Biological Agents as Potential Threat Resources - a Review

Internship Report Master Degree in Veterinary Medicine BIOLOGICAL AGENTS AS POTENTIAL THREAT RESOURCES – A REVIEW Mariana Martins Marrana Tutor Professor Doutor João Niza Ribeiro Co-tutor Tianna Brand Porto 2016 Internship Report Master Degree in Veterinary Medicine BIOLOGICAL AGENTS AS POTENTIAL THREAT RESOURCES – A REVIEW Mariana Martins Marrana Tutor Professor Doutor João Niza Ribeiro Co-tutor Tianna Brand Porto 2016 i Foreword This report concerns the curricular internship from the Master’s Degree in Veterinary Medicine, subordinated to the Public Health field. The internship took place between 22nd February and 24th June 2016 at the World Organisation for Animal Health (OIE) headquarters, in Paris, France. During this training period, I was under the supervision of Tianna Brand, who is the Chargée de Mission for Biological Threat Reduction. I integrated the Scientific and Technical Department and I was assigned some projects besides writing the present report. During the first month, I updated the technical disease cards available at OIE website. I made changes and updates based on OIE Terrestrial Animal Health Code, OIE Manual for Diagnostic Tests and Vaccines and also on relevant scientific publications, such as those from the Iowa State University’s Center for Food Security and Public Health (CFSPH). Besides, I built a database for organising information regarding Laboratory Twinning projects. This assignment allowed me to exponentially develop my Microsoft Access skills, since the data output concerning project reports delivery dates is complex. From the beginning of April onwards, I started to create another database, this one for cross referencing potential biological threat agents between the CFSPH publications, Center for Disease Control and Prevention (CDC) and OIE listed diseases. The latter assignment sparked my interest for the biological threat reduction field, so I decided to further develop the subject and embrace it as my report’s theme. I also had the opportunity of writing an article for OIE Bulletin. I wrote about the IVSA Animal Welfare Conference, which I attended from the 22nd to the 24th April in Utrecht, The Netherlands. Afterwards, I was assigned to update the information available on “Rinderpest – Posteradication” website, which allowed me to deepen my notions on international cooperation and policy making. Also regarding biological threat reduction, I was asked to help in the preparation of the 2017 OIE Biological Threat Reduction Conference. My tasks were to investigate was had been done regarding previous conference recommendations (2015) and to explore what activities, partnerships, and publications relevant organizations had been developing in meantime. I also created an internal newsletter – “Biothreat watch”, which is going to be sent periodically to the Scientific and Technical Department colleagues. ii Furthermore, from the 21st to the 27th of May, I attended OIE 84rd General Session, in Paris. This was a great chance to be at the centre of all decisions concerning animal health in the world, to have contact with the 180 delegates and their commissions, and my colleagues at OIE. My next project was the creation of a web portal about peste des petits ruminants (PPR) and the Global Strategy for its control and eradication. I also updated Rinderpest’s web portal, which now focuses on post-eradication activities. I took that opportunity to update the PPR and rinderpest Disease Information Summaries. Finally, I restructured the Biothreat Reduction portal, including the strategy document, factsheet and PowerPoint presentations available there. My last assignment was a cooperative project with Tongan farmers, for whom I provided information on how to assemble a duck raising farm. In the final analysis, this internship has exceeded every expectation I might have had, even though they were quite high. I had the chance to collaborate with almost every department, to attend many meetings and had hoc group reunions and to be a part of several OIE events. iii Summary The use of biologic agents as means of causing distress is as ancient as human conflict. However, biologic agents can pose a threat even without a mischievous perpetrator planning their release. The evolution of scientific and technological resources allows for the creation of new agents, new pathways of introduction and new threats to arise. These emerging threats, in combination with climate change and growth in international trade and human migration pose increasing challenges upon surveillance systems and response mechanisms. This report comprises a review of possible ways of introduction of biological threats, agents of concern and the role International Organizations play on the prevention of natural and deliberate outbreaks, as well as their response mechanisms and cooperation agreements. It has been made a reflexion on the likeliness of the occurrence of a deliberate biological attack comparing it to the occurrence of accidental or natural episodes and how to differentiate both. The purpose of this report is to make a revision of the current situation regarding biological agents which have potential to pose a significant threat to humans, animals and the environment, both on health and economic perspectives. iv Sumário O recurso a agentes biológicos como meio de causar vicissitudes é tão antigo como o conflito humano. De todo o modo, estes podem representar uma ameaça, mesmo sem um prevaricador que planeie a sua introdução no meio. A evolução dos recursos científicos e técnicos permitiu a criação de novos agentes, novas vias de introdução e novas ameaças. Estas ameaças emergentes, em combinação com as alterações climáticas e o crescimento do comércio global e dos movimentos migratórios humanos, representam um desafio crescente para os sistemas de vigilância e mecanismos de resposta. Este relatório inclui uma revisão das possíveis vias de introdução de ameaças biológicas, dos agentes de interesse e do papel que as Organizações Internacionais desempenham na prevenção de surtos quer naturais, quer intencionais, assim como os seus acordos de cooperação. Além disso, foi feita uma reflexão acerca da probabilidade e impacto da ocorrência de um ataque biológico, em relação à ocorrência de episódios acidentais ou naturais e de como os distinguir. O objetivo deste relatório é a realização de uma revisão dos potenciais agentes de ameaça biológica e as suas vias de introdução, ou fatores que predispõem a sua ocorrência, com especial enfoque nos agentes que possam causar especial prejuízo à saúde humana, animal e ambiental, para além de trazer consequências económicas significativas. v Acknowledgements Aos meus pais, por todas as oportunidades que me proporcionaram e pela confiança que sempre depositaram em mim e nas minhas escolhas. Aos amigos, por me ouvirem, aconselharem e estarem sempre disponíveis. Aos Professores, especialmente ao Professor Niza Ribeiro, pelos conselhos, orientação e contactos. To Tianna Brand and all the OIE staff, who could not be more welcoming, inclusive, and committed to provide me the best learning experience possible. “What is surprising is not the magnitude of our forecast errors, but our absence of awareness of it. This is all the more worrisome when we engage in deadly conflicts: wars are fundamentally unpredictable (and we do not know it). Owing to this misunderstanding of the causal chains between policy and actions, we can easily trigger Black Swans thanks to aggressive ignorance-like a child playing with a chemistry kit.” Nassim Nicholas Taleb, The Black Swan: The Impact of the Highly Improbable vi Abbreviations ASF – African Swine Fever BSE – Bovine Spongiform Encephalopathy BTWC – Biological and Toxin Weapons Convention CCHF – Crimean-Congo haemorrhagic fever CDC – Centres for Disease Control and Prevention DNA – Deoxyribonucleic Acid EU – European Union EVD – Ebola virus disease FAO – Food and Agriculture Organization FMD – Foot-and-mouth disease GHSA – Global Health Security Agenda IHR – International Health Regulations OIE – World Organisation for Animal Health PVS – Performance of Veterinary Services SARS – Severe Acute Respiratory Syndrome STEC – Shiga toxin E. Coli UN – United Nations UNISDR – United Nations Office for Disaster Risk Reduction UNODA – United Nations Office for Disarmament Affairs UNSGM – United Nations Secretary General Mechanism US – United States of America VEE – Venezuelan Equine Encephalomyelitis WHO – World Health Organization WTO – World Trade Organisation WWI – First World War WWII – Second World War vii Index Foreword ..................................................................................................................................................... i Summary .................................................................................................................................................. iii Sumário..................................................................................................................................................... iv Acknowledgements .................................................................................................................................. v Abbreviations ........................................................................................................................................... vi Index......................................................................................................................................................... vii 1. Biological Warfare ............................................................................................................................ 