IAHJ Spring 2020

Volume 7 Issue 1

PEER REVIEWED

Current Practices and Challenges For the Control of Sea Lice on Salmon Farms Frogs The Present of the Future Protein Source Proposals to Annex 2 Of the European Regulation 2019/6 on VMPs Plant-Based Diets for Dogs Separating Fact from Fiction

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MANAGING DIRECTOR Martin Wright PUBLISHER Mark A. Barker PUBLICATION MANAGER Hercules Went hercules@iahjmedia..com EDITORIAL MANAGER Ana De Jesus ana@pharmapubs.com RESEARCH AND CIRCULATION Virginia Toteva virginia@pharmapubs.com DESIGNER Jana Sukenikova www.fanahshapeless.com BUSINESS DEVELOPMENT Andy Plantin andy@pharmapubs.com ADMINISTRATOR Barbara Lasco FRONT COVER © istockphoto PUBLISHED BY Pharma Publications 50 D, City Business Centre London, SE16 2XB Tel: +44 0207 237 2036 Fax: +0014802475316 Email: info@pharmapubs.com www.animalhealthmedia.com International Animal Health Journal – ISSN 1758-5678 is published quarterly by PHARMAPUBS.

06 Vaccinating for Mycoplasma Bovis – The Future of Disease Control Cases of Mycoplasma bovis in the UK have soared in recent years; it’s the main cause of pneumonia in calves and is extremely difficult to treat. As Mycoplasma bovis is a bacterium which doesn’t have a cell wall, it does not respond to some common antibiotics. The most common presentation of Mycoplasma bovis is respiratory disease in calves but it can also cause a plethora of other symptoms, including mastitis, arthritis, immunosuppression and otitis. Ruth Willis at Agrihub explains why prevention is better than cure, highlighting how stringent biosecurity is a must, to counteract this multi-factorial disease in young and adult cattle.

08 The Key to Animal Welfare Walks on Two Legs One of the greatest disruptors in livestock innovation is one of the oldest tools we have – manpower.

A growing body of research reinforces that to continuously improve animal welfare, you must first focus on people. It takes an incredible team, made up of dedicated staff to care for animals, as they are complex, sentient beings that require special care and attention from highly skilled experts. Michelle Calvo-Lorenzo at Elanco explores the factors that are critical in understanding what caretakers need and want, knowing that livestock require care all year round.

REGULATORY & MARKETPLACE 10 Proposals to Annex 2 of the European Regulation 2019/6 on VMPs With the support of the EMA/ CVMP, the European Commission appears well on track with the process of drafting the delegated act (Art.146) on Annex II of the Regulation (EU) 2019/6. The scientific recommendations provided by EMA/CVMP on Annex II will require a variety of further guidance documents, which need to be adapted for the development of new and innovative products. Dr. Klaus Hellmann and Dr. Regina Wolf at Klifovet examine how the contents of Title IIa, Title III.8 and IV define new specific requirements to obtain marketing authorisations for non-immunological biological veterinary medicinal products (VMPs) and novel therapies.

RESEARCH & DEVELOPMENT

The opinions and views expressed by the authors in this Journal are not necessarily those of the Editor, Publisher or the Supporting Organisations which appear on the front cover.

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14 Why Should I Measure Serum Magnesium in Cats with Chronic Kidney Disease?

A recent publication has suggested that low and high serum magnesium are important prognostic factors in feline CKD. Plasma total magnesium concentrations are relatively stable in cats with IRIS stage 2 and 3 CKD and become elevated when renal excretory function is severely impaired in IRIS stage 4 CKD. Jonathan Elliott at RVC and Henk van den Broek at Utrecht University look at their recent study involving 174 cats with azotemic CKD, identifying hypomagnesemia (defined as serum total magnesium concentration <0.71 mmol/l) in 9%, 18% and 10% of cats with IRIS stage 2, 3, and 4 CKD, respectively.

International Animal Health Journal 1

CONTENTS 20 Frogs, The Present of the Future Protein Source Frog farming, or raniculture, encompasses activities related to frog production, including maintenance, reproduction and breeding, as well as being part of the aquaculture industry. The objectives of raniculture can be commercial, such as human feeding (frog legs), animal feeding, or non-commercial such as repopulation with threatened species. Jose Barrio and Fabián Simón at Grenoucerie investigate why an interdisciplinary approach is needed in frog farming to replace wild-caughts that damage natural populations, whilst developing captive breeding programmes to ensure species survival.

AQUACULTURE 24 Defining and Monitoring Atlantic Salmon “Health” Farming of Atlantic salmon is predominantly carried out in Norway, Chile, Scotland, and Canada. Biphasic in nature, salmon are raised in freshwater inland sites and then typically transferred to saltwater net pens.

Despite being regarded as the most industrialised aquaculture sector, bearing lower economic and biological risk than production of other aquatic species, Mark Braceland at CATC points out that Atlantic salmon culture still faces several challenges spanning engineering of culture systems to the assessment and monitoring of stock health.

26 Current Practices and Challenges for the Control of Sea Lice on Salmon Farms The salmon louse is a crustacean ectoparasite of Atlantic salmon and other marine salmonid fish.

L. salmonis is one of several parasitic copepods which cause disease in farmed fish and probably the most economically significant fish pathogen in the major salmon farming regions of the northern hemisphere, which include Norway, Faroe Islands, Scotland, Iceland and Ireland. Bill Roy at Moredun Scientific examines why sea louse epizootics are a major concern for salmon farmers due to the financial cost, impact on fish health, the risks to wild salmon and the environmental threat from sea lice medicines.

FOOD & FEED 30 Plant-based Diets for Dogs: Separating Fact from Fiction Recent advances in biology and veterinary nutrition are challenging the long-held assumption that dogs require conventional animal meat to thrive. There is increasing evidence to suggest that the nutrients domestic dogs require no longer need to come exclusively from the flesh of other animals. Alice Oven, the co-author of The Clean Pet Food Revolution: How Better Pet Food Will Change the World, and Dr. Ernie Ward at Wild Earth, delve into how modern-day pet dogs have biologically adapted to receive essential nutrients, in bioavailable form, from plant-based food.

34 Postbiotics: Unlocking Microbiome Health Benefits in Pet Food Novel pet food products have been marketed based on ingredients obtained through fermentation. In the USA, Wild Earth pet food products were originally founded on the inclusion of a fungi-based protein source. This protein source is referred to as a clean 2 International Animal Health Journal

protein source due to it being produced by fungi.

Gregory D. Sunvold at Sunvold Technology reviews how fungi-based protein sources not only have a strong sustainability message, but also have myriad probiotic-related health benefits that make fermented foods appealing for consumption.

MANUFACTURING 38 Study Offers Solution to the Battle Against Antibiotic Use The subject of antimicrobial resistance is one that everyone involved in animal health should be concerned with. With an estimated 1.1 million beef calves reared annually in the UK originating from dairy herds, reducing antibiotic use in this sector whilst maintaining calf growth and welfare is essential. Vet Alana McGlade at Dechra Veterinary Products examines how the use of a nonsteroidal anti-inflammatory (NSAID) could offer a glimmer of hope in the battle against antimicrobial resistance.

LIVESTOCK DISEASES 40 A Case Study Use Test and Removal Strategy to Contain an ASFV Outbreak in a Farm African swine fever is an infectious disease, causing high mortality of pigs, and is notifiable to the World Organization of Animal Health (OIE). The etiological agent is African swine fever virus, with a main characteristic of high mortality, and it has an incubation period varying from four to 19 days. Jiancong Yao at PIC shows how the main routes of disease transmission are through direct contact between susceptible and sick animals or their fluids or excretions, and why the identification of potential sources of the virus is extremely important, considering its phenomenal survivability.

IT AND LOGISTICS 42 Xenotransplantation of Biotech Companies to Bridge the One Health Divide Animal health is a cornerstone of public health through provision of animal products, risk of zoonotic infections and the positive impact of animals on our wellbeing.

Where synergies exist in disease and treatment modes, it would appear to make a lot of sense to develop diagnostics and therapeutics in concert. This begs the question why is it not more commonplace for biotech to develop co-incidentally in both human and animal health. Liz Barton at Companion Consultancy explores both the benefits and the barriers to a One Health approach in diagnostic and therapeutic research and development.

SPECIAL FEATURE 46 Vet Career Check – Moving from Veterinary Practice to a Commercial Role Becoming a vet is no easy task. You’ve spent 5-6 years at university, more if you’ve gone on to achieve further qualifications such as a PhD or a Masters in a chosen specialist field. Tony Noble at Noble Futures offers useful advice on why a vet might consider making such a move, how best to go about the transition and what factors a transitioning vet might need to consider.

Volume 7 Issue 1

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FOREWORD Here, in the UK, we have suffered a dismal winter. The major issue has been the impact of storms with torrential rain and inundations. Parts of the UK have experienced exceptional rainfall, resulting in catastrophic flooding and severe damage to properties and livelihoods. Suddenly, spring has arrived with sunshine and blue skies – and coronavirus 2019 (COVID-19) which has now affected many countries and has resulted in severe respiratory symptoms, deaths, financial disruption and the curtailing of some social and civil liberties. Welcome to the Spring edition of the Journal.

As is always the case, this edition carries a range of articles covering diverse topics. For me, it seems appropriate to focus on two of these, both of which concern infectious diseases, because of the situation which humans are now faced with. Neither are caused by viruses!

Mycoplasma are bacteria, but bacteria with a difference. Unlike other bacteria, they have no cell walls.

This has two major consequences. They cannot be easily identified on the basis of appearance because, lacking cell walls they are pleomorphic – the cells vary in shape and size so they cannot be classed as rods, cocci, etc. More importantly, perhaps, diseases caused by mycoplasmas cannot be treated with antimicrobial drugs which act on the cell wall. Consequently, drugs such as the β-lactams are ineffective. Mycoplasmas are pathogens of a wide variety of species including humans.

Mycoplasma bovis, as the name indicates, is a pathogen in cattle. It causes respiratory disease and is particularly associated with a chronic bronchopneumonia but it is also incriminated in arthritis, otitis, mastitis and reduced fertility as well as with other conditions. It is associated with major economic losses due to reduced milk yields and loss of carcase condition. Infections with Mycoplasma bovis can be treated with antimicrobial drugs including tetracyclines, macrolides and florfenicol, but treatment may be prolonged and expensive. Prophylactic measures are effective in preventing the spread of disease. The disease can be spread by contaminated workers and so effective biosecurity measures are essential. In addition, there are effective vaccines available. In this edition, Ruth Willis at Agrihub discusses the measures necessary to counter this disease.

Farming of Atlantic salmon and other salmonids is a remarkable success story. In addition to providing a source of high-quality protein, aquaculture is also a major economic activity frequently providing employment in areas where jobs are scarce. Salmon farming is not without its difficulties. For example, many aquaculture endeavours are carried out in locations that appear idyllic in summer conditions but are anything but idyllic in the winter. Like other farmed animals, salmon and other farmed species are susceptible to disease, including infectious disease. Sea lice are ectoparasites of Atlantic salmon and other farmed salmonids. In the northern hemisphere, the copepod Lepeophtheirus salmonis is a major pathogen of salmonids, aided and abetted by Caligus elongatus. Sea lice cause major animal welfare issues to affected fish, which may sustain major tissue damage and subsequent secondary infection. As a direct consequence of infection, there may be substantial economic losses. There are a number of chemotherapeutants available to control sea lice, including organophosphorus compounds, hydrogen peroxide, emamectin benzoate, and the acyl ureas. I have been lucky enough to have been involved, and continue to be involved, in the development of several of these substances. They can be very effective in controlling lice numbers but they are not without problems. These can involve the development of resistance in lice as well as their potential for adverse environmental effects.

Before veterinary medicinal products can be authorised or approved, they must meet rigorous standards for safety (including environmental safety), efficacy and quality but, from time to time, questions are raised over environmental issues. In this edition, Bill Roy at Moredun Scientific addresses the financial and fish health aspects of sea lice infections, and the possible consequences of the use of chemotherapeutants.

I can certainly commend these articles for your attention but I also recommend that, whatever your interests or profession, you read the other excellent contributions in this issue. Many of us may end up selfisolating or maintaining appropriate social distancing in the coming weeks. This is a good opportunity to read this edition of the Journal. When you’ve finished that, why not look again at past editions? Please stay safe and keep well.

Kevin Woodword, Managing Director, KNW Animal Health Consulting

EDITORIAL ADVISORY BOARD Germán W. Graff Research Reference Laboratory Specialist, IDEXX BioResearch Fereshteh Barei - Health Economist & Strategy Advisor, Founder of BioNowin Santé Avenue Association Carel du Marchie Sarvaas Executive Director Health For Animals Kimberly H. Chappell - Senior Research Scientist & Companion Animal Product Development Elanco Animal Health Dr. Sam Al-Murrani - Chief Executive Officer Babylon Bioconsulting & Managing Director at Bimini LLC Sven Buckingham - Buckingham QA Consultancy Ltd. Dan Peizer - Director Animal Health at Catalent Pharma Solutions Dawn Howard - Chief Executive of the National Office of Animal Health (NOAH) Jean Szkotnicki - President of the Canadian Animal Health Institute (CAHI) Dr Kevin Woodward - Managing Director KNW Animal Health Consulting Norbert Mencke - VP Global Communications & Public Affairs Bayer Animal Health GmbH 4 International Animal Health Journal

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Vaccinating for Mycoplasma Bovis – The Future of Disease Control Cases of Mycoplasma bovis in the UK have soared in recent years; it’s the main cause of pneumonia in calves and is extremely difficult to treat. Prevention is therefore the best option – stringent biosecurity is a must – but now a new multi-strain import vaccine could offer another tool in the armoury.

The disease affects both young and adult cattle, and does not respond to some common antibiotics, says Graeme Fowlie, director of Meadows Vets. “Mycoplasma bovis is a bacterium which doesn’t have a cell wall, which makes it extremely difficult to treat, as many antibiotics work by attacking the cell wall.”

The most common presentation of Mycoplasma bovis is respiratory disease in calves, but it can also cause a plethora of other symptoms, including mastitis, arthritis, immunosuppression and otitis, leading to increased antibiotic use and hampering herd performance, explains Mr Fowlie. “UK Veterinary Investigation Diagnosis Analysis data shows a sharp rise in Mycoplasma bovis diagnoses since 2013 – it is a serious problem, which needs addressing.”

He believes that the industry should treat the disease like bovine viral diarrhoea; adopting a nationwide strategy to identify the prevalence of the disease and adopting best practice to prevent it. “You shouldn’t be living with BVD on your farm and it’s the same with Mycoplasma bovis – it needs to be the next target for eradication.”

Given that the disease cannot be treated by many common antibiotics, prevention is much better than cure – and with a multi-factorial disease like Mycoplasma bovis, it’s important to adopt a multi-pronged approach to tackle it.

One consideration is when buying in stock – farmers should check that animals are coming from a farm without a history of clinical problems and buy from as few sources as possible, says Mr Fowlie. An additional option could be an antibody test to check if stock are carriers before bringing them onto the unit.

On farm, focusing on good building design and husbandry will help to limit the risk of any disease – therefore producers should ensure good ventilation in housing and minimise stresses at challenging times like weaning.

It is also important to be aware of the clinical presentation of the disease and to follow up if there is no response to control methods.

“Control is difficult and involves individual or group treatments, and isolation of clinical cases,” says Mr Fowlie.

“As a vet it’s frustrating not being able to prevent the most common cause of pneumonia, despite utilising extensive vaccines for other diseases. I’m also keen to promote best practice in trying to reduce antibiotic dependence.”

Unlike many other diseases, there is no licensed vaccine for Mycoplasma bovis in the UK; autogenous vaccines are an 6 International Animal Health Journal

option but can be slow and expensive to produce. However, Mr Fowlie has recently assisted the VMD in securing a license to import, via Kernfarm, a multi-strain bacterin-based vaccine from the US, which can now be prescribed in the UK under the Cascade system. “I’m delighted to be working to introduce what might be the missing link to pneumonia prevention. The vaccine has been used across the UK this winter, with very positive comments from vets who are reordering stocks.”

He has also set up the UK’s first on-farm study to ascertain the effectiveness of the vaccine. This features four dairy farms, varying from 170 to 400 cows, which have tested positive for Mycoplasma bovis. Cows and in-calf heifers are vaccinated at drying off or at least four weeks pre-calving, and calves born into the trial will receive a booster at 60 days old in line with the standard vaccine licence.

Calf performance will be recorded before and after the use of the vaccine to assess its efficacy, with assessments made on changes in liveweight gain, mortality, antibiotic usage and farmer opinions.

“My belief is that Mycoplasma bovis is too complicated a disease for a young calf’s immune system to control by vaccinating at 7-10 days old,” says Mr Fowlie. “Some calves are also born with the disease, which is why I’m looking at vaccinating the cows so they can pass on the immunity through their colostrum. I expect to see an impact from weaning onwards, when calves are most susceptible to the disease.”

In US trials, arthritis cases fell by 45%, with the severity of arthritis falling from 72.7% of animals with three or more affected joints in the control group to just 15% in the vaccinated group. As a result, lameness more than halved in the 13 days post-challenge. The trials showed a net saving of $2,500/100 head (£1,975/100 head).

“Mycoplasma bovis is often well advanced by the time it is picked up, so prevention is definitely better than cure, and will help to reduce antibiotic use on farm,” says Mr Fowlie. “But as the disease is endemic in the UK dairy and beef herds, it can be hard to avoid it unless you run a strictly closed herd. I’m extremely hopeful that this new vaccine will be the answer that I and lots of other vets and farmers are looking for.”

Ruth Willis Coming from a sheep farm in Cornwall with a degree in Rural Business Management Ruth Willis joined the Agri-Hub team in May 2018. She regularly contributes to a wide range of publications and was runner up in the John Deere / BGAJ training award in 2018.

Email: ruth@agri-hub.co.uk

Volume 7 Issue 1

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Tradition meets innovation in the true tales of these farmers dedicated to a legacy they’ll leave to the next generation.

