Control Tools

• Diagnostics availability

• Commercial diagnostic kits available worldwide

  Yes, A lateral flow immunoassay kit is commercially available.

  List of commercially available diagnostics

  Full gap analyses matrices can be found on the website and downlaoded here.

• Diagnostic kits validated by International, European or National Standards

  None

• Diagnostic method(s) described by International, European or National standards

  WOAH (OIE) and EURL have harmonized methods and describes:RT-qPCR, cell culture, pathology – immunohistochemistry and immunofluorescence.

  GAPS

  For the WOAH/EURL methods the validation is limited to level 1: analytical sensitivity and specificity, as defined by WOAH

• Commercial potential for diagnostic kits worldwide

  Most Atlantic salmon farming operations have access to PCR laboratories to test for ISAV infection for health management purposes.

  GAPS

  The tests rely on “in-house” standards and QA systems including some proficiency/ring testing.

• DIVA tests required and/or available

  Serology is at present not applied for diagnostic purposes. Nucleic acid from vaccine strains can be detected in the vaccinated fish for a period of time post injection. Sequencing has been used to link the detected NA to the applied vaccine strain.

  GAP

  How long after vaccination can virus strain be detected.

• Vaccines availability

• Commercial vaccines availability (globally)

  Vaccines against ISA are commercially available in most salmon-producing countries where the disease is a problem, and vaccination is mandatory in Chile and the Faroe Islands. Most vaccines are multivalent water-in-oil formulations where the ISAV-component is mixed with other bacterial and viral components in the same formulation. The ISAV antigen is either an inactivated whole virus particle or recombinant ISAV proteins. The antigens used in commercial vaccines are based either EU- and NA-genotype, depending on manufacturer. Vaccination is done by intraperitoneal injection.

• Marker vaccines available worldwide

  None available

• Effectiveness of vaccines / Main shortcomings of current vaccines

  Protection during development and documentation of commercial vaccines is measured by challenging vaccinated fish HPRdel in experimental infection trials. These trials typically show a high survival in vaccinated fish, although the measured RPS (protective effect) can vary based on trial design and external factors. Cross-protection against strains of ISAV from across the phylogenetic tree is generally good, but a reduced level of protection can be found in trials where strains from the NA-genogroup are used to challenge fish vaccinated with EU-genogroup virus, and vice versa. Protection has only been tested for up to seven months.

  GAPS

  There is a lack of randomised field trials on the effectiveness of vaccines at reducing ISAV infection over the production cycle. Do current vaccines provide immunity for all variants of ISAV HPRdel Current epidemiological evidence strongly indicates that vaccination does not prevent infection or transmission of ISAV HPR0, posing a risk for the emergence of novel HPRdel variants. A key knowledge gap remains as to whether vaccination can mitigate the risk of these emerging variants evading host immunity, replicating in endothelial tissues, and spreading to new hosts, thereby triggering ISA outbreaks. In this context, field outbreak investigations, particularly those where epidemiological and phylogenetic data suggest a recent transition from HPR0 to HPRdel, may offer more relevant insights into vaccine efficacy than traditional laboratory challenge studies.

• Commercial potential for vaccines

  ISAV vaccines have been commercialized.

• Opportunity for barrier protection

  N/A

• Pharmaceutical availability

• Current therapy (curative and preventive)

  None

• Future therapy

  Since detection of HPRΔ triggers regulatory interventions, treating populations infected with HPRdel is not a viable option. Consequently, future therapeutic strategies should focus on targeting HPR0.

  GAP

  Future strategies developed for viruses with similarity to ISAV, such as avian influenza, could offer promising avenues for adaptation or further research in the context of ISAV.

• Commercial potential for pharmaceuticals

  Probably low

• New developments for diagnostic tests

• Requirements for diagnostics development

  A multiplex PCR for ISAV HPR0 and HPRdel, as well as methods for whole genome sequencing have been published, but validation lacks, especially in the context of mixed infections. Current diagnostic methods require blood sampling or harvest of tissues.

  GAPS

  Validation of methods to detect mixed infections with ISAV HPR0 and HPRdel (as compared to sequencing) as well as possible non-lethal surveillance methods such as eRNA in water and/or mucus

• Time to develop new or improved diagnostics

  Time to a successful cell isolation for ISAV HPR0 (with no F-protein virulence characteristics) may take long as cell culture has not been successful. Finding good inoculates from the natural, asymptomatic ISAV HPR0 infection is a challenge, and also there could be a lack of permissive cell culture/line as suggested by the fact that other pathogens targeting the same gill lamellar cells as ISAV HPR0 are also uncultivable (e.g Salmon Gill Pox Virus).

