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Pharmaq AS | Date: 2017-07-26

A parasiticide formulation is provided. The formulation is not toxic to fish when administered by intraperitoneal injection. The formulation is a homogeneous non-aqueous parasiticide solution. The formulation comprises: (a) a hydrophilic polymer; and/ or, (b) a non-aqueous polar solvent, present in the formulation an amount of 5-40% by weight, and a solubilizer.

Infectious pancreatic necrosis virus (IPNV) is a member of the family Birnaviridae that has been linked to high mortalities in juvenile salmonids and postsmolt stages of Atlantic salmon (Salmo salar L.) after transfer to seawater. IPN vaccines have been available for a long time but their efficacy has been variable. The reason for the varying immune response to these vaccines has not well defined and studies on the importance of using vaccine trains homologous to the virulent field strain has not been conclusive. In this study we prepared one vaccine identical to the virulent Norwegian Sp strain NVI-015 (NCBI: 379740) (T217A221T247 of VP2) and three other vaccine strains developed using the same genomic backbone altered by reverse genetics at three residues yielding variants, T217T221T247, P217A221A247, P217T221A247. These 4 strains, differing in these three positions only, were used as inactivated, oil-adjuvanted vaccines while two strains, T217A221T247 and P217T221A247, were used as live vaccines. The results show that these three residues of the VP2 capsid play a key role for immunogenicity of IPNV vaccines. The virulent strain for inactivated vaccines elicited the highest level of virus neutralization (VN) titers and ELISA antibodies. Interestingly, differences in immunogenicity were not reflected in differences in post challenge survival percentages (PCSP) for oil-adjuvanted, inactivated vaccines but clearly so for live vaccines (TAT and PTA). Further post challenge viral carrier state correlated inversely with VN titers at challenge for inactivated vaccines and prevalence of pathology in target organs inversely correlated with protection for live vaccines. Overall, our findings show that a few residues localized on the VP2-capsid are important for immunogenicity of IPNV vaccines. © 2013 Munang'andu et al.

Karlsen M.,PHARMAQ AS | Tingbo T.,PHARMAQ AS | Solbakk I.-T.,PHARMAQ AS | Furevik A.,PHARMAQ AS | Aas-Eng A.,PHARMAQ AS
Vaccine | Year: 2012

Pancreas disease (PD) in salmonid fish is caused by an infection with Salmonid alphavirus (SAV) and remains as one of the major health problems in the European fish farming industry. Sequence studies have revealed a genetic diversity among viral strains. A subtype of SAV (SAV3) is causing an epizootic in farmed salmonids in Norway. Here we evaluate efficacy and safety of an inactivated virus vaccine based on ALV405, a strain of SAV3 that was isolated from Norwegian salmon. The vaccine provided an average relative percent survival (RPS) of 98.5 in an intraperitoneal challenge model, and induced nearly total protection against PD in a cohabitant challenge model. It provided significant protection against SAV-induced mortality also in a field trial under industrial conditions. Local reactions seen as melanization and adhesions in the visceral cavity were less severe than those induced by two commercial vaccines. Finally, we demonstrated that the protection is not impaired when the ALV405 antigen is combined with other viral or bacterial antigens in a polyvalent vaccine. The results confirm that efficient and safe protection against SAV infection and development of PD is possible using an inactivated virus vaccine, both alone and as a component in a polyvalent vaccine. © 2012 Elsevier Ltd.

