al. CYTED Network to develop an immunogen compatible with integrated management strategies
for tick control in cattle. Vaccine (2018), https://doi.org/10.1016/j.vaccine.2018.09.064
2 A. Rodríguez-Mallon et al. / Vaccine xxx (2018) xxx–xxx

2. Immunological tick control in field conditions ectoparasites. Many authors agree that the combination of several
antigens involved in different physiological processes could con-
Anti-tick vaccine researchers over the world have conducted tribute to increase the efficacy of the vaccines against ticks. There
vaccination trials with a series of new antigens. The results of some is currently a strong trend towards the use of reverse vaccinology
of these trials have been disappointing and other studies have to discover new vaccine antigen candidates [29], nevertheless,
shown attractive candidates for further evaluations [9–14]. How- none of these proposed antigens has gone beyond the proof of con-
ever, these studies have been limited to the concept demonstration cept in laboratory conditions. Recent data provides an interesting
in the laboratory. The process of developing these candidates as foundation on the range of candidate proteins to be screened to
commercial products is very expensive. Generally, this develop- discover target tick antigens. One of the key observations is that
ment depends on the interest of a biotechnology company willing housekeeping-like proteins were immunogenic. As a consequence,
to carry out all the studies required for the registration of such can- new perspectives are opened in our search for vaccine candidate
didates [15]. As a result, the progress of vaccine candidates against antigens against ticks [30].
ticks has been very slow and there are very few studies that have Recently, the CIGB (Center for Genetic Engineering and Biotech-
been conducted and published on the application of anti-tick vac- nology) research group working on this topic demonstrated a high
cines in field conditions. Only Gavac, the Cuban vaccine against efficacy of a vaccine candidate against ticks of several species of the
ticks which is a registered product and commercially available, genus Rhipicephalus using a 20 amino acid peptide of the ribosomal
has published studies with more than 2 million of cattle heads vac- protein P0 (pP0) as antigen [31,32]. The P0 is a multifunctional pro-
cinated [16]. This is the largest published evidence on the success- tein whose better known function is to be essential for the assem-
ful application of tick immunological control in cattle production bly of the 60S ribosomal subunit in its cytoplasmic location in the
conditions. cells. Ribosomes are the backbone of the protein synthesis machin-
The active pharmaceutical ingredient of this vaccine is the ery in all living organisms. The absence of P0 leads to inactive ribo-
Bm86 protein that is found in the midgut epithelium of Rhipi- somes for protein synthesis and cell death [33]. In addition, it is
cephalus microplus ticks [17–19]. In vaccinated cattle, Gavac is able also known that dephosphorylated P0 is involved in DNA repair
to control the R. microplus infestations with effectiveness ranging and apoptosis acting as a regulatory element that helps to adjust
51–91% depending on the specific tick strain at diverse geograph- the metabolism of organisms to different environmental condi-
ical locations [20]. These levels of control are only achieved when tions [34,35]. On the other hand, it has also been described as being
the immunogen is applied with a strict technological discipline and present in the cell membrane of parasites such as Plasmodium sp.
within an Integrated Control Program (ICP) in which all available and Toxoplasma gondii, and in the membrane of yeast and mam-
resources are harmoniously combined [20–24]. Some of the guide- malian cell lines from hepatocytes, kidney tubular cells and fibrob-
lines for an ICP program include: using an efficient rotation of pad- lasts, but its function in this location is unknown [36,37]. Recent
docks preventing ticks from finding a host, with the consequent studies have shown that ribosomal proteins are also present in
induction of tick’s death by hunger and dehydration; the genetic the tick saliva [30]. Indirect evidence suggests that other parasites
selection of hosts with higher resistance to ticks; the limited appli- use these proteins to evade host defenses [38]. It is conceivable
cation of acaricide baths by intensity of infestation and only with that they could be part of the tick system to evade the host’s
chemicals of proven efficacy and, most importantly, not introduc- inflammatory response during feeding.
ing non vaccinated animals in the herd in order to guarantee that The high sequence identity of the P0 peptide among different
ticks feed always on vaccinated animals. tick species and its significant efficacy against them when this pep-
The best results of the immunological control have been tide was chemically conjugated to a carrier protein and used to
achieved when it is applied within ICPs as a policy of local govern- immunize animals, suggest that a vaccine developed with this anti-
ments as well as when it includes specialized technical support to gen could have a broader action spectrum than those based on
train farmers and producers in its application. The overall results of Bm86. However, after the concept demonstrations in controlled
an immunological control correctly implemented are manifested experiments are finished, a product development pipeline for vac-
through a significant decrease in tick populations after several gen- cine candidates should be performed. Currently, the P0 peptide has
erations feeding on vaccinated animals and a dramatic reduction of several successful concept demonstrations; nevertheless, it is nec-
diseases induced by hemoparasites not only by lessening in tick essary the validation of these results before to assume the complex
infestation but also by reduction in the vector capacity of ticks phase known as the Valley of Death to develop a technical and eco-
[25]. Furthermore, from the economical point of view, it is evident nomically feasible commercial product based in this antigen [39].
an increase in animal production [16,26] and a drastic diminish- This phase is generally assumed by a commercial partner that also
ment in the cost of tick control as a result of a more rational use pays for the corresponding clinical trials, the development of effec-
of chemical acaricides. This fact has a positive impact on decrease tive formulations, the scale up of production process, development
of environment pollution and food contamination and produces of a robust analytic and finally the process of sanitary registration
also a delay or elimination of tick’s chemical resistance. of the vaccine candidate.

