1. Introduction
The rate of infectious diseases is at a higher level in animals, which is very dangerous as it may affect humans also based on zoonotic infections. There are more than 200 zoonoses in the world [
1] and some of the zoonotic diseases such as avian influenza, severe acute respiratory syndrome, coronavirus disease have become highly contagious [
2,
3,
4]. Zoonoses can directly affect the production and trade of animals for food, industrial and other applications. Hence it is essential to identify, manage and prevent infectious diseases in animals. Infectious diseases in animals, including fish are caused mainly by microorganisms such as bacteria, viruses, fungi, parasites etc. Some of the infectious agents and their causative diseases are explained in
Table 1. In countries such as India with dominant species of cattle, buffalo, sheep, goat etc., the prevalence of infectious diseases are prominent, that 5-6% of cattle buffaloes are affected by contagious diseases [
5,
6]. Another infectious agent is bovine herpes virus that infects more than 68% of bovine species [
7]. In such cases, vaccines have significant role for the management of live stocks (
Figure 1 and
Figure 2).
Overview of management of fisheries, modified after Holsman et al., (2020) (Holsman et al., 2020). Left panel of the figure indicates the ecosystem level management including the environmental and disease management while the right panel represents fish immunity management with multi-source approaches for their better production. (Figures are produced form Biorende.com).
In order to develop immunity in animals and reduce the susceptibility of animals to infectious diseases, vaccination is crucial. The prominent examples of reducing infectious diseases in animal, including in fish, is the application of vaccines. Application of vaccines as preventive measures was used to reduce the chance of diseases such as rabies and rinderpest, which can be endemic in nature [
8,
9]. Even though vaccines are available for animals based on the type of disease, prioritizing them is very necessary. Due to variations in temperature and other animal husbandry conditions, frequent pathogenic infections occur in animals. Numerous vaccines are developed such as live vaccines, and recombinant vaccines in prevention of these infectious diseases, but still the recovery rate from contracting the diseases is very low. For example, bovine viral fever affects cattle and buffaloes and for that, vaccines such as modified live virus (MLV) and killed virus (KV) vaccines are preferred to reduce the infections. Unfortunately, MLV vaccines are not stable whenever there is a temperature variation and get denatured and inactivated when other compounds interfere. KV vaccines are stable as opposite to MLV and KV vaccines cannot activate cytotoxic T-cells, and are moreover costly too [
10,
11]. However, wide range of commercial vaccines available according to the infectious disease types and rate of infection in animals (as given in
Table 1) but availaibility of such vaccines in fish may able to check the contagious diseases which affect their production and redporduction value (
Figure 3).
The practice of wild harvest began in the 1600s when English fishermen made their first voyages to the Gulf of Maine [
13]. Since then, several advances in technology have given rise to new fishing methods such as handline, and longline. The 20th century marked the beginning of exponential growth for the industry, where global fish harvest has quadrupled over the last 50 years [
14]. As per statistics provided by The Food and Agriculture Organization (FAO), capture fish production is expected to hit 95 million tons (Mt) but will stand second when compared to the aquaculture production which is anticipated to reach 105 Mt [
15]. The total fish weight is estimated to double in India, Mexico and Brazil by 2050 as stated by FAO food balance sheets and the total fish demand for the top 10 countries for human consumption is listed in
Table 1 [
16,
17]. The controlled production of aquatic organsims such as fish, algae, molluscs, and other aquatic plants is known as aquaculture or aquafarming. In contrast to commercial fishing, which includes wild fish capturing, aquaculture involves raising populations of freshwater, brackish water, and saltwater species in controlled or semi-natural environments. However, their production is hamprered severely by several (infectious) diseases.
Artisanal fisheries ecosystems can naturally home for many diseases, and many of these have negative economic effects on aquaculture or fisheries. Diseases are also can be contagious in oceanic ecosystems. In hosts, different levels/percentage of infections occur, for example, 49% in fish, 21% crustaceans, 28% in molluscs and 1% in echinoderms are susceptible to various diseases [
16,
17]. Exotic fishes may become more susceptible to diseases in the new enviromental conditions compared to the local wild varieties. Opportunistic infections may impair the aquaculture sector due to reasons such as high stocking densities of monoculture, leading to greater host contact with pathogenic organisms, which in turn cause increased stress for the fish and degrade the water quality [
16,
17]. The main objective is to prevent the occurrence of diseases in aquaculture which can be met by maintaining good water quality, moderating stocking density, production of disease resistant genetically modified stocks, use of immuno-stimulants and therapeutics against fish pathogens, and utilization of vaccines against bacteria, viruses and other pathogens in fish [
16,
17].