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International Animal Health Journal 7

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The Key to Animal Welfare walks on Two Legs

One of the greatest disruptors in livestock innovation is one of the oldest tools we have – manpower. A growing body of research reinforces that to continuously improve animal welfare, you must first focus on people.

As a Chief Animal Welfare Officer, I spend my days (and nights) thinking, studying, observing and talking about animal behaviour and their overall wellbeing.

Farmers and ranchers do the same thing – they worry about the weather during winter calving, they make sure that the conditions are perfect inside their chicken barns, and spend countless hours working with nutrition and veterinary experts to ensure their animals have a high quality of life. The more I work with livestock caretakers, the more I realise that there is a great opportunity to enhance animal welfare (and sustainable farming) when producers are able to focus on the “people welfare” aspect of farming.

It takes an incredible team, made up of dedicated staff, to run any type of organisation. Caring for animals is no different. The team works countless hours to ensure everything works right, and while innovation has certainly helped to make the work on a ranch more efficient, manual labour is still required. Why? Farm animals are complex, sentient beings that require special care and attention from highly-skilled experts to meet both the physiological and mental needs (and wants) of animals.

Technology alone cannot do this and producers have spent time, arguably all of their time, attending to and thinking about their animals. While scientists and veterinarians have done a tremendous job over the years in creating numerous tools and metrics to help livestock caretakers know what their animals need and want, the unintentional consequences of focusing solely on our animals has resulted in a lack of understanding the needs and wants of the caretakers. This has resulted in high employee turnover rates in farming and ranching, making it one of the most critical issues in livestock production today.

Factors that are critical in understanding what caretakers need and want includes knowing that livestock require care year-round despite seasonal extremes, there are safety risks involved in caring for large animals (like cattle), there may be barriers of language and/or literacy levels that impact workers, and sometimes life off the farm may have significant impacts on workers when they are on the farm (i.e. limited access to healthcare, disruptive home environment, documented/undocumented status, etc.).

The reality of working on a farm or ranch is that most jobs around livestock care involve working outdoors in all weather conditions, 365 days a year. Moreover, handling cattle and other livestock always involves the risk of being hurt physically by an animal that is frightened or startled, as well as the risk of being hurt due to the misuse of equipment or equipment that is poorly maintained.

8 International Animal Health Journal

Stephanie Berkeley from the Farm Safety Foundation adds: “In fact, many livestock accidents are not directly related to the animals themselves, but caused by improper use of equipment – or poorly maintained or poorly built facilities.”1 Safe equipment is more of an investment than an expensive luxury, said Berkely.

Ensuring that workers feel safe, confident in their job responsibilities, comfortable with their animals, and acknowledged for their hard work requires an active leadership style from farm/ranch managers and owners that focuses both on its animals and people. This active leadership approach can begin with effective training and frequent check-ins/feedback to inform workers not just how to improve the ‘how’ and ‘what’ of their work performance and human-animal interactions, but also the ‘why’. Increased engagement (with objective metrics) that is focused on setting each worker up for success can help set a positive workplace culture, which is known to enhance worker motivation, morale and performance.

While high farm employee turnover rates are a serious threat to farming, they are also a golden opportunity for all producers to look at their operations through a different perspective. From ergonomics to trainings that incorporate cultural differences, the importance of having a happy and engaged team is just as invaluable as having animals that are stress-free and healthy.

We can’t produce meat, milk and eggs without the qualified and highly-skilled people needed to appropriately and ethically care for animals. On average, it is reported that 22% of staff turnover occurs within the first 45 days of starting a job2. With statistics like this, it’s imperative that the livestock industry invest in their workforce as they do their animals.

And it doesn’t have to be “big”. From helping to bridge the gap between leadership and staff, to trainings that account for cultural and language differences, these seemingly small initiatives are game-changers to the producers and the people that work for them. For instance, when farm employees are explained to as to why best management practices work (not just the ‘how’ and ‘what’ relative to job responsibilities), they become more engaged and motivated team members; and this is especially true for new hires.

Employees have told me they feel valued and appreciated when managers provide incentives beyond salary, like appreciation meals, bonuses, breakrooms, comfortable work environments, opportunities to contribute to their community, or even a simple six-pack of soda as a ‘thank you’ after a hot summer’s day of work. Moreover, when employees are presented with opportunities to grow as a professional on the farm, I’ve witnessed many workers seize those opportunities with pride and loyalty.

Research shows that a stable and highly-motivated workforce is strongly associated with improved outcomes – like higher retention rates – across all industries.

Improvements are also seen in productivity, job satisfaction, Volume 7 Issue 1

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employee engagement, and contentment of workers.

When it comes to animal welfare, all these improved outcomes are critical, because when workers feel safe, supported, empowered, and confident, the human-animal interactions that occur all day on a farm are also positive and profound.

No matter what industry you are a part of, it’s always about the people. For those of us who work in an industry that is centred on its animals, we have to remember that it’s not just about our four-legged friends; the bigger picture must include our two-legged teammates too.

REFERENCES 1.

2.

https://www.agriland.ie/farming-news/farmers-challengedto-improve-livestock-handling-systems/ https://www.prnewswire.com/news-releases/bersin-bydeloitte-research-strategic-onboarding-can-help-newhires-get-off-on-the-right-foot-and-provide-an-on-rampto-long-term-employee-success-746324006.html

Dr. Michelle Calvo-Lorenzo Dr. Michelle Calvo-Lorenzo is the Chief Animal Welfare Officer for Elanco Animal Health and joined Elanco in 2015 as an expert in livestock welfare.

In her current role, Michelle leads discussions and develops strategies related to animal welfare, with a focus on the areas of research, communication, guidance, and innovative services to the livestock industry, practicing Veterinarians, public, and Elanco’s customers and employees.

Michelle graduated with a Master’s degree and Ph.D. from the University of California, Davis in 2008 and 2012, respectively. Prior to joining Elanco, she was an Assistant Professor at Oklahoma State University and developed a research and teaching program centered on livestock behavior and welfare. Working within the industry and academia over the past decade, Michelle is proud to work alongside hard-working producers, packers, industry representatives, academics, and veterinarians every day.

She strives to have a positive impact on livestock welfare and enhance its role in sustainable agriculture.

Email: mcalvo-lorenzo@elanco.com

www.animalhealthmedia.com

International Animal Health Journal 9

REGULATORY & MARKETPLACE

Proposals to Annex 2 of the European Regulation 2019/6 on VMPs With the support of the EMA/CVMP, the European Commission appears well on track with the process of drafting the delegated act (Art. 146) on Annex II of the Regulation (EU) 2019/61. It appears that Annex II is well progressed and may be finalised earlier than the deadline set for 28 Jan. 2022. The scientific recommendations provided by EMA/CVMP on Annex II2 will require a variety of further guidance documents, which need to be adapted or created; however, the current version of the proposal allows flexibility and room for maneouvre for both regulators and industry to adapt to new approaches for the development of new and innovative products. While the structure of the Annex II, Title I, Title IIb and Title III.1 to III.7 are more or less identical to the previous Directive 2009/9, the contents of Title IIa, Title III.8 and IV define new specific requirements to obtain marketing authorisations for non-immunological biological veterinary medicinal products (VMPs), novel therapies and provide more detail on particular veterinary medicinal products.

Introduction The status of the “Scientific recommendations on the revision of Annex II to Regulation EU 2019/6” issued by EMA/ CVMP on 18 July 20192 has been circulated to the council members without much change (internal communication of author) by the European Commission (EC). As a draft was not published by the EC at the time this article was written, the authors used the cited document2 as the basis for this article. The basic structure of Annex II is displayed in Table 1.

As indicated by CVMP in their initial consideration and rationale to modify the previous Annex 1 of Directive 2001/82 in the form of Annex II of the new regulation, the guidance regarding the technical requirements on the quality, safety and efficacy of VMPs worked sufficiently well in practice before. It did and does assure a sufficient level of detail to ensure legal certainty and harmonisation, but it is considered necessary to adjust in order to respond to identified discrepancies in the international scientific progress or latest developments including guidance from VICH, WHO and OECD. There is a mandate to avoid major changes2.

The marketing authorisations in Europe will be granted based on Article 8, or 18 to 25 for any VMP where a dossier is submitted on or later than 28 January 2022. Such a dossier has to follow Volume 6B, all other applicable parts of the Notice to Applicants3, and the requirements for electronic format (VNeeS) when submitting documents as published by the agency and making such documents legally binding.

Also binding in the generation of data for a product’s marketing authorisation application are the current state of veterinary medicinal knowledge, the scientific guidelines related to quality, safety and efficacy of VMPs as published

by CVMP, the monographs of the Eur.Ph., GMP, OECD-GLP, and VICH-GCP standards, the application of animal welfare based on Directive 2010/63/EC in all studies submitted, and where applicable, Directive 2001/18/EC in case of release of VMPs containing genetically modified organisms (GMOs).

The EMA-CVMP proposal makes reference to Art. 343, 10 International Animal Health Journal

allowing an applicant to apply for a status of “not subject to veterinary prescription” together with the MAA dossier. Such an application should follow the legal requirements outlined in Art 34 (3 a-g) of the Regulation, including a critical review of the safety profile aimed to justify the suitability of such classification2.

Overview While Title I remains primarily unchanged (minor updates to the technical requirements to VMPs other than biological VMPs), the major structural difference is in Title II, now covering all kinds of biological products. Title IIb represents an update to the technical requirements to immunological VMPs very similar to Title II of Directive 2009/9/EC. Title IIa defines for the first time the technical requirements for biologial VMPs not exerting an immunological action, covering a product category that has experienced increasing attention in veterinary medicine over the past years.

The specific marketing authorisation applications (MAA) in Title III underwent a set of changes: the paragraphs on similar biological VMPs and mixed MAA categories were deleted while the well-established use may be covered by ‘applications based on bibliographic data’ or covered by other applications. As shown in Table 2, specific requirements for hybrid applications, limited markets and novel therapies were defined.

In Title IV, the specific chapter on homeopathic VMPs has been deleted while the requirements on immunological VMPs has been extended. More detailed requirements are proposed to be added to both in the form of the vaccine antigen master file as well as the multi-strain-dossier and the concept of a vaccine platform technology. All of these are valuable changes and tools for applicants seeking marketing authorisations for new innovative technologies.

The structure of the dossier, independent of the product category, remains unchanged with Parts 1, 2, 3 and 4 reflecting the summary of the dossier (administrative part), the physicochemical, biological and microbiological information (quality), safety and residue tests (safety) and pre-clinical and clinical trial(s) (efficacy). Critical expert reports are further required on all parts of the dossier, while the detailed description of the pharmacovigilance system (DDPS) will be replaced by a pharmacovigilance master file, that needs to be defined in a separate implementing act based on Art. 776.

Title IIa: Requirements for Biological VMPs other than Immunologicals This new part of the Annex II is specifically dedicated to biological VMPs without immunological action. It follows the well-known principles, structure and headers as already known from Title I and II of Directive 2009/9/EC. Beyond all the criteria applicable for any VMP, specific attention is required based on the characteristics of the biotechnological or biological substance, its microbiological characteristics, potential impurities and contaminations, and the source and definition of the starting materials, during the manufacturing process to the final product.

The qualitative and quantitative composition must be well defined and biological activity per unit should be indicated.

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REGULATORY & MARKETPLACE minimum safety and efficacy data. The MUMS guideline on safety is currently under review and stakeholders are asked for their comments in early 2020.

Applications for Novel Therapies

Method descriptions and validation of release tests, including potency tests, are obligatory; validated biological assays may be used when physicochemical methods are not sufficient. Sterility, batch-to-batch consistency and stability have to be proven. Safety and efficacy testing follow the principles as established for pharmaceutical products.

Title III.1–7 As indicated in Table 2, specific marketing authorisations are defined for three new kinds of applications: hybrid applications, applications intended for limited markets and for novel therapies. At the same time, the so-called biosimilars are not mentioned any more and no mention of mixed applications has survived. Most of these will fall under other categories of applications (e.g. generics, hybrids, informed consent) as the well-established use (e.g. bibliographic data). Hybrid applications have increased during the last decade and it appears logical that these are mentioned in the Annex now.

For applications for limited markets, Article 23 of the regulation 2019/6 clearly stipulates that, in the “absence of comprehensive safety and/or efficacy data the applicant can demonstrate that the product is intended for use in a limited market and that the benefit of availability of the new product outweighs the risk associated with the omission of some of the safety or efficacy data required by this annex”, an MA shall be granted. The Annex makes reference to the current MUMS guidelines, but the definition of the regulation appears to go beyond the current MUMS requirements for

Comparison of Product Categories www.animalhealthmedia.com

Title III.8: Requirements for Novel Therapies For all those interested in new innovative products, the most exciting part of the future Annex II appears to be the part on novel therapies including those therapies still nascent, thus unknown. In order to allow for a high level of flexibility, the approach described mainly focuses on a risk evaluation of such new technology and therapy, while best managing and controlling such risks to be able to conclude on a positive benefit:risk balance, the basis for the granting of a marketing authorisation in Europe. A thorough risk profiling methodology must be applied to identify all inherent risks and contributing factors and to be able to control them efficiently. In many cases, advice from the competent authorities will be highly recommendable to run an efficient product development programme. Table 3 lists the different types of novel therapies currently defined and provides a hint to the potential major additional areas of focus that should be applied. Depending on the nature of the product (biological, non-biological, immunological, non-immunological), another part of the Annex II (Title I, Title IIa or Title IIb) will have to be followed, allowing for some flexibility, if justified. While there are five types of novel therapies mentioned (Table 3), only one product has been registered in Europe until the end of 2019 falling within the scope of these categories; it is the first stem cell-based product Arti-Cell® Forte, GST, Belgium4. It will be interesting to observe if the goal of the EC fostering innovation will be confirmed by new technologies reaching the market with the implementation of Annex II. It is anticipated that further guidance will be appreciated by applicants to de-risk the development process of their innovative technologies and products as VMPs. Title IV: Requirements for MAAs for Particular VMPs While the proposal provides a clearer definition and more detailed advice on the requirements of vaccines where a vaccine antigen master file may be applicable, it also provides further confirmation on the evaluation and certification of such a master file. As any certificate issued shall apply throughout the European Union, this supports the harmonised approach and values the effort.

The multi-strain dossier has been opened to all inactivated vaccines against antigenically variable viruses, where a rapid and frequent change in the composition of the vaccine formulation is needed to ensure efficacy with regard to the epidemiological situation in the territory of use. Each multistrain dossier is applicable only to one virus species. It clearly mentions that, based on the epidemiological situation where the vaccine is intended to be used, a number of strains could be selected from those included in the dossier to formulate a final product. It will be interesting if this approach will also be applicable for other technologies, e.g. phage therapy.

The new chapter on vaccine platform technology first of all gives a definition: Vaccine platform technology is a collection of technologies that have in common the use of a ‘backbone’ carrier or vector that is modified with a different antigen or set of antigens for each vaccine derived from the platform. This includes, but may not be limited to, protein-based International Animal Health Journal 11

REGULATORY & MARKETPLACE when submitting MAA after 28 January 2022. While the regulation stresses the importance of benefit:risk evaluation when granting MA, Annex II puts even more focus on a detailed benefit:risk evaluation of all aspects of new products; especially for novel therapies, a risk profiling methodology to identify all risks inherent to a specific product and the risk factors contributing to those risks are fundamental to a successful MAA. This will be the basis and may allow future new innovative technologies to obtain market access in Europe, even in the absence of specific mention in the current Annex II.

Comparison of Specific MAs

platforms (virus-like particles), DNA vaccine platforms, mRNA-based platforms, replicons (self-replicating RNA) and viral and bacterial vector vaccines. Such applications are eligible for reduced data requirements, after a full dossier has been provided for the first product based on the technology. A 'platform technology master file' comprising all data relative to the platform, for which there is reasonable scientific certainty that it will remain unchanged regardless of the antigen(s)/gene(s) of interest, may be submitted with the first full dossier based on the platform technology. A positive evaluation shall result in a certificate of compliance to the European legislation for the platform technology master file, which shall apply throughout the Union.

Does Annex 2 meet the objective? Not surprisingly, there are topics appreciated and others criticised. While in principle, innovation is supported by a couple of measures in the Regulation, the administrative burden certainly has rather increased. Reasons for this are provided by the industry, Animal Health Europe, and EGGVP who provided their view on the proposal5 which is recommended to those interested.

Conclusion In summary, the advice given by EMA/CVMP in the form of the scientific recommendation on the revision of Annex II meets the vast majority of expectations of interested stakeholders and it appears likely that the European Commission, after consultation with the Council, will use most of the proposals for the final version. It will be more than welcome if Annex II will be finalised well in time to allow applicants to follow it

REFERENCES 1.

2.

3.

4.

5.

Regulation (EU) 2019/6 of the European Parliament and of the council of 11 December 2018 on veterinary medicinal products and repealing Directive 2001/82/EC Advice implementing measures under Article 146(2) of Regulation (EU) 2019/6 on veterinary medicinal products – Scientific recommendation on the revision of Annex II to Regulation (EU) 2019/6 on veterinary medicinal products, 29 August 2019, EMA/CVMP/351417/2019 The rules governing medicinal products in the European Union, Volume 6 B, Notice to applicants, Veterinary medicinal products, Presentation and Contents of the Dossier Arti-Cell Forte, Summary of opinion: https://www.ema. europa.eu/en/documents/smop-initial/cvmp-summarypositive-opinion-arti-cell-forte_en.pdf Comments by stakeholders on the “Scientific recommendation on the revision of Annex II to Regulation (EU) 2019/6 on veterinary medicinal products”, https:// ec.europa.eu/food/animals/health/veterinary-medicinesand-medicated-feed/imp-regs-2019_en

Dr. Klaus Hellmann Dr. Klaus Hellmann is a veterinarian with nearly 30 years of experience in the animal health industry. Prior to founding Klifovet in 1997 as a CRO and regulatory consultant, he worked in practice, science and industry. As a board-certified veterinary pharmacologist, Dipl.ECVPT, and Auditor (EOQ), he is the CEO of KLIFOVET, consulting various clients on the best approaches to successfully develop new animal health products.

