Review

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Vaccines for fish in aquaculture

Ingunn Sommerset, Bjrn Krossy, Eirik Biering and Petter Frost

CONTENTS
Aquaculture: agriculture
of the oceans
Vaccines & disease control
Administration methods &
factors affecting efficacy
Limitations in
vaccine development
Bacterial fish vaccines
Viral fish vaccines
Fish vaccines
against parasites
Expert opinion &
five-year view

Vaccination plays an important role in large-scale commercial fish farming and has
been a key reason for the success of salmon cultivation. In addition to salmon and trout,
commercial vaccines are available for channel catfish, European seabass and
seabream, Japanese amberjack and yellowtail, tilapia and Atlantic cod. In general,
empirically developed vaccines based on inactivated bacterial pathogens have
proven to be very efficacious in fish. Fewer commercially available viral vaccines and
no parasite vaccines exist. Substantial efficacy data are available for new fish vaccines
and advanced technology has been implemented. However, before such vaccines can
be successfully commercialized, several hurdles have to be overcome regarding the
production of cheap but effective antigens and adjuvants, while bearing in mind
environmental and associated regulatory concerns (e.g., those that limit the use of live
vaccines). Pharmaceutical companies have performed a considerable amount of
research on fish vaccines, however, limited information is available in scientific
publications. In addition, salmonids dominate both the literature and commercial focus,
despite their relatively small contribution to the total volume of farmed fish in the world.
This review provides an overview of the fish vaccines that are currently commercially
available and some viewpoints on how the field is likely to evolve in the near future.

Key issues
References
Affiliations

Author for correspondence

Intervet Norbio AS,
Thormhlensgate 55,
N-5008 Bergen, Norway
Tel.: +47 55 543 958
Fax: +47 55 960 135
ingunn.sommerset@intervet.com
KEYWORDS:
aquaculture, bacteria,
disease, fish, immunology,
parasites, salmon, vaccination,
vaccine, virus

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Expert Rev. Vaccines 4(1), 89101 (2005)

Aquaculture: agriculture of the oceans

Aquaculture is growing more rapidly than all

other food animal-producing sectors; its contribution to global supplies of fish, crustaceans
and molluscs increased from 3.9% of total production by weight in 1970 to 29% in
2001 [101]. As the capture fishing industry has
declined and wild stocks diminished, the aquaculture industry has become an important
source of seafood. China is the largest fish producer, with 70% of the total volume and 53%
of total value in 2002 [102,103]. Today, carps,
barbels and other members of the cyprinid
family dominate fish aquaculture (FIGURE 1).
These fish species have a relatively low value
compared with other types of farmed fish and
are typically raised in simple pond systems
where they are a food source for families in
developing countries. The tendencies are, however, that all fish farming will become more
industrialized with the increasing investment

10.1586/14760584.4.1.89

from multinational companies. Today, highvalue species, such as salmon and trout,
account for 7% of total volume and 16% of
total value of cultivated fish worldwide. Atlantic salmon is one of the most intensively
farmed fish in the world, with Norway, Chile,
the UK and Canada being the major producers. Farming of high-value marine species such
as European seabass and seabream, halibut,
flounder, cod, tuna, eel and amberjack/yellowtail will probably increase as appropriate intensive aquaculture systems are developed.
Although crustaceans (e.g., shrimp), molluscs
(e.g., clams and oysters) and aquatic plants are
important in global aquaculture, they do not
possess an adapted or specific immune system.
Therefore, vaccines (at least by their traditional
definition) are not appropriate for invertebrates and plants, and prophylactics in the
farming of these aquatic organisms will not be
reviewed in this article.

2005 Future Drugs Ltd.

ISSN 1476-0584

89

Sommerset, Krossy, Biering & Frost

Vaccines & disease control

antigens in one oil-adjuvanted vaccine was the product of

choice. The excellent efficacy of these vaccines soon resulted in
their extensive use and an immediate and permanent reduction
in the use of antibiotics, concurrent with a three fold increase in
fish production (FIGURE 2). With the exception of the introduction of a recombinant virus vaccine in 1995 [4], vaccination
strategies in the salmon farming industry have been more or
less unchanged over the last 10 years.
Proper fish management with good hygiene and limited stress
are key factors in the prophylaxis of infectious diseases and are
also a necessity for the optimal effect of vaccines [57]. Today, vaccination is an integratal part of most salmon farms and the use of
antibiotics is very limited, at least in Northern Europe and North
America. The development of fish vaccines is, as with the development of human and veterinary vaccines, an ongoing interaction between academia, the pharmaceutical industry and regulatory authorities. Until the early 1990s, most fish vaccines were
developed and commercialized by small local companies. During
the 1990s and to date, five multinational animal health companies have acquired, or formed, joint venture companies with the
smaller companies specializing in the field of aquaculture vaccines. The major producers of fish vaccines are now: Intervet
International (The Netherlands), Novartis Animal Health (Switzerland), Schering-Plough Animal Health (USA), Pharmaq
(Norway; was part of Alpharma Animal Health until 2004) and
Bayer Animal Health (Bayotek)/Microtek, Inc. (Germany/Canada). The major commercial markets for these companies are
currently the salmon and trout industries in Northern Europe,
Chile, Canada and the USA, where the
value of a healthy population justifies the
price paid per vaccine dose. Vaccines used
Marine fishes
not identified Flounders, halibuts
in Japan are mostly developed and distriband soles
Diadromous fishes 1%
uted by Japanese companies. Commercial
1%
2%
vaccines are also available for the catfish
industry in the USA and, on a smaller scale,
Pelagic fishes
5%
for European seabream, seabass and tilapia.
Some limited-use, locally developed vacCoastal fi
5%
cines are also available in countries such as
Tilapias and
China, Russia, Spain and Germany.