  GAPS

  There is no successful cell isolation protocol for ISAV HPR0. A protocol to successfully infect fish with ISAV HPR0 would help research on this variant.

• Research requirements for new or improved diagnostics

  GAP

  Tools (cell lines) that allow us to determine if ISAV HPR0 detected by molecular tools reflect infectious virus or RNA remnants.

• Technology to determine virus freedom in animals

  Presently RT-qPCR is used in surveillance as described by EURL/WOAH to determine virus freedom in populations/compartments. Also testing of single broodfish is done to minimize the risk of virus dissemination.

  GAPS

  Methods to reliably test eggs for virus presence and procedures that makes such testing meaningful is needed. Especially the emergence of ISAV HPRdel in HPR0 infected brood fish populations is a challenge. Literature is contradictory regarding the true vertical transmission of ISAV. Good protocols to maintain ISAV freedom from hatcheries, and to monitor hatcheries (surfaces, water and compartments) could prevent the recurrence of the virus in smolts. Surveillance Se/Sp and Diagnostic Se/Sp for HPR0 and for early emergence of HPRdel at the population level.

• New developments for vaccines

• Requirements for vaccines development / main characteristics for improved vaccines

  Relatively few outbreaks of ISA have been registered on vaccinated fish in Chile, Faroe Islands and Norway. This could suggest that there is a limited potential for further improvement of vaccine efficacy within reasonable cost. More vaccines against ISAV could improve redundancy in case one vaccine producer becomes unable to deliver product for some time. An ISAV component in new multivalent and/or co-injected combinations could be required in some locations.

  GAPS

  It is not known if current vaccines can reduce spread of HPR0. Cross protection between divergent genotypes such as EU- and NA- strains is probably partial and could possibly be improved in Canada where both genotypes are present.

• Time to develop new or improved vaccines

  5-10 years, given that an efficacious candidate has been identified.

• Cost of developing new or improved vaccines and their validation

  High

• Research requirements for new or improved vaccines

  ISAV has two surface proteins (HE and F, encoded by segment 6 and 5, respectively) that are potential targets for neutralising antibodies. The receptor-binding domain of ISAV is found in the HE protein. The fusion peptide is found in the F protein. Antibodies that target the HE receptor binding domain prevents ISAV binding and infection. Based on what we know from other infections, it is likely that antibodies to other viral proteins also may contribute some level of protection. The amino acid sequence of the ISAV HE protein varies due to both genotype and differences in the HPR region. Genotypic variation is driven by non-synonymous mutations accumulated over time, resulting in distinct North American and European genotypes, along with multiple subtypes. In contrast, variation in the HPR region occurs during the transition from HPR0 to HPR-deleted forms.

  GAPS

  Antibodies that prevent HE receptor-binding block infection. What is the level of cross-protection between different HE genotypes and viruses with different HPR-deletions? Better knowledge of ISAV-receptor interactions could facilitate the design of more efficacious vaccines. Do antibodies to the F protein have a complementary role in protection? To what extent could RNA-based vaccines enhance the efficacy and adaptability of current immunization strategies?

• New developments for pharmaceuticals

• Requirements for pharmaceuticals development

  The regulatory focus on culling HPRdel positive fish populations makes the development of traditional therapeutic solutions less attractive.

• Time to develop new or improved pharmaceuticals

  5-10 years given that an efficacious therapeutic exists

• Cost of developing new or improved pharmaceuticals and their validation

  Most likely quite high

Disease details

• Description and characteristics

• Pathogen

  Infectious salmon anaemia virus (Isavirus salaris, ISAV) is a pleiomorphic enveloped virus, 100-130 nm in diameter with surface protrusions of 10-12 nm. It is an orthomyxovirus with an eight-segment, negative sense RNA genome.

  GAP

  The significance and function of alternative or truncated ORFs as well as isoforms of specific viral gene segments remain incompletely understood or experimentally unverified.

