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Plasma activated water effects on behavior, performance, carcass quality, biochemical changes, and histopathological alterations in quail

Plasma-activated water (PAW) is an innovative promising technology which could be applied to improve poultry health. The current study investigated the effects of drinking water supply with PAW on quail behavi...

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Tryptophan regulates the expression of IGFBP1 in bovine endometrial epithelial cells in vitro via the TDO2-AHR pathway

This study aimed to identify the roles of L-tryptophan (Trp) and its rate-limiting enzymes on the receptivity of bovine endometrial epithelial cells. Real-time PCR was conducted to analyze the differential exp...

Detection and molecular characterization of major enteric pathogens in calves in central Ethiopia

Calf diarrhea is a major cause of morbidity and mortality in the livestock sector worldwide and it can be caused by multiple infectious agents. In Ethiopia, cattle are the most economically important species w...

Terminalia bellirica and Andrographis paniculata dietary supplementation in mitigating heat stress-induced behavioral, metabolic and genetic alterations in broiler chickens

Heat stress (HS) is one of the most significant environmental stressors on poultry production and welfare worldwide. Identification of innovative and effective solutions is necessary. This study evaluated the ...

Molecular evidence of hepatozoonosis in tigers of Vidarbha region of Maharashtra State of India

Hepatozoonosis has been reported in many species around the world. Few incidences have been reported in various species of wild felids. Tigers are endangered large cats and are protected under the Wildlife Pro...

The assessment of zeolite addition to diets with or without urea on some productive and physiological indicators in Awassi lambs

Interest is growing in the search for alternatives to traditional feed additives, so this study aimed to investigate the effect of adding zeolite to the concentrate diets of Awassi lambs with or without urea o...

Innovative molecular and immunological approaches of heterophyiasis infecting some Egyptian marketed fishes

Heterophyiasis is a highly endemic disease in the Nile Delta, Egypt, where people consume raw or undercooked Oreochromis niloticus and Mugil cephalus . Birds and rats play a crucial role in fish-borne zoonotic tre...

The effect of Norethisterone acetate on the uterus of albino rats: histological, histochemical and ultrastructure study

Norethisterone acetate (NETA), also known as norethindrone acetate is a progestogens medication that is widely used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological di...

Selenium elicited an enhanced anti-inflammatory effect in primary bovine endometrial stromal cells with high cortisol background

An elevated endogenous cortisol level due to the peripartum stress is one of the risk factors of postpartum bovine uterine infections. Selenium is a trace element that elicits anti-inflammation and antioxidati...

Development of polymerase chain reaction-lateral flow dipstick assay for detection of Mycoplasma bovis in cattle

Mycoplasma bovis ( M. bovis ) is capable of causing a range of diseases in cattle, encompassing calf pneumonia, arthritis, conjunctivitis, meningitis, and mastitis. It is widely recognized as one of the predominant...

Inter-laboratory comparison of eleven quantitative or digital PCR assays for detection of proviral bovine leukemia virus in blood samples

Bovine leukemia virus (BLV) is the etiological agent of enzootic bovine leukosis and causes a persistent infection that can leave cattle with no symptoms. Many countries have been able to successfully eradicat...

Unveiling the mix-up: investigating species and unauthorized tissues in beef-based meat products

Customers are very concerned about high-quality products whose provenance is healthy. The identification of meat authenticity is a subject of growing concern for a variety of reasons, including religious, econ...

Influence of an iron dextran injection in various diseases on hematological blood parameters, including serum ferritin, neonatal dairy calves

Feeding milk substitutes with low iron content or whole milk without iron supplementation is considered a major factor in developing iron-deficiency anemia in neonatal dairy calves. Young calves are often supp...

Identification of Enterococcus spp. by MALDI-TOF mass spectrometry isolated from clinical mastitis and bulk tank milk samples

Throughout a three-year study period, 1,577 bovine clinical mastitis samples and 302 bulk tank samples were analyzed from ten Brazilian dairy herds. Enterococcus spp. was isolated and identified in 93 (5.9%) clin...

Streptococcus equi subspecies equi from strangles suspected equines: molecular detection, antibiogram profiles and risk factors

Strangles, caused by Streptococcus equi subspecies equi , is a highly infectious disease of equines causing major health issues and financial losses. The aim of the study was to detect the presence of the SeM gene...

