Climate change and antimicrobial resistance (AMR) are complex challenges that pose significant threats to society. The triple planetary crisis of climate change, pollution and impacts on biodiversity, highlighted by the UN, are likely to impact AMR emergence and transmission. It is essential to account for the social, cultural and physical environments of AMR, including the impacts of climate change. Increasing temperatures and changing patterns of rainfall will affect AMR evolution and transmission, patterns of migration, and will change food production, land use and freshwater use. Conversely, antimicrobials may impact microbial geochemical cycling, such as nitrogen cycling in soils and methane production in ruminant microbiomes. These interactions raise the intriguing possibility that a bidirectional relationship exists between climate change and AMR. The Climate AMR Network (CLIMAR) will examine the relationship between climate change and AMR via a Planetary Health framework that examines AMR in terms of planetary boundaries within which humans and ecosystems can continue to develop and thrive. Network themes will include climate change, novel chemical and biological entities (including antimicrobials and AMR bacteria), impacts on microbial biodiversity, land system changes and freshwater use, all of which have mechanistic links with AMR. This Planetary Health framing builds on the One Health approach (which interweaves the health of humans, non-human animals and environments) by adding additional layers of mechanistic understanding, urgency, social dimensions and intergenerational justice, whilst also providing a transdisciplinary framework based on five Planetary Health pillars: (1) interconnection within Nature, (2) the Anthropocene and health, (3) equity and social justice, (4) movement building and systems change, and (5) systems thinking and complexity. These five Pillars will inform our activities including white paper production and research projects by focusing on key knowledge gaps in AMR, climate change and their intersection. These objectives will be informed by an initial systems mapping exercise that will identify the relationships between climate change and AMR, facilitating calibration of network objectives and incorporating input from members joining post-award. It will be necessary to ensure that CLIMAR network activities complement, rather than replicate, planned activities in all other funded networks. We aim to integrate this consideration into this network's activities from its inception. Additionally, professional communications expertise in combination with specialisation in policy development will ensure real impact and change results from network activities. Bringing a Planetary Health perspective to AMR, with a specific focus on interactions with climate change, provides an opportunity to develop AMR narratives beyond a One Health framing. The latter recognises the linkages between "human health", "animal health" and "environmental health" but does not fully convey the fundamental contribution of planetary processes or social determinants, encapsulated by the planetary boundaries and transdisciplinary pillars, to the mental models that facilitate reasoning and decision making. If we aspire to achieve transdisciplinary solutions and interventions, and to reduce AMR infections whilst promoting drug discovery and innovation of alternatives to stay one step ahead of AMR, we need evidence to support decision making as well as compelling narratives to facilitate understanding and encourage action; recognising that solutions may be found in domains that are traditionally outside the interests of AMR researchers.

Highly pathogenic avian influenza (HPAI) viruses cause substantial economic losses to the poultry industry, and pose a significant threat to animal and human health. HPAI first came to prominence in the late 1990s with the emergence from Asia of the H5N1 lineage, which resulted in the culling of 100s of millions of birds and more than 500 human deaths. HPAI resurfaced as a global threat in 2013, with the emergence in China of a novel strain belonging to subtype H5N8. The speed of global H5N8 spread since 2014 has surprised scientists. The strain spread rapidly through Asia, North America, Europe, and most recently, Africa. The spread to North America is unprecedented, at an estimated cost of ~$3.3 billion to businesses there. A report published last October concluded that H5N8 global spread was driven primarily by long-distance bird migration. Reports of H5N8 outbreaks in both wild and farmed birds across Europe increased in autumn 2016, spreading westwards until they reached the UK in late December. Cases in wild birds have been reported in Wales, Scotland and England. The largest outbreak to date is ongoing within a large population (~750) of wild mute swans in Abbotsbury, on the Dorset coast in southern England. Although only 9 swans (so far) have laboratory confirmed H5N8 infections, more than 175 untested swans have died since the start of the outbreak, vastly in excess of normal mortality. The first H5N8 infection was detected in a dead swan found at the Swannery on 23rd December 2016. Although mortality appears to have decreased from the apparent peak in the second week of January 2017, an above-normal number of dead birds are still being recovered and the outbreak is still considered to be current and ongoing by the authorities (2nd February 2017). This outbreak, whilst devastating for the bird population, could tell us much about how HPAI spreads in wild birds. The long-lived swans have been subjected to long-term ecological study by ornithologists at the University of Oxford and are individually ringed; for most birds we know age, sex, parentage and other variables. Crucially, exactly the same population suffered an outbreak of H5N1 HPAI in early 2008. However, in 2008 only 10 swans died, almost all of which were <3 years old. Our research after the 2008 outbreak showed that older birds were more likely to have antibody responses that might help give immunological protection against avian influenza. Specifically almost all birds >3 years old harbour influenza antibodies and older birds have antibodies to a broader range of different influenza strains. Thus we hypothesise that previous exposure to common, mild forms of influenza may have protected these wild birds against H5N1 infection. The current outbreak offers the potential to directly compare H5N1 and H5N8 HPAI epidemiology in the same population of wild birds, an opportunity that we think is unique worldwide. High bird mortality during H5N8 outbreaks have been reported elsewhere in Europe, and by comparing the ecology and epidemiology of the H5N8 and H5N1 outbreaks at Abbotsbury we may be able to find out the cause of this. We aim to find out how, and from where, the H5N8 virus entered the population, how long it was present locally before it was detected, and how the virus spread through the population. To do this we will sequence the genomes of the viruses recovered from affected birds, and analyse these genomes using established statistical methods. We will look at the antibodies that birds in the population carry, to see if some birds, particularly the older ones, are protected against severe disease as a result of previous exposure to harmless strains of avian influenza. This will help us understand if immunity to flu in humans and long-lived birds is similar or different, and extend our understanding of how this virus spreads in wild birds.