• Variability of the disease

  ISAV exists as an ancestral form that has not been reported to cause disease (ISAV HPR0) and a pathogenic form (ISAV HPRdel) that has emerged from HPR0 in multiple independent transitions. The transition to virulence is characterized by both a deletion in the highly polymorphic region (HPR) of gene segment 6, encoding the haemagglutinin esterase, and a change (insert or mutation) close to the region of genomic segment 5 that encodes the activating cleavage site of the F protein. While pathotypic changes in either segment 5 or segment 6 have been reported on a few occasions, the by far most common scenario is that these changes occur together. Together, these changes increase the ISAV fusion efficiency, required for cellular entry. This is believed to direct the cellular tropism of the virus, as ISAV HPR0 infects surface epithelium and is not easily propagated in the laboratory, while ISAV HPRdel also replicates efficiently in vascular endothelial cells and the Atlantic salmon kidney cell line, ASK. Furthermore, ISAV HPRdel isolates differ in virulence, suggesting that other segments, such as viral polymerases, nucleoprotein, or regulatory proteins also influence the ability to replicate and/or cause disease. However, the impact of such variation remains unclear.

  GAPS

  It is not known how frequent transitions from ISAV HPR0 to HPRΔ are, or which factors influence the risk of such transitions. Is stocking HPR0 free smolts in cages a mean of reducing future outbreaks. Research into this preventive mitigation measure would be needed. Identification of additional (genomic) virulence markers to explain differences between HPRdel isolates. What is the role of viral population dynamics (quasi-species) in the emergence of virulent strains.

• Stability of the agent/pathogen in the environment

  ISAV is inactivated rapidly by UV irradiation. The dosage, turbidity, and water depth affect the outcome.

  GAPS

  The degree of stability in biofilms, or biofilters, is unclear. Stability in water (fresh or saline) is unknown.

• Species involved

• Animal infected/carrier/disease

  Atlantic salmon (Salmo salar) is the only species reported to develop infectious salmon anaemia after natural infection with ISAV. In addition, rainbow trout (Oncorynchus mykiss) and brown trout (Salmo trutta) are considered susceptible to ISAV infection by the WOAH.

  GAPS

  What 4-O-acetylated sialosides act as ISAV receptors in Atlantic salmon, how does their anatomical distribution influence infection dynamics and disease, and what factors (genetic, environmental) affect their expression?

• Human infected/disease

  Not applicable

• Vector cyclical/non-cyclical

  ISAV HPRdel has been detected in sea lice feeding on infected Atlantic salmon, but the virus does not replicate in the lice. This suggests that the louse does not act as an active vector, but that passive transmission can not be excluded.

• Reservoir (animal, environment)

  Species with incomplete evidence for susceptibility include Atlantic herring (Clupea harengus), amago trout (Oncorynchus masou), and Coho salmon (Oncorynchus kisutch).

  GAPS

  Which wild fish species have potential to act as reservoirs for ISAV, and what role do these reservoirs play in transmitting and maintaining ISAV in the marine environment? How long can ISAV persist in biofilms?

• Description of infection & disease in natural hosts

• Transmissibility

  ISAV HPRdel and HPR0 appear very different both with regard to disease and virus dissemination. HPR0 infects superficial gill epithelial cells, while HPRdel infects vascular endothelial cells – seemingly without harming the host cell much (low cytopathogenicity). The virus sheds apically from the cells, meaning that HPR0 ends up in the water and then appears to spread rapidly to other fish. HPRdel is shed to the blood vessel lumen and may then cause severe anemia and circulatory disturbances leading to high mortality. Shedding of HPRdel to the environment could be relatively low until severe disease and mortality ensue: The removal of net pens with infected fish early in the course of the infectious period appears to slow down disease development in neighbouring net pens considerably.

  GAPS

  Host, management, and environmental factors that limit or favour ISAV HPR0 infection, shedding, and/or persistence. The spread of ISA disease after detection in one or a few of many net pens of a farm may take months. Knowledge of the determinants of this spread, including transmissibility of the virus, could help to design rational slaughtering, fallowing, and zoning/biosecurity requirements.

• Pathogenic life cycle stages

  GAP

  Host, management, and environmental factors that influence the risk of new transitions from ISAV HPR0 to HPRdel.

• Signs/Morbidity

  Anemia, vascular congestion, bleeding.

• Incubation period

  Notably, data on incubation periods and mortality are derived from experimental infections, which may not accurately reflect infection kinetics under field conditions. In bath challenge (where fish are exposed to a high dose of virus, giving a synchronous infection), mortality after infection with strains of suspected high virulence typically begins after approximately 10 days. Strains with suspected low virulence tend to give mortality approximately one to two weeks later.