Genome characterization of Rift Valley fever virus isolated from cattle, goats and sheep during interepidemic periods in Kenya

Rift Valley fever virus (RVFV) is a mosquito-borne RNA virus of the Phlebovirus genus in the phenuviridae family. Its genome is trisegmented with small (S), medium (M) and large (L) fragments. In nature, the viru...

Intravenous injection of allogenic canine mesenchymal stem cells in 40 client-owned dogs: a safety assessment in veterinary clinical trials

The aim of this study was to evaluate the adverse effects of allogeneic mesenchymal stem cells (MSCs) transplanted via intravenous infusion in dogs and examine their safety. We performed a retrospective analys...

Green tea extract reduces viral proliferation and ROS production during Feline Herpesvirus type-1 (FHV-1) infection

Feline Herpesvirus type-1 (FHV-1) is a worldwide spread pathogen responsible for viral rhinotracheitis and conjunctivitis in cats that, in the most severe cases, can lead to death. Despite the availability of ...

Determining lactate concentrations in Korean indigenous calves and evaluating its role as a predictor for acidemia in calf diarrhea

Calf diarrhea leads to high mortality rates and decreases in growth and productivity, causing negative effects on the livestock industry. Lactate is closely associated with metabolic acidosis in diarrheic calv...

Proneurogenic actions of follicle-stimulating hormone on neurospheres derived from ovarian cortical cells in vitro

Neural stem and progenitor cells (NSPCs) from extra-neural origin represent a valuable tool for autologous cell therapy and research in neurogenesis. Identification of proneurogenic biomolecules on NSPCs would...

A study on selected responses and immune structures of broiler chickens with experimental colibacillosis with or without florfenicol administration

Colibacillosis in broiler chickens is associated with economic loss and localized or systemic infection. Usually, the last resort is antibacterial therapy. Insight into the disease pathogenesis, host responses...

Cortisone in saliva of pigs: validation of a new assay and changes after thermal stress

Cortisone is derived from cortisol through the action of the enzyme 11β-hydroxysteroid dehydrogenase type II, and it has gained importance in recent years as a biomarker of stress. This study aimed to develop ...

Toxoplasma gondii genotypes and frequency in domestic cats from Romania

Toxoplasma gondii is a zoonotic protozoan parasite with a heteroxenus life cycle that involves felids as the definitive hosts and any warm-blooded animal, including humans, as intermediate hosts. Cats are key pla...

Effects of dietary supplementation with Bacillus velezensis on the growth performance, body composition, antioxidant, immune-related gene expression, and histology of Pacific white shrimp, Litopenaeus vannamei

In recent decades, probiotics have become an acceptable aquaculture strategy for shrimp growth promotion and immune modulation. This study aimed to evaluate the effect of Bacillus velezensis on Litopenaeus vannam...

Effects of long-term dehydration and quick rehydration on the camel kidney: pathological changes and modulation of the expression of solute carrier proteins and aquaporins

Recurrent dehydration causes chronic kidney disease in humans and animal models. The dromedary camel kidney has remarkable capacity to preserve water and solute during long-term dehydration. In this study, we ...

Immunomodulatory effect of tibetan medicine compound extracts against ORFV in vitro by metabolomics

Ovine contagious pustular dermatitis (ORF) is one of the main diseases of sheep and is a zoonotic disease caused by Ovine contagious pustular dermatitis virus (ORFV) infection, posing a significant constraint ...

Feline vector-borne haemopathogens in Türkiye: the first molecular detection of Mycoplasma wenyonii and ongoing Babesia ovis DNA presence in unspecific hosts

Cats are hosts and reservoirs for many haemopathogens such as piroplasms, Rickettsia , hemotropic Mycoplasma , Bartonella , Ehrlichia , and Anaplasma , which are transmitted by various vector arthropods and some of wh...

Grazing camels under semi-extensive production system: selectivity, feed intake capacity, digestion and energy expenditure

It was proposed that camels are more effective than other livestock species in selecting plants for their nutritional value. They may self-regulate their voluntary feed intake to satisfy their nutritional need...

Meconium microbiota in naturally delivered canine puppies

Microbial colonization during early life has a pivotal impact on the host health, shaping immune and metabolic functions, but little is known about timing and features of this process in dogs. The objectives o...

Whole-genome sequencing and pathogenicity analysis of Rhodococcus equi isolated in horses

Rhodococcus equi ( R. equi ) is a Gram-positive zoonotic pathogen that frequently leads to illness and death in young horses (foals). This study presents the complete genome sequence of R. equi strain BJ13, which w...