In all forms of intensive culture, where single or multiple species are reared at high densities, infectious disease agents are
easily transmitted between individuals. Fish such as carp, often
farmed in muddy ponds, appear to be more robust than, for
instance, Atlantic salmon that are adapted to spend their early
life in clean, running fresh water. Independent of high- or lowtechnology farming, good environmental conditions are important to maintain a healthy fish population. For species reared in
nets in an open aquatic environment, exposure to pathogens is
impossible to avoid. Due to the effectiveness of pathogen transportation in water and the high density of animals used in commercial large-scale farming, pathogens quickly spread within a
population of cultured fish. During the 1980s, salmon farming
in Norway experienced huge losses due to bacterial diseases
(mostly Vibrio spp.) and a total crash in the industry was only
prevented by the use of vast amounts of antibiotics (FIGURE 2).
Fish immersion vaccines based on formalin-inactivated broth
cultures had proven to be effective against vibriosis in the USA
in the 1970s [3] and similar vaccines were quickly developed
against the salmonid Vibrio diseases. The good efficacy of these
vaccines immediately resulted in a decline in the use of antibiotics. However, a new bacterial disease, furunculosis (Aeromonas salmonicida) appeared and, as immersion vaccines proved
ineffective against this pathogen, injectable vaccines containing
adjuvants were developed in the early 1990s. Following a few
years of testing with different vaccine adjuvants and a range of
different antigen combinations, it soon became evident that all

other cichlid
6%

Carps, barbels and

other cyprinids
46%

Miscellaneous
freshwater fishe
15%

Salmons, trouts and smelts

16%

Figure 1. Major fish species cultured in the world in 2002, as measured in value terms.
Based on data available at [103].

90

Administration methods & factors

affecting efficacy

Oral vaccination with antigen included in

the feed would be the ideal method of vaccine delivery to fish and much effort has
been put into the development of such vaccines. However, poor and inconsistent
responses have been reported by conventional oral vaccines due to antigen destruction in the gut [8,9]. Different approaches to
protect the antigen from degradation, such
as entrapping in liposomes or alginate beads
[10,11], neutralization of gastric secretions or
application of biofilm vaccines [12], have
demonstrated some promising results.

Expert Rev. Vaccines 4(1), (2005)

Fish vaccines

Antibiotics used

Vibriosis/coldwater vibriosis

Production of farmed fish

60,000

50,000

600,000

40,000

500,000
400,000

30,000

300,000

Tons of fish

Kg active substance antibiotics

700,000
Furunculosis

20,000
200,000
10,000

0
1985

100,000
0
1987

1989

1991

1993

1995

1997

1999

2001

2003

Year
Immersion vaccines (l)

Water-based injection vaccines

Oil-based injection vaccines
200,000

25,000
150,000
20,000
15,000

100000,

10,000
50,000
5000
0

0
1985

Injection vaccine doses 1000

Liter of immersion vaccines

30,000

1987

1989

1991

1993

1995

1997

1999

2001

2003

Year
Figure 2. The use of antibiotics (A) and different types of vaccines (B), during the growth of Norwegian aquaculture industry from 1986 to 2003.
Information from [1,2], The Directorate of Fisheries in Norway and Intervet Norbio AS, Bergen, Norway. Information on vaccines from 19871993 is partly
estimates based on incomplete marked information and should be considered illustrative and not absolutely accurate.

However, a large quantity of antigen is usually necessary and the

protection achieved is generally weak and of short duration.
Therefore, the two main methods of vaccine delivery to fish are
still, immersion in a diluted suspension of the vaccine or injecting
it into the body cavity (typically by intraperitoneal injection).
Immersion vaccines are effective for a number of bacterial pathogens and are cheap and easy to administer to small fish. In contrast, vaccination of fish by injection is labor intensive and

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requires the fish to be over a certain size, making vaccination of fry

difficult. Nevertheless, many fish vaccines today are multicomponent injection vaccines, because at least one of the components
requires injection and an oil adjuvant to be effective. The advantages of injection vaccines is that the volume of vaccine needed is
relatively low and that every fish is vaccinated and with the correct
dose. In industrial salmonid farming, professional vaccination
teams or automated vaccination machines are used (FIGURES 3 & 4).