PLoS ONE | Year: 2012

Heart and skeletal inflammation (HSMI) of farmed Atlantic salmon (Salmo salar L.) is a disease characterized by a chronic myocarditis involving the epicardium and the compact and spongious part of the heart ventricle. Chronic myositis of the red skeletal muscle is also a typical finding of HSMI. Piscine reovirus (PRV) has been detected by real-time PCR from farmed and wild salmon with and without typical changes of HSMI and thus the causal relationship between presence of virus and the disease has not been fully determined [1]. In this study we show that the Atlantic salmon reovirus (ASRV), identical to PRV, can be passaged in GF-1 cells and experimental challenge of naïve Atlantic salmon with cell culture passaged reovirus results in cardiac and skeletal muscle pathology typical of HSMI with onset of pathology from 6 weeks, peaking by 9 weeks post challenge. ASRV replicates in heart tissue and the peak level of virus replication coincides with peak of heart lesions. We further demonstrate mRNA transcript assessment and in situ characterization that challenged fish develop a CD8+ T cell myocarditis. © 2012 Mikalsen et al.

Fredriksen B.N.,University of Tromsø | Brudeseth B.,PHARMAQ AS | Kuo T.-Y.,National Ilan University | Dalmo R.A.,University of Tromsø
Vaccine | Year: 2012

Two strains of IPNV made by reverse genetics on the Norwegian Sp strain NVI-015 (GenBank AY379740) backbone encoding the virulent (T217A221) and avirulent (P217T221) motifs were used to prepare inactivated whole virus (IWV), nanoparticle vaccines with whole virus, Escherichia coli subunit encoding truncated VP2-TA and VP2-PT, VP2-TA and VP2-PT fusion antigens with putative translocating domains of Pseudomonas aeruginosa exotoxin, and plasmid DNA encoding segment A of the TA strain. Post challenge survival percentages (PCSP) showed that IWV vaccines conferred highest protection (PCSP=42-53) while nanoparticle, sub-unit recombinant and DNA vaccines fell short of the IWV vaccines in Atlantic salmon (Salmo salar L.) postsmolts challenged with the highly virulent Sp strain NVI-015 (TA strain) of IPNV after 560 degree days post vaccination. Antibody levels induced by these vaccines did not show antigenic differences between the virulent and avirulent motifs for vaccines made with the same antigen dose and delivery system after 8 weeks post vaccination. Our findings show that fish vaccinated with less potent vaccines comprising of nanoparticle, DNA and recombinant vaccines got infected much earlier and yielded to higher infection rates than fish vaccinated with IWV vaccines that were highly potent. Ability of the virulent (T217A221) and avirulent (P217T221) motifs to limit establishment of infection showed equal protection for vaccines made of the same antigen dose and delivery systems. Prevention of tissue damage linked to viral infection was eminent in the more potent vaccines than the less protective ones. Hence, there still remains the challenge of developing highly efficacious vaccines with the ability to eliminate the post challenge carrier state in IPNV vaccinology. © 2012 Elsevier Ltd.

Niklasson L.,Gothenburg University | Sundh H.,Gothenburg University | Fridell F.,PHARMAQ AS | Taranger G.L.,Norwegian Institute of Marine Research | Sundell K.,Gothenburg University
Fish and Shellfish Immunology | Year: 2011

The gastrointestinal (GI) tract has many important biological functions. One is to serve as a barrier between the fish and the external environment. A decreased physical barrier function of the intestine may lead to increased inflow of luminal content and subsequent activation of the intestinal mucosal immune system. This activation is governed by the ability of various compounds to induce cytokine release and immune cell activity, leading to an immune response. In mammals, the impact of stress on the intestinal barrier is well documented and results in increased intestinal permeability and thus increased stimulation of the mucosal immune system. Fish reared in sea cages may at times be exposed to unfavourable environmental conditions leading to chronic stress and disturbed intestinal integrity. This change in permeability may increase the exposure of the mucosal immune system to activating compounds. In the present study, the effect of a prolonged stress on the intestinal mucosal immune system of fish is therefore addressed. Atlantic salmon were exposed to low levels (50%) of dissolved oxygen (DO) for 6-7 weeks in consecutive experiments performed at 8 and 16 °C. Immune parameters were assessed in terms of mRNA expression of the key cytokines, interleukin-1β (IL-1β), IL-8, IL-10, interferon-γ (IFNγ) and transforming growth factor-β (TGFβ) as well as the immune regulatory inhibitor of nuclear factor κB (IκB). In the experiment at 8 °C also mucosal neutrophil infiltration was monitored. Subjecting the fish to low DO levels at 8 °C resulted in an increased mucosal neutrophil infiltration together with a down-regulation of IκB. At the higher temperature, 16 °C, low DO levels created decreased expression of the pro-inflammatory cytokine IL-1β in both intestinal regions as well as an increased expression of IL-10 in the proximal intestine. These results suggest that husbandry conditions in sea cages with DO levels as low as 50% clearly affects the intestinal mucosal immune system and results in a chronic inflammation. Moreover, the effects of low DO levels on the immune factors examined were more pronounced in the 16 °C experiment suggesting additive effects of high temperatures. © 2011 Elsevier Ltd.