Clinical, histopathological and phylogenetic analysis of Myxobolus lentisturalis (Myxozoa: Myxobolidae) infecting the musculature of farmed population of goldfish ( Carassius auratus ) in Iran: 2021–2022

There is a claimed increase in the global prevalence and incidence of emerging diseases observed in many organisms. Myxozoa represents an essential group of metazoan parasites that hold both economic and ecolo...

Seminal plasma removal for medium-term preservation of ram sperm at 5 °C

This study aimed to investigate if washing ram sperm from seminal plasma (SP) could be an effective tool to extend sperm lifespan in medium-term preservation in liquid form to optimize ovine artificial insemin...

Chrysosporium articulatum mimicking Trichophyton spp. infection in a cat: a case presentation and literature review

Dermatophytosis is a common skin infection of cats and many other animals. A reliable diagnosis is crucial because of the zoonotic potential of dermatophytes. The routine mycological diagnostic procedures for ...

The lipopolysaccharide structure affects the detoxifying ability of intestinal alkaline phosphatases

Lipopolysaccharide (LPS) is one of the most potent mediators of inflammation. In swine husbandry, weaning is associated with LPS-induced intestinal inflammation, resulting in decreased growth rates due to mala...

Porcine beta defensin 2 attenuates inflammatory responses in IPEC-J2 cells against Escherichia coli via TLRs-NF-κB/MAPK signaling pathway

Porcine beta defensin 2 (pBD2) is one of the porcine beta defensins that has antibacterial activity, and plays an important role in the immunomodulatory activity that protects cells from pathogens. It has been...

Whole-genome sequencing of multidrug-resistant Klebsiella pneumoniae with capsular serotype K2 isolates from mink in China

Klebsiella pneumoniae is a zoonotic opportunistic pathogen, and also one of the common pathogenic bacteria causing mink pneumonia. The aim of this study was to get a better understanding of the whole-genome of mu...

Alterations in the diversity and composition of the fecal microbiota of domestic yaks ( Bos grunniens ) with pasture alteration-induced diarrhea

Diarrhea is a common issue in domestic yaks ( Bos grunniens ) that can occur with pasture alterations and significantly impacts growth performance. Previous research has examined the microbiota of diarrhetic yaks; ...

Significance of scattered small echogenic foci floating in urinary bladder as ultrasonography finding in dogs

Despite the prevalence of echogenic foci floating in the urinary bladder seen in ultrasonography in dogs, surprisingly little has been written on its significance, including its potential association with urin...

A forecasting model for suitable dental implantation in canine mandibular premolar region based on finite element analysis

In recent years, dental implants have become a trend in the treatment of human patients with missing teeth, which may also be an acceptable method for companion animal dentistry. However, there is a gap challe...

Sildenafil-induced priapism in a dog : an unusual case report

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Probiotics are becoming increasingly popular as eco-friendly alternatives in aquaculture. However, there is limited research on their impacts on the reproductive efficiency of Red Tilapia ( Oreochromis niloticus x...

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The current study was conducted to assess the impact of different LED light colors on welfare indicators in Muscovy ducks. These welfare parameters encompassed growth performance, specific behaviors, tonic imm...

Interactive effects of water temperature and dietary protein on Nile tilapia: growth, immunity, and physiological health

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Leptospiraceae comprise a diverse family of spirochetal bacteria, of which many are involved in infectious diseases of animals and humans. Local leptospiral diversity in domestic animals is often poorly unders...

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IGF-I and GH Genes polymorphism and their association with milk yields, composition and reproductive performance in Holstein–Friesian dairy cattle

The insulin-like growth factor ( IGF-I ) and growth hormone ( GH ) genes have been identified as major regulators of milk yield and composition, and reproductive performance in cattle. Genetic variations/polymorphism...