Email: klaus.hellmann@klifovet.com

Dr. Regina Wolf Dr. Regina Wolf is a veterinarian with over 16 years of experience in the pharmaceutical industry. She was the CRA for human clinical trials and manager for veterinary trials for EU development. Before she joined Klifovet AG as Head of Product Development, she served as an Assessor for Immunologicals at the Veterinary Medicines Directorate, UK. She is now heading the regulatory affairs unit at Klifovet AG. Email: regina.wolf@klifovet.com

12 International Animal Health Journal

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International Animal Health Journal 13

RESEARCH AND DEVELOPMENT

Why Should I Measure Serum Magnesium in Cats with Chronic Kidney Disease?

Magnesium is an important mineral for various physiologic processes, such as ATP generation and bone formation, and an inhibitor of soft tissue calcification1,2.

It is primarily stored in bone and muscle tissue, and only 1% of the total body magnesium stores is located in serum, in which it can be found in three fractions: ionised, proteinbound, and complexed with anions1,3,4. A recent publication has suggested that low and high serum magnesium are important prognostic factors in feline CKD. Magnesium and CKD IRIS Stage Plasma total magnesium concentrations are relatively stable in cats with IRIS stage 2 and 3 CKD, and becomes elevated when renal excretory function is severely impaired in IRIS stage 4 CKD5,6. In our recent study involving 174 cats with azotemic CKD, we identified hypomagnesemia (defined as serum total magnesium concentration <0.71 mmol/l) in 9%, 18% and 10% of cats with IRIS stage 2, 3, and 4 CKD, respectively6.

Hypermagnesemia was only identified in 3% of cats with IRIS stage 2 CKD and 6% of cats with IRIS stage 3 CKD, but in 50% of cats with IRIS stage 4 CKD. Information on ionised magnesium was unavailable6.

Magnesium as a Predictor of the Severity of Bone and Mineral Disturbances in CKD In human haemodialysis patients, an inverse relationship between serum magnesium and FGF23 concentrations has been observed7. FGF23 is a novel phosphaturic hormone which has been shown in cats to increase with IRIS stage8, predict the onset of azotemia in healthy adult cats9 and predict progression and survival in cats with established azotemic CKD10. FGF23 is accepted as being the earliest indicator of bone and mineral disturbances (previously called secondary renal hyperparathyroidism) associated with CKD. There is no commercially available assay for FGF23 at the present time for veterinary patients. However, we have found plasma total magnesium concentrations to be inversely associated with plasma FGF23 concentrations in each CKD IRIS stage6 suggesting that the lower the magnesium concentration is within IRIS CKD stages 2 and 3, the greater the chance that the cat has severe bone and mineral disturbances and the more focus there should be on restricting phosphate intake in that individual cat.

Rodent studies suggest that dietary magnesium intake influences plasma FGF23 concentrations11.

Dietary magnesium supplementation could potentially be an additional management strategy to lower plasma FGF23, just as dietary phosphate restriction is efficient in reducing plasma FGF23 concentrations12. We are not in a position to comment on the effectiveness of dietary magnesium supplementation in the cat at this stage as studies have not been done – hence we recommend strict control of phosphate in these patients where we know this reduces FGF23 and improves outcome for the cat12,13.

Magnesium as a Prognostic Indicator Various observational studies have identified hypomagne14 International Animal Health Journal

semia (based on serum total magnesium) as a risk factor for death in human patients with dialysis-dependent CKD and non-dialysis-dependent CKD14–17. Moreover, higher serum magnesium appears to attenuate the mortality risk associated with hyperphosphatemia in human CKD patients18. In cats, hypomagnesemia at diagnosis of azotemic CKD was also significantly associated with an increased risk of death, independent of age, packed cell volume, plasma FGF23, and severity of CKD and proteinuria6. Furthermore, low serum magnesium was associated with reduced survival and increased risk of progression in the unadjusted analysis. Thus cats with low magnesium need closer attention and more focus on control of phosphate. Our results also suggested that higher plasma magnesium attenuates the risk of death associated with hyperphosphatemia in cats, as it does in humans, but this observation needs further investigation.

However, hypermagnesemia was also associated with an increased risk of death, but not after correction for CKD IRIS stage (50% of the cats in IRIS Stage 4 were hypermagnesemic).

Therefore, this association was likely due to the increased prevalence of hypermagnesemia in cats with end-stage CKD6.

Measuring Magnesium – is it Necessary to Measure Ionised Magnesium?

Total magnesium can be measured by most laboratories in patient serum or heparinised plasma samples, but EDTA plasma needs to be avoided as it will lead to an erroneously low result19. Ionised magnesium is biologically active and therefore might better reflect magnesium status than total magnesium20,4. However, there is no consensus whether total or ionised magnesium best reflects body magnesium status and the current knowledge derived from the studies on humans and cats presented above is based on measurement of total magnesium. We derived a reference interval for plasma total magnesium from 120 apparently healthy senior cats of 1.73–2.57 mg/dL or 0.71–1.06 mmol/L6.

Bone Disease and Soft Tissue Calcification – Why do Magnesium and Phosphate Interact?

The clinical focus in veterinary medicine has mainly been on the biochemical abnormalities associated with CKD in cats and dogs. Less attention has been paid to bone disease (i.e. renal osteodystrophy) and soft tissue calcification, which do occur in cats and dogs with CKD – albeit in the more advanced stages of disease.

Osteitis fibrosa cystica and bone resorption most likely occur as a result of high bone turnover caused by secondary renal hyperparathyroidism and have been reported in early radiographic and necropsy studies in cats with CKD21,22.

In dogs, osteodystrophy affecting the maxillofacial and mandible bones, and ultimately “rubber jaw” is observed23.

Two recent studies using micro-CT compared the bone structure of cats and dogs with CKD to that of healthy controls.

Bones of cats with IRIS Stage 3 and 4 CKD had decreased mineral density and an increased cortical porosity24. A similar study on dogs found relatively mild changes in bone quality in animals with CKD, which is probably due to the shorter duration of disease in dogs compared to that of cats and humans25.

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International Animal Health Journal 15

RESEARCH AND DEVELOPMENT

Vascular calcification, by the deposition of calcium phosphate salts in the medial layer of the vessel wall, is an important predictor of patient mortality due to cardiovascular disease in human CKD patients26,27.

Increases in serum phosphate and calcium stimulate calcification of vessel walls, which leads to increased vascular stiffness, elevated pulse pressure and left ventricular hypertrophy26,28,29. In cats, radiographic evidence exists for soft tissue calcification of the thoracic and abdominal aorta, as well as of other soft tissues such as the gastric wall, kidneys and interdigital space22,30–33. Chronic kidney disease leads to an imbalance of serum promotors (e.g. phosphate, calcium) and inhibitors (e.g. magnesium, fetuin-A) of calcification, and the effects of these imbalances on the propensity of individual patient’s serum to calcify can be measured by an assay, the T50 test34. Increased serum calcification propensity has been associated with increased risk of death and mineral imbalances in humans with CKD35,36. Recently, we presented data showing that more severe CKD-MBD appears associated with an increased tendency of individual cat’s serum to calcifya. Whether vascular calcification is of clinical significance and what its relationship is to systemic arterial hypertension in dogs and cats with CKD is unknown.

Summary In conclusion, the importance of restricting dietary phosphate intake in the CKD patient has been recognised for many years and is a key component of the management of CKD in veterinary and human medicine. Recent advances in understanding the role of FGF23 – a Klotho axis in the pathophysiology of bone and mineral disorders associated with chronic kidney disease and recognition of the way in which serum magnesium impacts on this hormonal system and influences the propensity for vascular calcification are important. Routine measurement of magnesium could identify those veterinary patients that will benefit most from intensive management, through dietary phosphate restriction, 16 International Animal Health Journal

of these bone mineral disturbances. In the future, magnesium supplementation may be possible to recommend as an additional treatment for feline CKD. REFERENCES 1.

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Jahnen-Dechent W, Ketteler M. Magnesium basics. Clinical Kidney Journal 2012;5:i3–i14.

Louvet L, Buchel J, Steppan S et al. Magnesium prevents phosphate-induced calcification in human aortic vascular smooth muscle cells. Nephrology Dialysis Transplantation 2013;28:869–878.

Elin RJ. Assessment of magnesium status for diagnosis and therapy. Magnesium Research 2010; 23:S194-8.

Humphrey S, Kirby R, Rudloff E. Magnesium physiology and clinical therapy in veterinary critical care. Journal of Veterinary Emergency and Critical Care 2015;25: 210-225.

Barber PJ, Elliott J. Feline chronic renal failure: calcium homeostasisin 80 cases diagnosed between 1992 and 1995.

Journal of Small Animal Practice 1998;39:108–116.

Van den Broek DHN, Chang Y-M, Elliott J, Jepson RE. Prognostic importance of plasma total magnesium in a cohort of cats with azotemic chronic kidney disease. Journal of Veterinary Internal Medicine 2018;32:1359-1371.

Iguchi A, Watanabe Y, Iino N et al. Serum magnesium concentration is inversely associated with fibroblast growth factor 23 in haemodialysis patients. Nephrology 2014;19:667–671.

Geddes RF, Finch NC, Elliott J et al. Fibroblast growth factor 23 in feline chronic kidney disease. Journal of Veterinary Internal Medicine 2013;27:234-241.

Finch NC, Geddes RF, Syme HM et al. Fibroblast growth factor 23 (FGF23) concentrations in cats with early nonazotemic chronic kidney disease (CKD) and in healthy geriatric cats.

Journal of Veterinary Internal Medicine 2013;27:227-233. xGeddes R, Elliott J, Syme H. Relationship between plasma fibroblast growth factor-23 concentration and survival time in cats with chronic kidney disease. Journal of Veterinary Internal Medicine 2015;29:1494-1501.

Matsuzaki H, Kajita Y, Miwa M. Magnesium deficiency increases serum fibroblast growth factor-23 levels in rats.

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RESEARCH AND DEVELOPMENT

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Geddes R, Elliott J, Syme H. The effect of feeding a renal diet on plasma fibroblast growth factor 23 concentrations in cats with stable azotemic chronic kidney disease. Journal of Veterinary Internal Medicine 2013;27:1354-1361.

Elliott J, Rawlings JM, Markwell PJ et al. Survival of cats with naturally occurring chronic renal failure: effect of dietary management. The Journal of Small Animal Practice 2000;41:235-242.

Ishimura E, Okuno S, Yamakawa T, Inaba M, Nishizawa Y. Serum magnesium concentration is a significant predictor of mortality in maintenance hemodialysis patients. Magnesium Research 2007;20:237– 244.

Kanbay M, Yilmaz MI, Apetrii M et al. Relationship between serum magnesium levels and cardiovascular events in chronic kidney disease patients. American Journal of Nephrology 2012;36:228–237.

Van Laecke S, Nagler EV, Verbeke F et al. Hypomagnesemia and the risk of death and GFR decline in chronic kidney disease. American Journal of Medicine 2013;126:825–831.

Sakaguchi Y, Fujii N, Shoji T et al. Hypomagnesemia is a significant predictor of cardiovascular and noncardiovascular mortality in patients undergoing hemodialysis. Kidney International 2014a;85:174–181.

Sakaguchi Y, Fujii N, Shoji T et al. Magnesium modifies the cardio-vascular mortality risk associated with hyperphosphatemia in patients undergoing hemodialysis: a cohort study. PLoS One. 2014;9:e116273 Sharrat CL, Gilbert CJ, Cornes MC et al. EDTA sample contamination is common and often undetected, putting patients at unnecessary risk of harm. International Journal of Clinical Practice 2009;63:1259-1262.

Bateman S. Disorders of magnesium: magnesium deficit and excess. In: DiBartola SP, ed. Fluid, electrolyte, and acidbase disorders in small animal practice. St. Louis, MI: Elsevier Saunders; 2012:212–229.

Lucke VM. Renal disease in the domestic cat. The Journal of Pathology and Bacteriology 1968;95:67-91.

DiBartola SP, Rutgers HC, Zack PM et al. Clinicopathologic findings associated with chronic renal disease in cats: 74 cases (1973-1984). Journal of the American Veterinary Medical Association 1987;190:11961202.

Davis EM. Oral manifestations of chronic kidney disease and renal secondary hyperparathyroidism: a comparative review. Journal of Veterinary Dentistry 2015;32:87–98 Shipov A, Segev G, Meltzer H et al. The effect of naturally occurring chronic kidney disease on the micro-structural and mechanical properties of bone. PloS One 2014;9:e110057.

Shipov A, Shahar R, Sugar N, Segev G. The Influence of Chronic Kidney Disease on the Structural and Mechanical Properties of Canine Bone. Journal of Veterinary Internal Medicine 2018;32:280-287.

London GM, Guérin AP, Marchais SJ et al. Arterial media calcification in end-stage renal disease: impact on allcause and cardiovascular mortality. Nephrology Dialysis Transplantation 2003;18:1731-1740.

Górriz JL, Molina P, Cerverón MJ et al. Vascular Calcification in Patients with Nondialysis CKD over 3 Years. Clinical Journal of the American Society of Nephrology 2015.

Lomashvili K, Garg P, O’Neill WC. Chemical and hormonal determinants of vascular calcification in vitro. Kidney International 2006;69:1464-1470.

Shanahan CM, Crouthamel MH, Kapustin A et al. Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. Circulation Research 2011;109:697-711.

Jackson HA, Barber PJ. Resolution of metastatic calcification in the paws of a cat with successful dietary management of renal hyperparathyroidism. The Journal of Small Animal Practice 1998;39:495-497.

Bertazzolo W, Toscani L, Calcaterra S et al. Clinicopathological findings in five cats with paw calcification. Journal of Feline

18 International Animal Health Journal

Medicine and Surgery 2003;5:11-17.

32. Chakrabarti S, Syme HM, Elliott J. Clinicopathological variables predicting progression of azotemia in cats with chronic kidney disease. Journal of Veterinary Internal Medicine 2012;26:275–281.

33. McLeland SM, Lunn KF, Duncan CG et al. Relationship among serum creatinine, serum gastrin, calcium-phosphorus product, and uremic gastropathy in cats with chronic kidney disease. Journal of Veterinary Internal Medicine 2014;28:827837.

34. Pasch A, Farese S, Graber S et al. Nanoparticle-based test measures overall propensity for calcification in serum.

Journal of the American Society of Nephrology 2012;23:17441752.

35. Smith ER, Ford ML, Tomlinson LA et al. Serum calcification propensity predicts all-cause mortality in predialysis CKD. Journal of the American Society of Nephrology 2014;25:339348.

36. Bielesz B, Reiter T, Marculescu R et al. Calcification Propensity of Serum is Independent of Excretory Renal Function. Scientific Reports 2017;7:17941. a.

Van den Broek, D.H.N., Chang, Y.M., Elliott, J., and Jepson, R.E. (2018) Serum calcification propensity in cats with chronic kidney disease. Abstract presented at ACVIM Forum 2018, Seattle, USA

Henk van den Broek Henk van den Broek received his DVM from Utrecht University in 2013. In 2018 he completed a PhD on Mineral and bone disorder in feline chronic kidney disease at the Royal Veterinary College, University of London. He currently works in the division of Veterinary Diagnostic Imaging at Utrecht University.

Email: hvandenbroek@rvc.ac.uk

Jonathan Elliott Jonathan Elliott graduated from University of Cambridge Veterinary School in 1985. After a year as an Intern in Small Animal Medicine and Surgery at the University of Pennsylvania, he undertook a PhD in vascular pharmacology in the Department of Pharmacology, Cambridge. In 1990 he was appointed to a lectureship in Veterinary Pharmacology at the Royal Veterinary College and developed research interests in feline kidney disease and hypertension, canine mitral valve disease and equine laminitis. He was awarded the Pfizer Academic Award in 1998, and the BSAVA Amoroso Award in 2001, the Petplan Scientific Award in 2005, the ESVNU Award in 2007 and the BSAVA Woodrow Award in 2019 for contributions to companion animal medicine.

Jonathan is a Diplomate of the European College of Pharmacology and Toxicology and a past member of the UK Government’s Veterinary Products Committee.

He is President of the European College of Veterinary Pharmacology and Toxicology (2018–2021). He is currently a Professor in Veterinary Clinical Pharmacology and Vice Principal for Research and Innovation at the RVC. Email: jelliott@rvc.ac.uk

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International Animal Health Journal 19

RESEARCH AND DEVELOPMENT

Frogs, the Present of the Future Protein Source

Frogs, alongside the rest of amphibians, are facing extinction. A series of interacting agents like climate change, freshwater pollution, illegal trade, and emerging diseases are pushing species into the abyss. As they don&#39;t tolerate high temperatures global warming is having a great impact on them and even mountain amphians are being affected. Aditionally, fertilizers used on farming activities increase water nitrate concentrations making them toxic for aquatic species as frogs. Illegal trade has an important role too. Lots of amphibians are taken from the wild to become a terrarium pet or a tasty dish, or even a traditional medicine. The pet amphibian trade is responsible for the worldwide spread of at least two deadly amphibian pathogens: Batrachochytrium dendrobatidis, which infects frogs and toads and Batrachochytrium salamandrivorans, affecting newts and salamanders. Wild freshwater fishes which act as carriers are related to Ranavirus spread, another emergent disease of amphibians.

Frogs are really complex creatures. Their life cycle includes 46 larval development stages (Gosner stages) and they go trough gradual changes on anatomy and phisiology involving, among others, the respiratory and digestive system. This makes them difficult to care for and their farming a true adventure.

Frogs are invaluable environmental sentinels, due to the permeability of their skin, as they act as the “canary in the coalmine” being among the first species affected by contamination in a certain place.

An interdisciplinary approach is needed to develop captive breeding programmes to ensure species survival.

Frog farming has a major role in replacing wild-caughts that damage natural populations and poses a risk for food safety.

Compared to the farming of other species, frog farming is a young sector with less than a century of development. There is a need for a deep knowledge of frog`s biology to unlock the secrets of frog farming.

Frog farming, or raniculture, encompasses activities related to frog production (maintenance, reproduction, breeding, fattening...) and is part of the aquaculture industry. The objectives of raniculture can be commercial, such as human feeding (frog legs), animal feeding, by-products (skin...), substances for the pharmaceutical industry, individuals for research, or non-commercial, like repopulation with threatened species.