Therapeutics can be used to controll any diseases in aquatic system but a preventive approach to the management of diseases is by the administration of vaccines (
Figure 1). A vaccine can be a suspension of weakened or killed microorganisms, toxins or any other biological preparation. It usually consists of a protein or a polysaccharide antigen which produces an immunological response in an organism to provide protection from the infecting pathogen [
18]. There are different types and generations of vaccines, that are classified based on their mode of action in the below mentioned
Figure 1and
Table 1. Currently, there are three major modes of administration of vaccines to fish such as oral vaccines that are incorporated into the feed. This is an easy to apply method, causing less stress in the fish. Immersion vaccines are applied by dipping the fish for a short time in concentrated solution of vaccine, and injection vaccines as the name suggests, are injected into the fish. The current review is an attempt to update information on fish vaccines and their efficacy and future prospect using a systematic literature survey [
16,
17,
18]. It is to be noted that different commercial veterinary vaccines available in the current scenario such as Canine (Canileish Leishmania vaccines), Avian (Trovac Flu vaccines), Equines (Proteq Flu), Salmonoid (Apex IHN), Food (iPED+) and (PureVax rabies vaccine) are available currently [
12].
4. Contemporary Need of Vaccines for Fish, a Growing Field of Research
Fisheries production was estimated to be 90.3 million tonnes across the world with a decline of 4% in 2020-21 [
16]. Etiological diseases in fish and their treatment methods are always challenging. Immunization of fish is to combat the normal diseases and have a renewable production for its sustainability in aquaculture. Spreading of any infectious diseases in fish may be mutliplied under the environmental stress caused due to the pollutants. One of the species affected due to such stress is the production of shrimps. A total loss of one billion US dollars was reported by Briggs et al. [
43]. Infectious agents or parasites are normally present in water such as bacteria, viruses, algae, etc. Some of the major etiological agents and infected species of fish are shown in
Table 3 [
44].
Reviews have focused on various vaccines for fishes, among which mRNA vaccines are in huge demand in comparison with conventional vaccines. Live attenuated vaccines (LAV) are successful in reducing diseases, but their safety and efficacy are still doubtful. The mRNA vaccine on the other hand is non-infectious, hence is safer [
51,
52]. Other types of vaccines used are nanoparticulate vaccines (nanogels, micelles), liposomal vaccines (natural or synthetic lipids) which combat infectious diseases [
53,
54].
The history, types and mode of administration of vaccines in fish are different for different vaccines. The first ever vaccine was a killed
Aeromonas salmonicida vaccine for immunization of trouts against
Aeromonas bacterial infections [
55]. The application of adjuvants and immunostimulants in fish vaccines, along with their delivery methods have been identified by some key researchers working in this area. The data was obtained based on alternative methods (other than injection) for vaccine delivery, and the protective efficacies of traditional and promising new-generation adjuvants [
56,
57]. Tafalla et al. [
58] defined and perceived the commercially available fish which evolved over time. More than 26 licensed fish vaccines are available commercially and globally in the current scenario [
33]. Vaccines have been approved for use by the United States Department of Agriculture (USDA) for diverse species of aquaculture, and most of them are produced by conventional methods which culture target pathogens. The appropriate collection of vaccines has successfully protected fish against some of the severe fish diseases up to an extent.
Some of the vaccines available for infectious diseases are inactivated (IPNV, ISAV), nucleic acid (DNA, RNA) vaccines and attenuated live vaccines. DNA vaccines are studied to be effective against viral infections and are developed for a series of pathogens in the water [
59]. Another interesting exploration was the discovery of RNA vaccines which are self-replicating based on the alphavirus genome [
60]. Even though numerous types of vaccines have been explored, tested and controlled successfully for many diseases, huge challenges persist in delivering an effective immunization in fish.Viral disease outbreak, mitigatory species of fish, anthropogenic activities, and morbidity rate increase are the challenges being faced by the farming and trading of aquatic species. Some of the activities such as mining and construction works in near by area lead to viral infections in marine ecosystems. Moreover, consumption of infected fish, used as a protein source for farm fish, result in the infection of farm fish species. Another major drawback is the lack of disease diagnosis tools and disease surveillance measures, especially in the underdeveloped countries [
61,
62,
63]. Different management strategies and policies should be designed and developed to manage aquaculture trading and diseases. A multifaceted approach needs to be developed for further prevention of emerging etiological agents and infectious diseases caused by them. (
Table 3).
7. Plant-Derived Fish Vaccines, a New Perstective in Immunology
An emerging expression system through which recombinant genes are expressed in plant cells, is called plant molecular farming. In this technique, foreign proteins are expressed in plants with the purpose of using only the protein rather than the plant [
157]. In the late 1980s, attempts were made to express recombinant proteins in plants [
158,
159]. Initially plants were used to express pharmaceutically important proteins. In 2012, a plant produced enzyme Glucocerebrosidase was the first plant expressed product to be commercialized for human use [
160]. Since then, numerous research has been carried out for production of human and animal recombinant proteins in plants. Three different platforms are used to express recombinant protein in plants viz., stable nuclear expression, stable expression of transgenes in chloroplasts and transient expression of transgenes [
161] (
Figure 4). Each approach has benefits and drawbacks, and the choice of platform is mostly determined by the amount of required protein.