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BMC Veterinary Research

ISSN: 1746-6148

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• Published: 06 March 2021

Research perspectives on animal health in the era of artificial intelligence

• Pauline Ezanno   ORCID: orcid.org/0000-0002-0034-8950 1 ,
• Sébastien Picault 1 ,
• Gaël Beaunée 1 ,
• Xavier Bailly 2 ,
• Facundo Muñoz 3 ,
• Raphaël Duboz 3 , 4 ,
• Hervé Monod 5 &
• Jean-François Guégan 3 , 6 , 7  

Veterinary Research volume  52 , Article number:  40 ( 2021 ) Cite this article

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Leveraging artificial intelligence (AI) approaches in animal health (AH) makes it possible to address highly complex issues such as those encountered in quantitative and predictive epidemiology, animal/human precision-based medicine, or to study host × pathogen interactions. AI may contribute (i) to diagnosis and disease case detection, (ii) to more reliable predictions and reduced errors, (iii) to representing more realistically complex biological systems and rendering computing codes more readable to non-computer scientists, (iv) to speeding-up decisions and improving accuracy in risk analyses, and (v) to better targeted interventions and anticipated negative effects. In turn, challenges in AH may stimulate AI research due to specificity of AH systems, data, constraints, and analytical objectives. Based on a literature review of scientific papers at the interface between AI and AH covering the period 2009–2019, and interviews with French researchers positioned at this interface, the present study explains the main AH areas where various AI approaches are currently mobilised, how it may contribute to renew AH research issues and remove methodological or conceptual barriers. After presenting the possible obstacles and levers, we propose several recommendations to better grasp the challenge represented by the AH/AI interface. With the development of several recent concepts promoting a global and multisectoral perspective in the field of health, AI should contribute to defract the different disciplines in AH towards more transversal and integrative research.

1 Introduction

Artificial intelligence (AI) encompasses a large range of theories and technologies used to solve problems of high logical or algorithmic complexity. It crosses many disciplines, including mechanistic modelling, software engineering, data science, and statistics (Figure  1 ). Introduced in the 1950s, many AI methods have been developed or extended recently with the improvement of computer performance. Recent developments have been fuelled by the interfaces created between AI and other disciplines, such as bio-medicine, as well as massive data from different fields, particularly those associated with healthcare [ 1 , 2 ].

Interactions between animal health (AH), artificial intelligence (AI), and closely related research domains. This illustration is pinpointing only the links between AH (in blue), AI and its main subfields (in red), and other related fields of research (in black). It can be naturally complexified through the interactions between AH and other research topics (e.g., human medicine) or between core disciplines (e.g., statistics and physics).

AI addresses three challenges that also make sense in animal health (AH): (1) understanding a situation and its dynamics, e.g., epidemic spread; (2) the perception of the environment, which corresponds in AH to the detection of patterns (e.g., repeated sequence of observations), forms (e.g., of a protein) and signals (e.g., increased mortality compared to a baseline) at different scales; (3) computer-based decision making, or, more realistically, human decision support (e.g., expert systems, diagnostic support, resource allocation).

To answer these challenges, a wide range of concepts and methods are developed in AI. This includes machine learning (ML), a widely known AI method nowadays, which has been developing since the 1980s [ 3 ]. Since the 2000s, deep learning is developing with the rise of big data and the continuous increasing of computing capacities, enabling the exploration of massive amount of information that cannot be processed by conventional statistical methods. In addition, this also includes methods and algorithms for solving complex problems, automating tasks or reasoning, integrating information from heterogeneous sources, or decision support (Figure  1 ). These methods are now uprising in the human health sector, but are still rarely used to study animal health issues that they would help to revisit.

Part of the scientific challenges faced in AH can be approached from a new perspective by using some of these AI methods to analyse the ever-increasing data collected on animals, pathogens, and their environment. AH research benefits from advances in machine and deep learning methods, e.g., in predictive epidemiology, individual-based precision medicine, and to study host–pathogen interactions [ 2 , 4 ]. These methods contribute to disease diagnosis and individual case detection, to more reliable predictions and reduced errors, to speed-up decisions and improved accuracy in risk analysis, and to better targeting interventions in AH [ 5 ]. AH research also benefits from scientific advances in other domains of AI. Knowledge representation and modelling of reasoning [ 6 ] allow more realistic representations of complex socio-biological systems such as those encountered in AH. Examples include processes related to decision-making and uncertainty management [ 7 , 8 ], as well as of patient life courses like in human epidemiology [ 9 ]. This contributes to making them more readable by noncomputer experts. In addition, advances in problem solving under constrained resource allocation [ 10 ], in autonomous agents [ 11 ], multi-agent systems [ 12 ], and multi-level systems [ 13 ], as well as on automatic computer code generation [ 14 ] can be mobilised to enhance efficient and reliable epidemiological models. Interestingly, this may aid to anticipate the effect of control and management decisions at different spatial and temporal scales (animal, herd, country…).