91

Sommerset, Krossy, Biering & Frost

Figure 3. Large-scale vaccination of juvenile Atlantic salmon. Fish are transported in pipes from the rearing tanks to an anesthetic bath and anaesthetized
fish are injected by the vaccination team.

Fish are cold-blooded animals with a body temperature that

equals their surroundings. Dependent upon fish species and temperature, vaccination must be performed within a certain minimum period of time before the risk of their exposure to
pathogens [6]. The onset of an immune response is faster in warmwater species than in cold-water species. At an optimal temperature for Atlantic salmon (1012C), antibodies are typically not
detected until at least 46 weeks after vaccination, whereas a
warm-water species such as seabass, with an optimal temperature
of 22C, can have detectable antibodies 1 week after immunization [13]. In addition to temperature, stress caused by environmental or man-made factors such as photoperiod, seasonal changes,
salinity, heavy metals, crowding, handling and transport, can
induce immune suppression and be a limiting factor for vaccine
efficacy [14]. Unlike wild fish exposed to similar stressors, farmed
fish cannot escape from these factors, and both acute and chronic
stress can render fish susceptible to different opportunistic as well
as pathogenic microorganisms.

exists as a tetramer in its secreted form [17]. No isotypes corresponding to mammalian IgG, IgA or IgE have been identified in
fish and the secondary humoral immune response in fish is, if
present at all, less prominent than in mammals. Due to ease of
measurement, the presence and titer of specific antibodies is a frequently used immunologic assay. Assays to measure specific T-cell
responses are still in their infancy, however, cell lines from cloned
fish lines (matching major histocompatibility complex [MHC]
molecules) are now available for carp and rainbow trout [18]. Even
among the relatively few fish species that are commercially farmed
today, it is important to keep in mind that fish immunology cannot be considered a homogenous system. The number of fish species is much greater than the number of mammalian species and
the evolutionary distance between different teleost (bony fish)
families are considerably larger than between mammals. Furthermore, there are more than 25,000 species of fish living in habitats
ranging from polar regions to the tropics, from muddy fresh

Limitations in vaccine development

The major goal of vaccination is to induce a

specific long-term protection against a certain disease. It has been debated whether the
effective long-term protection of oil-adjuvant injection vaccines is due to immunologic memory in the fish or constant stimulation from the antigen depot. As the
existing empirically developed vaccines can
induce protection after a single administration and until the fish are harvested, less
effort has been put into the investigation of
the actual mechanisms behind the protection. In evolutionary terms, fish are the first
group of animals with the basic aspects of
the immune system of higher vertebrates.
Although fish immune systems are primitive compared with mammals, there seem to
be more similarities than differences [15,16].
In the limited number of fish species studied, the major antibody type is an immunoglobulin (Ig)M-like isotype that typically

92

Figure 4. Manual vaccination of Atlantic salmon. Two metallic bows are attached to the injection
unit to aid a correct intraperitoneal injection of the vaccine dose.

Expert Rev. Vaccines 4(1), (2005)

Fish vaccines

water to the ocean, from dark high-pressure depths to bright lowpressure surface areas. It is therefore likely that different species
have major differences in how they combat pathogens and also in
their response to vaccines. Lack of detailed knowledge of the
immune systems in different fish species limits the possibilities to
study both pathogen and vaccine-induced immunity.
As with all veterinary vaccines, cost effectiveness in the field
is an essential limitation to commercial vaccine development.
For example, the calculations would be very different for a
population of sturgeon used to produce Russian caviar versus a
population of carp in a Chinese village pond. Fish generally
need a large antigen dose compared with terrestrial animals
and cost-effective inactivated viral vaccines have proven difficult to develop. In some species, all types of injection vaccines
(or even immersion vaccines) are simply too expensive. Other
species are too vulnerable to handle the stress induced during
the vaccination or may develop severe side effects post vaccination. Yet, in other species, the major disease problems may
appear in the larval or fry stages, before the animal is large
enough to be vaccinated or have even developed a functional
immune system. The apparent lack of maternal immunity in
fish also limits the possibilities to protect offspring by parental
vaccination [19,20].
Bacterial fish vaccines