3. New vaccine antigen candidate 4. CYTED Network

The antigen Bm86 has limited or no efficacy against some other The Ibero-American Program of Science and Technology for
tick species [27,28]. However, antigens with vaccination efficacies Development (CYTED) was created in 1984 through an Inter-
higher than those shown by this gut protein are very few. Even institutional Framework Agreement signed by 21 countries of
though Bm86 has been used as anti-tick antigen since the 90s, its Spanish-Portuguese language. Its main purpose is to contribute
biological function is still unknown and it is clear our lack of to the harmonious development of the Ibero-American region
understanding of what makes a particular tick species susceptible through cooperation mechanisms to obtain scientific and techno-
to the vaccination with this immunogen. logical results transferable to productive systems and social poli-
Obtaining new effective antigens to be used alone or combined cies. It also aims to act as a bridge for interregional cooperation
with Bm86 becomes of great relevance in order to improve the in Science and Technology between the European Union and Latin
practical application of vaccines in the fight against ticks and other America.

Please cite this article in press as: Rodríguez-Mallon A et al. CYTED Network to develop an immunogen compatible with integrated management strategies
for tick control in cattle. Vaccine (2018), https://doi.org/10.1016/j.vaccine.2018.09.064
 A. Rodríguez-Mallon et al. / Vaccine xxx (2018) xxx–xxx 3

‘‘The strategies for prevention and control of ectoparasites and and tick species as models doing emphasis in the control of Rhipi-
associated diseases in ruminants” was one of the research lines cephalus ticks in cattle. Taking advantage from the wide experience
opened in the Agro-food Area for the 2017 CYTED call. INCOGARR in biomaterial productions of the IMIDA’s laboratory, nanotechnol-
is the acronym of the project ‘‘Immunogens compatible with inte- ogy will be one of the addressed approaches. Training in the prepa-
grated management strategies in tick control” which was approved ration and management of a biocompatible and stable biomaterial
to be financially supported by four years starting in 2018. The net- patented by the Institute and their chemical modification to
work which will develop this project is integrated by seven labora- improve the transport and presentation of proposed antigens with
tories and one company from six countries (Fig. 1 and Table 1). immunizing effect against ticks will be assumed by the project.
In current science, cooperation between groups and multidisci- Another important network objective will be sharing experi-
plinary laboratories is increasingly imperative to address the scien- ences in the immunological control of ticks using as a start point
tific problems using different approaches and technical the Cuban experience in its implementation within an ICP. After
competencies. This thematic network can enhance the scientific training on this topic, all researchers involved in the project will
and technical capabilities of each individual laboratory to achieve be able to promote the application of these Programs in their coun-
the proposed objective related to obtaining an effective and attrac- tries and will disseminate their advantages for producers in the
tive formulation for the vaccine candidate against ticks based on cattle industry and for other sectors of the society.
pP0 which could be transferred to the industry included in the net- Training in the characterization of the tick species found in the
work. To reach this goal, several formulations for the P0 peptide Ibero-American countries and their sensitivity to chemical acari-
will be developed by involved laboratories. Efficacy trials will be cides and to the formulations of the anti-tick vaccine candidate
conducted with these formulations using several mammalian host are also scheduled in the network activities since they are impor-

Fig. 1. ‘‘INCOGARR” CYTED Network.