Nearly 99% of total frog legs consumed worldwide are from furtively fished animals, with frog farming representing less than 0.5% of total aquaculture. The American Bullfrog (Lithobates catesbeianus) is the “prince” of raniculture, by far the most cultured species in Asia and South America. It is big, voracious and highly adaptable, but those virtues for farming also make it fearsome. It is considered an invasive alien species in many countries and banned in the European Union.

So there is a need to develop the farming of native species with lower environmental impact. There are many species suitable 20 International Animal Health Journal

for frog farming, such as the genus Pelophylax in Europe and North Africa and Leptodactylus latrans in South America.

According to FAO, there are some criteria that a species needs to meet to be suitable for aquaculture including high growth rate, climate tolerance, ability to reproduce in captivity and acceptance of artificial food.

The demand for frog legs is related to traditional cuisine with an estimated demand in Europe of over five thousand tons per year (mainly in France and to a lesser extent in countries like Belgium, Spain, and Italy). In the United States, the second-biggest consumer of these delicacies, the demand surpasses the two thousand tons per year, mostly in Southern states. There are mature markets based on traditional specialities (cuts and preparations) where consumption is no longer growing due to a shortage of supply. There is a new market in Asia, especially in China, which is rapidly increasing its consumption with huge commercial potential. Frogs are steadily jumping into the kitchens of the most important chefs around the world.

Indonesia and, on a smaller scale, Turkey and Vietnam, are the main exporters of frog legs. As previously stated, the vast majority are from the wild, which poses a threat to food safety and species survival. Efforts should be made to develop frog farming in these countries before depleting natural resources. While not considered lovely animals, their extinction will lead to plagues of insects like malariacarrying mosquitos in tropical regions.

Even if they are an unfamiliar food source for the majority of the population, frog legs have a wide range of health and nutritional benefits. Among other benefits, frog legs are a great source of protein (around 16%) with all the essential amino acids and hypoallergenic properties, less than 1% fat (with omega-3 fatty acids) and high digestibility. Frog legs are also an important source of calcium, phosphorus, selenium, potassium and vitamins of groups A and B. It is also an ideal meat in the fight against hypertension due to its low sodium content. Ready-to-eat meals are a path to be explored in the journey to publicise this healthy product.

Facilities dedicated to the commercial production of frogs are known as frog farms. Depending on the number of animals per square metre and the degree of technification, we can distinguish the following production systems: extensive, semi-intensive and intensive. It is mainly semiintensive farming with some geographical differences according to climate conditions. Raniculture is a challenge in terms of management due to the complexity of the biological cycle of frogs. This sector is scarcely technified, relying on hand labour (for tasks such as feeding, corpse removal, and frog catching) and based on ponds or outdoor pools such as the “ranario” system (Brazil, Asia) or indoors in greenhouses such as the “amphifarm” system (France, Turkey). There have even been a few attempts for intensification, with poor results on health management.

In this scenario of global population growth and climate change, the search for new protein sources is one of the biggest challenges for humanity. In contrast with other farmed species, frog farming demands little in terms of Volume 7 Issue 1

RESEARCH AND DEVELOPMENT impact on their programmes. Furthermore, there is a huge need for labour for daily operations of frog farms such as feeding, size classification (to avoid cannibalism), pond cleaning and corpse removal. The identification of death individuals is a time-consuming task on heavily-stocked raniculture ponds, with individuals tending to stay close to each other.

Zootecnic indexes on bullfrog farming show up a mortality rate of 30–40% for the whole production and an estimated feed conversion ratio between 2:1 and 2.5:1. These values must be improved through investigation on topics such as health and feeding.

water and housing space, and thus is a good alternative for rural areas and developing countries.

The main costs of operation are represented by labour and feed. The economic viability is based on getting cheaper food sources and performing more efficient task management to increase production with the same workforce. Before achieving the intensification of frog farming, labour cost and other management problems must be resolved.

The main challenge for frog farmers is the fact that frogs only eat food that is moving. Artificial feeding techniques involve selecting the appropriate pellet size based on the smallest organism in the population, and administering food to the pond so that all frogs can eat and have access at the same time. They generally refuse to eat dead or at least nonmoving food. This implies insect farming or training frogs to eat feed pellets by inducing their movement or mixing with live insect larvae.

The recent ban on bullfrog farming in Argentina due to the risk of ranavirus spread to wild populations illustrates the hazard of emerging diseases. Frog farm veterinarians have to deal with both the great variety of pathogens and the fact that little is known about amphibian pathology. Additionally, specific drugs are also out of the picture. Correct quarantine measures are the best available tool against amphibian diseases. Some of the most important diseases are the following:

Small-scale fly farms are present in nearly all frog farms for adult frog feeding, while tadpoles feed readily on common aquaculture fry feeds or vegetable by-products. It must be stated that frogs, like amphibians, have two different lives: one as a “fishlike” herbivorous tadpole and the other as a ground-dwelling insectivorous adult. Frogs go through two stages of fasting, the first one while the newly-hatched tadpole is reabsorbing the vitelium and the other one when the metamorphosised froglet reabsorbs the tail. There is a need to investigate a frog`s nutritional demands throughout its different stages to improve zootechnical indexes and thereupon business profitability. As insectivore frogs’ diets will naturally be 30% to 60% protein and between 10% to 30% fats on a fresh weight basis, future specialised feeds must be based on agro-industrial by-products and industrialscale farmed insects to achieve so-called environmental sustainability.

•

The lack of skilled labour is another deterrence for the development of this sector. While there are a lot of courses worldwide about aquaculture, frog culture has little or no

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•

•

•

Chytridiomycosis: the so-called amphibian deadly fungus (Batrachochytrium dendrobatidis) has been involved in mass extinctions of frogs since the 1990s.

Tadpoles act as carriers as they only have keratin (the targeted tissue) in their mouthparts. It mainly affects newly metamorphosed frogs disturbing skin respiration and water uptake with a fatal outcome. New frogs must be sampled for the disease and quarantine measures must be taken to protect the whole farm. Itraconazole has proven effective on chytrid fungus treatment but more trials should be done. Due to its intolerance to hot temperatures, frog farms sited in the tropics are less likely to suffer this disease.

Ranavirus: this emerging disease of amphibians affects anurans in any stage of their life cycle. There are no external pathognomonic signs to state that ranavirus is present and therefore necropsy is advised. Quarantine and disease testing are the only effective measures against this virus. Massive deaths in the wild amphibians group are a clue to determine the presence of this virus in the area.

Red-leg disease: it appears as hyperemia of the ventral skin of legs and abdomen caused by a systemic infection of gram-negative bacterias. It can be treated through antibiotic baths but to avoid antibiotic resistance, previous antibiogram and sensitivity tests are advised.

Lung nematodes: they are one of the most common pathogens affecting captive frogs. Rhabdias bufonis causes loss of appetite and decreased growth rates triggering death if not treated. Captivity stress could lead to nematode infestations that must be prevented through antihelmintic treatments.

Saprolegniasis: this is a pathogenic water mould of amphibian eggs. It appears as a superficial cotton-like growth that can affect already weakened egg clutches.

A quarantine area and a small lab are necessary to isolate diseased frogs and newcomers and perform routine procedures such as necropsies, treatment preparations and water checks. www.animalhealthmedia.com

International Animal Health Journal 21

RESEARCH AND DEVELOPMENT

Frogs, like other aquatic animals, depend entirely on water. In the tadpole stage, water parameters like pH, ammonia, temperature and oxygen concentration must be monitored frequently because incorrect values could be lethal. When adults, frogs must have access to water and high relative humidity with at least a daily water change to remove faeces and food debris. Common aquarium water tests should be enough to measure basic water quality parameters, but a spectrophotometer would be advisable when working with a high number of water samples.

Beyond human feeding, there are other reasons to farm frogs such as biotechnology or conservation. The so-called dart frogs (family Dendrobatidae) are a group of new world frogs characterised by producing deadly toxins. These toxins are also raw materials for promising drugs against cancer and other human diseases.

Other amphibians like toads and salamanders have their own toxins with a similar pharmaceutical interest.

For reintroduction purposes, extreme precautions must be taken to avoid the introduction of diseased individuals.

Poorly managed conservation efforts could have a terrible outcome. Pet food is another sector where frog meat could occupy a relevant place due to its nutritional value.

Frog farming is still an incipient and underdeveloped branch of aquaculture. The future development relies on the technification of farms, labour training and a deeper knowledge of amphibian diseases. There is a long walk ahead of professionals involved in frog farming.

Jose Barrio Jose Barrio is a Frog Farming technician at GrenouCerie and an Aquaculture Specialist Veterinarian. Jose is also a former public aquarium quarantine and lab manager and dart frog breeder.

Email: frogtor@gmx.com

Fabián Simón Fabián Simón is the CEO at FEROD and the founder of Grenoucerie.

Fabián Simón is also an Agricultural Engineer and frog farming R&D specialist. He has a broad knowledge of frog farming and frog leg trade.

Email: fabian@ferod.es

22 International Animal Health Journal

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International Animal Health Journal 23

AQUACULTURE

Defining and Monitoring Atlantic Salmon “Health”

Farming of Atlantic salmon (Salmo salar L.) is predominantly carried out in Norway, Chile, Scotland, and Canada. Biphasic in nature, salmon are raised in freshwater inland sites and then typically transferred to saltwater net pens. Whilst production of salmonids contributes only 4.4% to global seafood supply, production of Atlantic salmon has increased by >800% since 1990. Despite being regarded as the most industrialised aquaculture sector, bearing lower risk (economic and biological) than production of other aquatic species, Atlantic salmon culture faces several challenges spanning engineering of culture systems to the assessment and monitoring of stock health.

Output Farming in an open environment, such as the sea, has several advantages and disadvantages. For instance, intrinsically, production does not require environmental maintenance, which has clear economic and environmental benefits; however, many factors including temperature cannot be controlled. Therefore, when environmental conditions are sub-optimal, significant economic and biological costs can be incurred. In extreme conditions, mortalities are observed and husbandry stress can lead to outbreaks of disease.

Furthermore, pathogen exposure through wild reservoirs and passive horizontal drift takes place between sites which are hydrodynamically linked. Unlike the production of terrestrial livestock species, the isolation of infected individuals and populations is not possible in aquaculture production systems, which can lead to high profile culls of stocks, e.g. infectious salmon anemia virus outbreaks in Scotland in 2008 and Chile in 2013. Although culls and remarkably high mortality events are atypical, and despite rapid improvements in culture of the species, full cycle mortality rates of 15–20% are often reported, which is greater than in

24 International Animal Health Journal

other intensely cultured species such as in poultry at 3–5% mortality. Losses are multifaceted and are continuously being addressed and improved within the industry. One key area for advancement is in the definition, assessment and routine monitoring of fish health.

Pathogen Screening Screening of populations for the presence of aetiological agents of infectious disease is ubiquitously utilised in salmon culture. Indeed, all producers incorporate routine pathogen screening in their individual health monitoring programmes. Furthermore, mandatory testing is also performed by governmental agencies to understand livestock status and identify any risks to wild populations.

Analytical methodologies depend on the company, management area, country, and the specific pathogen(s) of interest. However, reverse transcription polymerase chain reaction (RT-PCR) is by far the most widely utilised method for screening. This method is comparatively sensitive and quick compared to other assays, e.g. ELISA, and bacterial and viral isolation respectively. However, for many pathogens, positive detection by RT-PCR may not infer clinical outbreaks or immediate risk of such. Therefore, monitoring of pathogen profiles and inferred loads (by gene target copy number) are continuously being improved, as is the understanding of interactions when multiple pathogens are present and R1 of these diseases. Typically, fish tissues collected for pathogen detection are accrued through lethal sampling which can lead to a reluctance for proactive screening of live fish. In an effort to minimise lethal sampling, small percentages (< 0.1%) of total populations are sampled or, a screening bias introduced when only moribund and/or dead fish are sampled. When mortalities begin to rise on sites, sampling of larger numbers of animals often occurs but such practices are reactive and can leave minimal scope for successful intervention. Whilst the aquatic environment and ex vivo stability of disease agents can leave stocks vulnerable, it also

Volume 7 Issue 1

AQUACULTURE

A typical Atlantic salmon net pen production site in Eastern Canada

offers the opportunity for monitoring of the environment to understand risk in a non-invasive manner. Indeed, dramatic advances in biosensors and methods for pathogen detection in water column, waste, and biofilms have been made in the last five years. Despite this, a focus on pathogens and clinical disease – rather than health – reduces the welfare and economic benefits of any monitoring regimen.

Health The presence of pathogens does not infer clinical disease, nor does their absence infer good health. Histopathological examination of tissues remains the gold standard for defining diseases and normality. However, the destructive nature of sampling has associated issues that can limit the effectiveness of proactive stock screening as previously mentioned. Non-destructive gross examination is now utilised in all health screening regimens with health and welfare indicators used to identify stock quality and any abnormalities.

Recently, gross examination procedures have become more sophisticated and standardised, though, at best, these are semi-quantitative in nature and sensitivity is dependent on presentation of the disease. Despite this, recent advances in facial recognition and automated monitoring technology has led to interest in how gross indicators can be monitored in situ.

This is an exciting area of research, which has the potential to revolutionise the way in which we think about and monitor salmon health. Identifying abnormalities is comparatively simple to defining a normal, healthy salmon. This is true in philosophical and analytical senses. For instance, the use of clinical biochemistry, routine in animal and human health monitoring, has increased dramatically with its usefulness in identifying multiple pathological conditions, diseases, and responses to treatment/interventions. However, despite recent efforts, standardised reference intervals are not yet established for the Atlantic salmon. This is made complex given salmon’s anadromous and ectothermic nature, which means many analytes alter in abundance based on life stage and environmental conditions. Furthermore, biochemical markers have typically been transferred from other species www.animalhealthmedia.com

based on ontology, which may not always be accurate and the methodologies themselves may not be transferable. It is possible that performing assays in a manner as one would for mammalian species at 37°C is not directly transferable to a fish sampled at 5°C. Indeed, individual variability, as well as inter and intra assay CV, is greater in fish, which may be in part due to analytical methodology rather than biological variance. Despite this, blood, mucus, and tissue biopsy sampling offer the ability to assess a greater proportion of a population as the sample collection is non-destructive, and the use of these methods is anticipated to increase through time.

As biological boundaries continue to be pushed in the salmon farming industry, decreasing risks to stocks and increasing product quality are intrinsically linked to proactive health monitoring. Further development and standardisation of analytical methods offer a promising scope for growth.

Recent advancements in multiple technologies and how we think about salmon health have led to dramatic improvements in productivity. These developments, coupled with the industry’s openness to improvement, make this an exciting time in aquatic animal health.

Mark Braceland Mark Braceland joined The Center For Aquaculture Technologies, where he is the Director of Fish Health, in January 2016. Previously he obtained a PhD in Animal Health at the University of Glasgow in 2014 and was then a PostDoctoral Fellow at the University. He and his team are passionate about Fish and Shrimp Health, working with multiple warm and cold-water species and diseases.

Email: mbraceland@aquatechcenter.com

International Animal Health Journal 25

AQUACULTURE

Current Practices and Challenges for the Control of Sea Lice on Salmon Farms The salmon louse, Lepeophtheirus salmonis, is a crustacean ectoparasite of Atlantic salmon and other marine salmonid fish. L. salmonis is one of several parasitic copepods which cause disease in farmed fish and probably the most economically significant fish pathogen in the major salmon farming regions of the northern hemisphere, which include Norway, Faroe Islands, Scotland, Iceland, Ireland and east and west coast Canada. In Chile, currently the second largest producer of farmed salmon, Caligus rogercressyi, is the main sea louse species. Sea louse epizootics are a major concern for salmon farmers due to the financial cost, impact on fish health, difficulties of the technical challenge and, fairly or unfairly, the reputational fallout due to public concern over the effect of sea lice on the welfare of farmed salmon, the risks to wild salmon and the environmental threat from sea lice medicines.

The cost of sea lice to the Norwegian industry alone, which is responsible for ca. 60% of global farmed salmon production, is estimated to be approximately NOK 5.2 billion (£440m) per annum1. Costs are due to reduced harvest weight, increased mortality as a result of secondary disease, downgrading or rejection of carcasses and the costs of monitoring and control.

Wild Atlantic salmon hatch from eggs laid in freshwater streams and rivers. Fry develop rapidly in freshwater to become smolts which are physiologically able to survive in saltwater. During the seawater phase they feed and grow, typically undergoing extensive marine migrations before returning to their home river to spawn. Sea trout, likewise, spawn and hatch in freshwater and migrate to sea but tend to remain in coastal areas close to their freshwater origin.

The salmon louse is well adapted to the migratory behaviour of its host. It has a free-living larval phase which moults through microscopic nauplius and copepodid stages. The copepodid larva has an astonishing ability to locate, manoeuvre into position and attach to its fish host in an environment where its location is largely controlled by large-scale effects of tide and weather-driven water movement. It does this by exhibiting positive swimming response to light (positive phototaxis), which bring it toward the surface, and to chemical signals (semiochemicals) produced by the salmon, which draw it to the fish. The larvae attach using appendages which bear large hooks and, once firmly attached, they moult to sessile, chalimus larvae which are anchored into the skin of the fish. Once attached, the larvae are able to suppress the host defence response, enabling them to survive, feed and grow. The larvae develop through two chalimus stages to pre-adult and then adult stages which are motile and able to move across the body surface of the host, and indeed to jump from one fish to another. Adult male and female lice pair and, during mating, the female receives a spermatophore which provides a reservoir of spermatozoa to fertilise multiple batches of eggs. These fertilised eggs are extruded as egg strings, which remain attached or are shed by the female and hatch to release larvae to begin the cycle again. In ideal conditions, the cycle can be completed within around six weeks, so that 26 International Animal Health Journal

large numbers of parasites can amass within a relatively short time.