  GAPS

  Early signs are vague – probably hematology to demonstrate increased numbers of immature RBC would be most sensitive and could shed more light on the pathogenesis. Clinical detection relies on moribund fish with signs of circulatory disturbances, while RT-qPCR testing will detect the systemic virus replication early, appr 3-4 days post bath challenge.

• Mortality

  Historically, field outbreaks often resulted in high mortality, however, current management regimes are designed to detect disease early, and mortality in infected net pens is often low, in the range of 0.5-1‰. In contrast, experimental bath challenge with strains of suspected high virulence can give 100% mortality after approximately 3-4 weeks. One strain with suspected low virulence has been observed to give cumulative mortality of 10-15 % after approximately one month. Some strains have been observed to be infectious to naive fish without causing any mortality.

  GAPS

  In the field, numerous factors will influence the outcome of an ISAV infection, beyond those accounted for in controlled challenges. Nevertheless, strain differences in virulence appear to play a significant role, and better insight into these differences could be valuable for improving disease management strategies. It would also be useful to identify host and environmental factors involved in the shift from a largely subclinical infection where it is difficult to find infected individuals to a more severe outbreak where increasing numbers of fish become diseased and die.

• Shedding kinetic patterns

  For HPR0, rapid shedding appears to be the rule, judging from epidemiology studies. For HPRdel, shedding is proportional to the RT-qPCR results obtained in tissues. Based on knowledge from influenza A virus, it is likely that shedding requires viral receptor destruction. ISAV HPRdel infection causes extensive loss of the viral binding sites from vascular and red blood cell surfaces in infected fish, and this loss is mediated by the viral esterase. This has not been explored in the context of epithelial cells. The active site of the ISAV receptor destroying enzyme is formed by HE Ser32, Asp261, and His264, all highly conserved. Different ISAV isolates vary in their receptor destroying activity, suggesting that additional sequence features contribute to determining esterase activity. However, these features have not been identified.

  GAPS

  It would be useful to identify the sequence features that determine the receptor destroying activity of ISAV HE, and whether such variation affects shedding.

• Mechanism of pathogenicity

  ISAV HPR0 only replicates in surface epithelium and has not been reported to be associated with disease. ISAV HPRdel replicates in surface epithelium in the early stage of infection. After some days, the infection changes and becomes systemic with extensive viral replication in vascular endothelial cells. Infective virus particles are released into the blood and bind red blood cells, which are poorly permissive to viral replication. There is variable removal of red blood cells from the circulation, possibly contributing to immune clearance, but also causing anaemia. Signs of disease include vascular congestion, pinpoint bleeds, vascular leakage, and necroses. The exact mechanism of pathogenicity has not been defined.

  GAPS

  The cellular events during transition from an epithelial to endothelial infection have not been well defined, but are of interest, as endothelial infection appears to be central to pathogenesis. Host factors that limit or favour the shift from local epithelial to systemic endothelial infection, replication in endothelium, and/or development of disease. To what degree is virulence variation among HPRdel variants a robust, isolate-specific trait, and which genomic sites apart from the defined virulence markers in segments 5 and 6 contribute to this variation?

• Zoonotic potential

• Reported incidence in humans

  Never reported

• Risk of occurence in humans, populations at risk, specific risk factors

  Minimal risk: The optimal replication temperature is 10-15 °C, with replication reduced to <1% at 20 °C. Moreover, infection depends on the ISAV receptor 4-O-acetylated sialic acid, which do not appear to be expressed in human tissues.

  GAPS

  It would be beneficial to have documentation / easily read information included in the manuals on the lack of zoonotic potential to use when confusion arises and stops trade. Listing non-susceptible species is not rational, but the manuals could include “zoonotic potential” explicitly.

• Symptoms described in humans

  Not applicable

• Likelihood of spread in humans

  Not applicable

• Impact on animal welfare and biodiversity

• Both disease and prevention/control measures related

  Fish with clinical or subclinical disease will have poor welfare.

• Endangered wild species affected or not (estimation for Europe / worldwide)

  ISAV has been detected in wild Atlantic salmon by qPCR, and the species develops infectious salmon anaemia disease after intraperitoneal injection of ISAV HPRdel. It remains unclear whether wild Atlantic salmon populations develop infectious salmon anaemia in the natural situation, but the possibility can not be excluded.

• Slaughter necessity according to EU rules or other regions

  Slaughter is not mandatory in some jurisdictions /countries, e.g., east coast of Canada.