1 Historical context .................................................................................................................................. 1 Definitions .............................................................................................................................................. 2 Synthetic agents ................................................................................................................................... 2 Current situation ................................................................................................................................... 3 2. Natural and Intentional Spread of Disease ................................................................................... 5 Wildlife and Invasive Species ............................................................................................................. 5 Emerging infectious diseases ............................................................................................................. 6 Steps in the emergence of pandemic zoonosis ............................................................................ 8 Deliberate usage................................................................................................................................... 9 Accidental releases .............................................................................................................................. 9 How to differentiate? .......................................................................................................................... 10 3. Biological Resources ...................................................................................................................... 13 Concerning agents and diseases ..................................................................................................... 13 Agents/diseases overview ................................................................................................................. 13 Anthrax (Category A) ..................................................................................................................... 14 Plague (Category A) ....................................................................................................................... 14 Smallpox (Category A) ................................................................................................................... 14 Tularemia (Category A) ................................................................................................................. 15 Botulism (Category A) .................................................................................................................... 15 Viral Haemorrhagic Fevers ............................................................................................................ 15 Food safety threats (Category B) ................................................................................................. 16 Water safety threats (Category B) ................................................................................................ 17 Alphaviruses (Category B) ............................................................................................................ 18 Glanders (Category B) ................................................................................................................... 19 Hantavirus (Category C) ................................................................................................................ 19 Nipah (Category C) ........................................................................................................................ 19 6 More recently, in May 2016, Australian authorities announced that, after conducting extensive research on the possible impacts of such measures, they are going to release Cyprinid Herpesvirus-3 over the European Carp population that has invaded the Murray-Darling basin area. These fish account for more than 90% of the local biomass and are nearly useless as a fishing product.[10] The risk of dispersing invasive species through acts of bioterrorism, especially human pathogens, cannot be neglected. However, that risk appears quite low in comparison to the risk of intentionally releasing animal pathogens that could disrupt the livestock producing industries of countries which rely on them economically.[29] Although it is not directly related to bioterrorism, the intentional release of unwanted exotic companion animals (such as Burmese python and prairie dogs) also has a major environmental and economic impact and, possibly, animal and human health impact, in case of accidental release of zoonotic agents. Taking prairie dogs as an example – tularaemia and plague are two zoonotic diseases that have occurred in animals intended for companion animal trade. Keeping prairie dogs as pets in the US is no longer possible, after a monkeypox outbreak in 2003.[7] Emerging infectious diseases According to current literature, the frequency with which new pathogens emerge is increasing, even if the increased global surveillance is taken into account. Also, the global distribution of all the major groups of emerging diseases strongly correlates with human population density, supporting the theory that disease emergence is driven by largely anthropogenic changes – namely the expansion of agriculture, travel routes, trade, and land use.[28] Zoonotic disease risks are predicted to further increase as environmental changes continue and population continues to grow exponentially.[55] Despite their substantial repercussion on global public health and our growing understanding of the process by which they emerge, no pandemic has so far been predicted before infecting human beings. However, patterns in the origin and spread of new pathogens can be noted and are an intrinsic, although necessarily tailored, as part of a surveillance strategy.[28] Emerging infectious diseases, including those which are evolving to evade currently available control options (vaccines and antimicrobials), pose an increasing risk to health. The mechanisms for disease emergence are complex and often incompletely understood, but it is likely that the trend for new diseases to emerge will only continue as global movements of people and animals increases and as human behaviours change the environment around us.[36] 7 Emergence in new regions is caused primarily by pathogen movement, due to trade and travel, whereas local emergence is driven by a combination of environmental changes, that affect vectors and wildlife hosts, and social changes (e.g., poverty and conflict), that affect human exposure to vectors.[25] Endemic animal diseases are a daily burden for health and agriculture in some of the world’s poorest countries, obstructing economic and social development and limiting food availability.[36] Increasing demand for food due to an expanding global population has led to a substantial susceptibility of our populations to food-borne zoonosis. Pathogens in the livestock production chain are a particular risk, with repeated outbreaks from meat, eggs, milk, and cheese, or meat by-products incorporated into foods as flavouring, oils, or stock. Globally, most types of domesticated and wild vertebrates and many invertebrates are food for people – thus capable of harbouring zoonotic bacteria, viruses, or parasites.[24] The same diseases, whether they are or not foodborne, when introduced to developed countries, which may have already eliminated them, spread rapidly through naïve animal populations and represent severe consequences for livestock production, for business, and for the availability/y and price of food on domestic and international markets.[36] Transmission rates are usually higher in dense than in sparse populations, due to higher frequency of contacts and feebler immune systems, and spread is often greatly enhanced by air travel or human migration.[28] The ease associated with air travel, enabling global transit in a single day (Figure 1), has accelerated introductions since it has allowed many pathogens that cause acute infections to reach other continents within the few days that hosts are infectious (e.g., Chikungunya and West Nile viruses), and even during the latent period for some diseases. Several of these pathogens were also favoured by the climate changes of the XX century, which resulted in the introduction of another key vector - Aedes spp. in areas previously free from its presence.