Inevitably, much of the sea louse life-cycle is concentrated in coastal lochs, fjords and estuaries. These relatively sheltered areas are the natural habitat of sea trout and provide a protective staging post for juvenile salmon on their outward journey and returning adult fish. Traditionally, these sheltered, marine locations have also been the preferred sites for seawater salmon farms and sea lice represent a potential health and welfare risk to both wild and farmed salmonids.

Most farmed salmon are produced in floating cages in which fish are retained using nets which are open to the environment. Cages typically contain tens of thousands of fish and these grow from smolt to harvest weight in around 18 months. This method of production is relatively low-cost and relies on the natural flow of water through the cage to provide oxygen and remove dissolved waste products (carbon dioxide, ammonia). Particulate waste (uneaten feed and faeces) falls to the sea bed where its impact is monitored to ensure it remains within acceptable levels.

Sea lice numbers on farms are surveyed on a regular basis, typically weekly, and this information supports management decisions to fallow, stock, treat or harvest a site. The information is made publicly available and is monitored by the responsible fish health authorities to ensure that average lice numbers remain at acceptable levels (i.e. below an average of 0.2 to 1.0 gravid female lice per fish, depending on geographical location and time of year). Collection of sea lice data is valuable but time-consuming. Traditionally, a sample of fish from each pen is captured and anaesthetised and sea lice counted by eye. This is a skilled process, since it is important to accurately recognise and record different sea lice species and life stages. Automated sea lice monitoring systems are being developed using image acquisition and analysis and machine learning to identify and count sea lice in situ2,3,4. This technology has potential to save labour and increase the counting accuracy.

The industry has invested in the development of an integrated approach to sea lice management, using a wide range of measures for prevention and control, and this strategy is backed by regulation in most salmon-farming countries5. Formal area management agreements are in place which require sharing of data between companies and coordination of stocking and treatment operations to minimise lice impacts. Sea lice data is a valuable research resource and an understanding of sea lice dynamics within farming zones, although rudimentary at present, may in time contribute to decisions on suitable farm locations and permitted capacities. The majority of farm sites are relatively well-sheltered and close to shore, but new sites are required in order to achieve production targets. New farming equipment is being developed in order to exploit more exposed marine sites and these ‘high-energy’ and offshore sites, which are more difficult to farm, are expected to be less susceptible to sea lice infestations. The impact of sea lice has also driven attempts to move more production onto land. Large onshore, tank-based farms are being developed to produce larger smolts which reach harvest weight within a shorter period Volume 7 Issue 1

AQUACULTURE and, therefore, are at less risk from sea lice infestations during the marine on-growing phase.

Fish welfare concerns relate to the effects of high-level sea lice infestations. The industry has worked with animal welfare groups to develop externally audited welfare standards which include specific standards for sea lice management5.

Practical measures to reduce infestation success take advantage of the positive phototaxis behaviour shown by sea lice larvae which results in a concentration of the infective larval stages in the top few metres of the water column. The use of fine mesh ‘lice nets’ positioned around the circumference of a cage is intended to restrict the access of sea lice larvae in surface waters into cages containing salmon. Submersible cages, in which fish are grown in deeper water away from the concentration of larvae on the surface, are in use in some locations and sea lice traps, which take advantage of positive attraction to light and semiochemical signals to attract larvae away from the host, are also available. Floating, semi-closed, containment systems, fed by deep water intakes, are also in development7.

Some progress has been achieved in selectively breeding stocks with reduced susceptibility to sea lice infestation.

Genetic markers for high susceptibility have been identified experimentally and used to identify and exclude the worst performing stock from broodstock populations8. Although the incremental benefits are modest, these gains can be expected to accrue in successive generations.

Vaccines against many of the major microbial pathogens of farmed salmon are widely and successfully used but no effective vaccines against sea lice are currently available.

Vaccines for ectoparasites are generally challenging but the potential benefits are widely recognised. Research efforts to identify suitable antigens and delivery systems are underway and some promising results have been reported9,10.

Veterinary medicines have been an important tool for the control of sea lice. Originally, in the 1970s and 80s, control was by bath immersion using the organophosphate, dichlorvos, which was subsequently withdrawn. Bath immersion treatments currently available include the second-generation organophosphate, azamethiphos, the pyrethroids, cypermethrin and deltamethrin and hydrogen peroxide and, in Chile only, hexaflumuron. Traditionally, bath immersion treatments have been administered by reducing the depth of the net and surrounding it with a tarpaulin bag to reduce water exchange. The treatment is introduced at several points and mixed thoroughly. Following exposure for the required duration, the tarpaulin is released and the medicinal product allowed to disperse. Recently, the industry has developed treatment protocols where fish are transferred from the cage into the holding tanks of ‘wellboats’ used for temporary holding and transportation of

salmon. Fish in these tanks can be exposed to a precisely controlled dosage in order to optimise efficacy and minimise safety issues and detached sea lice can be collected to minimise the risk of re-infestation. The release of bath treatments from a farm is strictly controlled by regulations which ensure that any use of these products remains within the capacity of the environment, but any release of medicinal residues into the environment is recognised as a concern to the public. New water treatment technology which is able to remove the medicinal product (and detached lice) from the treatment water prior to discharge back into the sea is expected to provide useful benefits by reducing both the environmental impact and restrictions on the use of bath immersion treatments for control of sea lice11.

In-feed medicines offer useful advantages over bath treatments including ease of administration and reduced handling and disturbance of fish. The avermectin, emamectin benzoate has been widely used as the method of choice for treatment of sea lice infestations and other in-feed treatments, including the benzoyl urea chitin synthesis inhibitors, teflubenzuron, diflubenzuron and lufenuron which are available in some regions. Some in-feed medicines show a duration of efficacy of several weeks as a result of slow depletion of the active ingredient in the tissues. The risk that medicine residues in waste feed and faeces may accumulate in sediments, causing environmental damage, has resulted in close control over the use of these products. The development of systems for control of feeding and collection of waste feed and faeces, which are primarily intended to improve feeding efficiency and reduce organic enrichment of the sediment, will also help to reduce the risk of accumulation of medicine residues in the environment.

Resistance of sea lice to many of the available medicines has been reported. The short generation time and panmictic population structure of sea lice, together with practical difficulties in ensuring the effective dose is delivered to populations of fish of varying size and feeding rates or in cages where the contained volume may vary or be difficult to estimate, may promote the development of resistance.

Methods are available for testing the susceptibility of sea lice to the available products using genetic markers and bioassay methods in order to assist fish health personnel to identify effective medicinal treatments12.

Several new medicinal products are in development, but the requirements for demonstration of efficacy and safety for the target species, consumer, operator and environment are challenging and it has been several years since a product containing a novel active ingredient was released into the European market. From 2022, Atlantic salmon will no longer be considered to be a major species under the EU veterinary medicine regulations and allowing products for farmed salmon may be authorised through the Minor Use Minor Species (MUMS) route13. Where implemented, this change will reduce the regulatory burden for marketing authorisation, but compliance with local environmental regulations will remain challenging.

The need for alternative control measures has stimulated an innovative approach to developing a range of nonmedicinal treatments. Several sea lice removal ‘devices’ have been developed which use a variety of approaches, including mechanical removal using brushes or turbulent water flow, freshwater and temperature-adjusted water, to detach lice14,15.

Live fish pumps and handling systems are used to deliver fish.

Whilst these are effective at treating large numbers of fish, the capital and operational costs are high. The development and marketing of these devices is not subject to formal regulatory

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International Animal Health Journal 27

AQUACULTURE

Photo courtesy of the Scottish Aquaculture Innovation Centre

licensing and there have been incidents where high losses have occurred following treatment. In addition, there is speculation that in some cases infectious diseases, such as flavobacteriosis and winter ulcer syndrome, may be linked to trauma and stress caused by such systems16. These devices are in commercial use, but the technology is still relatively new, and the design and operation of these systems will be refined in the light of experience.

3.

Non-medicinal methods which do not require handling of fish offer major benefits. A laser-based system to identify and target individual lice on fish swimming in cages is in development17 and systems using ultrasound are being investigated18 but these systems are not yet widely used.

7.

Biological control by cleaner-fish which cohabit with the salmon and remove sea lice is employed on an increasing number of sites. In Norway and the UK, the principal species used are lumpsucker (Cyclopterus lumpus) and ballan wrasse (Labrus bergylta). These can provide effective in situ control of sea lice, but the cleaner-fish themselves require care and attention and must be provided with hides and supplementary feed in cages. The majority of cleaner-fish are wild caught and there is concern over the impact on wild populations and that their introduction may provide a route of entry for pathogens into the farm. Farming systems for hatchery production of cleaner-fish have been developed and, although some health and welfare challenges have been identified, farm reared lumpfish and ballan wrasse are becoming available in large numbers.

10.

In summary, the farmed salmon sector is profitable and sales are buoyant. Farming companies are investing to achieve substantial increases in production (targeting 5% year-on-year growth) but sea lice remain a major challenge.

Considerable efforts are made to prevent infestations. Gains have been made by improved management practices and further benefits are likely through breeding programmes which target reduced susceptibility of stock to sea lice. New vaccine technology has the potential to lead to a major breakthrough but sea lice are an extremely challenging target.

17.

Access to safe and effective medicines is important to safeguard fish welfare, and environmental safety is likely to be a key consideration in future product development programmes.

New engineering solutions are being developed which will alleviate the environmental impact of these medicines.

REFERENCES 1.

2.

https://www.fishfarmermagazine.com/news/salmon-licecosting-norway-nok-5-billion-a-year/ https://www.aquafalcon.com/

28 International Animal Health Journal

4.

5.

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16.

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https://www.theexplorer.no/solutions/hyperspectralcamera-for-counting-sea-lice/ https://www.aquabyte.no/index.html https://www.asc-aqua.org/the-current-state-of-sealice-management/ https://science.rspca.org.uk/documents/1494935/ 9042554/RSPCA+welfare+standards+for+farmed+ Atlantic+salmon+%28PDF+2.56MB%29.pdf/60ae55ee7e92-78f9-ab71-ffb08c846caa?t=1557668417384 https://ntnuopen.ntnu.no/ntnu-xmlui/handle/11250/ 2456881 https://gsejournal.biomedcentral.com/articles/ 10.1186/s12711-016-0226-9 https://www.fishfarmingexpert.com/article/vaccinecuts-lice-loads-by-97-in-lab-tests/ https://www.moredun.org.uk/news/press-releaseresearchers-have-gut-instinct-new-feed-sea-licevaccine-0 https://www.benchmarkplc.com/news/cleantreat-bybenchmark/ Sevatdal, et al. Monitoring of the sensitivity of sea lice (Lepeophtheirus salmonis) to pyrethroids in Norway, Ireland and Scotland using bioassays and probit modelling.

Aquaculture 244, 19-27.

Hellman, K and Wolf, R. European Regulation 2019/6 on VMPs: Implications on Innovation. International Animal Health Journal, 6 (1), 22-25. 2019 https://smir.no/products/hydrolicer/?lang=en https://optimar.no/optilice.html https://www.vetinst.no/rapporter-og-publikasjoner/ rapporter/2019/fish-health-report-2018 https://www.stingray.no/delousing-with-laser/?lang= en#module-2 https://www.lgsonic.com/news/sea-lice-control-usinglgsonic-ultrasound-technology/

Bill Roy Bill Roy is the Head of Aquaculture at Moredun Scientific, responsible for the development and delivery of commercial projects on farmed fish health and welfare. He has a PhD in aquaculture from the Institute of Aquaculture, University of Stirling, and more than 30 years of experience in aquaculture R&D, leading studies to identify, evaluate and support registration of fish vaccines, veterinary medicines and feed additives.

Email: wroy@moredun-scientific.com

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International Animal Health Journal 29

FOOD & FEED

Plant-based Diets for Dogs: Separating Fact from Fiction Recent advances in biology and veterinary nutrition are challenging the long-held assumption that dogs require conventional animal meat to thrive. There is increasing evidence to suggest that the nutrients domestic dogs require no longer need to come exclusively from the flesh of other animals. This article explores how modern-day pet dogs have biologically adapted to receive essential nutrients, in bioavailable form, from plant-based food.

It discusses the evidence that plant-based diets may be healthier for dogs than animal-meat-based foods, and addresses the obstacles preventing owners from switching to plant-based feeding. Calling for further longitudinal, large-scale studies that verify the benefits of plant-based diets for dogs and more education on plant-based nutrition in the veterinary profession, it concludes with an overview of the pet food companies creating complete animal-free diets for dogs today.

Nutritional Requirements of Domestic Dogs Protein is essential for canine health, helping grow and maintain muscle, hair, and connective tissues, transporting nutrients throughout the body, synthesising hormones, and supporting the immune and neurological systems. The minimum amount of dietary protein required for canine growth is 22.5 per cent of daily food consumption (NRC) and the Association of American Feed Control Officials (AAFCO) requires dry food for adult dogs to contain at least 18 per cent protein. The food must also be proven to contain bioavailable nutrients, that can be digested and absorbed within the body.

Protein molecules are “strings” comprised of amino acids, which are broken down by the dog’s digestive system. Ten of these amino acids are classified as essential nutrients for dogs, or amino acids they must consume in their diet to live.

The 10 canine essential amino acids are: arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. A nutritionally complete dog food must contain all of these 10 amino acids in adequate levels. The canine body uses these essential amino acids to synthesise the remaining required 12 amino acids, including taurine and carnitine.

Can Dogs Get the 10 Essential Amino Acids from Plant-based Food?

High quality plant, yeast, bacterial, or algal protein sources can, and do, contain all 10 essential amino acids for dogs. It

30 International Animal Health Journal

is common in pet food marketing to portray domestic dogs as ‘miniature wolves’ that must consume their ‘natural’ meal of animal flesh. However, canine mitochondrial DNA (mtDNA: genetic material passed from mother to puppy) gives us a different understanding of canine evolution. Canine mtDNA analysis proves that dogs began to phylogenetically diverge from grey wolves between 15,000 and 40,000 years ago. The most common evolutionary theory proposes that as the boldest, friendliest wolves secured the most scraps from the caveman’s camp, these fierce animals became ‘tame’, humans benefiting from the protection offered by their canine associates. These ‘friendly and collaborative’ or ‘trainability’ traits were transferred to offspring and amplified later through selective breeding and domestication. Archaeological evidence suggests that as far back as 11,500 years ago, humans and dogs likely hunted animals collaboratively (Yeomans et al., 2019). Many thousands of years later through hundreds of generations, dogs and humans have biologically adapted to become more similar in terms of social communication, energy requirements, temperature adaptation, behaviour, and, most significantly, dietary requirements.

As domestic dogs coevolved with humans, their biology adapted in terms of both physical features and internal functionality. In 2013, researchers conducted wholegenome resequencing of dogs and wolves and identified 36 key genomic regions associated with canine domestication (Axelsson et al., 2013). Ten of the adapted dog genes were responsible for changes in starch digestion and fat metabolism: specific genetic mutations that have allowed dogs to digest and metabolise the starches in plant-based foods far more efficiently than wolves. A second paper confirmed that dogs have more copies of a gene called AMY2B than wolves. This gene is crucial for producing amylase, a primary enzyme involved in starch digestion.

In dogs, amylase activity is around 30 times higher than in wolves. Further validating the domestic dog’s biological adaptation for starch digestion is the presence of a longer version of the amylase gene that produces maltase, another key enzyme required for starch digestion (Arendt et al., 2014) and found in herbivores and omnivores. More recent research discovered that dog populations 7000 years ago in South Eastern Europe and Southwest Asia also contained duplications of the AMY2B gene (Ollivier et al., 2016), allowing dogs in the region to thrive on a plant-rich diet, especially within early farming societies. The evidence

Volume 7 Issue 1

FOOD & FEED is mounting that domestic dogs have been thriving as omnivores for thousands of years. Further nutritional distinctions between dogs and carnivores such as felids (cats) is the fact that dogs can convert plant-based betacarotene, also known as “provitamin A”, to retinol, the “pure” or biologically-active form of vitamin A. Cats cannot make this conversion and must obtain retinol either from animal sources or supplements. Dogs can also convert linoleic acid, an omega-6 fatty acid found in plant-based sources, to the essential arachidonic acid, while carnivores are unable to make this conversion.

Increasing Evidence for Healthy Plant-based Dogs In 2016, Knight and Leitsberger published an article in the journal Animals entitled “Vegetarian versus Meat-Based Diets for Companion Animals” which provided convincing evidence that dogs fed a nutritionally complete plantbased food can thrive. That article has been downloaded about 20,000 times, the second highest in the history of the journal, suggesting significant interest in the topic. In fact, a number of scientific studies now support animal meat-free

Percentages of dogs in good to excellent health, vs. time as vegetarians (PETA, 1994)

pet diets. Over 25 years ago, the organisation People for the Ethical Treatment of Animals (PETA) published the results of a systematic survey of the health of 300 vegetarian dogs sourced from 33 US states and Canada (PETA, 1994). These dogs, representing a wide range of ages and breeds, were maintained on animal meat-free diets for two to over nine years, with an average being fed plant-based food for 5.7 years. Over 80 per cent of dogs maintained on vegan or vegetarian diets for 50 to 100 per cent of their lifetimes were documented as being in “good to excellent health”.

The few health problems found were those also commonly reported within the animal-meat-eating dog population, such as obesity, skin infections, and arthritis.

This was scientifically rigorous research, providing adequate numbers of animals for the results to be reliably extrapolatable to the wider population. More recently, a 16week study of 12 sprint-racing Siberian huskies (Brown et al., 2009) evaluated the health and performance of six of the canine athletes fed a commercial meat-based diet and six on a vegetarian diet. Both diets used in the study were formulated to the exact same nutritional composition and were the dogs’ sole nutrient source for the four-month study, which included a period of intensely competitive racing. All the dogs appeared to be extremely fit and there were no adverse effects reported for the huskies fed a vegetarian diet. Despite the small number of dogs in this study, these findings suggest that plant-based canines can thrive even when undergoing intense and prolonged physiological demands.