• Geographical distribution and spread

• Current occurence/distribution

  After emerging in Norway in 1984, outbreaks of infectious salmon anaemia caused by ISAV HPRdel have occurred in most Atlantic salmon farming regions, including Canada (east coast only), Chile, Faeroe Islands, Iceland, Scotland, and the USA. ISAV HPR0 appears to be enzootic in salmonid populations of all major salmon-producing countries, and persistent infections have been reported in fresh-water smolt farms.

  GAPS

  What risk factors predict or influence the emergence of disease-causing variants? Identification of husbandry or environmental variables that influence viral fitness and/or evolution to virulence may offer opportunities for control.

• Epizootic/endemic- if epidemic frequency of outbreaks

  Yes, if not effective control measures are put in place.

• Speed of spatial spread during an outbreak

  Hydrographic spread may appear rapid and localized (single tidal cycle’s extent).

  GAPS

  Is the limitation for hydrographic spread related to dilution or virus persistence or both? Studies on the risk to neighbouring farms based on epidemiology and oceanographic connections and modelling are important.

• Transboundary potential of the disease

  Yes

• Route of Transmission

• Usual mode of transmission (introduction, means of spread)

  Horizontal spread is the most common form of transmission for both ISAV variants. Waterborne transmission is likely limited to local spread (ISAV persists detectably in water only hours to days). Virus transmission by boat traffic (well boats and other service boats visiting sites) is a relevant factor in transmission. For ISAV HPRdel, vertical transmission appears to be possible, but has not been observed in hatcheries. For ISAV HPR0, available evidence indicates that vertical transmission is rare or non-existent.

  GAPS

  What accounts for spatiotemporal relationships described over longer periods (than days)? How is HPR0 spread across larger distances?

• Occasional mode of transmission

  Occasionally, new pathogenic ISAV HPRdel emerge from HPR0. On several occasions in the last decade, new ISAV HPRdel variants have been detected in fish delivered from smolt farms infected with closely related ISAV HPR0 viruses. In some geographic regions, new transitions appear to be the most common source of ISA outbreaks. Sea lice may act as mechanical vectors (and also impact susceptibility). Subadults/adults can move between fish.

  GAPS

  How important are sea lice in transmission when the fish are not densely populated? Is the apparent transience of HPR0 explained by persistence of the HPR0 virus at high prevalence, or by extirpation/re-introduction? If the former, what instigates the resurgence in replication (waning immunity, stress, environment)? If the latter, what are the reservoirs?

• Conditions that favour spread

  The oceanic connectivity between farms is a known factor that favour horizontal transmission of ISA. Vessel movements between farms are also risk factors.

• Detection and Immune response to infection

• Mechanism of host response

  ISAV triggers innate and acquired immune responses in salmon. Fish that recover from natural HPRdel infection develops antibodies and long-term immunity to new infections.

• Immunological basis of diagnosis

  Immunological parameters are not used for diagnosis.

• Main means of prevention, detection and control

• Sanitary measures

  Virulent strains: Early detection/response, processing plant effluent management, closed hold harvest vessels, etc., limit virus buildup in the water column and seemingly reduce waterborne spread. All-in/all-out important to prevent spread between year-classes; fallowing (to reduce virus and vectors) is most effective if synchronized across hydrographically-defined management areas. Implementation of biosecurity measures related to boat traffic/contacts.

  GAP

  ISAV HPR0 appears self-limiting in the absence of stress. Is this true, or do viral loads and/or prevalence just dip below detection thresholds?

• Mechanical and biological control

  Not relevant.

• Prevention through breeding

  Yes, different disease resistance is demonstrated, but the effect is polygenic and at best moderate.

  GAP

  Will breeding hide subclinical infection?

• Diagnostic tools

  Sensitive RT-qPCR assays are used to detect very low viral copy numbers.

• Vaccines

  Yes

  GAP

  Does the vaccine provide immunity for all variants of ISAV HPRdel

• Therapeutics

  No

• Biosecurity measures effective as a preventive measure

  Yes

  GAP

  Does stocking ISAV HPR0-free smolts reduce the likelihood of subsequent ISA outbreaks?

• Prevention tools

  Good husbandry (stocking density, handling) appears protective against the occurrence of virulent strains. Some companies screen smolt populations for HPR0 before transfer to sea. The previous generation may also be tested for HPRdel at slaughter to avoid stocking smolt in a contaminated sea site (lengthen fallowing period etc when detecting HPRdel ISAV). Screening of broodfish and disinfection of eggs.

