|Year : 2021 | Volume
| Issue : 3 | Page : 183-192
Current status and future prospects of multi-antigen tick vaccine
BC Parthasarathi1, Binod Kumar2, Srikant Ghosh1
1 Entomology Laboratory, Parasitology Division, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, India
2 Department of Veterinary Parasitology, College of Veterinary Science & Animal Husbandry, Junagadh Agricultural University, Junagadh, Gujarat, India
|Date of Submission||05-Mar-2020|
|Date of Decision||28-Dec-2020|
|Date of Web Publication||15-Feb-2022|
Entomology Laboratory, Parasitology Division, ICAR-Indian Veterinary Research Institute, Izatnagar-243122, Bareilly
Source of Support: None, Conflict of Interest: None
Ticks are blood sucking ectoparasite that transmit several pathogens to humans and animals. Tick management focusing on use of chemicals has several drawbacks including development of multi-acaricide resistant tick populations. To minimize the use of chemicals on animals and on the environment, immunization of natural hosts is considered a viable component of Integrated Tick Management System. Most of the tick vaccine trials are focused on single antigen immunization directed against homologous challenge. From commercial point of view, vaccination against one given tick species is not a feasible option. In this context, multi-antigen vaccines comprising of candidate antigens of multiple tick species or both ticks and tick-borne pathogens have commercial potential. Different strategies are considered for the development of multi-antigen tick and/or tick-borne pathogen vaccines. Further, the efficacy of vaccine can be improved by adopting the ‘omics’ tools and techniques in selection of novel antigens and efficient delivery like Lipid Nano Particle (LNP)-mRNA vaccines, viral vector vaccine, live vector vaccine etc. into the host. The subject has been reviewed to address the current status of multi antigen tick vaccines and formulations of the future strategies for the control of TTBDs of human and animals.
Keywords: Tick; tick-borne pathogen; multi-antigen tick vaccine; chimeric vaccine; co-vaccination; multi-antigen oral vaccines.
|How to cite this article:|
Parthasarathi B C, Kumar B, Ghosh S. Current status and future prospects of multi-antigen tick vaccine. J Vector Borne Dis 2021;58:183-92
|How to cite this URL:|
Parthasarathi B C, Kumar B, Ghosh S. Current status and future prospects of multi-antigen tick vaccine. J Vector Borne Dis [serial online] 2021 [cited 2023 Mar 29];58:183-92. Available from: http://www.jvbd.org//text.asp?2021/58/3/183/321739
| Introduction|| |
Ticks with a worldwide distribution are exclusively hematophagous ectoparasite. In addition to inflicting direct damage by their voracious blood feeding activities, ticks are ranked second after mosquitoes as the vector of different kind of pathogens to humans, domestic and wild animals. In recent years, the number of cases of Kyasanur Forest Disease (KFD), Crimean Congo Hemorrhagic fever (CCHF),, Lyme disease and Indian Tick Typhus (ITT), Tick relapsing fever, have been on the rise in India. These changes are also reported from USA, Europe and Australia, largely due to spreading of tick vectors in new areas. Tick control is the one of the key solutions to prevent the spreading of tick-borne diseases (TBDs). Currently, the tick control method is focused on the use of chemical acaricides on animals and on animals shed usually located adjacent to the humans and animal habitat. However, indiscriminate use of chemical acaricides led to the development and establishment of acaricide-resistant tick populations,. These groups of chemicals also create environmental concerns and the effects on human health have been reported,,.
On broad literature analysis, fourteen major TBDs have been reported from India. The vector potential of ticks and epidemiological pattern of TTBDs are likely to change with the changing environmental conditions and the failure to manage tick infestations in sustainable manner is expected to impact TBDs scenarios significantly. Among the existing tick management methods, immunization of hosts against targeted tick species is an environmentally friendly, cost-effective and easy to use approach to minimize the use of chemical acaricides for the management of TTBDs,. One of the success stories linked with parasite management programme is the identification and establishment of Bm86 protein (tick midgut antigen) based commercial vaccines, TickGARD and Gavac, which were utilized in the integrated tick management program in Australia and in Latin American countries against Rhipicephalus microplus infestations,,.
Every year there is an increasing trend of tick-borne human disease outbreak being reported from India and this data are regularly updated by National Centre for Disease Control, New Delhi (compiled in [Figure 1]) and also in other parts of the world,. Subsequently, the demand of anti-tick vaccine was increased many folds due to establishment of multi-acaricide resistant tick populations in different parts of the globe,,,,,,,,. Development of acaricide resistant tick populations, increased public awareness towards food safety and non-sustainable nature of chemical-based tick management system, prompted an effective environment friendly approach involving cross-protective vaccines as a sustainable tick management option,,,.