Other anecdotal cases show pets on plant-based diets may have increased overall health and vitality; decreased incidences of cancer, infections and hypothyroidism; improved coat condition; fewer allergic conditions; lower rates of obesity; decreased arthritis; and diabetes remission. In 2009, a veterinary publication on vegetarianism in the domestic dog concluded that as long as the animal-meat-free diet is correctly formulated to meet nutrient requirements and is sufficiently palatable to ensure adequate dietary intake,

Iditarod Trail Sled Dog Race 2010 www.animalhealthmedia.com

International Animal Health Journal 31

FOOD & FEED “then it is a suitable diet for the dog, irrespective of the owner’s motivation for feeding a vegetarian diet” (Brown, 2009).

Is a High Animal Protein Diet Healthy for Domestic Dogs?

With raw meat pet diets soaring in popularity, there is a widespread belief that high-protein animal flesh is the healthiest diet for dogs. However, high-animal-meat diets are generally high-calorie diets, leading to weight gain and obesity. Feeding pet dogs high-meat meals as if they were wolves is a fallacy, given that wolves burn about 70 per cent more calories a day compared to domestic dogs.

Wild wolves may roam up to 50 miles before finding or killing a meal, yet surveys indicate that most domestic dogs are walked less than 30 minutes a day. The Association for Pet Obesity Prevention (APOP) finds that more than half of all US dogs and cats are overweight or have obesity, placing them at elevated risk for weight-related disorders including diabetes, arthritis, hypertension, kidney disease, and cancer. Bramble, a blue merle Collie in the UK, once held the Guinness World Record for being the “oldest living dog” at 27 years of age. She lived on a strict plant-based diet of rice, lentils, and organic vegetables and nutritional yeast, eating once a day and exercising regularly. In stark contrast to Bramble’s outstanding health and longevity, the American Veterinary Medical Association (AVMA) estimates over half of all dogs will develop cancer after age ten. Most scientists put the contribution of inherited genetic mutations at about five to 10 per cent of an individual’s risk of developing cancer.

The vast majority of cancers are believed to be caused by environmental contributors, including the potential longterm impact of the food our pets consume throughout their life. Dogs and cats are being exposed, over many years, to toxins not severe enough to cause acute reactions, but sufficient to cause hidden cellular damage. Veterinarians such as Knight (2020) believe many of these toxins come from factory-farmed animals and contemporary animal meat processing.

Although studies proving the long-term safety of either meat-based or plant-based diets for pets are still relatively few, those showing that vegetarian pet diets are less healthy than animal-meat pet food are even more lacking. In fact, Knight points to at least 11 academic studies showing that animals fed various animal-protein diets suffer with a variety of health conditions over time (Knight, 2020).

Diseases documented to be more likely when cats and dogs eat commercial animal-meat-based diets include those

affecting the kidneys, liver, heart, thyroid, neurological system, neuromuscular structure, and the skin, as well as leading to infectious diseases and bleeding disorders. Only one study (Bednar et al., 2000) compared the nutrient digestibility and faecal characteristics of dogs fed animal- and plant-protein sources and concluded that digestibility of the plant-based dog food was marginally lower than the animal-protein food. Yet only four dogs were included in that study, and the researchers stated that all diets were “well utilised” by the dogs in terms of digestibility and faecal characteristics.

Animal proteins are also the leading cause of food sensitivities in dogs. A recent study revealed that animalbased ingredients were responsible for 236 cases of food allergies in dogs. By contrast, plant-based ingredients were responsible for only 77 cases (Mueller et al., 2016). Eight out of ten of the top allergens in pet foods are animal products (Pitcairn and Pitcairn, 2017). Many veterinary therapeutic dermatologic or “prescription” diets are made without any animal meat to reduce their allergenicity. Plant-based diets such as Purina HA Vegetarian Canine Formula is formulated “to be less likely to cause an adverse food reaction in certain dogs”. Royal Canin advertises their Canine Vegetarian Dry Dog Food “for dogs with food sensitivities”. Some of the most effective protein sources for preventing and treating canine food allergies are plant-based, and an animal-free diet can be a remedy for other common allergies or inflammatory conditions, such as inflammatory bowel disease (IBD).

Why are Plant-based Dog Diets Still Controversial?

In the past, nutritionally complete-and-balanced plantbased pet foods have been hard to find. Vegan dog foods such as Halo, V-dog, Natural Balance, and a few other small pet food companies haven’t been available at most large pet retailers or grocery stores. Animal-free pet foods can also be expensive. Producing an affordable plant-based dog food could be a lucrative ambition for pet food companies.

However, there is an even bigger challenge: public perception.

Pet owners are bombarded with marketing messages from major pet food producers insisting that feeding a meat-based diet is best, and that they will somehow deprive their dogs by omitting animal flesh. In 2019, Dodd et al. surveyed 3673 dog owners and found that vegans were the only owners who omitted meat from their pets’ diets (plus one vegetarian).

Of the vegans surveyed, only 27 per cent (58 of 212) reported feeding their dog a plant-based diet. Yet 78 per cent of vegan pet owners indicated they would feed a meat-free diet to their pet if one were available that met their required criteria.

Indeed, 35 per cent of all survey respondents (N= 1083) who did not already feed a plant-based diet to their pet indicated interest in doing so, provided they received further evidence of nutritional sufficiency, veterinary approval, and greater availability.

Despite the growing evidence base cited here and the growing number of complete-and-balanced AAFCO- and FEDIAF-approved plant-based pet foods, more longitudinal, large-scale studies are needed to convince both the public and the veterinary industry of the long-term safety of plant-based feeding. Veterinary recommendation is a key factor in owner feeding habits, and there is currently little veterinary nutritional education on plant-based canine diets. Owners whose dogs are thriving on meat-free diets are quick to advocate the practice, but anecdotal evidence is not a substitute for rigorous academic studies.

Meat-based dog treats on sale in the UK. Photograph by David Wright, CC by 2.0 32 International Animal Health Journal

Do Dogs Like Plant-based Food?

Many dog owners worry that they will be depriving their dog by removing animal meat from their meals. It is true that until recently, most commercial plant-based dog foods focused Volume 7 Issue 1

FOOD & FEED on nutritional completeness and balance rather than flavour.

However, the perceived blandness of vegetarian pet foods is changing as new protein sources and production techniques advance, with new startups producing appealing savoury flavours from koji and yeast, as well as tasty peanut-butter or sweet potato treats. Furthermore, owners should be careful not to confuse canine concepts of edible or palatable with their own human concept of what is ‘tasty’. The images of succulent beef, juicy chicken breasts and fresh-caught salmon that line pet food aisles are designed to appeal to the tastes of pet owners, not their pets. The reality is that the kibble or wet food inside the packaging bears little resemblance to these pictures. Meat-based pet food companies typically enhance the palatability of their dry pet foods for dogs and cats by spraying them with “digest”, the entrails of chickens and other animals. Philadelphia startup Because Animals are working on an animal-free palatant as an alternative, and many new meat-free pet food companies are creating products that taste delicious to dogs without any artificial enhancement.

REFERENCES

Who Are the Plant-based Pet Food Companies to Watch?

Because Animals is a new pet food company working on creating plant-based treats. Their dental cookie for dogs is made of chickpea flour, nutritional yeast, chia seeds, and kelp: the latter ingredient is rich in iodine with high levels of other nutrient minerals and vitamins. California startup Wild Earth also have animal-free pet food on the market, their peanut butter-flavoured dog snacks combining flax, oats, and green tea with koji, an ancient mushroom superfood, which contains all 10 of the amino acids that dogs require. Their animal-free, complete and balanced dog food contains over 30 per cent protein. Meanwhile, established brands like V-dog, Benovo, Halo, Wysong, and Natural Balance plant-based pet foods are becoming more readily available. In Europe, Green Petfood and Ami Pet Food are creating vegetarian and vegan pet foods that, as Ami Pet Food puts it, pave the way for “an ethical, eco-friendly and successful economy”. In the UK, three times as many vegetarian pet foods were launched in 2014 as in the previous three years (Knight and Leitsberger, 2016).

In March 2019, 16 global leaders in plant-based veterinary nutrition and science contributed presentations to the world’s first “The Plant-Powered Dog Food Summit”, created for people interested in learning more about feeding their dog a plant-based diet. For this growing market of conscientious consumers, there is a wealth of new innovative plant-based canine pet foods out there: they just need to be convinced to try them.

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Arendt, M. et al. (2014) Amylase Activity Is Associated with AMY2B Copy Numbers in Dog: Implications for Dog Domestication, Diet and Diabetes. Animal Genetics 45(5): 716–722.

Axelsson, E. et al. (2013). The Genomic Signature of Dog Domestication Reveals Adaptation to a Starch-rich Diet. Nature 495: 360–364.

Bednar, G.E. et al. (2000). Selected Animal and Plant Protein Sources Affect Nutrient Digestibility and Fecal Characteristics of Ileally Cannulated Dogs. Archiv für Tierernaehrung 53(2): 127–140.

Brown, W.Y. (2009) Nutritional and Ethical Issues Regarding Vegetarianism in the Domestic Dog. Recent Advances in Animal Nutrition—Australia 17: 137–143.

Brown, W.Y. et al. (2009). An Experimental Meat-free Diet Maintained Haematological Characteristics in Sprint-racing Sled Dogs. British Journal of Nutrition. 102(9): 1318–1323.

Dodd, S.A.S. et al. (2019). Plant-based (Vegan) Diets for Pets: A Survey of Pet Owner Attitudes and Feeding Practices. PloS one.

Knight, A. (2020). Vegepets.info. Available at: http://www. vegepets.info [Accessed 3 January 2020].

Knight, A. and Leitsberger, M. (2016). Vegetarian versus MeatBased Diets for Companion Animals. Animals 6(9): 57.

Mueller, R.S. et al. (2016). Critically Appraised Topic on Adverse Food Reactions of Companion Animals (2): Common Food Allergen Sources in Dogs and Cats. BMC Veterinary Research, 12(9).

Ollivier, M. et al. (2016). Amy2B Copy Number Variation Reveals Starch Diet Adaptations in Ancient European Dogs. Royal Society Open Science 3(11).

People for the Ethical Treatment of Animals (PETA). (1994). Animal Companions, 1994. Available at: http://www.helpinganimals. com/h-vegcat-survey.html [Accessed 2 January 2020].

Pitcairn, R. and Pitcairn, S.H. (2017). Dr. Pitcairn’s Complete Guide to Natural Health for Dogs & Cats. New York: Rodale.

Wakefield, L.A. et al. (2006) Evaluation of Cats Fed Vegetarian Diets and Attitudes of Their Caregivers. Journal of the American Veterinary Medical Association, 229(1): 70–73.

Yeomans, L. et al. (2019). Close Companions: Early Evidence for Dogs in Northeast Jordan and the Potential Impact of New Hunting Methods. Journal of Anthropological Archaeology 53: 161–173.

Alice Oven Alice Oven is co-author of The Clean Pet Food Revolution: How Better Pet Food Will Change the World, with Ernie Ward and Ryan Bethencourt. She is a freelance animal ethics writer and Senior Editor for Veterinary and Life Science books at Taylor & Francis Publishing. Alice is researching pet owner attitudes to feeding cell-based meat as part of her MSc Animal Welfare Science, Ethics and Law at University of Winchester.

Email: aliceoven@gmail.com

Dr. Ernie Ward Dr. Ernie Ward, “America’s Pet Advocate” is an internationally recognized veterinarian, author, and speaker. He is known for his innovations in general small animal practice, nutrition and pet obesity, and advocating for the special needs of senior dogs and cats. Dr. Ward is co-founder and Chief Veterinary Officer for Wild Earth a plant-based sustainable pet food company based in Berkeley, California.

A selection of plant-based dog treats, food and supplements already on the market www.animalhealthmedia.com

Email: ernie@wildearth.com

International Animal Health Journal 33

FOOD & FEED

Postbiotics: Unlocking Microbiome Health Benefits in Pet Food Humans have consumed fermented foods (and drink) for millennia. Christ turned water into wine, a fermented drink. Cultures around the world have consumed various fermented foods such as German sauerkraut, Korean kimchi, Russian kefir, Japanese miso, Norwegian rakfisk, Indian pitha, and so forth. Almost all human cultures have in common the culturing of dairy products (e.g., cheese, yogurt, cottage cheese, etc.) that provide healthy nutrition to people around the world.

Fermented foods for human use appear to be popular due to their stability, being a good source of nutrients, safety, and palatability (Rezak et al., 2018). Fermented foods are associated not only with addressing human gastrointestinal disease, but also type II diabetes and cardiovascular disease.

In a survey of fermented foods, Rezak et al. (2018) found live bacteria levels ranging from 105 to 109 cfu per gram in these foods. Consumer awareness of fermented food benefits is growing, as a 2018 trends survey of restaurant menu items indicated a 149% increase in fermented food offerings (Resendes, 2019).

Novel and unusual pet food products have been marketed based on ingredients obtained through fermentation. In the USA, Wild Earth pet food products were originally founded on the inclusion of a fungi-based protein source (dried aspergillus oryzae fermentation product). This protein source is referred to as a “clean” protein source due to it being produced by fungi. Further, Wild Earth food products also contain yeast and are touted as “clean protein” due to not being produced from animals, with “90% fewer resources required than meatbased” foods. While this food makes a strong “sustainability” message, there are myriad probiotic-related health benefits that make fermented foods appealing for consumption.

Probiotics are generally considered to be live organisms which are typically taken as a dietary supplement or added to food. Benefits of consuming probiotics involve decreased gut pathogens, improved immune function, reduced levels of pro-carcinogens available in the intestine, suppressed tumour formation, normalised stool formation, and so forth (Dicks and Botes, 2010).

With all the interest in fermented foods and common use of probiotics by humans and associated health benefits, why haven’t more mainstream brands pet food leveraged the benefits of fermentation or probiotics in their products? The simple answer is that the main product forms, extruded and retorted (canned), are not conducive to keeping probiotics alive. These forms create harsh processing conditions and (or) packaging environments which normally don’t maintain live cultures. (An exception to this is sporeforming bacteria that can survive extrusion. However, the fact remains that the commonly used product forms, extrusion and retort, greatly limit which live organisms can be added to pet foods.)

While live organisms are the “machines” or “minimanufacturing plants” inside one’s intestines to 34 International Animal Health Journal

Attribution: "The Sponge" by Melinda Stuart is licensed under CC BY-NC-ND 2.0

produce many of the benefits of fermentation, they are not the only way that fermentation benefits can be conferred upon the pet. To understand how we can achieve probiotic benefits without the need for ongoing gut-level fermentation, we need to take a step back and understand how probiotics are positively influencing the gut environment.

Microorganisms’ Innate Defences While we often focus on the impact of pathogens, such as Salmonella, on our health or our pet’s health, microorganisms of all types (including beneficial ones) are constantly under threat. As a result, microorganisms have natural defences such as the ability to secrete anti-microbial compounds to make themselves more competitive in their environment. For example, a lactic acid bacteria, Lactococcus lactis, actively secretes hydrogen peroxide (Ito et al., 2003). As such, it has been known for many years to be effective against foodborne pathogens. More broadly, several antimicrobial compounds are produced by bacteria to aid their survival in a harsh environment. A class of compounds called lantibiotics is an example of this (Mantravadi et al., 2019). Mantravadi et al.

(2019) noted almost twenty unique compounds considered lantibiotics. These researchers also noted that since lantibiotics have several modes of action, there is no known antibiotic resistance to them, creating excitement over the power of naturally sourced anti-pathogenic compounds.

Further, other classes of antimicrobial compounds exist, indicating the power of post-fermentative derived mixtures (fermentates) to play an important role in shifting gut

Attribution: "IMG_1814" by shok is licensed under CC BY-NC-ND 2.0 Volume 7 Issue 1

FOOD & FEED microflora populations. The net result of this is that these fermentates do not necessarily need to contain live probiotic bacteria to effect gut-based changes to the host. Hence the term, postbiotics.

(live cells) stability during: 1) distribution shipping conditions and 2) shelf-life of the product. In contrast, postbiotics have the potential to play an important role in improving pet health due to their ability to be stable in these product forms.

Postbiotics Defined The term postbiotic is relatively new. As such, its definition is still evolving. With that said, postbiotics are defined as “any factor resulting from the metabolic activity of a probiotic or any released molecule capable of conferring beneficial effects to the host in a direct or indirect way” (Tsilingiri et al., 2013 as described by Malashree et al., 2019). More simply stated, postbiotics are the compounds produced during the growth of probiotics, including the probiotics themselves (see Figure 1). As discussed previously, many of these compounds are antimicrobial/anti-pathogenic. To clarify, postbiotics do not need to contain live microorganisms to be effective. And some postbiotics are specifically created by disrupting the live probiotic organisms so their cellular contents are available to enhance the efficacy of the postbiotic material.

An emerging and growing trend for alternative pet food forms exists with lightly processed pet foods. Due to their high moisture and the type of packaging used, many of these lightly processed pet foods are kept under refrigerated conditions (rather than ambient conditions). These products typically have a shorter shelf-life than extruded or retorted products (about six months). Postbiotics not only offer potential health benefits in these foods, but they also may offer ways to uniquely stabilise and thus extend shelf-life in these products.

Examples of Postbiotic Postbiotics’ efficacy lies in the compounds produced and, in addition, in the contents of the probiotic microbes’ cells. As such, postbiotics do not need to, and often don’t, contain live microorganisms. To begin with, postbiotics are not necessarily new to the pet food industry (Table 1).

However, current postbiotics in use are under-recognised for their role in animal health. Current postbiotics include by-products of the brewing industry (i.e., brewer’s yeasts), isolated fractions of yeast (e.g., mannanoligosaccharides, B-glucans), and organic acids. Additional postbiotic options include a variety of fermentates, tyndallised (i.e., heat-killed) probiotics, lysates of bacteria, and isolated fractions obtained from a fermentation process. While examples of additional postbiotic options in current pet applications do exist, there is much more potential to utilise them as well as expand the use of existing current applications of postbiotics.