  GAPS

  Do optimal husbandry and early detection/removal of virulent strains favour the maintenance of HPR0? Do stress events and higher density increase HPR0 replication and favour emergence of virulent strains? There is a need for science-based justification for fallowing procedures and the size of risk- and observation zones.

• Surveillance

  Essential for early detection and to prevent high prevalence and high shedding in outbreak situations.

  GAPS

  Diagnostic Se difficult to evaluate for HPR0 (need reference animals and/or parallel conditionally-independent tests). Data indicates that approximately 5% of HPR0 infections are detected if using only kidney in surveillance. Transient nature of HPR0 limits the value of routine (e.g., twice annual) surveillance and may misguide trade.

• Past experiences on success (and failures) of prevention, control, eradication in regions outside Europe

  In some countries frequent surveillance (targeting moribund fish and recent mortalities), rapid response (cage-level), and synchronous management of bays have helped control the HPRdel outbreaks.

• Costs of above measures

  High

  GAP

  Is there a cost analysis done on the value of surveillance to reduce outbreak impacts, vs the alternative (passive survelliance)

• Disease information from the WOAH

• Disease notifiable to the WOAH

  Infection with ISAV HPR0 and HPRdel are listed as notifiable to the WOAH. Infection with ISAV HPRdel is listed as a notifiable disease (category C+D+E) in the EU.

  GAPS

  Disconnection between surveillance for HPR0 and justification for reporting.

• WOAH disease card available

  Direct links to the WOAH.

  GAP

  Not applicable

• WOAH Terrestrial Animal Health Code

  WOAH Aquatic Animal Health Code (reference)- Direct links to the WOAH.

  GAP

  Not applicable.

• WOAH Terrestrial Manual

  WOAH Aquatic Animal Health Code (reference)- Direct links to the WOAH.

  GAP

  Not applicable.

• Socio-economic impact

• Zoonosis: impact on affected individuals and/or aggregated DALY figures

  Not applicable

• Zoonosis: cost of treatment and control of the disease in humans

  Not applicable

• Direct impact (a) on production

  Yes, farm losses due to mortality.

• Direct impact (b) cost of private and public control measures

  Destruction of fish, early slaughtering, costly fallowing routines and increased surveillance.

  GAP

  Communication and public perception could be improved.

• Indirect impact

  Some markets are closed on suspicion/detection. Can have large socio-economic impact for small companies and their local communities when termination of a significant part of their biomass is required. The emergence of ISA in Chile in 2007-2008 had unprecedented socio-economic impact on societies in southern Chile.

  GAP

  In some locations/countries, resistance to aquaculture is strong, and understanding the fundamentals behind this resistance and how to improve communication would be helpful.

• Trade implications

• Impact on international trade/exports from the EU

  There is currently an equal focus on ISAV HPR0 and HPRdel in international standards. This should be questioned. Conventional surveillance strategies are expensive and may have low SSe. ISAV demands two distinct sampling strategies: one for HPRdel (targeting internal tissues, moribund fish and recent mortality, can be lower numbers) and another for HPR0 (targeting gills, seasonal, focus on periods for spawning and smoltification). Surveillance strategies should reflect the objectives. For example, production animal surveillance might focus on virulent strains (lower cost, higher impact) by targeting dead and moribund fish. Goal would be early detection/removal to minimize shedding into the water column and subsequent spread. Sampling for HPR0 might be reserved for select times in select populations, e.g., spawning events for brood populations, with the goal of subverting potential spread through egg distribution. WOAH Code Article 10.4.6 mistakenly discusses absence of clinical expression as an indicator of freedom from HPR0 (point 2). The Code also implies you can demonstrate country freedom from the virus (ISAV) via historical absence as long as conditions are conducive to disease expression (which they never are for HPR0).

  GAPS

  Consider changing stance around ISAV HPR0. HPR0 is relatively ubiquitous, and transition to virulence may be driven more by husbandry/environment than by exposure pressure. Furthermore, standard testing may misrepresent status. Guidance is needed for more effective HPR0 surveillance (since infections seem highly transient and triggered by physiology and environment). ISAV surveillance is not one-size-fits-all. Requirements for disease freedom claims for HPR0 should be reviewed. SSe conclusions may be inaccurate. DSe is unknown for HPR0. Appropriate prevalence thresholds are not defined. Its transience questions the frequency/timing of surveys required for long-standing claims.