[45] This mosquito can carry many viral pathogens, including the Yellow Fever virus, Zika virus, Dengue and Chikungunya, as well as several filarial nematodes. Thus, the most recent wave of pathogen introductions, and those likely to occur in the near future, are strikingly abrupt when is taken in consideration the smooth establishment of vectors in the last centuries.[25] Figure 1 – Global aviation network. In Kilpatrick et al, 2012 8 Steps in the emergence of pandemic zoonosis Among the several described processes for the emergence of zoonotic diseases, Daszak’s model (Figure 2) is the most adequate for the purposes of this report, as it focus on the dynamics of infection, rather than pathogen proprieties. It comprises three stages: - The first stage - disease emergence, takes place within the reservoir host species. Ecological, social, or socioeconomic changes alter the dynamics of pathogen transmission within the host or between hosts and allow the pathogen to expand within its host population, spread to a new region, or to be transmitted to another non-human host population or species. Each of these changes increases the likelihood of the pathogen making contact with and spilling over into human beings (and thus progressing to stage 2).The drivers that cause stage 1 emergence tend to be large-scale environmental, agricultural, or demographic shifts. - The second stage - localised emergence, represents the initial spill-over of a wildlife or livestock pathogen to people. Causes vary widely, from handling of carcasses, to exposure to fomites in markets, or in the wild. - The final stage - full pandemic emergence, is rarely achieved. It represents sustained person-to-person transmission and large scale spread. Alternatively, some pathogens can spread among human beings without evolutionary change from the genotypes present in the wildlife host (e.g., Ebola virus) and thus can enter human population at stage 2. The ultimate goal of successful pandemic prevention is to move the control point to the first stage. Spill over infections, just below the threshold for self-sustainment in people (R0<1), have been suggested as prime epidemics in waiting. Also, pathogens can transfer from human beings to animals and between animal species before being transferred back to people, allowing remixing and evolution with spillback and potentially enhanced pathogenicity.[28] Understanding the complex population biology and transmission ecology of multi-host parasites has been declared as one of the highest priorities for biomedical sciences during the XXI century.[55] Figure 2 – Emergence of zoonotic disease. In Morse et al, 2012 9 Deliberate usage To use biological agents as weapons is not as easy as it might seem. Besides the presence of the agent, it is required a delivery system, either to convey the agent, or to facilitate its dispersion. However, almost any disease-causing organism (such as bacteria, viruses, fungi, prions or rickettsiae) or toxins (natural or synthetically produced) can be used in biological weapons. The agents can be enhanced from their natural state, to make them more suitable for mass production, storage, and dissemination as weapons.[32] Regarding delivery mechanisms, there is a variety of methods. Past programmes have constructed missiles, bombs, hand grenades and rockets to deliver biological weapons. A number of programmes also designed spray-tanks to be fitted to aircraft, cars, trucks, and boats. On a less sophisticated side, and on a smallerscale, delivery mechanisms can be as simple as a pen or a stick contaminated with the agent and brushed on susceptible animals. There have also been documented efforts to develop delivery devices for assassinations or sabotage operations, including a variety of sprays, brushes, and injection systems as well as means for contaminating food and clothing.[32] Accidental releases Working with highly virulent or highly pathogenic strains of virus or bacteria is a double edged sword. On the one hand, the development of vaccines and antimicrobials is essential for human and animal health, and the preparedness for the emergence of pandemic strains can spare many lives. But on the other hand, the risk of laboratory escape of these high-consequence pathogens far outweighs any potential advance. Accidental laboratory releases are a recurrent scenario. The risk of a manmade pandemic sparked by a laboratory escape is not hypothetical: one occurred in 1977 in China, with H1N1 Influenza. It occurred because of concerns that a natural pandemic might be imminent, due to reports of large outbreak of swine Influenza in the US .[19] From 1938 to 1972, the Venezuelan Equine Encephalitis vaccine caused most of the very outbreaks that it was called upon to prevent, due to poor inactivation of vaccine strains - a clear self-fulfilling prophecy.[19] The first fully acknowledged laboratory escape occurred in 1972, with the infection of a laboratory assistant at the London School of Hygiene and Tropical Medicine, who was working with live smallpox virus. The assistant got sick and infected healthcare workers, other patients, and their visitors.[19] The 2003 Severe Acute Respiratory Syndrome (SARS) outbreak spread to 29 countries. Since 21% of all cases involved hospital workers, it had the potential to shutdown health care services wherever it struck. This pathogen is particularly dangerous to handle in the laboratory because 10 there is no vaccine, and it can be easily transmitted via aerosols. SARS has not re-emerged naturally, but there have been six escapes from virology labs: one in Singapore (August 2003) and one in Taiwan (December 2003), and four different escapes at the same laboratory in Beijing (2004).[19] Regarding FMD, the disease reappeared in Britain in 2007, 4 kilometres away from a biosafety level 4 laboratory (see chapter 4). The identified strain was the same that had caused an outbreak in 1967 in the United Kingdom, but was not then circulating in animals anymore. It was, however, used in vaccine manufacture at the nearby Pirbright facility. Investigations concluded that construction vehicles had carried mud contaminated with FMD from a defective wastewater line at Pirbright to the first farm. The resulting major outbreak disrupted UK agricultural production and exports, and cost an estimated 200 million pounds.[19] In 2010, WHO released a guidance document named Responsible life sciences research for global health security with the purpose of informing Member States about the risks posed by accidents or the deliberate misuse of life sciences research and to propose measures to minimize them within the context of promoting and harnessing the power of the life sciences to improve health for all people. This guide also focuses on one measure of biorisk reduction, namely the biorisk management framework for responsible life sciences research (Figure 3). The framework emphases a vision of promoting excellent, high-quality, responsible, safe and secure research, where the results of the research promote advancements in health, economic development, global health security, evidence-informed policymaking and public trust in science.[58] How to differentiate? It is possible to differentiate between deliberate and natural occurrences of disease through current genome sequencing technologies. The field of studies designated to such investigations is called microbial forensics – its ultimate goal is to identify and criminally prosecute the responsible parties for a deliberate outbreak of disease. It is an important part of a strengthened capability to respond to biocrime and bioterrorism, and works in parallel with an epidemiological investigation. The latter aims to find the source of the outbreak and to clarify its Figure 3 – Biorisk management framework for responsible life sciences research. Source: WHO: Responsible life sciences research for global health security; 2010. 11 routes of transmission, in order to hinder its further spread, and reduce the risk of future outbreaks, through effective preventive measures. The epidemiologic investigation might begin before or after the microbial forensics intervention, depending on the nature of the outbreak – in deliberate overt outbreaks, when the perpetrator informs authorities of his intentions, both investigations take place at the same time.[50] Gene sequencing technologies allow the differentiation between closely related isolates. While in human DNA the chances of finding two samples with coincidental profiles are minimal, the same does not happen with asexually reproducing organisms. Regarding bacterial populations, the genetic variation inducing mechanisms make it possible for a cell to differ from its ancestor and can also cause unrelated organisms to contain shared sequences.[50] Therefore, when comparing individual strains of a microbial species, a complete or near-complete match between individual strains does not necessarily reflect identity. Similarly, minor genetic differences between strains do not necessarily exclude the possibility that they might originate from the same source. However, the assumption when using genome-sequencing systems is that individual isolates that share marker profiles are related. Most bacterial genetic comparisons that have been reported to date rely on genetic marker systems, in which each marker reflects a specific part of the microbial genome.