Pigs can get many diseases but amongst the most serious are those caused by bacteria that can live in their throats, airways or tonsils but can also cause severe lung (or brain) infections. Large numbers of animals may die quickly (acute infection) or fail to grow normally (chronic infection). Such infections cost the world's pig industry huge sums of money each year. A major problem is that such infections are difficult to diagnose. Some strains of a particular bacterium cause disease and others do not and there is no reliable method to distinguish them. Most experts agree that the best way to control the spread of bacteria is to use a vaccine. However, current vaccines are poor. They do not prevent the spread of bacteria from animal to animal and only work against a few strains. We plan to target four of the most common bacteria that cause infections in pigs: Actinobacillus pleuropneumoniae, Haemophilus parasuis, Mycoplasma hyopneumoniae and Streptococcus suis. The last of these can also cause serious disease in humans such as blood poisoning (septicaemia) and brain infection (meningitis) especially in people who work with pigs. Our aim is to develop (1) tests that can tell which strains can cause disease or not and (2) a single vaccine that protects against more than one of the pig pathogens. We will isolate bacteria from UK pigs and, using genetic techniques, find out how many different sorts of each bacterium are present. The results will be used to develop a diagnostic test and also help in choosing appropriate vaccine candidates. The work will be done in collaboration with partners in the Veterinary Laboratories Agency, Scottish Agricultural College, Agri-Food and Biosciences Institute and Huazhong Agricultural University (Wuhan, China). A successful conclusion to the project (diagnostics and vaccines) will prevent animal suffering (through reduction in infections via vaccination, early diagnosis and treatment, prevention of unnecessary treatment) and save the pig industry substantial amounts of money contributing to the prosperity of the UK.

Bovine tuberculosis (BTB) presents a significant challenge to animal and public health globally. BTB is also a significant cause of zoonotic TB (zTB), mainly in developing/low and middle income countries (LMIC) as highlighted in the recently published roadmap to zTB eradication jointly produced by WHO, WOAH and the International Union against TB & Lung Disease (UTLD). Their One Health approach acknowledged that TB eradication in animals will impact zTB in humans. Eradication could be accelerated by improved diagnostic tests that overcome limitations associated with Purified Protein Derivative (PPD) tuberculin: limited performance, standardisation, vaccine-interference. These could be overcome by defined antigens. PPDs are used both in tuberculin skin tests and blood interferon-gamma release assays (IGRA). More sensitive blood test platforms that complement the IGRA test could further enhance diagnostic performance. BTB tests primarily target cellular immunity, yet serological tests can also be useful for additional case detection. Thus, our proposal aims to address these constraints to optimise test performance in an inter-connected manner. We will conduct field validation for test sensitivity and specificity of the defined antigen formulation DST-F (fusion protein of ESAT6, CFP10, Rv3615c) in domestic ruminants (cattle, goats, buffalos) in different epidemiological settings (WP1, skin test, IGRA). Environmental exposure to mycobacteria in the farms will be also evaluated. We will develop a multi-cytokine platform (MCP) to enhance test performance beyond the current IGRA, (WP2) and also develop novel antigen capture and lateral flow assays (WP3). The performance of these innovative tests will be assessed with samples generated in WP1. WP4 will critically assess data generated in WP1-3 and provide recommendations for the optimal combinations of test platforms to accelerate BTB eradication.

Leptospirosis is the fourth most common zoonotic (transmitted from animals to man) disease worldwide and has a number of major farmed, companion and feral animal reservoirs. Vaccination has been widely used to control disease in animals and consequently incidence in humans. Each vaccine batch must be tested for potency before market release. Hamsters are particularly sensitive to leptospirosis and consequently used as a model species to test the potency of vaccine batches. Typically five vaccinated and five unvaccinated hamsters are challenged with virulent (lethal) Leptospira bacteria. Four of the vaccinates must survive and four unvaccinates must show signs of leptospirosis or die. The effects of the disease on hamsters are severe (usually death), the test is time consuming (minimum duration 40 days) and expensive. The RSPCA, pharmaceutical industry and government recognise the pressing need to replace this hamster vaccine batch potency test with a humane alternative. The current proposal seeks to replace the hamster model with alternative generic in vitro (test tube) tests. These will exploit recent technological developments in mass spectrometry enabling the analysis of large biological molecules found in vaccines. The protective components from virulent and avirulent Leptospira bacteria and a commercial vaccine preparation will be separated and detected with antibodies from vaccine immunised hamsters. Active components will be purified, identified and measured by mass spectrometry. This will enable the active components to be compared between batches of vaccines to ensure consistency. A similar approach has been attempted using antibodies to measure vaccine components but these are not widely available and the molecules they measure are poorly defined. In contrast, mass spectrometry is now widely applied across the biological sciences, such methods are transferable and analytes can be readily identified. The Veterinary Laboratories Agency has unique expertise in Leptospira vaccine batch testing and key contacts with industry. This expertise will provide a unique environment for the current project which will focus on the two component canine vaccine, the twin batch test for which is considered to be particularly severe. Dissemination of information will be a critical success factor for the uptake and implementation of any replacement test by vaccine manufactures. This will be achieved by publication in peer reviewed journals, presentation at conferences and discussion with industry contacts. Finally, this new approach to vaccine batch testing could provide an alternative to some of the 35,000 animals currently used for this purpose each year.