Why Postbiotics are Important in Pet Foods The current primary pet food product forms commercially sold today are: 1) dry, extruded and 2) retort (canned). These products are typically stored at ambient conditions with shelf-life length up to about 18 months. Neither of these forms normally offer a conducive environment to assure probiotics

Evidence for Postbiotics’ Efficacy From a health perspective, postbiotics have been shown to be effective anti-obesity agents. Lactobacillus reuteri was isolated from dog’s saliva and heat-treated to kill the bacteria. The heat-killed L. reuteri was then administered to mice that resulted in less age-associated weight gain compared to control mice (Varian et al., 2016). More broadly, Reynes et al. (2019) reviewed several postbiotic compounds including short-chain fatty acids (SCFA) and reported their ability to increase thermogenesis and insulin sensitivity, thus explaining other benefits of postbiotic compounds on conditions related to obesity. These findings agree with dogs fed fermentable fibres (sources of SCFA) and their ability to improve insulin sensitivity through increasing GLP-1, a potent insulin secretagogue (Massimino et al., 1998).

A particular strain of probiotic which has considerable data behind it is Bifidobacterium longum 35624. Schiavi et al. (2018) recently reported that the exopolysaccharide obtained from B. longum 35624 was able to decrease the allergic responses in lung and airway tissues. Patten and Laws (2015) reviewed a number of studies involving the exopolysaccharide (EPS) from a variety of Lactobacilli strains. Authors concluded that Lactobacilli EPS had benefits related to immunomodulation, antioxidant properties, and heavy metal binding.

Preserving food products is essential to assure proper shelf-life before consumption. Seidler et al. (2019) discuss numerous compounds excreted by lactic acid bacteria (LAB) including phenyllactic acid, propionic acid, salicylic acid, diacetyl, fatty acids, cyclic dipeptides, etc. which could influence product stability. Authors cite at least four different mechanisms at work that can inactivate spoilage organisms and (or) pathogens: 1) cell wall instability/permeability, 2) proton gradient interference, 3) oxidative stress, and 4) enzyme inhibition. These compounds and mechanisms are found sometimes in all LAB or select LAB such as L. plantarum, L. reuteri, Propionibacterium freudenreichii, L. spicheri, L. buchneri, L. diolivorans, L. amylovorus, L. rhamnosus, L. brevis, L. acidophilus, etc. A literature review done by da Costa et al.

(2019) described bacteriocins produced by LAB and how they apply to use in meat products. Authors found that Lactococcus, Enterococcus, Pediococcus, and Lactobacillus were the most

Table 1. Postbiotic Examples and Usage in Pets www.animalhealthmedia.com

International Animal Health Journal 35

FOOD & FEED question, what stands in the way of broader adoption of postbiotics in the pet food industry? And further, what will be the impetus to more widespread adoption of these healthpromoting ingredients?

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prevalent LAB studied, with examples of them producing bacteriocins including nisin, enterocin, pediocin, pentocin, and sakacin.

The applications of postbiotics to enhancing health are clear, as conditions such as obesity and skin health (e.g., dermatitis) are obvious maladies in pets. The role of postbiotics in improving shelf-life is especially important in lightly processed, extruded, semi-moist treats, and virtually all non-retorted food and treat products. The potential role of postbiotics in stabilising meats is also a great opportunity given the high susceptibility of meat to degradation as well as contamination from pathogens such as Salmonella.

Sustainability Postbiotics as ingredients for pet foods are generally quite sustainable, whether sourced as a by-product of the brewing industry or newly created in a fermentation vessel. The ability of these organisms to be scaled and replenished is nearly limitless.

Conclusions Given their: 1) role in promoting health, 2) product compatibility, and 3) sustainability, one must ask the

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Exopolysaccharide from Bifidobacterium longum subsp. longum 35624™ modulates murine allergic airway responses.

Beneficial Microbes 9:761 – 773.

Siedler, S., R. Balti and A.R. Neves. 2019. Bioprotective mechanisms of lactic acid bacteria against fungal spoilage of food. Curr. Opinion Biotechnol. 56:138–146.

Varian, B.J., T. Levkovich, T. Poutahidis, Y.M. Ibrahim, A. Perrotta, E.J. Alm and S.E. Erdman. 2015. Beneficial dog bacteria upregulate oxytocin and lower risk of obesity. J. Prob. Health 4:1-9.

Gregory D. Sunvold With over 25 years of pet food industry experience, Dr. Greg Sunvold currently serves as Principal of Sunvold Technology, LLC, where he assists clients with tough technical challenges. Leveraging his deep technical knowledge of the microbiome, Dr. Sunvold is currently focusing on how to apply innovations arising from this area into the pet food industry.

Email: greg@sunvoldtechnology.com

36 International Animal Health Journal

Volume 7 Issue 1

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To find out how Orego-Stim can help your business, visit www.anpario.com/orego-stim or email orego-stim@anpario.com www.animalhealthmedia.com

International Animal Health Journal 37

MANUFACTURING

Study Offers Solution to the Battle Against Antibiotic Use The subject of antimicrobial resistance is one that everyone involved in animal health should be concerned with. With an estimated 1.1 million beef calves reared annually in the UK originating from dairy herds, reducing antibiotic use in this sector whilst maintaining calf growth and welfare is essential. Vet Alana McGlade, the Equine and Farm Animal Business Manager at Dechra Veterinary Products, examines how the use of a non-steroidal anti-inflammatory (NSAID) could offer a glimmer of hope in the battle against antimicrobial resistance.

Almost one million beef calves coming from the dairy sector are reared annually in the UK. The majority are initially reared at specialist units, typically from around four- to fiveweeks-old to four- to five-months-old. This is a high-risk period for calf pneumonia and consequently it is a time when antibiotics are used most frequently.

It is acknowledged that calf-rearing units face a number of challenges in maintaining growth rates among livestock.

Respiratory disease is common among animals brought together from a variety of sources.

Just like in humans, an outbreak can cause the animal to go off its food and water within as little as a day of developing symptoms. This can lead to a downward spiral in its health as it lacks the nutrition to combat the illness.

Additionally, routine procedures such as de-budding and castration can impact on the willingness of calves to continue feeding at consistent rates. Growth loss is almost inevitable.

Injectable analgesics can be given, but this is timeconsuming, can be costly and can itself be a stressor for the animal, which has to be caught and restrained in order to be treated.

Ongoing learning about welfare is changing approaches with regard to best practice for post-procedure pain management, while pressure is rapidly growing to limit

38 International Animal Health Journal

antibiotic use as far as possible due to concerns about growing antimicrobial resistance in both humans and animals.

There is a growing understanding around sensation and pain, and pain pathways, within all animals and increasingly this is an area of research within veterinary medicine.

Farmers have obviously always been interested in the welfare of their animals, but there is a growing awareness of how analgesics, particularly if given ahead of procedures such as castration and disbudding, can not only provide pain relief but ultimately relieve stress.

This is important because an animal in pain or under stress won't feed properly, which can directly affect the farm's bottom line. There is a welfare issue here but there's also evidence that in relieving pain a farm can maintain productivity.

Pressures to maintain efficiency and keep costs under control do not diminish in the face of these challenges, meaning calf-rearers can benefit from any advantage to be gained in productivity and potentially also from cost savings associated with lower antibiotic use.

In humans we have simple, affordable and effective solutions for straightforward analgesia. In short, we might take a widely available, low-risk painkiller or anti-inflammatory in the form of paracetamol, ibuprofen or aspirin. In all but the most serious circumstances, these can very quickly make us feel better and able to function as close to our normal state as possible – at least until their effects wear off with time.

In addition, the suppression of symptoms analgesics provide takes pressure off the immune system, enhancing the body’s natural ability to recover.

Reproducing this effect in calves can be achieved with the use of a non-steroidal anti-inflammatory drug (NSAID). This can be given to provide routine cover in a herd facing disease spread or undergoing procedures or other forms of stress.

The benefits of making the animals feel less unwell by lowering temperatures, managing pain and reducing

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inflammation can be the same as in humans. If they feel better, they keep eating and maintain normal behaviour, supporting their immune system and ability to recover without antibiotic intervention.

In 2018, Dechra published the results of a practice-based clinical research project that was carried out at three English calf-rearing units. It aimed to discover the impact that giving a routine dose of a non-steroidal anti-inflammatory, Solacyl®, which has the active ingredient sodium salicylate, would have on subsequent antibiotic use.

The 258 calves were given the analgesic in feed on the five days immediately upon their arrival at the units – a high-risk period for animals to contract bovine respiratory disease.

The results were independently analysed by a Royal College of Veterinary Surgeons recognised specialist in cattle health and production and made for fascinating reading.

They revealed that the use of prophylactic oral treatment for five days when calves first arrived on the unit resulted in an overall antibiotic reduction of 43 per cent across the three farms.

The findings also stated that the substitution of prophylactic antibiotic for prophylactic NSAID also did not compromise the health of the calves or the profitability of the calf-rearing operations overall. There were no perceptible disadvantages to calf health and welfare according to all of the calf-rearers involved in the study, and mortality rates and daily live weight gains remained similar. Although not a strictly controlled trial so results should be viewed with caution, the findings are still significant, as is the potential for reducing antibiotic use using this protocol.

Sodium salicylate has the same fever-controlling, painmanaging and inflammation-reducing benefits in livestock as aspirin can have in humans.

It can be administered to groups of animals, which means it can be given prior to known stress points in animals’ lives. This can be continued through and after those events, providing a welfare benefit and reducing the risk of a loss of appetite and its resulting effects.

A convenient solution is another plus for farmers.

They need to know that the act of giving the animals the www.animalhealthmedia.com

medication isn't going to take time and money. It can go into the herd's water, into the feed, they can treat the whole herd or if they know there's a procedure on the horizon for some of the calves, they can easily target and deliver to those animals.

NSAIDs that can be administered without the supervision of a vet are a cost-effective option for farmers and a practical solution that can lead to a notable reduction in routine antibiotic use whilst protecting the welfare of a herd.

Overall, controlling fever, pain or inflammation enhances animal welfare, and managing these symptoms to support food and fluid intake could prevent conditions from worsening, thereby removing the need for antibiotic treatment in more instances.

This has to be a major step in the battle to reduce antibiotic resistance that still supports the efficient rearing of animals more likely to consistently reach their optimum weight.

Calculations show that adopting an approach of routine administration of an NSAID like sodium salicylate could reduce overall antibiotic use nationwide by an estimated 4.4 tonnes per year, going some way to tackling this major issue.

There is undoubtedly more work to be done to establish a deeper understanding of the benefits and cost savings available, but the findings of this study were significant. It points to an effective and sensible way to tackle the issues of antimicrobial resistance, enhanced animal welfare and productivity on rearing units.

Alana McGlade Alana McGlade BVmedsci (hons) BVM BVS MRCVS is the Equine and Farm Animal Business Manger at Dechra Veterinary Products. She is a graduate of Nottingham University and a former equine vet.

Email: alana.mcglade@dechra.com

International Animal Health Journal 39

LIVESTOCK DISEASES

A Case Study: Use Test and Removal Strategy to Contain an ASFV Outbreak in a Farm African swine fever (ASF) is an infectious disease causing high mortality of pigs and is notifiable to the World Organization of Animal Health (OIE). The etiological agent is African swine fever virus (ASFV), with a main characteristic of high mortality, and it has an incubation period varying from four to 19 days.

The main routes for disease transmission are direct contact between susceptible and sick animals or their fluids or excretions, and indirect contact through contaminated feed, pork, people, vehicles, or fomites1.

Research also indicated the viral DNA and/or infective virus might be detected from blood (first detection at 3.75 ± 1.4 days post infection (dpi)), nasal and oral fluids (at 5.4 ± 1.3 dpi), and rectal swabs (4.9 ± 1.4 dpi) of the infected animals.

For within pen contact pigs, time to onset of infectiousness took two to six more days after inoculation of the seeder pig.

The viral DNA and/or infective virus might be detected from blood (first detection at 10.3 ± 1.6 dpi), nasal and oral fluids (at 8.5 ± 1.5 dpi), and rectal swabs (9.3 ± 2.9 dpi) of the pigs infected via direct contact2,3.

Fig 1. Layout of farm and inside

10 out of 11 were contracted trucks from a third party, and tested for ASFV by PCR before admission. They were then thoroughly washed, disinfected, and baked at 56°C for 70 minutes at a dedicated truck-washing facility. All truck-

Since being detected and reported in China on August 03, 2018, ASFV has spread across the country and become endemic. After that, in 2019 it was spreading to Mongolia, Vietnam, Cambodia, North Korea, Laos, South Korea, and the Philippines4.

Since there is still no vaccine or treatment available, the only approach to control the disease is biosecurity.

Identification of potential sources of the virus is extremely important considering its phenomenal survivability1.

washers and drivers were trained to observe and comply with biosecurity standards.

The disease has directly and indirectly caused many farms to close in China, increased costs of pig production, driven up the prices of live hogs and pork in China to a historical high, and has largely disrupted the supply chain. The impacts of this disease are enormous, and it continues to challenge the veterinarians, as well as the pig production industry in terms of heightened risks.

At day 13 DPA (13 days post arrival), one pig was found dead in pen 4 (Fig 2), and a couple of pigs were seen showing signs of reduced appetite and less feed intake. They were all from one truckload of 70 pigs. The nasal swabs, faecal swabs, and inguinal lymph node samples were collected from this dead pig, then the pig was sent to be incinerated in a biosecure way.

To prevent the introduction of ASFV and to contain the outbreaks when being introduced have been the central focus of veterinarians and production managers nowadays.

At 14 DPA, the nasal swabs were collected from each pig in pens 3, 4 and 5; oral fluids were collected from each pen every day in the whole facility; samples from personnel, supplies and equipment, and environmental samples were infrequently sampled and sent to a company-owned lab for ASFV PCR testing, and results were available within 24 to 48 hours. After 21 days, the oral fluids from each pen were collected every three days for ASFV testing. Throughout the whole quarantine process, a total of 1840 samples were tested for presence of ASFV nucleic acids to monitor the presence of virus.

This paper distills the test removal strategy and how it succeeded in containing the ASF outbreak in one control case in China in the situations as described.

Materials and Methods Following an upgrade in biosecurity infrastructure, the farm under discussion was used as a temporary isolation facility for incoming gilts. It has five barns and each barn has 12 pens of 60m2 /pen (housing 40–45 pigs), with a total capacity for 2800 finisher pigs, and serves as a quarantine for a large sow production compound 300km away.

The Transport of Gilts and ASFV Detection The transport of 1400 gilts to this facility by 11 trucks started on Sep 8th and was completed on Sep 20th.

40 International Animal Health Journal

Fig 2. The transport trucks and the inside barn layout

Removal and Decontamination Strategy On 14 DPA, the ASFV positive pigs were humanely euthanised (electrocution), packed in impermeable plastic bags, and moved out of the farm to be incinerated, with the hallway sealed with impermeable plastics. In the evening of 14 DPA, the left half of the barn (pens 1–6) was evacuated, with the hallway being sealed with plastics and the door sealed to protect the right half of the barn. After completing the Volume 7 Issue 1

LIVESTOCK DISEASES evacuation, the left side and hallway was covered with caustic soda, and the whole part was fumigated with formaldehyde.

Workers for each barn stayed inside the barn to perform the duties. Internal and external biosecurity was strictly reviewed and implemented to prevent further contamination from the infected area.

part) which are separated by a hallway and doors. In each pen, there is a concrete wall as a solid separation. These infrastructures effectively worked as biosecurity barriers to prevent or reduce the transmission if one or two pigs were found sick and infected in a pen.

It is critical to avoid missing positive pigs by a robust surveillance plan, and prevent contamination and spread of the virus from the infected and contaminated area by fomites. So thorough cleaning and disinfection, together with measures to prevent leakage of any fomites and proper removal of fomites, are pivotal to protect other pigs in the facility.

It is probably more difficult for a barn or facility with steel bars as pen separation to succeed, as it allows more opportunity for infected pigs to contact with uninfected ones.

So likely more pens will have to evacuated from the barn to protect remainder pigs.

Fig 3. The use of plastic canvas to create segregation to remove the pigs from the barn

Results On 14 DPA, six nasal swab samples from pen 4 (4 positives (3+)), 3 (1+) and 5 (1+) in barn 1 were tested ASFV positive by PCR. There were no further positives detected after 14 DPA. The remainder of the gilts stayed in the facility for further quarantine and after about 55 days, they were moved into the sow herds. The evacuation of 250 pigs in six pens in the left side of barn 1 represented 17.86% loss of the total population in the facility.

Fig 4. Barn of ASFV detection, and disease progression and removal map

The team performed a thorough investigation for the source of the virus. Key risk factors such as people, supplies and equipment entry, feed, medicines, etc. were all examined. It is pinpointed that the transport posed the most likely source of introduction, and the one truck was the most likely source of the virus. The contamination of the truck can happen either on the roads, at the rest stations, or it can happen because of the drivers having contacts with fomites and then contaminating the trucks.

With this in consideration, improvements were recommended and it was decided that future shipments must strictly follow the biosecurity protocol, and that drivers need to be further trained to observe the protocol and know what the right practices and behaviours are to avoid contamination.

Acknowledgement PIC colleagues Qing Yang, Congmin Liu, Tian Xia, Marisa Rotolo, Dan Tucker, and New Hope Liuhe veterinarian Dr Zhigang Liang have coauthored this paper. Dr Dan Tucker is also a professor at University of Cambridge. The author is grateful to PIC consultant Dr Rodney Baker for his comments, and Dr Fuhao Fan for he has pioneered the test and removal practices using oral fluids for ASFV early detection.

REFERENCE 1.

2.

3.

4.

Fig 5. Environmental sampling

Jeffrey Zimmerman et al., Diseases of Swine. African Swine Fever Virus, p.443.

Natalia Mazur-Panasiuk et al., African swine fever virus: persistence in different environmental conditions and the possibility of its indirect transmission. J Vet Res 63, 303-310, 2019.

Claire Guinat et al., Dynamics of ASFV shedding and excretion in domestic pigs infected by intramuscular inoculation and contact transmission. Veterinary Research 2014, 45:93. www.fao.org

Jiancong Yao

Conclusion and Discussion As ASFV normally transmits slowly, and it primarily transmits via direct contact or contacting with ASFV contaminated fomites, in a specific farm setting, if early detection and rapid and biosecure responses are assured, ASFV can be contained in a barn or facility using the test-removal strategy subject to local regulations.