[50] Collections of reference strains have been created and can be used to compare new isolates, in order to analyse population structures and the relationships between the species’ individual strains. Sequencing and analysis of the entire genome of an organism can reveal subtle genetic differences that would not be detected by older methodologies. Until recently, the process of whole-genome sequencing and analysis was meticulous, expensive, and time-consuming. However, the recent development of the so called “next-generation sequencing technologies” has revolutionized biology by greatly reducing the time and expenses required. The development of whole-genome sequence databases will be extremely valuable in successfully tracing pathogens in the future.[50] 12 Microbial forensic investigations have been described as consisting of three interrelated stages described in detail on Figure 4:  identification of the biological agent(s) responsible for the event;  characterization of the event as either intentional or unintentional;  if the event is deemed illegitimate, attribution of use to a specific perpetrator. Many of the questions asked during the first two stages of a microbial forensics investigation are identical to those examined in an epidemiologic investigation, and the same methods and technologies are generally used to answer them. However, the third stage is unique to microbial forensics. At this stage, in addition to the usual forensic analyses of recovered materials from the crime scene, detailed analyses are conducted of the attack strain. Epidemiologic and microbial forensic investigations are generally conducted in parallel, and over time they may converge and diverge. The course of the investigation, will be influenced by whether the attack is overt or covert and especially by whether investigators are in possession of the utilized strain. Figure 4 – Characterization of a suspect occurrence investigation stages. Source: Sjodin A et al: The need for high-quality whole-genome sequence databases in microbial forensics. Biosecur Bioterror 2013 [50] 13 3. Biological Resources Concerning agents and diseases Different health-related organizations have distinct lists of pathogens of concern regarding biological threat agents. While there is an extensive list of pathogens identified as agents of interest, there are a few which are considered to have a higher risk of being used as biological or agricultural weapons. The criteria for such classification[8] are:  highly pathogenic or highly infective;  broad dispersion or availability;  low levels of immunity to the agent in the target population;  overall negative effects of their release, regarding biologic and economic sectors;  not posing a threat to the perpetrator;  predictable clinical course;  passible of being attributed to a natural outbreak.[60] The agents of interest change, according to our focus on human or animal threat potential (Figure 5). Domestic animal pathogens are primarily considered from the perspective of economic trade impacts and/or ease of transmissibility. Whereas human pathogens are considered mainly from the perspective of potential mortality rates and/or public fear of the disease.[17] Agents/diseases overview According to the list of critical biological agents for public health preparedness created by the American Centres for Disease Control (CDC), on the next section follows an overview of the most relevant ones, concerning the purposes of this report. CDC’s list classifies agents in three categories (A, B, C) according to:  their ease of transmission;  associated morbidity and mortality;  likelihood of use. Figure 5 – Examples of linkages between important diseases of wildlife, domestic animals and humans. Source: Friend M; Biowarfare, Bioterrorism, and Animal Diseases as Bioweapons. In: Disease Emergence and Resurgence: The Wildlife-Human Connection. Circular 1285 (2006) - Modified MERS-CoV 14 Anthrax (Category A) Anthrax is the disease caused Bacillus anthracis, a bacterial zoonotic agent, which can be transmitted through inhalation or ingestion.[14] Despite being endemic in some areas of the world, it usually causes a limited number of animal cases and, quite rarely, human cases. Its prevalence has decreased consistently in the last few years.[40] In the past, anthrax has been used as a biowarfare resource. Namely, during WWI when Germany targeted horses, reindeers, mules and cattle in the US, Spain, Norway, and France with unknown, although possibly successful, results.[60] Also, in 1978-80 in Rhodesia (now Zimbabwe), anthrax was introduced by the Rhodesian security forces as an attempt to undermine the moral of those seeking freedom, through the destruction of cattle populations.[60] In 2001, an unknown perpetrator sent “anthrax letters” to strategic targets in the US, killing five people and infecting 17 others.[41] More recently, in May 2016, Kenyan Intelligence Services foiled an attack by an ISIS group which intended to release Anthrax spores on civilians, through a “large-scale” attack.[22] Plague (Category A) Plague is caused by Yersinia pestis, which is a zoonotic, vector-transmitted bacteria, that can also be transmitted through inhalation.[14] The plague pandemic that swept through Eurasia and North Africa in the mid-XIV century was probably the greatest public health disaster in recorded history. Given the explosive nature and history of disease spread over wide areas, plague could be a dangerously effective biological weapon. In fact, during WWII, Japan successfully initiated a plague epidemic in China through the release of 15 million laboratory-infected fleas per attack from aircraft over Chinese cities[17]. Plague continues to be a life-threatening disease unless detected and treated early. Following the reappearance of the disease during the 1990s in several countries, plague was categorized as a re-emerging disease, and remains of great significance under the International Health Regulations (2005), as a plague outbreak may constitute a public health emergency of international concern.[2] Smallpox (Category A) Smallpox, also known as Variola, is caused a poxvirus and is exclusively a human disease.[14] It was the first disease to be declared eradicated, in 1980. This was achieved through focused surveillance and ring-vaccination. The guidance and support provided by Pan-American Health Organization and WHO were decisive. After its official certification as eradicated, an agreement was reached under which all remaining stocks of the virus would either be destroyed or passed to one of two secure laboratories – one in the US and another one in the Russian Federation.[59] 15 Tularemia (Category A) Tularemia is the disease caused by Francisella tularensis bacteria. It is a zoonotic, vector-borne disease, that can also be transmitted through direct contact, inhalation and contaminated food and water.[14] It is one of the most infectious pathogenic bacteria known, requiring inoculation or inhalation of as few as 10 organisms to initiate human infection. It occurs widely in nature and can be isolated and grown in quantity in a laboratory, although manufacturing an effective aerosol weapon would require considerable sophistication. However, person-to-person transmission is uncommon and the dispersion of F. tularensis as a weapon would be unlikely to generate secondary human cases or persist within targeted human population.[7] There are reports from the beginning of the XXI century which describe the release of tularemia-infected squirrels in order to initiate epizootics and reduce small rodents populations.[17] Botulism (Category A) This disease is caused by Clostridium botulinum’s toxin and affects both humans and livestock. It can be present in contaminated food and water or be inhaled.[14] Botulism seems to be increasing in cattle, possibly due to the increase in use of plastic-packaged grass silage - these outbreaks can cause significant economic losses.[51] Human botulism is a serious but relatively rare paralytic disease. There are seven recognized types of the toxin that cause botulism, four of which (types A, B, E and rarely F) cause human botulism. Types C, D and E also cause illness in mammals, birds and fish.[2] Clostridium botulinum neurotoxin, especially A type, is one of the most lethal natural substances known.[34] Viral Haemorrhagic Fevers This name is a general term for severe illness, sometimes associated with bleeding, that may be caused by a number of viruses. These agents fall into different categories, according to CDC classification. The term is usually applied to disease caused by Arenaviridae (Lassa fever, Junin and Machupo), Bunyaviridae (Crimean-Congo haemorrhagic fever (CCHF), Rift Valley Fever, Hantaan haemorrhagic fevers), Filoviridae (Ebola and Marburg) and Flaviviridae (yellow fever, dengue, Omsk haemorrhagic fever, Kyasanur forest disease)[59]. Some of these are zoonotic diseases, most of them vector-borne (mosquitos, ticks, rats and bats), which also can be transmitted through direct contact between infected humans. and affect non-human primates and guinea pigs.