Accordingly, for vaccine development, the first challenge is the identification of antigen(s) which should be accessible to the host immune system and are conserved across the tick species. Various molecules were identified in different tick species viz., Bm86, Bm91, Bm95, Calreticulin, Subolesin, Ferritin-2, Glutathione S-transferase, Aquaporin-1, Reprolysin [BrRm-MP4], Glutathione s-transferase mu (DmGstm1), cystatin 2a (Racys2a), but, none of these antigens provide significant level of immunity against multi-ticks infestations and tick-borne pathogens.
In India, initially, native tick proteins were used for experimental immunization of laboratory and natural hosts with some encouraging results,,,,,,,. However, due to non-availability of funding support to most of the laboratories working on the subject and also due to non-availability of trained manpower on the area, the positive results obtained using native antigens could not be progressed further. Later, Azhahianambi et al while working on Hyalomma anatolicum cloned and expressed recombinant Haa 86 (homolougus to R. microplus Bm86 gene) of H. anatolicum in E. coli and tested against challenge conditions. The efficacy of the immunogen against adults was 61.4-82.3 % and 47% against larvae of H. anatolicum. Subsequently, the post challenge efficacy of immunization of calves with recombinant Subolesin (rHa-SUB), Calreticulin (rHa-CRT) and Cathepsin L (rHa-CathL) were recorded 65.4%, 41.3% and 30.2% against H. anatolicum and 54.0%, 37.6% and 22.2%, respectively against R. microplus. Further, the Ferritin2 (FER2) and Tropomysin (TPM) genes of H. anatolicum were cloned, expressed in E. coli system and tested. The efficacy of the antigens was 51.78% and 63.77%, respectively, against the challenge infestation
In most of the laboratories the tick vaccine research is focused on single antigen immunization with limited or no cross protection. Another approach to enhance the efficacy of tick vaccines is use of a combination of protective antigens. It has been reported that combination of two tick/ pathogen antigens can significantly increase the vaccine efficacy,,,,,,,,,,,,,,,,,. Some of the tick protective antigens producing long-lasting immunity can be used to prevent or reduce tick infestations and pathogen infection and transmission in domestic animals, wild reservoir hosts and humans.
Livestock population of India, Africa and other south Asian countries are infested with more than one tick species. Till date none of the identified antigens have been shown to have significant cross-protective efficacy, and cross-protective efficacy is one of the key characteristics of ticks for commercial exploitation. Hence, to develop sustainable solution to fight against multiple tick species, conserved multi antigen tick vaccine is the best possible option. The advantages of multi antigen tick vaccine over single antigen vaccines are:
- Immunity against different tick species/ stages can be achieved following immunization.
- Vaccines consisting of multi tick and tick transmitting pathogen antigens can block host pathogen multiplication cycle.
- The vaccines will be commercially viable and can be incorporated in integrated tick management system in countries where animals are infested with multiple tick species.
However, identification of ideal vaccine candidates targeting multiple physiological functions of ticks is most challenging. This review is focused on the updated status of development of multi-antigenic vaccine for the control of TTBDs.
Multi-antigen tick vaccines
In most countries, multi-tick infestations on animals are the major issues. A universal anti-tick vaccine that renders protection against multiple tick species is the commercial need posing a steep challenge before the scientific community working in this area. Majority of the literature addresses the single-antigen immunization protocol for development of prophylactic measures against ticks. However, no single-antigen vaccine is providing appreciable cross-protection to establish a commercially successful entity. Willadsen et al and Parizi et al are of the opinion that an anti-tick vaccine containing multiple antigens is more likely to be more effective than single antigen vaccine. Accordingly, focus has been directed to study the synergistic effect of multi-antigens tick vaccine which have different mechanisms of action to produce broad-spectrum effects on tick biology. In the process of identification of antigens, initially, RNAi technology was used to study the gene function, characterization of tick-pathogen interface, and to establish the feasibility and practicality of multi tick vaccine. The salient observation of the experiments is compiled in [Table 1].
“Chimera” means combination of two different forms/ antigens. This technology is used to enhance the immunization efficacy or to develop new vaccine constructs targeting multiple functions. It was proposed that different tick antigens/epitopes can be expressed as a single protein which can elicit cross-protection against heterologous tick challenges. However, chimeric tick vaccine development is still in its early stage and few attempts were made involving vector and pathogen components.