Agency: European Commission | Branch: FP7 | Program: CP-TP | Phase: KBBE.2012.3.2-01 | Award Amount: 9.93M | Year: 2012

SeaBioTech is a 48-month project designed and driven by SMEs to create innovative marine biodiscovery pipelines as a means to convert the potential of marine biotechnology into novel industrial products for the pharmaceutical (human and aquaculture), cosmetic, functional food and industrial chemistry sectors. SeaBioTech will reduce barriers to successful industrial exploitation of marine biodiversity for companies more accustomed to terrestrial biotechnology. SeaBioTech directly addresses five key challenges to remove bottlenecks in the marine biodiscovery pipeline, leading to (1) improvements in the quality of marine resources available for biotechnological exploitation, (2) improvement in technical aspects of the biodiscovery pipeline to shorten time to market, and (3) developing sustainable modes of supply of raw materials for industry. The two last challenges centre on enabling activities to enhance the marine biodiscovery process: first, clarification of legal aspects to facilitate access to marine resources, their sustainable use, and their secure exploitation; second, to create an improved framework for access to marine biotechnology data and research materials. To achieve its goals, SeaBioTech brings together complementary and world-leading experts, integrating biology, genomics, natural product chemistry, bioactivity testing, industrial bioprocessing, legal aspects, market analysis and knowledge exchange. The expertise assembled within the consortium reflects the industry-defined needs, from the SME partners initial definition of market and product opportunities to their ultimate proof-of-concept demonstration activities. SeaBioTech will have significant impact on research and technology, on innovation, on European competitiveness and on economic growth. It will provide a model to accelerate the development of European biotechnology into a world leading position.

Holvold L.B.,University of Tromsø | Fredriksen B.N.,PHARMAQ AS | Bogwald J.,University of Tromsø | Dalmo R.A.,University of Tromsø
Fish and Shellfish Immunology | Year: 2013

The use of poly-(. D,. L-lactic-. co-glycolic) acid (PLGA) particles as carriers for DNA delivery has received considerable attention in mammalian studies. DNA vaccination of fish has been shown to elicit durable transgene expression, but no reports exist on intramuscular administration of PLGA-encapsulated plasmid DNA (pDNA). We injected Atlantic salmon. (Salmo salar L.) intramuscularly with a plasmid vector containing a luciferase. (Photinus pyralis) reporter gene as a) naked pDNA, b) encapsulated into PLGA nano- (~320nm) (NP) or microparticles (~4μm) (MP), c) in an oil-based formulation, or with empty particles of both sizes. The ability of the different pDNA-treatments to induce transgene expression was analyzed through a 70-day experimental period. Anatomical distribution patterns and depot effects were determined by tracking isotope labeled pDNA. Muscle, head kidney and spleen from all treatment groups were analyzed for proinflammatory cytokines (TNF-α, IL-1β), antiviral genes (IFN-α, Mx) and cytotoxic T-cell markers (CD8, Eomes) at mRNA transcription levels at days 1, 2, 4 and 7. Histopathological examinations were performed on injection site samples from days 2, 7 and 30. Injection of either naked pDNA or the oil-formulation was superior to particle treatments for inducing transgene expression at early time-points. Empty particles of both sizes were able to induce proinflammatory immune responses as well as degenerative and inflammatory pathology at the injection site. Microparticles demonstrated injection site depots and an inflammatory pathology comparable to the oil-based formulation. In comparison, the distribution of NP-encapsulated pDNA resembled that of naked pDNA, although encapsulation into NPs significantly elevated the expression of antiviral genes in all tissues. Together the results indicate that while naked pDNA is most efficient for inducing transgene expression, the encapsulation of pDNA into NPs up-regulates antiviral responses that could be of benefit to DNA vaccination. © 2013 Elsevier Ltd.