Jiancong Yao currently works with PIC as its Health Assurance Director for Asia region. He had studied virology and holds Master Degrees in Preventive Veterinary Medicine; he also holds Master degrees in Agricultural Economics and General Management.

In this specific case, pigs are stocked into five separate barns, and each barn has two parts (six pens in each

Email: miles.yao@genusplc.com

www.animalhealthmedia.com

International Animal Health Journal 41

IT & LOGISTICS

Xenotransplantation of Biotech Companies to Bridge the One Health Divide The concept of One Health is essentially the collaborative work across all sectors affecting public health in order to improve outcomes. Animal health is a cornerstone of public health through provision of animal products, risk of zoonotic infections and the positive impact of animals on our wellbeing. Where synergies exist in disease and treatment modes, it would appear to make a lot of sense to develop diagnostics and therapeutics in concert. This begs the question why is it not more commonplace for biotech to develop co-incidentally in both human and animal health? This article explores both the benefits and the barriers to a One Health approach in diagnostic and therapeutic research and development.

Mutual Gains Healthier animals lead to healthier people, and vice versa. In the field of medicine, there are advantages to collaborative working across the species barriers and transferring tech between the spheres of human and animal health. The concentrated genetic pool within species, and breeds within those species, can aid genetic target discovery. This may have reciprocal benefit where the genetics are conserved from animals to humans. Shorter lifespans of many animals reduce the time to end point for clinical trials. For example, canine cognitive dysfunction shows many pathological similarities with Alzheimer’s disease. Treatment outcomes are similar for dogs with CCD as they are for people with AD, making dogs a useful therapeutic model. Reduced regulatory barriers in animal health increases speed to market delivery and financial returns. Why, therefore, does parallel research and development not happen more frequently where there is shared physiology? Let’s look at the benefits and challenges of these comparable markets and discuss why companies should consider both in their strategic plan.

Reducing Uncertainty The degree of uncertainty of the future of medicine is growing, driven by the exponential growth of molecular technologies, digital health tech, AI and big data. There is also a shift in emphasis from ‘sick’ care to ‘health’ care, focusing on wellbeing, prevention and early intervention. Both human patients and animal owners are demanding increased personalisation, accessibility and convenience for their healthcare, with a growing C to B relationship, rather than the historic paternalistic B to C model. This is driving the emergence of smart health communities to improve efficiency in innovation and delivery, increase access and affordability, and improve quality. Surely, as the degree of both uncertainty and consolidation rise it makes sense to de-risk by having a foothold in both markets?

Streamlining tech development should prove more efficient, while protecting against jolts in the human market as animal health tends to lag behind.

Market Size The size of the global animal health market is approximately $150 billion1. The size of the human health market is an order of magnitude greater at around $8 trillion2. Continued healthy industry growth rates of 5–7% annually predicted to continue for both markets. The global population continues 42 International Animal Health Journal

to rise and live longer, and with it an increased demand for animal products and pet healthcare.

The companion animal sector has seen huge growth, thanks to the humanisation of pets seen increasingly as valued family members. This has driven consistent year on year increased spending in the pet and animal health segments. The size of the pet expenditures in the US grew from $43 billion in 2008 to $73 billion in 20183. Multiple data points suggest sustained strength in companion animal markets. These include continued rising pet adoption and prescription trends, increasing spend per pet, and healthy pet insurance markets4. Ironically, as we value our companion animals more, we value our individual production animals less with the rising demand for cheap meat driving intensive farming. Meat consumption per capita is on the rise, alongside growing populations. The sands are shifting, however, with increasing concerns over welfare and environmental impact gaining traction in the Westernised world. It will be interesting to follow these trends, which also champion local higher welfare and more natural farming methods, for which people are increasingly prepared to pay premium prices.

Table: Human and animal health industry comparisons

Barriers to Market Entry The size of the markets may be the headline, but ease of accessing a market share is more important in delivering returns. While the potential gains are significantly less in the animal health sector, it is de-risked with fewer barriers to entry, reduced regulatory time and costs, and fewer competitor products and companies. Product lifecycle development from new concept to market is 5–7 years compared to 12–13 years for human drugs1. In addition, the approval barrier for an animal therapy is to outperform a placebo, but the bar is set higher in human health to beating an existing standard of care.

The animal health industry is largely free from the constraints of healthcare reforms, direct reimbursement models and generic conversions. There are vastly reduced R&D costs (see table) and fewer onerous regulatory hoops to jump through compared to human drug development.

Access to the market is much more direct and efficient, rather than the complex, indirect routes to buyers in human health.

Venturing Into the Unknown So, what deters companies from developing parallel tech? Is it the act of venturing into the relative unknown?

Concerns and considerations over species differences?

Lack of funding to pursue both avenues? Or is it the bottom line of a contracted animal health market seeming less worth the investment? The smaller overall industry market Volume 7 Issue 1

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size is a crude guide to potential returns, as the size and profitability of different sectors varies greatly.

There are additional factors and idiosyncrasies of a market where the end user (owner/farmer) is an intermediary between the professional (vet) and end target patient (the animal). In the companion animal sector, there is a large emotive component to consider with messaging and positioning within the market. It is important to thoroughly research not only the potential number of targets, but also the receptiveness of both veterinary professionals and, ultimately, owners to the type of treatment. The therapeutic focus shifts more from maximising longevity to preservation of quality of life. A deep understanding of the factors influencing animal care not only informs strategy and direction, but also the avoidance of faux pas and negative brand associations which can be hard to shake off.

A true understanding is needed to avoid marketing pitfalls, such as throwing sticks for dogs, or using images of extreme breed types. Portfolio marketing with an audience-centric go-to-market strategy, incorporating deep buyer insights, creating messaging that resonates, and taking a strategic approach to launch, should develop alongside product R&D. Fostering and maintaining customer relationships will influence customer decision-making on new market entrants.

For the production animal sector, the situation is somewhat different. Economies of scale drive down the value of the individual animal, and only cost-effective treatments will be adopted on a large scale. This will need to be reflected in pricing strategy. The role of the veterinarian in food animal medicine and technology should not be under-estimated. They will need to be convinced of the value to their clients, in addition to ensuring high welfare is maintained. There is the need for substantial, robust, and compelling performance, efficacy and economic consequences for food animal products.

Risks With the current Brexit uncertainty and global trade deals to be done, the future influences on the UK human and animal health markets is uncertain. Globally, these markets are extremely resilient. Despite being historically similarly www.animalhealthmedia.com

resilient, socioeconomic conditions are more likely to impact the animal health market. Trends and concerns about food animal production and sustainability may potentially offset the continuing trend for higher demand for animal protein.

Unexpected downturns in macroeconomic conditions could negatively impact consumer discretionary income, i.e. spending on their pets. The rise in online pharmacies and telehealth are changing the traditional models of pet care, necessitating a more anticipatory approach to regulation.

Factors affecting both markets include the consolidation of larger health companies, intensifying competition and making it harder for smaller players to gain a foothold.

How to Succeed For start-ups wanting to succeed, it’s vital to understand the potential role of the technology, technically and financially, for both markets. This involves undertaking due diligence necessary to have rational and credible pricing and sales projections for the products (and regulatory where applicable). Competitor analysis and anticipating that others are developing similar competing products should drive a healthy sense of urgency. A detailed manufacturing plan should be considered, with contingency planning for potential hurdles in terms of regulatory, delays and additional costs. Distribution channels need to be considered, bearing in mind exclusivity arrangements and the rise of buying groups.

The landscape for animal health distribution is changing dramatically. Direct to consumer online channels and home delivery platforms continue to disrupt traditional distribution channels through veterinary practices. To counter this and improve efficiency, buying groups of distributors and both private and corporate practices continue to grow.

Remaining agile and responding to distribution trends will be important as the world increasingly moves online.

Suck It and See In both farm and companion animal sectors, the method of product administration is also a much more significant factor than in human health. Poor palatability or inappetence can be huge hurdles in oral drug delivery.

Frequency of dosing is an important consideration, International Animal Health Journal 43

IT & LOGISTICS

especially in farm animals where handling is both timeconsuming and causes stress and potential injury (both to the animals and their handlers). Remote dosing in drinking water or feed leads to unpredictable intake within groups of animals, necessitating high safety levels. Drugs must also be safe for human handlers and the environment, and disposed of appropriately. The issue of drug residues is also important for animal products, and ideally withdrawal periods should be short. Effect on performance must be taken into account with competitive sport horses and racing greyhounds.

The Funding Dilemma Traditional large pharma R&D is being increasingly augmented by increasing numbers of innovative start-ups. This means there are many smaller companies seeking to access funding pots. Few grants exist for the animal health sector unless it directly relates back to public health, such as antimicrobial resistance or zoonotic disease. Many more grants are available for human health projects, and this funding would likely have conditional use in a company working in both fields. Limited available capital may restrict companies to just one market segment. In this instance, the more familiar market with higher potential gains will likely win out.

Alternative funding models, beyond grants and venture capital, are becoming increasingly important to fuel innovation. Angel investors in animal health in the form of practice owners having sold on, provide a growing source of both advice and money. Equity crowdfunding capitalises on growing, engaged online communities. If companies are developing the technology in parallel this opens the door to funding, investments and partnerships from both market segments.

Growth of the One Health Approach Interest in working within both human and animal sectors is certainly an area of increasing attention and focus. The Humanimal trust was set up in 2014 to foster partnership and join up research efforts between doctors, vets and researchers in fields such as stem cells, oncology, neurodegenerative disease and antibiotic resistance.

Start-ups well on the road to developing cross-over tech include examples of taking tech from human to animal, vice-versa, and in parallel to both markets. An example of animal to human diagnostic is Test&Treat, which has developed point of care tests for the rapid detection of urinary tract infections (UTIs) and subsequent antibiotic sensitivity analysis. The patented technology has been launched into the veterinary market for use in companion animals. The same test can also be used for detection and antibiotic susceptibility of human UTIs and the next stage for the company is to develop diagnostic partners to license the technology for application on the human market.

Human to animal cutting-edge biotech can be seen with the likes of PetMedix, developing monoclonal antibody platforms for dogs and cats, following success of the team 44 International Animal Health Journal

in human drug development. Having seen the change these therapies have made to human health, what started as a PhD project to prove a platform to create fully canine Mabs has led to a rapidly growing enterprise working on multiple targets focussing on unmet clinical needs.

Pregenerate and VisusNano are both developing tech in parallel. Pregenerate combines the expertise of human doctors with an equine orthopaedic specialist in development of their biologic microchip. The wide range of potential applications include arthritis drug development and personalised medicine optimisation. VisusNano’s medicated intraocular lenses have potential applications in both canine and human cataract surgery, but are likely to enter the veterinary surgery years ahead of the human clinic.

Conclusions People and animals have a lot to gain from one another, both in terms of companionship and mutual health and wellbeing.

The increasing trend towards efficiency and consolidation to reduce waste, expenditure and time globally is a strong argument for increasing collaboration between human and animal health markets. The potential reciprocal gains for the patients, spread of risk, and revenue from two independent market sectors should encourage companies to fully explore the possibility of developing their technologies in parallel. If this approach can become more commonplace, the network of collaborators will grow, along with familiarity and understanding, and One Health can thrive.

REFERENCES 1.

2.

3.

4.

5.

CS Wall Street Perspectives on Animal Health – The Alternative Healthcare Investment https://www2.deloitte.com/uk/en/pages/life-sciences-andhealthcare/articles/global-health-care-sector-outlook.html Animalytix: “The Animal Health Industry’s Leading Supplier Of “Actionable” Business Intelligence”, C. Ragland, July 9, 2019 https://www.grandviewresearch.com/industry-analysis/ pet-insurance-market https://www.fdareview.org/issues/the-drug-developmentand-approval-process/

Liz Barton Liz Barton is Senior Account Manager at Companion Consultancy, providing PR, marketing and industry insight to the vet and pet trade. She is particularly interested in assisting companies to move between the animal and human health industries. Liz is a qualified vet and still undertakes regular locums, keeping one foot in the clinic. She also collaborates on a number of wellbeing projects within the industry.

Email: liz@companionconsultancy.com

Volume 7 Issue 1

BVD HARD TO SEE BUT

OFTEN LURKS

WITHIN

Bovine Viral Diarrhoea is now common and it can have huge negative economic impact on reproductive performance, growth and milk production. Vaccination - along with good biosecurity and the elimination of PIs - prevents this kind of exposure. Talk to your vet about protecting yourself from BVD.

TO LEARN MORE VISIT BVDZERO.COM

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MAKING

BVD HISTORY

International Animal Health Journal 45

SPECIAL FEATURE

Vet Career Check – Moving from Veterinary Practice to a Commercial Role Becoming a vet is no easy task. You’ve spent 5–6 years at university, more if you’ve gone on to achieve further qualifications such as a PhD or a Masters in a chosen specialist field. You’ve spent hours, days, weeks, months and years training, studying and dreaming about being a vet. You’ve made it. But then things just don’t quite fall into place.

Maybe you’ve not been able to find the veterinary job you’ve always dreamed of? Maybe you thought you’d found that job but the long hours, often inflexible work demands and associated drains on your family life are posing too much of a challenge? Or perhaps you’ve reached a stage in life when the physical demands of veterinary practice are no longer appealing and you’re looking to fresh pastures?

Whatever your reasons to consider moving out of traditional veterinary practice, it’s good to know that the industry is filled with possibilities and that the commercial world is your oyster. But it’s also important to recognise that working in the industry is a whole new ball game.

We spoke to Tony Noble about why a vet might consider making such a move, how best to go about the transition and what factors a transitioning vet might need to consider.

When working with vets looking to make the move into the commercial world, we find there are generally two primary motivating factors.

The first is that life as a vet has not really lived up to their expectations, or they are finding it harder going than they had originally thought.

The second is that industry has always beckoned, and the individual intended to use their veterinary qualifications to secure a ‘commercial’ career path from the very start. I use air quotes here because every business is commercial – vets must also consider the commercial aspects of their work (such as business management and client relationships) in everyday practice and unfortunately this is something that I believe receives insufficient focus in core veterinary training. But that’s a topic for another day!

Commercial roles provide a lot of opportunities for someone interested in a specialist area (such as nutrition, pharmaceutical, pharmacology / efficacy, for example) and also provide the potential to impact many more clients and patients than in clinical practice. It could also be argued that certain commercial roles provide a lot more variety than traditional first opinion veterinary medicine, but obviously roles and sectors do vary, so it’s important to do your research and try to pin down exactly what your dream career path looks like.

If you have always aspired to a commercial-type role throughout your veterinary training, it’s important to bear in mind that many such roles ask that a candidate has a 46 International Animal Health Journal

few years of clinical practice under their belt, so it’s good to spend some time in practice upon qualification. This will also have the added benefit of giving you the chance to make sure that you are making the right decision and you’re not missing out on a life in clinical practice. Such experience will also provide a good opportunity to solidify skills and allow you to start the research and networking process.

In looking to make the move, research and networking will prove to be time well spent.

Do your research into which industry segments most closely match your dreams, ambitions and desired lifestyle.

Bovine, equine or companion animal? Pharmaceutical research, nutritional specialist or veterinary product sales?

The possibilities are virtually endless.

Networking is an important step, not only in terms of the doors that could be opened for you by the right contacts, but also the insights you will glean about organisations, sectors and invaluable extra advice that you may receive along the way.

We find that many vets can experience a little bit of a culture shock when taking their first steps in the commercial sector, for a variety of reasons…

Even though commercial roles avoid the unpredictable nature of working hours that go hand in hand with being on call and emergency veterinary work, the job is not always going to be 9–5 and long hours and weekend work are often required for trade shows, exhibitions and important events such as the BSAVA Conference.

There’s also the fact that you’ll be losing direct contact with animals, which for many is the primary motivating factor to embark in a career in veterinary medicine in the first place.

We find that some vets that we have placed continue to maintain weekend work in private practice to keep their hand in, and many companies are appreciative of this dedication. It’s a great way to keep up direct animal contact, it helps keep you abreast of modern techniques, drugs and medical advances and gives access to CPD, which can be of great benefit in a new, professional role.

There are strong opportunities for vets to go into what are in effect ‘para-sales’ roles, where you provide technical and clinical support for frontline sales staff.

While such opportunities can be intimidating for vets that may feel uncomfortable in a sales-type role, they provide great opportunities for those who like to deal with people and who would relish the challenge of a career supporting the human side of the veterinary industry.

In the move to a commercial-type environment, as a veterinary surgeon it’s obviously crucial that you remain ethical and true to your qualifications. A commercial role will give you the opportunity to use your technical expertise in an interesting new environment and provide a Volume 7 Issue 1

SPECIAL FEATURE

commercial benefit to the business as well as the required results to the patient.

The last piece of advice we would have for a vet looking to embarking on new, corporate career is to think twice before you dress for an interview, or your first day on the job! While jeans, fleece and sturdy outdoor work boots may have been your daily attire in clinical practice, most commercial roles will require suit and shoes, or at least smart slacks. So don’t be caught out and fall at the first hurdle!

Tony Noble Managing director Tony Noble – an avid animal enthusiast – founded Noble Futures 16 years ago and has been immersed in the business ever since. With a contagious energy, enthusiasm and attention to detail that transcends the organisation, Tony has ensured that Noble Futures stands out from the competition. His commitment to excellence in recruitment and an intent to find the best person for every job, is driven by a desire to see the businesses of Noble Futures’ clients’ grow, develop and gain market share. With a drive to form long term partnerships with clients and to have a real understanding of their business vision, Tony enjoys working with each and every client to identify and secure great candidates to strengthen their teams and assist in their business’s growth. He finds watching candidates gain fulfilment in their career (whether they choose to scale the career ladder or find complete satisfaction within their role) immensely satisfying and his best advice for a successful career is to “prepare and work hard”. And Tony sure does lead by example.

Email: info@noble-futures.com

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International Animal Health Journal 47

AD INDEX

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GD Animal Health

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Herbavita

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IDEXX Laboratories Inc.

OBC

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IFC Moredun Scientific Page 19

Nordson

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Pharma Publications

I hope this journal guides you progressively, through the maze of activities and changes taking place in the animal health industry.

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ADDED VALUE TO ANIMAL HEALTH

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