BM95-MSP1a construct of chimeric protein using BM95 antigen of R. microplus and Major Surface Protein 1a (MSP1a) of Anaplasma marginale expressed in E. coli. This vaccine successfully induced significant antibody titers in rabbits. Almazan et al conducted vaccine trial using this vaccine in cattle and observed 54% reduction of R. microplus infestations and overall efficacy of 64%. A Subolesin-MSP1a chimeric construct of subolesin protein of R. microplus and Major Surface Protein 1a (MSP1a) of A. marginale expressed in E. coli. Vaccination of cattle showed 34% reduction of R. microplus infestation and overall efficacy of 81%. The vaccination of cattle showed 8-fold reduction in infestation percent of animals and vaccination of sheep reduced tick infestations by 63%. Weight of the female ticks was reduced by 32–55% compared to control ticks and Babesia bigemina seroprevalence was lowered by 30% in vaccinated cattle. The Elongation Factor 1a (EF1a) - MSP1a construct involved EF1a of R. microplus and MSP1a of A. marginale protective epitopes were fused and vaccination of cattle resulted in 38% reduction of R. microplus infestation, 7% reduction in tick weight, 22% reduction in egg fertility and 38% overall efficacy against tick infestations. Similarly, the Q41 Subolesin-Akirin construct consists of fused protective epitopes of Ixodes scapularis subolesin antigen and protective epitopes of Aedes albopictus akirin antigen. The Cysteine encoding nucleotides were inserted in between the selected subolesin and akirin epitopes to form disulphide bridges which helps in epitope conformation. Vaccination of mice with Q41 showed reduction of female mosquito survivability and fertility and overall, 99 % efficacy. Lastly, the Q38 Subolesin-Akirin construct comprised of fused protective epitopes of I. scapularis subolesin (SUB) and protective epitopes of A. albopictus akirin antigens was developed. A GGGS amino acids spacer was introduced for better exposure of epitopes. Vaccination with Q38 reduced oviposition of both mosquitoes (28%) and sand flies (26%) fed on vaccinated mice. The efficacy of Q38 vaccination against larvae of I. ricinus was 99.9% and 46.4% against D. reticulatus. Contreras et al conducted a vaccination study in the field condition using Q38 and showed promising results in controlling multiple tick species infesting roe deer (Capreolus capreolus) population in Spain. Unfortunately, except Q38 none of the above-mentioned chimeric constructs was tested in natural host against experimental challenge condition.
Cocktails of protein as vaccine
The vaccine formulation prepared using functionally different antigens with adjuvant is referred to as cocktails. This kind of vaccine is formulated to get broad spectrum activity or to reach the threshold level of protection where single antigen-based vaccines cannot achieve. The broad-spectrum vaccines are always a choice over the single species vaccine to address the multi-species infestations on animals in the field situation. A few immunization trials have been conducted using cocktails of protein and are listed [Table 2].
Recently, Ndawula Jr. et al worked on to develop the broad-spectrum cocktail vaccine contains recombinant GST (glutathione S-transferases) proteins of different tick species. They expressed the targeted proteins from five different tick species viz., R. appendiculatus, R. decoloratus, R. microplus, Amblyomma variegatum and Haemaphysalis longicornis in E. coli as rGST-Ra, rGST-Rd, rGST-Rm, rGST-Av, rGST-Hl. Immunization of animals using cocktails of all the recombinants showed significant humoral immune response and stronger cross-recognition of sera produced against rGST-Rd and rGST-Av to heterologous rGST compared to sera produced against rGST-Ra, rGST-Hl or rGST-Rm. Moreover, sera against all the rGSTs cross-recognize R. sanguineus crude egg protein extracts, however, sera against rGST-Ra and rGST-Rd showed highest reactivity. Accordingly, the cocktail vaccine of rGST-Rd and rGST-Av was formulated, which showed 35% reduction of female R. sanguineus infestations on challenged rabbits. The antigen selection is the crucial part in cocktail vaccine design. Though, it is reported that one individual antigen may interfere with the protection conferred by the other antigen and this can lead to reduction of overall protection of the cocktail vaccine, a systematic approach using combinations of different technologies like in-silico analysis using online software’s like VaxiJen needs to be followed for constituting cocktail-antigen vaccines.