[14] Surprisingly, most of these diseases do not cause significant clinical signs on their animal hosts, but can be fatal to humans.[3] The following paragraphs will cover the most relevant ones for the purposes of this report. CCHF (Category C) CCHF is an expanding tick-borne disease with increasing human and animal health impact. It can cause severe outbreaks in humans, with high mortality rates, but is asymptomatic in cattle and ruminants, which act as amplifying hosts and reservoirs for human infection.[2] It is endemic 22 4. Role of International Organisations and its mechanisms for coordinating efforts United Nations United Nations Organization has specific bodies assigned to deal with biological threats and disaster prevention and relief. The United Nations Office for Disarmament Affairs (UNODA) works on the promotion of disarmament as a means to achieve global peace. It supports the implementation of BTWC through a specific unit and raises awareness to the importance of disarmament issues. The UNODA works at a very high level, creating opportunities for governments to reach diplomatic agreements, and also at the field in specific missions. Besides, the UN Secretary General Mechanism for Investigation of Alleged use of Chemical and Biological Weapons conducts field operations to ensure that BTWC dispositions are fulfilled. The BTWC is revised periodically and the 8th Review Conference will take place in Geneva, in August 2016.[32] UNISDR is the UN Office for Disaster Risk Reduction. It promotes the coordination of efforts to ensure that natural disasters and deliberate attacks have the least possible consequences, through the improvement of preparedness, establishment of frameworks and avocation of cooperation between governments and organizations. Currently, the UNISDR is campaigning very actively in the application of Sendai Framework 2015 – 2030. This is a disaster risk reduction programme, which emerged from a voluntary agreement between nations, supported by the UNISDR. It is based on seven pillars, and its main goal is ‘The substantial reduction of disaster risk and losses in lives, livelihoods and health and in the economic, physical, social, cultural and environmental assets of persons, businesses, communities and countries’[52]. WHO The WHO is an organisation which falls under UN institutions. International Health Regulations (IHR), which entered into force on 15th June 2007, are WHO’s legal instrument for safeguarding public health - they require countries to report certain disease outbreaks and public health events to WHO.[35] Also, the OIE and FAO work closely with the WHO to improve the ability of National animal and public health systems to respond to current and emerging animal health risks with public health consequences.[9] Together, these organizations form a Tripartite Alliance which essentially addresses high priority transversal issues, such as rabies, zoonotic influenza and antimicrobial resistance. All the previously mentioned activities fall under the One Health framework. 23 FAO The FAO is the UN body responsible for the achievement of food security, eradication of hunger and malnutrition, and driving forward of economic and social progress, mainly in developing countries. FAO’s activities address many overlapping animal health issues, since animal products do not only represent a source of high-quality food, but are also a source of income for many small farmers and animal holders in developing countries. FAO supports countries’ capacity development to achieve their own goals in food security, nutrition and agricultural development. [16] OIE The OIE was created in 1924, before the United Nations, to assemble an appropriate response to the Rinderpest pandemics ravaging throughout Europe. The organisation plays an important role in minimising animal and public health risks attributable to zoonosis and other animal diseases, which can have severe consequences for global food safety and security.[9] Also, the OIE promotes animal welfare, while creating standards for safe trade of animals and their byproducts.[39] In 1995, the standards developed by the OIE were recognised by the Agreement on the Application of Sanitary and Phytosanitary Measures (SPS Agreement) of the WTO. SPS Agreement’s goal is to minimise the risk of importing pathogens and to remove unjustifiable sanitary restrictions to international trade. Hence, an importing country can only apply sanitary measures to imports if a similar level of protection is applied internally and to all imports. Member countries may introduce standards providing a higher level of protection than that provided by OIE standards if they have a scientific justification and had performed sciencebased risk analysis.[53] The National Veterinary Services which implement OIE animal and welfare standards and other measures, are the first line of defence against zoonotic and other animal diseases, and must meet the core requirements for its diagnostic and control. The OIE provides assistance to its member countries through ‘PVS Pathway’ initiative, which shifts the emphasis from short-term, emergency-type approaches, to improving veterinary services towards a more sustainable, long term strengthening of capabilities and resources.[9] Regarding disaster risk reduction and preparedness, OIE summoned a roster of experts on the theme to assemble an ad hoc group, whose purpose was to a set of guidelines to be applied in disaster management. These guidelines provide a framework that veterinary professionals can use to develop processes and procedures for managing the veterinary sector’s actions to reduce the adverse consequences of disasters as they outline guiding principles and the roles that Veterinary Services play in reducing the impact of disasters in all phases of the Disaster Management Cycle.[39] 24 Funds, Programmes, Solidarity The UN System comprises several institutions devoted to promoting international financial stability and to supporting capacity building in developing countries, such as the International Monetary Fund and the World Bank Group. These institutions are financed by Member Countries and external donors. Besides, some countries have their own programmes oriented to disaster reduction and relief. Some of these programmes work well over borders to help struggling countries and to donate to specific UN bodies, such as UNDC, UNDP, FAO, etc. The OIE has its own solidarity fund - The OIE World Animal Health and Welfare Fund. It was created on 2004 by the OIE World Assembly of Delegates and has been established ’for the purpose of projects of international public utility relating to the control of animal diseases, including those affecting humans, and the promotion of animal welfare and animal production food safety’.[39] The OIE World Fund’s goals are: to improve governance of animal health systems, to modernise existing national veterinary legislation, to develop veterinary education and to develop tools which empower Members to deal with urgent situations regarding the prevention and control of animal diseases (e.g. vaccine banks, communication programs). Also, it aims to improve the animal health scientific community worldwide through laboratory twinning projects, twinning projects on veterinary education, and twinning projects between veterinary statutory bodies. Lastly, it offers the PVS Evaluation Missions to improve compliance of Member Countries with OIE standards. [39] Global Health Security Agenda GHSA is a programme, launched in February 2014, endorsed by 50 nations and several organizations. It acknowledges the essential need for a multilateral and multi-sectoral approach to strengthen both the global capacity and nations' capacity to prevent, detect, and respond to infectious diseases threats whether naturally occurring, deliberate, or accidental. GHSA is facilitating collaborative, capacity-building efforts to achieve specific and measurable targets in biological threat reduction area, while accelerating achievement of the core capacities required by the WHO’s IHR, the OIE’s Performance of Veterinary Services Pathway, and other relevant global health security frameworks. It is comprised of Action Packages, subscribed by countries, which are sets of goals related to a pressing issue, to be achieved in a 5 year timeframe. Also, it offers an Assessment Tool, to measure countries’ status and progress in building capacity. This partnership is led and supported by a GHSA Steering Group composed of 10 member nations. In addition to individual countries, advisory partners include the WHO, the FAO and the OIE, Interpol, the Economic Community of West African States, the UNISDR, and the European Union. 25 Surveillance, Monitoring and Early Response Animals play an important role as biosensors for accidental or deliberate releases of infectious agents and toxins, and for emerging diseases. The same disease surveillance and intelligence systems that are in place to detect day-to-day occurrences of natural outbreaks in animals within countries and at national borders, will also detect deliberate and accidental releases.