At present, vaccines are available against many of the serious

bacterial diseases causing problems for the fish farming industries (TABLE 1) [21]. The first commercially available bacterial vaccines were against enteric redmouth disease (ERM, yersiniosis)
and vibriosis, introduced in the USA in the late 1970s [3].
These vaccines were based on inactivated whole-cell formulations and were administered by immersion. Such vaccines have
proven efficacious in preventing many of the major bacterial
diseases and the fact that these vaccines can be produced at low
cost makes them ideal for use in the aquaculture industry.
Vibriosis has a global distribution in a wide range of fish species. The bacterial species causing classical vibriosis is
Listonella anguillarum (previous nomenclature, Vibrio anguillarum), with more than ten serotypes characterized so far. For
the salmonid and cold-water marine fish species such as cod
and halibut, different serotypes might be involved in disease
outbreaks; thus, vaccines designed for salmonids cannot automatically be used for the marine species. In addition to using
the right serotypes, the main challenges for vaccination of
marine species are that vaccination often has to be performed
on very small juveniles/larvae and that outbreaks occur during
the entire lifecycle. This probably means that in some species
revaccination will be necessary if the fish are to be protected
during the entire production period.
Vibriosis is an example of a disease for which the simple inactivated bacterin vaccines works well but other bacteria have
proven more difficult to control by means of vaccination. In the
channel catfish industry, Edwardsiella ictaluri and Flavobacterium columnare are two of the most important pathogens, with
losses of up to US$6080 million annually in the USA [22].

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Vaccines containing E. ictaluri and F. columnare bacterins have

low efficacy and the use of live attenuated isolates is a new and
promising approach [23,24]. A live attenuated E. ictaluri vaccine,
licensed in the USA a few years ago, has proven efficacious by
immersion of fish as early as 710 days post hatching [25]. A
live vaccine has also been licensed for use in salmonids in
North America and Chile. This vaccine is based on the crossprotective property of Arthrobacter spp. against bacterial kidney
disease (BKD) caused by the intracellular bacterium Renibacterium salmoninarum [26]. Another intracellular bacterium for
which development of vaccines has proven difficult is Piscirickettsia salmonis. This is the causative agent of salmonid rickettsial septicemia (SRS, piscirickettsiosis), which is the most serious disease problem in the Chilean aquaculture industry.
Inactivated P. salmonis bacterins are available, however, due to
low efficacy, development of new vaccines based on recombinant proteins is ongoing [27]. These new approaches might
offer a solution for diseases where inactivated bacterins are inefficient, although the long-term performance of the vaccines
remains to be documented.
Viral fish vaccines

Today, most available virus vaccines for aquaculture are based on

inactivated virus or recombinant subunit proteins. Inactivated/killed viral vaccines are generally not efficacious unless delivered by injection and, as relatively high doses are needed to achieve
protection, cost-effective inactivated viral vaccines are difficult to
develop. Live viral vaccines have been tested with good results in
fish [2830] and should be the optimal regarding protection, administration and price. However, as discussed below, ecosafety aspects
of live virus vaccines are considered major drawbacks and currently
hinder their use as commercial vaccines.
The first viral vaccine for fish was produced by a Czechoslovakian company (Bioveta) in 1982. The vaccine was against a carp
rhabdovirus, causing spring viremia of carp (SVC) and was based
on two inactivated strains of SVC virus emulsified in oil and
administered by injection. TABLE 2 summarizes the viral fish vaccines commercially available today. Carp production is huge in
Asia, both for food (common carp) and ornamental (koi carp)
purposes. Although some severe viral diseases exist (e.g., caused
by koi herpes virus, grass carp hemorrhage disease virus and SVC
virus), few viral vaccine trials have been published. To the
authors knowledge, the only commercial carp vaccine in Asia is
an inactivated grass carp hemorrhage disease virus (a reovirus)
vaccine, which has been widely used in China. A koi herpesvirus
vaccine based on an attenuated strain of carp interstitial nephritis
and gill necrosis virus is available in Israel [30,104].
In salmonid farming, commercial vaccines exist for some of the
most common viral diseases. However, few, if any, of the viral
vaccines are as efficacious as the bacterial vaccines. Disease caused
by the birnavirus, infectious pancreatic necrosis virus (IPNV), is
a major problem in the salmonid industry [31]. Commercially
available IPNV vaccines are based on either inactivated cell culture-propagated virus or recombinant structural proteins. Most
IPNV vaccines exist as polyvalent oil-adjuvanted vaccines where

93

Sommerset, Krossy, Biering & Frost

Table 1. Major bacterial fish diseases in relation to vaccine availability.

Bacterial disease/pathogen

Major fish
species affected

Primary region(s)/
country(s)

Commercially
available vaccine(s)

Vibriosis (Listonella anguillarum and V. spp.)