In contrast to cocktail vaccine, multiple antigens prepared separately and injected separately as a vaccine may elicit better response and chances of interference of one antigen with other can be avoided. Only three reports of such vaccination study are available. A preliminary study of co-vaccination with Bm86 and Bm91 induced significantly higher immunogenicity than vaccination with Bm86 alone but no synergy was observed. McKenna et al purified BMA7 and Bm86 from R. microplus and following co-vaccination of cattle elicited strong Anti-Bm86 (4200-94000) and Anti-BmA7(1600-22000) antibody titer resulted in reduction of egg masses to 2.09–6.04 g/day of the feeding ticks. Co-vaccination of yeast expressed Bm86 and E. coli expressed Subolesin antigens in cattle showed 97% reduction against challenge infestations. Most of the co-vaccination trials were conducted in small number of animals. The dose rate, species of animals, type of tick antigens, adjuvants and site of vaccine administration needs to be standardized before going for co-vaccination using a greater number of animals.
Multi antigen oral vaccine
Oral vaccines against ticks are still in their early stage of development [Table 3]. Oral vaccines have several advantages over other vaccine delivery routes, viz., no need of adjuvants, easy to administer, speed of vaccine delivery is very quick, trained personnel is not required for administration of vaccine, no pain during vaccine administration, less risk of contamination or infection at the injection site,. Multi-antigens based oral vaccine formulations can be used for the immunization of wild life reservoirs against tick infestations to prevent tick borne pathogens from overpass the inter species barrier and cause disease in animals and humans. Two experiments were conducted, and the results are compiled in [Table 3].
The orally administered SUB-MSP1a is the first evidence of the protective capacity of the membrane antigen administered orally to immunize hosts and supported the use of membrane-bound antigens in vaccine formulations. Oral vaccines also have some disadvantages such as low immunogenicity and antigen stability after immunization. To counteract these disadvantages vaccines formulations with selected combinations of pre tested antigens, antigen stability enhancers in acidic stomach environment and vaccine delivery systems needs to be standardized before initiation of vaccine trial,,,. The protection observed using oral SUB+IV vaccine provided new path for future experiments but a number of variables are to be optimized for conducting oral vaccine trials in larger number of animals.
In the past 20 years, research on development of immunoprophylactic measure against ticks has grown rapidly along with technological development. But during the same period, several new TTBDs have been emerged worldwid,. To counter the emerging tread of TTBDs, there is a need to adopt technologies which are ecofriendly, less expensive, easy to use and have broader activity.
de la Fuente et al opined that identification of new target antigens is possible through tick-pathogen interaction study using systems biology approach that helps in selection of the best targets to control tick infestations and pathogen transmission. Vaccinomics involved integrated product of “omics” technologies such as transcriptomics, proteomics, immunogenomics and with systems biology and bioinformatics for the development of next-generation vaccines. With the advancement of new technologies, it has been hypothesized that for designing effective multi antigens vaccine targeting against both ticks and the pathogens it transmits, a combination of new tools viz., interactomics with proteomics, transcriptomics, metabolomics, regulomics together with Big Data analytic techniques are to be used strategically. Omics-based approach of selection of different adjuvants has already been utilized in human vaccine research, so, there is a strong need of omics-based selection of adjuvants in tick vaccinology research too.
Lipid nano particle (LNP)-mRNA vaccines
The mRNA encoding two genes of the Powassan virus, an emerging tick-borne virus, captured in lipid nanoparticles and reported that one dose of the vaccine was enough to induce robust immunity. No viremia or significant anamnestic antibody response was observed following POWV challenge. This immunization protocol produced cross protecting antibodies against other flavivirus viz., OHFV (Omsk hemorrhagic fever virus), KFDV (Kyasanur forest disease virus) and AHF (Alkhurma hemorrhagic fever virus). The mRNA encoding multiple selected tick and/or pathogen genes can be incorporated in lipid nanoparticles and this multi tick and/or pathogen antigen LNP-mRNA vaccine can provide significant protection against TTBDs.
Viral vector vaccines
The gene sequence of protective tick antigen can be incorporated in the genome of vector-borne virus and such viruses are inoculated in to host either through oral / nasal /subcutaneous routes. The inoculated virus produces tick protein along with viral proteins and these tick proteins induce immunity in host against tick antigens. Viral vector vaccines have several advantages viz.,
- Induce humoral as well as cell mediated immunity.
- No need of adjuvant.
- High efficiency of gene transduction.
Oral vaccination with subolesin expressing vaccinia virus inhibited tick infestation by 52% compared to control vaccination with vaccinia virus and reduced uptake of Borrelia burgdorferi by 34% among the surviving ticks that fed to repletion. A 40% reduction in transmission of B. burgdorferi to uninfected vaccinated mice in comparison to controls was recorded. The results of these studies suggest that subolesin incorporation in live vector vaccine may have potential as a component of a reservoir targeted vaccine, to decrease B. burgdorferi, Babesia and Anaplasma species infections in their natural hosts.