Please cite this article in press as: Rodríguez-Mallon A et al. CYTED Network to develop an immunogen compatible with integrated management strategies
for tick control in cattle. Vaccine (2018), https://doi.org/10.1016/j.vaccine.2018.09.064
4 A. Rodríguez-Mallon et al. / Vaccine xxx (2018) xxx–xxx

Table 1
Groups and researchers involved in the ‘‘INCOGARR” Network.

Laboratory Coordinator Participants

Animal Biotechnology Department, Centro de Dr. Alina Rodríguez-Mallon Dr. Mario Pablo Estrada García
Ingeniería Genética y Biotecnología (CIGB), MSc. Pedro E. Encinosa Guzmán
Havana, Cuba MSc. Llilian Gómez Pérez
BSc. Ana Laura Cano Arguelles
BSc. Yuselys García Martínez
Instituto de Higiene e Medicina Tropical- Prof. Ana Domingos Dr. Sandra Antunes
Universidade Nova de Lisboa (IHMT-UNL), Dr. Gustavo Seron
Lisboa, Portugal
Instituto Murciano de Investigación y Desarrollo Prof. José Luis Cenis Anadón Dr. Antonio Abel Lozano Pérez
Agrario y Alimentario, (IMIDA), Murcia, Spain Dr. Salvador D. Aznar Cervántes
Dr. Ana Pagán Bernabeu
Faculdade de Ciencias Agrarias e Veterinarias, Prof. Rosangela Zacarias Machado Prof. Marcos Rogério André
Universidade Estadual Paulista (FCAV-UNESP), Prof. Darci Moraes Barros Battesti
Jaboticabal, Brazil Prof. Maria I. Camargo Mathias
Pontifícia Universidade Católica do Paraná (PUCPR), Prof. Gervasio H. Bechara BSc. Francinea Alves Fonceca de Souza
Curitiba, Brazil BSc. Mayara Carolina Eloy Machado
BSc. Maria Cecilia Pianaro Mores
Instituto de Investigaciones Científicas y Servicios Dr. Ricardo L. Lleonart Cruz Dr. Carlos Restrepo
de Alta Tecnología (INDICASAT AIP), Panama Dr. Alejandro Llanes
Instituto de Investigaciones en Ciencias Dr. Alma R. Tamayo Sosa Dr. Sergio Arturo Cueto Gonzalez
Veterinarias. Universidad Autónoma de Baja Dr. Luis Tinoco Gracia
California (IICV-UABC), Mexico

tant points to be considered in the design of strategies to control developed by Mexican researchers will be much appreciated to
ticks in a specific territory. The vast experience from Brazilian perform these trainings. The molecular taxonomy using bioinfor-
researchers working on ticks as well as the epidemiology works matics will be addressed using the high analytical standards and

Fig. 2. Objectives and activities of the ‘‘INCOGARR” Network.

Please cite this article in press as: Rodríguez-Mallon A et al. CYTED Network to develop an immunogen compatible with integrated management strategies
for tick control in cattle. Vaccine (2018), https://doi.org/10.1016/j.vaccine.2018.09.064
 A. Rodríguez-Mallon et al. / Vaccine xxx (2018) xxx–xxx 5

the scientific competencies of the INDICASAT AIP’s researchers. In [3] Rehman A, Nijhof AM, Sauter-Louis C, Schauer B, Staubach C, Conraths FJ.
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‘‘in vitro” feeding, tick cell line cultures, microinjection, tick dissec- zones of Pakistan. Parasites Vectors 2017;10:190.
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Please cite this article in press as: Rodríguez-Mallon A et al. CYTED Network to develop an immunogen compatible with integrated management strategies
for tick control in cattle. Vaccine (2018), https://doi.org/10.1016/j.vaccine.2018.09.064
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