Salmonids
Cod/halibut
Sea bass/ bream
Amberjack/yellowtail

Globally

Yes
Yes
Yes
Yes

Coldwater vibriosis (Vibrio salmonicida)

Salmonids

Northern Europe,
Canada/USA

Yes

Wound disease (Moritella viscosa)

Salmonids

Northern Europe

Yes

Furunculosis (Aeromonas salmonicida subsp.salmonicida)

Salmonids

Northern Europe,
Canada/USA

Yes

Atypical Aeromonas salmonicida

Salmonids
Globally
Various FW/SW species

Yes
No

ERM/Yersiniosis (Yersinia ruckeri)

Salmonids, FW

Europe, Chile,
Canada/USA

Yes

Piscirickettsiosis (Piscirickettsia salmonis)

Salmonids

Chile

Yes

Bacterial gill disease (Flavobacterium branchiophilum)

Various species, e.g.,

salmonids and carp,
FW

Canada/USA, Europe,
Chile, Japan

No

Flavobacteriosis (Flavobacterium psychrophilum)

Salmonids, FW

Chile, Canada/USA
(West)

Yes

Columnaris (Flavobacterium columnare)

Channel catfish
Salmonids, FW

USA
Chile

Yes
Yes

Rainbow trout fry syndrome (Flavobacterium psychrophilum)

Salmonids, FW

Europe, Canada/USA,
Chile

No

Enteric septicaemia of catfish (Edwardsiella ictaluri)

Catfish species

USA
Asia

Yes
No

Edwardsiella septicaemia (Edwardsiella tarda)

Channel catfish
Eel, Japanese flounder

USA
Asia

No
No

Bacterial kidney disease (Renibacterium salmoninarum)

Salmonids

Chile, Canada/USA
Europe, Japan

Yes
No

Lactococciosis (Lactococcus garvieae)

Rainbow trout
Amberjack/yellowtail

Italy, France, UK
Japan

Yes
Yes

Pasteurellosis (Photobacterium damsela subspecies piscicida)

Sea bream/sea bass

Amberjack/yellowtail

Mediterranean
Japan

Yes
No

Streptococciosis (Streptococcus iniae)

(Streptococcus phocae)

Tilapia
Asian sea bass
Salmonids

Asia
Asia
Chile

Yes
No
No

FW: Fresh water; SW: Salt water.

the IPNV antigen(s) is mixed with one or several bacterins; this

appears to improve the efficacy compared with monovalent
IPNV vaccines [31]. Despite good efficacy data in laboratory trials
and extensive vaccination, IPN is still a problem, partly due to
the complex nature of this disease. Aquatic birnaviruses (also
called marine IPNV strains) are pathogenic for a number of
farmed marine fish species, such as halibut, turbot, European seabass, yellowtail and Japanese eel, however, vaccines are currently
not available.
94

An inactivated viral vaccine against pancreas disease (PD,

caused by an aquatic alphavirus) is available in Ireland under a
provisional license [32,33], and a vaccine against infectious salmon
anemia (ISA, caused by an orthomyxovirus) is available in Canada and the USA [105], but not in Europe, due to preventative legislation (stamping-out policy). The rhabdoviruses, infectious
hematopoietic necrosis virus (IHNV) and viral hemorrhagic septicemia virus (VHSV), cause devastating and highly infectious
diseases, predominantly affecting cultured salmonids in western
Expert Rev. Vaccines 4(1), (2005)

Fish vaccines

North America (IHNV), France (VHSV and IHNV) and Denmark (VHSV). For more than 30 years, several attempts have
been made to develop efficacious vaccines using the conventional
approaches of killed or live virus vaccines. Despite their ability to
induce good protection in laboratory studies, the live vaccines
were demonstrated to be unsafe for field use and inactivated vaccines required high doses [34,31]. Different recombinant subunit
vaccines based on the IHNV and VHSV membrane glycoprotein
have been less successful [3538]. However, DNA vaccines encoding the same viral glycoproteins are remarkably efficacious [3941].
Indeed, these DNA vaccines are protective when used at small
doses (as little as 10 ng in trout fry) and efficacious as early as
48 days and for up to 2 years post vaccination [4246].
Viral nervous necrosis, caused by betanodaviruses, is a major
problem in the farming of several marine fish species (e.g., European seabass, Atlantic halibut, barramundi and several groupers)
[47], yet commercial vaccines are unavailable. A few publications
have demonstrated the effect of recombinant subunit formulations
[4850]. However, in most marine species, disease caused by betanodaviruses strike early in the lifecycle of the fish (larval or fry stages),
before injection of these formulations are protective or applicable.

Instead, large amounts of antiparasitic pharmaceuticals are used

with potentially negative environmental effects. In general, fish
possess both humoral and cell-mediated defense mechanisms
against many parasites [5153] and there are many reports on
immunity/increased resistance among fish surviving natural parasite infections [5458]. Therefore, there are no principal biologic
limitations hindering vaccine development against at least some
parasitic diseases in fish. Experimental parasite vaccines based on
whole pathogens have been reported and live vaccines appear to
be superior to killed vaccines [5964].
Cultivation of parasites for potential killed or live vaccines is
even more expensive than virus cultivation, as a host population
rather than cell cultures are usually required. In addition to the
high costs, the use of natural hosts for cultivation of the parasite
would create major problems with respect to safety documentation. Therefore, identification and production of protective
antigens is probably the most feasible strategy towards commercial parasite vaccines, at least for low-cost vaccines. The successfully developed vaccine against cattle tick (Boophilus microplus)
[6567], a terrestrial ectoparasite of cattle, demonstrates that this
strategy is indeed feasible, albeit very difficult.