Kawano F.,Nippon Suisan Kaisha Ltd. | Hirazawa N.,Nippon Suisan Kaisha Ltd. | Gravningen K.,PHARMAQ Ltd. | Berntsen J.O.,PHARMAQ AS
Aquaculture | Year: 2012

We investigated the effects of dietary Rometr{script}30 (sulfadimethoxine-ormetoprim (SDMX-OMP)) on Cryptocaryon irritans infection in red sea bream Pagrus major and tiger puffer Takifugu rubripes. In Experiment I, 100% mortality of P. major due to C. irritans infection was observed at 10. days and 21. days after exposure to theronts (infective stage) in the a control group without Rometr{script}30 and the group treated with 50. mg Rometr{script}30/kg body weight (BW)/day for 14. days, respectively. Thus, mortality in the treated group was markedly delayed compared with that in the control group. In Experiment II, 100% mortality of P. major in the control group due to C. irritans infection was recorded at 11. days after exposure to theronts. In contrast, mortality due to parasite infection was not observed in the group treated with Rometr{script}30 at 50. mg/kg BW/day for 14. days, and no parasites were found in any surviving fish after 33. days exposure. In addition, the number of parasites on the gills of T. rubripes treated with 50. mg Rometr{script}30/kg BW/day for 14. days was significantly lower than that in the control group after 16. days exposure. These results show that in-feed Rometr{script}30 at 50. mg/kg BW/day for 14. days had antiparasitic and therapeutic effects against C. irritans in both P. major and T. rubripes. Thus, dietary Rometr{script}30 could be useful for controlling C. irritans infection. © 2012 Elsevier B.V..

Fredriksen B.N.,PHARMAQ AS | Olsen R.H.,PHARMAQ AS | Furevik A.,PHARMAQ AS | Souhoka R.A.,PHARMAQ AS | And 2 more authors.
Vaccine | Year: 2013

Flavobacterium psychrophilum is a well-known pathogen causing significant problems in aquaculture worldwide. In recent years an increasing number of disease outbreaks caused by F. psychrophilum has been reported on juvenile and post smolts of rainbow trout (Oncorhynchus mykiss) in Norway. The current study was performed to assess the efficacy of two autogenous water-in-oil formulated vaccines containing whole cell antigens of F. psychrophilum to induce protective immunity against challenge. The vaccines were formulated either as multivalent (FLAVO AVM6) or divalent (FLAVO IPN) and administered by the intraperitoneal route. Intramuscular challenge with a field strain of F. psychrophilum was carried out 552 day degrees post vaccination, at a time when the FLAVO AVM6 and FLAVO IPN vaccinated groups had significantly higher antibody responses compared to the negative control. Results from the challenge study showed that the multivalent and the divalent vaccines had capacity to induce significant protection, with RPS60>87% and RPSend>77.5% for both vaccines. The high level of protection seen in the vaccinated groups was also reflected in the reduced ulceration rates observed at the injection site. Combining our results demonstrate that vaccination with FLAVO AVM6 and FLAVO IPN induces responses capable of protecting rainbow trout against infections with F. psychrophilum. © 2013 Elsevier Ltd.

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