[36] The OIE Animal Health and Information System gathers daily data from around the world. The information is predestined at decision makers and other stakeholders, to enable them to take the necessary preventive measures. Under this system, the occurrence of a disease must be reported as soon as possible (within 24 hours) to the OIE Headquarters, which then redirects the information through appropriate channels.[53] The response to disease is the same whether it is directed against natural infection and deliberate or accidental release. In the case of zoonotic diseases, coordination of the animal health and public health response is essential, and control is often more successful if focused on eliminating or controlling the pathogen at the animal source.[36] Warning systems provide a worldwide surveillance network for the early detection and rapid reporting of any suspicious disease occurrence that is natural or could have its origin in an act of bio/agroterrorism. Currently, the ‘Global Early Warning System for major disease including zoonosis’ (GLEWS) is one of the mechanisms used together by the OIE, FAO, and WHO for monitoring health data from existing event-based surveillance systems and to track and verify relevant animal and zoonotic events.[15] However, GLEWS is not the only existing system for input of diseases epidemiological knowledge. Some other unofficial platforms, such as ‘ProMed’ (by the International Society for Infectious Diseases) and ‘Epicore’ (a newer tool by the same institution) use networks of professionals spread all over the world to communicate disease occurrence suspicions and to do rumour tracking. The early detection of high-risk diseases is, in most of the cases, done by suspicious field clinicians. That type of surveillance should be encouraged through regular educational sessions aimed at field players. The sensitiveness of surveillance networks may be greatly increased through analysis and modelling efforts, in order to guide and concentrate the surveillance activities.[13] When there is suspicion of malicious release, collaboration with law enforcement agencies becomes an important part of the response. Recent events (e.g. Ebola outbreaks in West Africa) have shown that in the absence of strong well governed health systems, infectious disease can rapidly spread and get out of control with devastating consequences and heightened risk for the whole world. It is much smarter and more economically viable to provide sustainable funding for animal and public health services than to deal with a large outbreak which has got out of hand because a national detection and response was insufficient. [36] 26 Unfortunately, pockets of civil instability continue to emerge in different parts of the world. This may exacerbate the risk of infectious disease threats since civil instability often leads to health systems falling apart. Infectious disease may also lead to instability because it may damage micro and macro economies or it may lead to reduction in food supply, both of which can motivate people to take unprecedented and unpredictable actions.[36] In order to respond promptly to crisis situations, the FAO and OIE launched jointly in 2006 the ‘Crisis Management Centre – Animal Health’. It works closely with the GLEWS and the ‘Emergency Prevention System’ to continuously track and analyse the animal disease situation worldwide missions to countries to help assess epidemiologic situations, diagnose outbreaks of animal diseases, and set up immediate measures to prevent or stop disease spread.[35] On what concerns human health, WHO has developed a comprehensive ‘event management system’ to verify critical information about outbreaks and ensure accurate and timely communications between key international public health professionals, including WHO Regional Offices, National Services, collaborating centres and partners in the Global Outbreak Alert and Response Network.[59] Laboratory safety Expert investigations carried out by health authorities are needed to establish the cause of a disease outbreak and veterinary laboratories are often the first to discover its source.[36] A veterinary laboratory is held accountable for a range of issues apart from the delivery of basic diagnostic services. These may include health and safety, biosecurity, animal welfare and ethics, environmental contamination, genetic manipulations and quality assurance. In addition to general health and safety issues, veterinary laboratories have the responsibility of containing pathogens and preventing their accidental release. Laboratory biological risk management practices should specifically recognise the potential for bioterrorist threats including the concept of the insider threat (e.g. the bioterrorist threat posed by a staff member).[38] Veterinary laboratories and other animal related facilities routinely handle biological materials that may constitute or contain infectious agents and toxins, which may cause adverse animal or public health and economic effects, due to uncontrolled release inside or outside the laboratory. Laboratory and animal facilities managers are responsible for providing a management system that ensures safe and secure handling, storage, and transport of these biological materials (a biological risk management system).[38] The laboratory is expected to perform a risk analysis process, as shown in Flowchart 1 (Annexes). Laboratory facilities are categorized as basic – Biosafety Level (BSL) 1; basic – BSL 2; containment – BSL 3; and maximum containment – BSL 4. BSL designations are based on a 27 combination of the design features, construction, containment facilities, equipment, practices and operational procedures required for working with agents from the various risk groups. It is available in Annexes section a table (Table 1) where laboratories and agents characteristics regarding BSL classification are described in further detail. There is a correspondence, although not direct, between agents’ CDC risk group (A, B and C) and the required BSL of laboratories working with them. Thus, the assignment of a BSL takes into consideration the pathogenic agent, the facilities available, and the equipment practices and procedures required to conduct work safely in the laboratory.[57] 28 5. Reality check Concerning issues Globalisation has made it far more difficult to keep animal diseases from spreading, and almost impossible to keep highly infectious diseases controlled.[1] Opposed to what happened with previous pandemics, such as bubonic plague or Spanish flu, which took months to spread, recent events like SARS and avian flu indicate that today’s pathogens either are more easily spread or have more opportunities to do so. Currently, we are witnesses of the coexistence of intensive farming methods, including the centralization of animal markets and high-density livestock rearing, with traditional agriculture. This reality may provide the ideal opportunity for the emergence of new pathogens and their quick spread through animal and human populations. However, many developed nations have not experienced a major human or animal disease outbreak in over half a century – meaning that their people and governments are unused to coping politically and socially with large-scale infectious disease, whether it may be natural or intentionally caused.[1] Since the beginning of the XXI century, a variety of extremist groups has shown interest in using biological weapons. Although, so far, most of their attempts have ended in failure, the 2001 ‘anthrax letters’ episode, in the US, exemplifies how it is certainly conceivable that these actors might attain biological weapons offensives. Also, it is expected that they might employ or target animals as part of their implementation of a terrorist attack, due to the economic consequences that such action might bring.[1] Additionally, rapid developments in synthetic biology and the advent of microbiological kits may improve capabilities of both state and non-state actors, regarding biological warfare. No terrorist has ever synthesised a pathogen from scratch, but this does not mean it will never happen.[1] There is a general concern that synthetic biology will lead to further simplification of laboratory work protocols and that, combined with open access to the genomic DNA sequences of pathogenic organisms, and the reduction of price for DNA synthesis, will make biology increasingly accessible to people operation outside well-equipped professional research laboratories, including people with malevolent intentions.[23] Human threats are even more dynamic than evolutionary factors, in that human beings can adapt their behaviour instantaneously, can strategize to avoid defences and can concentrate their efforts on vulnerabilities.[1] Nowadays, synthetic biology has been subject to a common narrative, supported by public health officers and government actors, regarding the biosecurity threat it poses. This framing may lead to some misconceptions, mainly from a public opinion 29 perspective. It is believed that, besides simplifying biology and making it accessible for common people without special facilities, the growth of Do-It-Yourself biology may offer dual-use knowledge. Also, the decrease in price of DNA synthesis would make it easier to create new pathogens, which could be used as biological weapons for high consequence, mass casualty attacks.