Fish vaccines against parasites

Expert opinion & five-year view

There is a wide range of parasites in both wild and cultured fish

stocks. Although parasitic diseases such as amoebic gill disease,
white spot disease, whirling disease, proliferative kidney disease
(PKD) and salmon lice infestation create severe problems in fish
farming, no parasite vaccines are commercially available (TABLE 3).

To date, trial and error has been the main strategy for the development of fish vaccines and this empirical approach will probably
continue in the short term. Development of vaccines for newly
cultivated species (or new diseases in already domesticated fish) is
usually restricted by a limited knowledge of the fish immune

Table 2. Major viral diseases in fish in relation to vaccine availability.

Viral disease/pathogen

Major fish species affected

Primary region(s)/
country(s)

Commercially
available vaccine(s)

Infectious pancreatic necrosis/IPNV,

other aquatic birnaviruses

Salmonids
Various marine species

Globally

Yes
No

Pancreas disease/PDV

Salmon

UK, Ireland, Norway

Yes

Infectious salmon anemia/ISAV

Salmonids

Canada/USA (East),
Norway, UK

Yes

Infectious hematopoietic necrosis/IHNV

Salmonids

Canada/USA (West)

Yes

Viral hemorrhagic septicemia/VHSV

Rainbow and brown trout, turbot,

Japanese flounder

Europe, Asia

No

Viral nervous necrosis/SJNNV and several

other betanodavirus

Several marine fish species, e.g., sea bass,

groupers, barramundi, halibut

Globally

No

Iridoviral disease/RSIV

Red sea bream, amberjack/yellowtail

Asia

Yes
Yes

Channel catfish virus disease/CCV

Channel catfish

USA

No

Spring viremia of carp: /SVCV

Mostly carp species

Europe

No*

Grass carp hemorrhage disease/GCHDV

Grass carp

China

Yes

*
Previously available inactivated virus vaccine but no longer commercially available; Previously available but may not be in use today.
CCV: Channel catfish virus; GCHDV: Grass carp hemorrhage disease virus; IHNV: Infectious hematopoietic necrosis; IPNV: Infectious pancreatic necrosis virus;
ISAV: Infectious salmon anemia; PDV: Pancreas disease virus; RSIV: Red sea bream iridovirus: SJNNV: Striped jack nervous necrosis virus: SVCV: Spring viremia of carp virus;
VHSV: Viral hemorrhagic septicemia virus.

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95

Sommerset, Krossy, Biering & Frost

Table 3. Examples of some major parasitic diseases in fish in relation to vaccine availability.
Pathogen(s)/disease

Major fish
species affected

Primary region(s)/country

Amoebae
Paramoeba spp. (Amoebic gill disease)

Salmonids

Europe, Asia, America, Australia

No

Flagellates
Cryptobia salmositica
Ichthyobodo spp.

Salmonids
Various fish

North America
Globally

No
No

Ciliates
Ichthyophthirius multifilis (White spot disease)
Cryptocaryon irritans
Trichodina spp.

FW fish
SW fish
Various fish

Globally
Globally
Globally

No
No
No

Microsporidia
Tetramicra brevifilum
Pleistophora anguillarum
Nucleospora salmonis

Turbot
Japanese eel
Salmonids

Europe
Japan
North America

No
No
No

Salmonids, FW
Salmonids

Europe, North America

Europe

No
No

Salmonids

North America (West coast)

No

Monogeneans
Gyrodactylus spp.
Dactylogyrus spp.
Benedinia spp.

Various fish
Various fish
Various fish

Globally
Globally
South East Asia

No
No
No

Cestodes
Eubothrium spp.

Salmonids, SW

Europe

No

Crustaceans
Lepeophtheirus salmonis
Caligus spp.

Salmonids
Various fish

Europe, North America

Globally

No
No

Myxosporeans
Myxobolus cerebralis (Whirling disease)
Tetracapsula bryosalmonae (proliferative kidney
disease; PKD)
Kudoa thyrsites

Commercially
available vaccine(s)

FW: Fresh water; SW: Salt water.

systems, the pathogenesis of the disease and the pathogen. However, the trial and error approach is less expensive for fish vaccine
development than for other veterinary vaccines. For most diseases, the efficacy of candidate vaccine formulations can be tested
on large groups of animals in relatively cheap challenge experiments where protection can be evaluated based on counts of dead
and surviving fish.
With a few exceptions, vaccination against the most serious
bacterial diseases of large-scale commercial farmed fish has been
quite successful. Besides small improvements to some of the
existing products, no major changes are expected to take place
within the next 5 years, at least for the salmonid vaccines. New
vaccines against the intracellular pathogens R. salmoninarum
and P. salmonis are now in use and field performance over the
next few years will demonstrate if these vaccines can bring the
diseases under control. A trend that has been observed and that
is expected to continue, is the use of more sophisticated techniques in the development of bacterial fish vaccines. Development of vaccines using attenuated strains (e.g., E. ictaluri) or
recombinant protein technology (e.g., P. salmonis) has been
introduced as inactivated bacterins have demonstrated limited