• Impact on EU intra-community trade

  See section above on (Impact on international trade/exports from the due to existing regulations).

• Impact on national trade

  See section above on (Impact on international trade/exports from the due to existing regulations).

• Links to climate

• Seasonal cycle linked to climate

  In Norway, clinical outbreaks tend to occur or exacerbate in early summer and early winter.

  GAPS

  The seasonal effect was noted early in the history of ISA, and we lack an explanation for this. PCR testing obscures this phenomenon unless clinical sign/mortality is recorded.

• Distribution of disease or vector linked to climate

  Rising temperatures will influence sea lice (mechanical vector, stressor) dynamics.

  GAPS

  Unknown impact on ISAV occurrence and virulence. The virus seems to affect fish more rapidly in warmer water, but mortalities will eventually be the same in colder vs warmer water.

• Sensitivity of disease or vectors to the effects of global climate change (climate/environment/land use)

  GAP

  Studies will be required to demonstrate the impact of higher temperatures than usual in sea cages.

• Main perceived obstacles for effective prevention and control

  The endemic presence of HPR0 is a difficult-to-control potential source of new pathogenic HPRdel viruses; though the rate emergence of outbreak strains appears to be low Many aspects of current knowledge to consider: HPR0 and HPRdel have distinct presentations. HPR0 is ubiquitous, and an undefined risk for the emergence of novel pathogenic variants and ISA outbreaks. Communication, especially concerning surveillance limitations and the lack of zoonotic potential, could be improved to support trade and public understanding. Current WOAH/EURL methods are validated only at analytical levels and depend on in-house QA systems with limited standardization.

  GAPS

  There is a need for epidemiological and modelling studies to support science-based fallowing, risk-zoning, and slaughter policies. There is a need for reliable, validated, and practical methods for detecting mixed infections (HPR0 and HPRdel), early emergence of HPRdel, and segment reassortment. Early detection tools (e.g., eRNA in cage water), non-lethal sampling (e.g., mucus swabs), and testing of eggs for virus presence also require further validation. There is a need to develop cell lines that permit ISAV HPR0 replication and can be used to determine if molecularly detected HPR0 represents infective virus. There is also a need for robust experimental infection of live fish with ISAV HPR0. The benefit of applying tailored surveillance strategies for HPR0 vs HPRdel should be explored. HPR0 as a risk factor for HPRdel outbreaks should be further studied and considered in regulations. Better knowledge on host and environmental factors influencing the emergence of HPRdel from HPR0 may also inform control.

• Main perceived facilitators for effective prevention and control

  • Effective molecular survelliance
  • Early detection and intervention
  • Vaccination
  • Biosecurity

Global challenges

• Antimicrobial resistance (AMR)

• Mechanism of action

  Not applicable

• Conditions that reduce need for antimicrobials

  Not applicable

• Impact of AMR on disease control

  Not applicable

• Established links with AMR in humans

  Not applicable

• Digital health

• Precision technologies available/needed

  Available

• Data availability

  GAP

  Transparency and availability can be improved.

• Data standardisation

  Available

• Climate change

• Role of disease control for climate adaptation

  GAP

  Lacking knowledge on the impact of climate change on infectious diseases.

• Effect of disease (control) on resource use

  Disease control generally optimizes animal production and reduces resource used over time.

  GAP

  Knowledge on cost-effectiveness of disease intervention.

• Preparedness

• Syndromic surveillance

  Prodecures available for HPRdel

• Diagnostic platforms

  Available for HPRdel and HPR0

  GAPS

  Cultivating HPR0

  Validation for diagnostic platforms for HPR0 and HPRdel

• Mathematical modelling

  Available

  GAP

  Gaps in knowledge of modelling parameters describing disease dynamics.

• Intervention platforms

  Interventions based on various (regulatory decide biosecurity measures (incl vaccination) and stamping out.

• Communication strategies

  Available

  GAPS

  Communications on the management of ISAV by the industry and government is in need of improvement, public perception on aquaculture and risk toward wild population Communication about the environment cost of production of salmon by comparison to other agro-food industries needs improvement.