[23] Myth busters Experts on biological threats studies, such as Sonia Ben Ouagrham-Gormley and Katherine Vogel, defend that the previously mentioned views overestimate the real bioterrorist threat. [23, 43] Due to their technical complexity and high developmental costs, as well as their reliance on living microorganisms that are highly sensitive to their environmental and handling conditions, the attempted use of biological agents is unpredictable in its outcomes. As shown by past governmental programs and independent terrorist plans — the failures in the developmental process cause extensive delays in program advancement. Furthermore, the stages of a bioweapon lifecycle — research, development, production, scale-up, weaponization, and testing — are highly interdependent, and the successful passage from one stage to the next requires organizational and managerial conditions that promote coordination, cooperation, and information exchange among the various teams of experts involved, which are particularly difficult to achieve. As a result, most past state and non-state bioweapons programs have been unsuccessful at reaching their goals.[23, 43] Perhaps, the most important point in the analysis of the possible development of synthetic biological agents is the consideration of how ‘tacit knowledge’ is implied in the process. Broadly, tacit knowledge refers to skills and techniques that cannot be readily codified but, rather, acquired by a process of ‘learning by doing’ or ‘learning by example’ and often take considerate time and effort to gain.[23] Training by experienced professional researchers and specialist skills acquired by trial and error, as well as the enculturation in laboratory practices, are still highly relevant to the success of synthetic biology projects.[23] On what concerns DNA synthesis, the public opinion disquietude about online orders of DNA sequences by common individuals – the de novo synthesis of poliovirus in 2002 and the “reconstruction” of Spanish flu virus in 2005 – specialists’ opinion is reassuring. Firstly, it is important to differentiate the synthesis of oligonucleotides (less than 100 nucleotides is length), from “gene synthesis” (de novo synthesis of “gene-length” DNA sequences, typically 200 to 3000 base pairs), and from the assembly of de novo synthetized gene-length fragments into genetic circuits and whole genomes. Obtaining the oligonucleotides is only the first step in a complicated process – even specialized DNA synthesis companies cannot synthetize de novo 30 any desired DNA sequence. DNA synthesis is error prone and some sequences are recalcitrant to chemical synthesis. [23] So, we are still better at reading DNA than actually writing it. In fact, the real challenge regarding the creation or virulence and transmissibility enhancement of biological agents is not their DNA synthesis, but rather the assembly of DNA fragments.[23] It is a painstakingly difficult process that requires expertise, adequate laboratory materials and a seemingly infinite succession of trial and error experiments, in order to build a functional genome, instead of constructing a genome-sized DNA fragment. Besides, although this cannot be taken as a definitive rule, as viruses suffer passages though host organisms during their production process in the laboratory, they tend to accumulate mutations that generate an attenuated strain. Similarly, bacteria cultured in laboratories tend to lose virulence.[23] Given these points, it is clear that public opinion and some governmental statements overlook significant difficulties faced with the process of designing or producing a pathogen, as they focus mainly on material features. Thus, missing important socio-technical factors, such as tacit knowledge and DNA synthesis and assembly specificities that go beyond currently automated processes, might be a gullible perspective.[23] 31 6. Conclusions Writing this report was a great opportunity to extend my knowledge to an unlikely field relating to Veterinary Medicine. While doing my research, I found myself rephrasing the report’s title several times, as my perception on the subject changed, and so changed the focus I wanted it to have. All things considered, the threats which humans, animals and the environment face, regarding biological agents are broad on their nature, on their sources, and on their likely impact and duration. The bioterrorist threat definitely exists, although it may not be as easily achievable as one might think, due to the technical constraints related to creating ‘weapons’ and not only ‘pathogens’. In fact, this type of threat ends up taking a bigger toll on one’s psyche than on concrete matters, due to the unpredictability associated with isolated individuals or with small extremist groups, rather than populations – which have foreseeable behaviour patterns. Moreover, the threat posed by laboratories and investigation centres must be carefully weighed in. Despite the application of strict biosafety rules, accidents have happened more than a few times. Although this may seem unavoidable or poorly relevant regarding the amount of existing facilities, that is not the case. One release or accidental escape of a highly virulent pathogen, for which quick response systems are not prepared, may represent the trigger of a pandemic. Additionally, the deliberate or accidental introduction of new species of animals and plants can disrupt entire ecosystems. Previous deliberate introductions have resulted in sanitary chaos, due to the lack of foresight regarding their evolution in the new environment. Also, accidental introductions tend to occur more frequently, due to increased international trade and increased transportation of people around the globe. In the final analysis, the importance of efficient surveillance methods and quick response strategies cannot be overstated. It may seem more relevant to be prepared for specific threats, for their consequences are already well known among us. However, the biggest turning points in history have been unexpected events. Thus, it makes sense to be prepared to the unexpected, through generalist surveillance systems and simulation exercises which involve stakeholders from different fields of knowledge, able to perform diverse response types, besides the traditional contingency plans aimed at specific disease events. “This idea that in order to make a decision you need to focus on the consequences (which you can know) rather than the probability (which you can’t know) is the central idea of uncertainty.” Nassim Nicholas Taleb, The Black Swan: The Impact of the Highly Improbable 38 Internship projects Technical disease cards updated Disease Last updated in African Horse sickness 2013 African swine fever 2013 Bluetongue 2013 Bovine babesiosis 2013 Classical swine fever 2009 Contagious bovine pleuropneumonia 2009 Contagious caprine pleuropneumonia 2009 Dourine 2013 Epizootic haemorrhagic disease 2009 Equine piroplasmosis 2009 Foot and mouth disease 2013 Glanders 2013 Haemorrhagic septicaemia 2013 Heartwater 2009 Highly pathogenic avian influenza 2009 Japanese encephalitis 2013 Lumpy skin disease 2013 Malignant catarrhal fever 2013 Newcastle disease 2013 Nipah (virus encephalitis) 2009 Peste des petits ruminants (TDC + DIS) 2013 Rabbit haemorrhagic disease 2015 Rabies 2014 Rift Valley fever 2009 Rinderpest (TDC + DIS) 2013 Screwworm 2013 Sheep pox and goat pox 2013 Swine influenza 2009 Swine vesicular disease 2013 Theileriosis 2009 Trypanosoma evansi infections (including SURRA) 2013 Trypanosomosis (tsetse-transmitted) 2013 Venezuelan equine encephalitis 2013 Vesicular stomatitis 2013 MERS-CoV Factsheet 2014 http://www.oie.int/en/animal-health-in-the-world/technical-disease-cards/ 39 “Biothreat Watch” newsletter Biothreat Watch, Issue 1, Jan – May 2016 General  Insights into the preparation of BWC review Jan/Feb 2016 http://www.armscontrol.org/ACT/206_0102/News/BWC-Parties-Prepare-for-Review-Meeting  New Developments in Biological and Chemical Terrorism Countermeasures; Ronald J. Kendall, Steven M. Presley, Seshadri S. Ramkumar, CRC Press, Feb. 2016 - 185 pages https://books.google.fr/books?id=l3SmCwAAQBAJ&hl=fr&source=gbs_navlinks_s  Preparing for non-traditional biothreats Feb 2016 http://online.liebertpub.com/doi/pdfplus/10.1089/hs.2015.0045  Contextual Factors Among Indiscriminate or Large Attacks on Food or Water Supplies, 1946- 2015 Feb 2016 http://online.liebertpub.com/doi/pdfplus/10.1089/hs.2015.0056  From over 90 000 cases to zero in two decades: the European Region is malaria free Apr 2016 http://www.euro.who.int/en/media-centre/sections/press-releases/2016/04/from-over-90- 000-cases-to-zero-in-two-decades-the-european-region-is-malaria-free  The Department of Homeland Security Will Test Bioterror Airflow in New York Subway System May 2016 http://nymag.com/daily/intelligencer/2016/05/dhs-will-test-bioterror-airflow-in-nyc- subway.html# Diagnostic methods  Expansion of Microbial Forensics. Schmedes SE, et al. J