96

effect. The use of DNA technology has also been tested against
P. salmonis where fish for example, have been vaccinated with a
crude genomic library [68]. Sequencing of several bacterial
genomes are currently ongoing and information obtained from
such projects can be used in the development of new vaccines.
For obvious practical reasons, there is a reluctance to
include more than one vaccination during a production
cycle. One of the most extensively used vaccines for salmon
contains antigens for six different pathogens and this number
is likely to increase as new diseases emerge. However, a constant demand for more complex products will sooner or later
result in antigens being immunologically incompatible, or
there may be a limit to the amount of antigens that can be
included in the water phase of an oilwater emulsion. Furthermore, the increasing numbers of antigens makes the
development, production and registration of such vaccines
more difficult. Manufacturers may become reluctant to make
small improvements, as any change usually requires a huge
effort in providing new documentation for licensing. It is
also difficult to constantly develop multivalent products that
keep pace with the changing disease situation in the field. It

Expert Rev. Vaccines 4(1), (2005)

Fish vaccines

is likely that this development will sooner or later make it

necessary to apply more than one vaccination, thus enabling
the development of vaccines with fewer antigens.
Adverse effects following vaccination with adjuvant vaccines are common problems and fish vaccines are no exception to this rule [69]. As injection of nonadjuvant vaccines or
adjuvant without antigens results in little or no side effects, it
is clear that it is the combination of adjuvant and antigens,
particularly crude bacterial broth antigens, which creates
problems. Adverse effects have been taken very seroiusly by
vaccine manufacturers in recent years. Products with a greater
benefit to risk ratio are now on the market and the quest for
new adjuvants with satisfactory efficacy and minimal side
effects will continue. As bacterial antigens contribute significantly to the side effects, another solution to this problem
would be to identify and separate the protective antigens
from those that induce side effects. For already effective bacterin vaccines, this is not likely to happen in the near future,
as the process of identifying and separating these components
is expensive and laborious.
Injection vaccines developed for some of the new marine species in aquaculture may require adjuvants other than oil. In many
species, both the liver and the eggs are valuable food sources (the
liver is also an important source of fish oil) and remnants of oil
adjuvants in these products will be undesirable. Delivery systems
for effective oral or immersion administration would be a major
improvement to fish vaccination in the future. Recently, a Canadian company has made interesting progress regarding oral
administration of antigens [106], but it is unlikely that this
approach will result in effective commercially available vaccines
within a 5-year view. Even in humans, only the live polio vaccine
has been widely used with oral administration [70].
The lack of effective viral vaccines is one of the main problems facing fish vaccinology. Within the next 5 years, new and
(or) improved virus vaccines will probably be developed for
ISA, PD, VHS and IHN. Experimental IHN and VHS DNA
vaccines are highly effective and the DNA vaccine against IHN
is currently being tested in controlled field trials in Canada. It is
likely that an IHN vaccine will be the first licensed DNA vaccine for fish. For aquaculture applications, DNA vaccines are
safer than attenuated live vaccines, but varying governmental
attitudes towards both DNA and genetically modified organism vaccines (North America being more liberal than Europe)
may limit the use of both these vaccine types.
Live attenuated virus vaccines would be the optimal fish
vaccines if cost, efficacy and ease of administration were the
only concerns. However, commercial fish vaccine development is limited by safety concerns to the consumers, and to
the environment. Most cultured fish live in ponds or nets
with no physical barriers to wild stocks. This limits the use of
live vaccines, whether they are attenuated by classical means
or by use of molecular biology. Although nonpathogenic to
the target animal, a live vaccine may have to be proven nonpathogenic to all other relevant species in the aquatic environment. Such safety data, if possible to generate at all, will