Currently, good manufacturing practices and the regulatory concerns with plant-made recombinant proteins have also been thoroughly developed. Plant molecular farming may utilize a wide range of plant species. In lettuce, tomato, potato, cabbage, and other edible plants, nuclear and plastid genome engineering has been used to produce a variety of recombinant proteins. It has been suggested that a chloroplast expression system is a promising method of producing oral vaccinations. Vaccines against viruses, bacteria, and parasites have been made using transgenic plants [
161].
7.1. Advantages of Plant Derived Fish Vaccines
Plant derived vaccines have been used for their multi-fold advantages such as 1) Plant expression system is safe, and the vaccines do not have any toxic metabolites and hyperglycosylated proteins, 2) Plants have greater capacity for biosynthesis of proteins in a large scale, and performs complex assembly and folding of proteins, 3) Plants are environmental friendly, cost effective and sustainable when compared to existing expression systems and 4) Plant-derived vaccines can be effectively used for oral delivery without the requirement of sophisticated and time-consuming downstream processes.
7.2. Prospective Plant-Derived Fish Vaccines
Financial cost is one of the crucial factors that needs to be considered while developing vaccines for the aquaculture industry. The plant expression system for vaccine production provides cost-effectiveness, safety and efficacy. The plant-derived fish vaccines will provide increased and sustainable fish health in flourishing global aquaculture industry. Research in the field of plant derived fish vaccines is few but now the numbers are increasing [
162]. In aquaculture there is a lot of potential for oral vaccinations for fish, made from edible plants. Additionally, a plant-generated recombinant vaccine can deliver multiple antigenic proteins simultaneously [
163].
Table 7 shows some plant-derived vaccines in fishand other animals. However, no fish vaccine made in plants has yet been made commercially available (
Figure 4). Therefore, it is vital to conduct more study on the development of fish vaccines employing plants as an important platform [
164].
Oral immunization offers a stress-free, time-saving delivery, with less labor costs and minimizes the need for expensive downstream processing, purification, and cold storage while transporting [
169]. By using plant as an expression system, recombinant major capsid protein (rMCP) from iridovirus affecting
Neoscorpis lithophilus was successfully expressed in rice callus. The rMCP was able to provide immune protection from iridovirus [
156]. Likewise, nervous necrosis virus (NNV) coat protein was stably transformed into
N. tabacum chloroplasts [
152]. AcrV and VapA antigens from
Aeromonas salmonicida affecting salmon were stably expressed in chloroplasts of
Chlamydomonas reinhardtii, showing elevated immune production during infection [
165]. White Spot Syndrome Virus (WSSV) affecting crustaceans causes huge economic loss, and the VP28 protein from WSSV was successfully expressed in
Chlamydomonas reinhardtii and
Dunaliella salina [
166,
167]. Successful transient expression of Atlantic cod nervous necrosis virus (ACNNV) VLPs in
N. benthamiana was demonstrated, and immunization study showed effective defense against virus challenge [
168]. Plant-based Virus like particle (VLP) against piscine myocarditis virus (PMCV) causing cardiomyopathy syndrome in wild Atlantic salmon, was transiently expressed in
N. benthamiana. Limited immune protection was induced by plant derived PMCV VLP vaccine against PMCV infection [
163].
To elicit effective immune responses in fish, studies on plant derived vaccines primarily focus on enhancing the quantity and purity of the produced antigens in the expressing plants (
Figure 5). For the maximum quantity and quality of antigens, it is crucial to target the most appropriate subcellular compartment in plant cells. While there are many challenges in the way of plant-derived vaccine manufacture and use, the possibility and promise of improved plant-based vaccinations is alluring. In conclusion, plant biotechnology offers a good choice to produce future aquatic vaccines.
8. Updates on Strategies to Develop Fish Vaccines
A vaccine should be safe for the fish, and the mode of administration if it is oral mode would be better and provide 100% protection as long as production cycle. The main challenge to produce and develop vaccines stay in a sequence of events starting from manufacture to marketing. Another important challenge is to provide a cost-effective vaccine and a readily available one [
170]. A major restriction is to commercialize the oral vaccines and preserve the antigens. Licensing of vaccines also is not practically applicable for all fish antigens. Autogenous vaccines can be used as an alternative. Brooker et al. [
172] have studied on autogenous vaccine and it was shown to be effective in controlling the A
eromonas salomonicida when administered via injection in cleaner fish. Adjuvants are limited for mucosal vaccines and adjuvant usage modulates the immunogenicity of an antigen [
7]. Vaccines need to be designed according to the type of fish species, production cycle, farming technology, environment etc. Strategies must be developed based on the genomes of a variety of fish, and the epidemiology with multi approach strategies need to be taken care of for better production (
Figure 5) [
7].