Main critical gaps

• List of the most important research gaps

  Epidemiological and modelling studies to support the design of policies and regulatory measures (see section on "Main perceived obstacles for effective prevention and control"). Improved diagnostic tools (see section on "Main perceived obstacles for effective prevention and control"). Better knowledge about vaccine efficacy and protection: Current vaccines appear reasonably effective at reducing clinical ISA outbreaks,but are unlikely to prevent the molecular events that trigger pathogenic changes in segment 5 and segment 6. However, it is important to establish if vaccination can reduce the risk of a newly emerged HPRdel virus successfully establishing infection and triggering an ISA outbreak.Moreover, the cross-protective potential of current vaccines remains unclear, both with regards to genotype (most relevant in regions where both European and North-American genotypes co-circulate) as well as gradual antigenic changes. In the case of a vaccine failure, the time to get a new vaccine on the market would be considerable (5-10 years). Easier adaptable alternatives such as RNA-based vaccines could be explored. Better knowledge about viral genetics, pathogenesis, and evolution: More knowledge is needed on factors promoting ISAV HPR0 persistence, resurgence, and clearance in fish populations. There is a specific need to understand the transition from HPR0 to HPRdel, particularly with regards to host, environment, or management factors that influence its likelihood. Moreover, the cellular processes underlying progression from local epithelial to systemic endothelial infection, a central event in pathogenesis, are not well described. Clarification is also needed regarding virulence variation among HPRdel variants: is virulence a robust, isolate-specific trait that can be predicted from its amino acid sequence, and which genomic positions beyond segments 5 and 6 contribute? Here, it is also relevant to explore the functional roles of alternative ORFs (open reading frames), isoforms, and segment reassortment (antigenic shift), as well as the role of the viral receptor destroying enzyme. The role of quasi-species dynamics in virulence emergence and persistence is another largely unexplored subject. Better knowledge about how host and environmental factors influence ISAV transmission and susceptibility: Further information should be obtained about factors influencing viral shedding (viral and host factors), environmental stability (biofilms, water), long-distance spread, and transmission dynamics. The anatomical distribution and regulation of sialic acid receptors (e.g., 4-O-acetylated sialosides) should be explored to inform vaccine development and understand host susceptibility

Conclusion

• Conclusion summary (s)

  Effective control of ISAV requires an integrated approach combining improved biosecurity, epidemiological understanding, enhanced diagnostics, and effective vaccines. The expert group has identified the endemic presence of HPR0 as a key challenge for the control of infectious salmon anaemia, because it represents a difficult to control source, of unclear relevance, of new pathogenic HPRdel viruses. Better model systems are needed to understand the infection dynamics and persistence/maintenance of HPR0. Moreover, more information is needed about environmental, management and host factors that influence the potential of emerging HPRdel variants to cause ISA outbreaks, including the impact of vaccination. There is also a need to understand how genomic variation among HPRdel viruses, beyond the pathotypic changes in segment 5 and 6, influence vaccine efficiency, virulence, and the potential for transmission. Moreover, it is central to identify host, management, and environmental factors that direct the susceptibility to both HPR0 and HPRdel infection, as well as the emergence of new pathogenic strains.

Sources of information

• Expert group composition

  Edgar Brun, Norwegian Veterinary Institute, Norway – [Leader]

  Johanna Hol Fosse, Norwegian Veterinary Institute, Norway

  Ole Bendik Dale, Norwegian Veterinary Institute, Norway

  Torfinn Moldal, Norwegian Veterinary Institute, Norway

  Espen Rimstad, Norwegian University of Life Sciences, Norway

  Are Nylund, University of Bergen, Norway

  Marius Karlsen, Zoetis, Norway

  Debes Hammershaimb Christiansen, Faroese Food & Veterinary Authority, Faroe Islands

  Lori Gustafson, USDA, Center for Epidemiology and Animal Health, USA

  K. Larry Hammell , Atlantic Veterinary College, University of PEI, Canada

  Nellie Gagne, Fisheries and Oceans Canada, Centre for Aquatic Animal Health Research and Diagnostics (CAAHRD), Canada

  Mark Polinisk, USDA-ARS, National Coldwater Marine Aquaculture Center, USA

• Date of submission by expert group

  19 May 2025

• References

  This analysis is based on expert insights and, in some instances, supported by selected references. However, some information may reflect expert opinions, which could influence interpretations. Readers are encouraged to seek additional sources if they require specific details.

  Recommended Citation: “Brun E., Fosse JH., Dale OB., Moldal T., Rimstad E., Nylund A., Karlsen M., Christiansen DH., Gustafson L., Hammell KL., Gagne N., Polinisk M., 2025. DISCONTOOLS chapter on Infectious Salmon anaemia. https://www.discontools.eu/database/119-infectious-salmon-anaemia.html.”