www.future-drugs.com

demand an enormous cost and effort to collect. However, for

high-value species reared in closed indoor tanks with sterilized
effluent water, attenuated virus vaccines may become acceptable. In addition, if live virus vaccines are to become a realistic
alternative also for species reared in nets in the ocean, they
need to have a high level of safety, for example, by development of a replication-deficient virus (infective but unable to
produce new infective virus). These viruses or other modified
microorganisms might be used as vehicles for other protective
antigens. Based on reverse genetics methodology, a new live
recombinant IHNV vaccine strain has been developed by a
French group [71,72]. As the small nonvirion protein Nv
proved to be nonessential for the recombinant IHNV, the Nv
gene may be used as a site of insertion for foreign gene expression and potentially serve as a vector for expressing additional
antigens in the host.
An interesting aspect of the fish rhabdovirus glycoprotein
DNA vaccines is their stimulation of strong innate antiviral
responses and the ability to induce early protection against heterologous viruses [41,44,45,73]. In fish, the innate immune systems
probably play a very important role in the protection against
infectious diseases [74]. More attention should be paid to aspects
of the innate immune responses in the search for specific
immune stimulants and adjuvants. Recently, Jrgensen and
coworkers demonstrated that short DNA fragments (CpG
DNA) protect salmon, to a certain extent, from IPNV challenge, suggesting that CpG DNA may be an effective adjuvant
in some viral vaccines [75].
With the use of modern genomics, strategies for fish parasite vaccine development should be feasible. The commercial
Boophilus vaccine in cattle is an example of how a single protein expressed in the tick gut, a protein that is not exposed to
the host during a natural infection (i.e., a concealed antigen),
can be used as a vaccine antigen, at least in parasites that feed
on host tissue that contains components of the immune system. To study a parasite in such detail that new essential biologic processes are identified, is a major task, both financially
and scientifically. This will probably limit this kind of vaccine development to high-value fish species where a single
parasite causes huge financial or ecologic problems. In our
opinion, the ectoparasitic copepods L. salmonis (salmon
louse) and Caligus spp., are currently the only fish parasites
that fit this description. On salmon ongrowing farms these
copepods are the major parasite problem and in the northern
hemisphere salmon lice alone cause 50100 million annual
losses through mortality, growth reduction, quality reduction
and pharmaceutical costs [76]. Caligus spp. currently causes
severe problems for the huge salmon industry in Chile.
Unlike the salmon lice, Caligus spp., are not salmonid specific and are found globally, and most cultured marine fish
species, present and future, are likely to experience Caligus
problems, as production is intensified. In addition, the pharmaceuticals currently used against ectoparasites may sooner
or later induce drug resistance. Therefore, efforts in basic
research and commercial vaccine development against these

97

Sommerset, Krossy, Biering & Frost

ectoparasites is likely to be intensified. As long as the market

potential is large enough and vaccine development feasible,
an effort towards product development is likely to take place.
Acknowledgements

Information regarding commercial fish vaccines worldwide

would have been difficult to obtain without the invaluable

assistance from colleagues in Intervet. In particular William

Enright, Oscar Parra, Luc Grisez, Marian McLoughlin, Roy
Olav Hovlid and Kari Thors are thanked for their effort.
Dag H Knappskog, Frank Nilsen and Stephane Villoing are
acknowledged for valuable comments during the preparation of this manuscript and Irene Nygrd for making the
FIGURE 3 collage.

Key issues
Most of todays fish vaccines have been developed and commercialized for the salmon and trout farming industry, but vaccines are
also available for other high-value fresh water and marine species.
Currently, most vaccines are based on simple empirically developed inactivated pathogens. A few recombinant subunit vaccines are
also available.
Vaccines against bacterial diseases are, with a few exceptions, highly effective while more variable efficacy is apparent for viral
vaccines. No vaccines against fish parasites exist.
Injectable multivalent oilemulsion vaccines for salmonids dominate the commercial fish vaccine market.
A relatively high antigenic mass is needed in most fish vaccines compared with similar vaccines used in higher vertebrates.
Environmental safety concerns currently hinder the development and use of live virus vaccines in fish.
Species diversity and limited knowledge of immune systems in fish limit the development of vaccines or new vaccine delivery
systems based on nonempirical strategies.
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International koi herpesvirus workshop report

www.frmltd.com/Workshop_KHV.htm
(Accessed January, 2005)
Expert Rev. Vaccines 4(1), (2005)

Fish vaccines

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Recombinant ISA vaccine information

www.microtekintl.com/research/Temp/IHNV&ISAVNE
W/ISAV/rrISAV%20vaccine.htm
(Accessed January, 2005)
Oral vaccine information
www.perosbio.com
(Accessed January, 2005)

www.future-drugs.com

Affiliations

Ingunn Sommerset, PhD

Intervet Norbio AS, Thormhlensgate 55,
N-5008 Bergen, Norway
Tel.: +47 555 439 58
Fax: +47 55 960 135
ingunn.sommerset@intervet.com
Bjrn Krossy, PhD
Intervet Norbio AS, Thormhlensgate 55,
N-5008 Bergen, Norway
Tel.: +47 5554 3769
Fax: +47 5596 0135
bjoern.krossoey@intervet.com

Eirik Biering, PhD

Institute of Marine Research, PO Box 1870,
Nordnes,N-5817 Bergen, Norway
Tel.: +47 5523 6949
Fax: +47 5523 6379
eirik.biering@imr.no
Petter Frost, PhD
Institute of Marine Research, PO Box 1870,
Nordnes,N-5817 Bergen, Norway
Tel.: +47 5523 6362
Fax: +47 5523 6379
petter.frost@imr.no

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