Live parasite vaccines
The gene sequence of tick antigen can be incorporated in genomes of low virulent live parasites. These low virulent parasites are given as a vaccine through oral/subcutaneous routes. The parasite in host body can express tick proteins and can induce protection against ticks as well as parasites. Oldiges et al developed live Babesia bovis strain S74-T3B expressing tick antigen, glutathione S-transferase from Haemaphysalis longicornis (HlGST). This type of low virulent Babesia can induce protective antibodies against babesiosis and anti-GST antibodies in host. Immunization trial induced detectable anti-glutathione S-transferase antibodies and showed reduced tick size and fecundity of H. longicornis and R. microplus feeding on experimentally immunized animals. This type of low virulent tick-borne pathogens expressing more than two tick protective antigens can be used for conferring protection against both ticks and pathogens.
New vaccine delivery systems
Amongst the existing antigen delivery systems, nano and micro-particles-based delivery are the most promising since it has better efficiency to enhance the cross-presentation of the antigen, and activate both innate and adaptive immune systems. Recently, Chopenko et al developed an effective nano vaccine against tick borne encephalitis virus. The chimeric antigen is consisting of tick-borne encephalitis (TBE) E protein domain III of virus and OmpFporin of Yersinia pseudotuberculosis incorporated in TI-complexes [TI-complexes are self-organized from mixture of Cucumaria japonica triterpene glycosides and marine macrophytes cholesterol and monogalactosyldiacyl glycerol (MGDG)]. The MGDG plays role in lipid matrix for subunit protein antigen interrupted in TI-complexes. Micro viscosity of MGDG was shown to influence the conformation and immunogenicity of protein antigen and provided a 60% protection. Virus-like immune stimulating complexes (ISCOMs) usually considered as “gold standard” delivery systems, which has greater adjuvant efficacy and stability than liposomes and aluminum. Kostetsky et al reported that the TI-complexes demonstrated high adjuvant efficiency in relation to OmpFporin isolated from Y. pseudotuberculosis in comparison to ISCOM and Freund’s complete adjuvant. Similarly, tick multi antigens can be incorporated in TI-complexes for effective delivery of the antigens. Other strategies like multi antigenic epitope-based DNA vaccines, self-assembling nanoparticle-based vaccines, gold nanoparticle carrying antigen vaccines also can be adopted for multi antigens vaccine development
A significant gap does exist in multi antigens tick vaccines research. For example;
- Worldwide different laboratories have identified a number of antigens with limited or no study on cross protective potential of the identified antigens;
- Limited studies have been conducted to understand protein-protein interaction which is very crucial while combining multiple antigens;
- A number of adjuvants are commercially available to potentiate and maintain immune response for longer duration, but again selection of adjuvants in multi antigens format is very tricky and has to be worked out experimentally;
- The different research groups working on tick vaccine are using different animal models mostly rabbits, guinea pigs, mice, rats etc. and in many cases the data generated in these models can not be repeated in the original hosts.
To overcome these drawbacks following strategies can be taken up:
- Currently only few tick databases are available Bmi-GI, Cattle TickBase and these are not enough to screen the tick vaccine candidates. There should be country specific tick databases which can be accessible by all the tick research groups worldwide;
- High throughput discovery and characterization of several tick antigens and pathogen derived protective antigens can be studied using intelligent big data analytic techniques (de la Fuente et al);
- Functional genomics studies of tick antigens and vector interface using large scale or high throughput experimental methodologies together with statistical, computational and bioinformatics analysis of the results are essential;
- The animal models should be selected based on the type of natural hosts. Initial experiments can be conducted on suitable animal models but in vivo immunization of natural hosts and challenge with suitable stage of the tick species is essential to prove potential of any combination of multiple antigens;
- There should be country wise specific bodies mandated to monitor TTBDs status and the consortium of these bodies should exchange important data maintaining IPR portfolio to solve the present problem and to manage future challenges.
In conclusion, multi antigens tick vaccine development is still in the early stage. But the results obtained in the last 5–10 years have demonstrated the possibilities of this approach for the management of TTBDs. A significant research shift towards omics approach has helped in understanding the functional aspects of the targets to be used in multi-targets vaccine formulation.
| Acknowledgements|| |
The authors are grateful to the Indian Council of Agricultural Research, New Delhi for funding through the National Agricultural Science Fund [Grant number NASF/ABA-6015/2016-17/357 and NFBSFARA/BSA-4004/2013-14].
Conflict of interest: None
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[Table 1], [Table 2], [Table 3]