Clin Microbiol. Feb 2016. Unofficial online version) https://www.researchgate.net/search.Search.html?type=publication&query=Expansion%20of% 20Microbial%20Forensics&tabViewId=57309dfded99e1394a514117&previous=researcher  Are public health microbiology laboratories in the European Union prepared for tracking infectious diseases? The first EULabCap report published, Feb 2016 http://ecdc.europa.eu/en/press/news/_layouts/forms/News_DispForm.aspx?ID=1359&List=8db 7286c-fe2d-476c-9133- 18ff4cb1b568&Source=http%3A%2F%2Fecdc.europa.eu%2Fen%2Fhealthtopics%2Fmicrobiology %2Fmicrobiology-activities%2Flaboratory-capability%2FPages%2Fdefault.aspx  Dong, M., et al. (Mar 2016), Standardized methods to generate mock (spiked) clinical specimens by spiking blood or plasma with cultured pathogens. J Appl Microbiol, 120: 1119– 1129. doi:10.1111/jam.13082 (The development of diagnostic platforms for detection of low prevalence pathogens such as biothreat or emerging agents is challenged by the lack of clinical specimens for performance evaluation. This deficit can be overcome using mock clinical specimens made by spiking cultured pathogens into human matrices.) http://onlinelibrary.wiley.com/doi/10.1111/jam.13082/abstract?systemMessage=Wiley+Online +Library+will+be+unavailable+on+Saturday+14th+May+11%3A00- 14%3A00+BST+%2F+06%3A00-09%3A00+EDT+%2F+18%3A00- 21%3A00+SGT+for+essential+maintenance.Apologies+for+the+inconvenience. 40  Mass spectrometry for the detection of bioterrorism agents: from environmental to clinical applications. Duriez E, et al. Mar 2016 http://www.ncbi.nlm.nih.gov/pubmed/26956386 (Restricted access)  First Commercial Zika Virus Test Gets FDA Approval, May 2016 http://globalbiodefense.com/2016/05/02/first-commercial-zika-virus-test-gets-fda-approval/ Emerging Diseases/ Emerging threats  Kenyan Police 'Foiled' Anthrax Attack Linked to IS Group, May 2016 http://www.voanews.com/content/kenyan-police-foiled-anthrax-attack-linked-to-is- group/3315042.html  European Union SHIPSAN ACT Joint Action publishes interim guidance on maritime transport and Zika virus disease http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=21453  Zika virus: 2.2 billion people in 'at risk' areas http://www.bbc.com/news/health-36090650  Edmonds, J et al. “Multigeneration Cross-Contamination of Mail with Bacillus Anthracis Spores.” Ed. Raymond Schuch. PLoS ONE 11.4 (2016): e0152225. PMC. Web. 9 May 2016. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849716/  Zeitlin, Larry et al. “Monoclonal Antibody Therapy for Junin Virus Infection.” Proceedings of the National Academy of Sciences of the United States of America 113.16 (2016): 4458–4463. PMC. Web. 9 May 2016. (Argentinian Haemorrhagic Fever) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843420/?report=classic Vaccines  Eurosurveillance, Volume 21, Issue 6, 11 February 2016 - News European Commission Horizon 2020 programme call for vaccine development research into malaria and neglected infectious diseases, including Zika virus http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=21376  Infographic about Zika vaccine development process March 2016 http://blog.dicksondata.com/2016/03/vaccinating-a-pandemic-the-hurdles-ahead-for-the-zika- virus/  Zika vaccine efficacy trials could start in 2017, May 2016 http://www.sciencemag.org/news/2016/05/zika-vaccine-efficacy-trials-could-start-2017  Defending against smallpox: a focus on vaccines, Emily A. Voigt et al. (Restricted Access) Expert Review of Vaccines http://www.tandfonline.com/doi/abs/10.1080/14760584.2016.1175305?journalCode=ierv20  Pakistan polio: Seven killed in anti-vaccination attack April 2016 http://www.bbc.com/news/world-asia-36090891  Particulate delivery systems for vaccination against bioterrorism agents and emerging infectious pathogens. Fan, Y. and Moon, J. J. (April 2016), WIREs Nanomed Nanobiotechnol (Preview available) http://onlinelibrary.wiley.com/doi/10.1002/wnan.1403/abstract?systemMessage=Wiley+Online +Library+will+be+unavailable+on+Saturday+14th+May+11%3A00- 41 14%3A00+BST+%2F+06%3A00-09%3A00+EDT+%2F+18%3A00- 21%3A00+SGT+for+essential+maintenance.Apologies+for+the+inconvenience. Events  14th Annual CDC International Symposium on Biosafety, Jan 30 – Feb 3, 2016, Atlanta, USA. “Biosafety Management: Planning for the Future by Learning from the Past” was this year’s theme. http://globalbiodefense.com/event/cdc-international-symposium-on-biosafety-2016/  The American Society of Microbiology Biodefense and Emerging Infectious Diseases 2016 Research Meeting Feb 8-10, 2016 in Arlington, Virginia, USA. http://www.asmbiodefense.org/  15th Medical Biodefense Conference Apr 26-29, 2016, Munich, Germany. It focused on medical aspects of biodefense, presenting the latest research findings and products in the areas of diagnostics, treatment and prevention of diseases caused by highly dangerous infectious agents. http://www.biodefense2016.org/#sthash.UbR5VOWj.dpuf  14th Annual Vaccines + Therapeutics Conference 2016 – “Biodefense, AMR, Emerging Infectious Diseases”, May 17-19, Washington DC, USA http://www.infocastinc.com/downloads_pdf/vaccines-therapeutics-2016-summit-agenda.pdf  NCT CBRNe USA 2016, May 31st – June 2nd http://cbrneusa.com/program/  World Conference on Disaster Management , June 7-8, 2016 in Toronto, Canada. http://www.wcdm.org/programs.html  The 12th International Symposium on Protection Against Chemical and Biological Warfare Agents, CBW Symposium 2016, will be held June 8-10, 2016 in Stockholm, Sweden. http://www.foi.se/en/Our-Services/Conferences-and-Seminars/12th-CBW-Protection- Symposium/  Preventing & Treating Biological Exposures – An Occupational Health Colloquium on June 13- 15, 2016 in Austin, Texas. Hosted by the Eagleson Institute, in partnership with the Elizabeth R. Griffin Research Foundation http://www.eagleson.org/conferences/occupational-health- colloquium  2nd Biodefense World Summit, June 27 – 30, Baltimore, USA http://www.biodefenseworldsummit.com/ Collaborating Centres Activities  Overview of the CSIRO Australian Animal Health Laboratory Lowenthal, John (Restricted access) Journal of Infection and Public Health , Volume 0 , Issue 0 http://www.jiph.org/article/S1876-0341%2816%2930024-7/abstract 42 OIE Bulletin article IVSA Animal Welfare Conference Utrecht, The Netherlands, 22-24 April 2016 The International Veterinary Students Association (IVSA) is a non-profit organization of veterinary students, representing approximately 30,000 students in more than 60 countries. Among its core objectives are raising the overall standards of veterinary education, supporting measures to improve the standard of animal welfare worldwide and encouraging cooperation between members, veterinary student associations and international organizations. In 27th May 2014, IVSA and the OIE signed a cooperation agreement. This document promotes the collaboration of the parties in common interest areas, such as veterinary education, animal welfare and in the scope of IVSA Standing Committee on One Health. Also, both parties agreed to invite the other to conferences and consultancies in which common interests would be addressed. With the support of the OIE, IVSA organized its first Animal Welfare Conference. This 3 day event was aimed at students from all over the world who have a special interest in this area. It represented an opportunity to learn about the current projects and research on this field, as well as to understand the role several organizations play in the welfare of animals and improving animal housing and transportation conditions, as well as raising the standards of animal welfare. Also, the conference allowed students to interact with representatives from international organizations, veterinary and other federations and associations, academia, policy makers and colleagues in general. The event was attended by around 150 students and recently graduated veterinarians, representing the five continents, and had the participation of 22 speakers. The OIE was represented by Dr Alex Thiermann (former President of the OIE Code Commission), who gave a lecture on the implementation of OIE welfare standards worldwide. Dr Thiermann talked about the pioneer role of the OIE in the organization of Global Animal Welfare Conferences, the evolution of the subjects addressed in each conference and the inclusion of aquatic animal welfare. Also, the roles of each Scientific Commission were explained, with special attention to Aquatic Animal Health Standards Comission, and the broad spectrum of topics it comprises. In addition Dr Sirah Abdul Rahman, also represented the OIE and provided a point of view with respect to animal welfare and religious practices. Participants found the event to be a success, especially regarding the presentations given by speakers from backgrounds other that veterinarian. The conference allowed to meet other cultures perspectives and realities on animal welfare and opened doors for future cooperation. 43 Cross referencing list 44 45 46 Other projects Not yet online  PPR portal  Rinderpest portal  Biothreat reduction strategy portal Confidential  Laboratory twinning database  Biothreat reduction conference – related research