Kole et al. [
172] proposed that a trivalent oral vaccine consisting of attenuated viral hemorrhagic septicemia virus (VHSV),
S. parauberis serotype I and antigens of
M. avidus, encapsulated in a chitosan-PLGA complex, could be an assuring strategy to prevent the outbreak of diseases in olive flounder. In addition to this, various other vaccination approaches are in their developmental phases such as algal-enclosed oral vaccines, bacterial biofilm-based antigens and exosome-derived vaccines [
173,
174,
175]. The partial immunization in the fish led to the utilization of epitope-based vaccines, where one could, with the help of bioinformatics, formulate an antigen with multiple epitopes that would be of potential benefit in creating effective vaccines [
176]. Orally delivered vaccines have a disadvantage of being disintegrated in the (acidic) gut of fish. As mentioned earlier, these vaccines or recombinant proteins, when encapsulated by a microalgal cell wall, is protected from such harsh environments and is also delivered to the system very easily via cell wall degradation [
173].
Control and prevention strategies need to be designed for the appropriate treatment of infectious diseases in fish. One of the strategies for control and prevention of vibriosis in Asian fish culture by Xu et al. [
177] has been established. As per their review, even though applicable measures are identified, less numbers of vaccine are available to treat the diseases in fish. General prevention strategies are highlighted in
Figure 6. Another major challenge in developing novel techniques is antibiotic resistance by microorganisms in fish.
The world need of fish is increasing everyday and the estimated demand of fish by 2050 is presented in
Table 8. Therefore, the loss due to infectious diseases in fisheries industries must be controlled. Various vaccines which have been proven to have a positive impact on reducing fish mortality were outlined in this review. However, the most effective vaccines are necessary to address the increased demand of fish and fisheries as well as the need for management of large-scale fish farming, which is discussed below.
The worldwide capture fisheries production has been recorded throughout various time periods in different nations (
Figure 7 and
Figure 8) reveals a slight decline in production in 2020 in inland fisheries system. Moreover, concerns about food security and sustainability will increase as the world population approaches 9 billion by 2050 (
Table 8) [
178]. Therefore, economic expansion, job growth, nutritional profile and gender empowerment are a few of the variables that have contributed to an increase in demand for fish and fisheries. The market expanded approximately 20 folds in 2020, compared to production in 1976. Billions of people depend on fishing and its allied sectors to meet their financial and health needs. Increase in fish consumption is largely driven by technological developments in processing and distribution, which has a direct effect on the increased demands for fish and fish products. Good management practices are crucial to reduce stress and minimize the prevalence of diseases (
Figure 5 and
Figure 6). Marine ecosystems are constantly bombarded with challenges that pose a serious threat to their sustainability. Several studies assert that climate change is the major player amongst all other factors [
179]. Currently, there seem to be no climate-change measures that have been added to the fisheries management policies [
180]. A shift in the regulatory guidelines of fisheries has only occurred recently, with governments opting for a more Ecosystem based approach to Fisheries Management (EAF). In simple terms, EAF considers all the species of a particular marine ecosystem, rather than focusing on one single species in isolation. Other components such as climate change, co-interaction with other species and pollution also come into picture (
Understanding Ecosystem-Based Fisheries Management, NOAA). Understanding the role of each of these factors helps in maximizing the benefits of fisheries and other marine ecosystems, by avoiding over exploitation of the available resources. It is vital to ensure that fisheries are managed appropriately to attain the goals of food security, employment and nutritional benefits. Apart from EAF, other existing strategies for management of fisheries include Rights-based Management and Management for Resilience [
181]. So, fish vaccination is one of the major tools for the management of aquaculture health, hence a need to move away from conventional vaccines and concentrating on novel fish immunization techniques are essential. Vaccine development employing advanced technologies like ‘Omics based’ [
182,
183] and nano carriers-based adjuvants [
184,
185] environmentally friendly vaccines like plant based vaccines [
186,
187], which are efficient, cost-effective, require small doses, and do not require the use of antibiotics, arises in light of the increasing importance that fish and fisheries are receiving globally in recent years.
Acknowledgments
The authors duly acknowledge the use of Central Instrumentation Facility of Odisha University of Agriculture and Technology. The language and grammatical correction made by Aidan Mark Webster, United Kingdom, presently at Department of Chemistry and Biochemistry, School of Sciences, Jain University, #34, JC Road, Bangalore, Karnataka, India is acknoledged. Funding for this review by DBT Star College Scheme snacionted by Department of Biotechnology, New Delhi, Govt. of India to the College of Basic Science and Humanities, OUAT, BBSR India is acknowledged.