Conducting research at the AH/AI interface also leads to identify new challenges for AI, on themes common with human health but considering different contexts and perspectives [ 15 ]. First, taking into account the particular agro- and socio-economic conditions of production systems is crucial when dealing with AH. Animal production systems depend on human activities and decisions. They can be a source of income (e.g., livestock) or labour forces and source of food in family farming. Citizens have also high expectations in terms of ethics and animal welfare [ 16 ]. Conventional measures to control animal diseases may no longer be acceptable by society (e.g., mass culling during outbreaks [ 17 ], antimicrobial usage, [ 18 ]). Alternatives must be identified and assessed, and AI can contribute. For example, individual-based veterinarian medicine is emerging, mobilising both AI methods and new AH data streams, these data differing from data in human health [ 19 ]. The integration of data from deep sequencing in AH, including emerging technologies for studying the metabolome and epigenome, is also a challenge [ 20 , 21 ]. Second, interactions between animal species, in particular between domestic animals and wildlife, lead to specific infectious disease risks (e.g., multi-host pathogens such as for African swine fever, pathogens crossing the species barrier facilitated by frequent contacts and promiscuity). The intensity of such interactions could increase due to separate or synergistic actions of environmental (e.g., landscape homogenisation, land use change for agriculture development, climate change), demographic (e.g., increasing global demand for animal production) and societal (e.g., outdoor livestock management) pressures. In addition, working on multi-species disease networks provides crucial information on the underlying molecular mechanisms favouring interspecific transmission [ 22 ]. Third, animal populations are governed by recurrent decision-making that also impacts health management (e.g., trade, control measures). Economic criteria as consequences on livestock farmers’ incomes are therefore essential indicators for evaluating AH control strategies, which can sometimes be misunderstood or may be at odds with societal expectations. These specificities make the AH/AI interface a theme of interest to stimulate new methodological work and to solve some of old and current locks faced by AH research today. With the development of new concepts in health such as One Health, Ecohealth and Planetary Health, promoting multidisciplinarity, stakeholders’ participation, data sharing, and tackling the complexity of health issues (e.g., multi-host pathogen transmission, short and long-term climatic impacts on disease patterns [ 23 ]), AI could participate in this new development by making it possible to technically solve some of the complex problems posed.

Mobilising the literature published at the AH/AI interface between 2009 and 2019 (Additional file 1 A), focusing our literature search on mainly livestock and wildlife, as well as interviews conducted with French researchers positioned at this interface (Additional file 1 B), we identified the main research areas in AH in which AI is currently involved country-wide. We explored how AI methods contribute to revisiting AH questions and may help remove methodological or conceptual barriers within the field. We also analysed how AH questions interrogate and stimulate new AI technical or scientific developments. In this paper, we first discuss issues related to data collection, organisation and access (Section  1 ), then we discuss how AI methods contribute to revisiting our understanding of animal epidemiological systems (Section  2 ), to improving case detection and diagnosis at different scales (Section  3 ), and to anticipating pathogen spread and control in a wide range of scenarios in order to improve AH management, facilitate decision-making and stimulate innovation (Section  4 ). Finally, we present the possible obstacles and levers to the development of AI in modern AH (Section  5 ), before making recommendations to best address the new challenges represented by this AH/IA interface (Section  6 ).

2 Collect, organise and make accessible quality data

A central point for research in AH remains the quality and availability of data, at the different organization levels of living systems and therefore at different spatial and temporal scales [ 24 ]. Data of interest are diverse. They can be obtained thanks to molecular analysis (e.g., genomic, metagenomics, or metabolic data), from observational data on individuals (e.g., body temperature, behaviour, milk production and composition, weight, feed intake), or from the production system (e.g., herd structure, breeding, management of sanitary issues). They can also be obtained at larger scales, beyond herds or local groups of animals (e.g., epidemiological data, demographic events, commercial movements, meteorological data, land-use occupation).

Even though the acquisition of these massive and heterogeneous data remain challenging (e.g., metabolome data), a large and diverse amount is already collected: (i) through mandatory reporting in accordance with regulations (e.g., commercial movements of cattle, epidemio-surveillance platform), (ii) by automatic devices (e.g., sensors, video surveillance systems), and (iii) on an ad hoc basis as part of research programs. This leads to a very wide diversity of data properties, and therefore of their management, access and possible uses. These data can be specifically obtained for certain animals or herds (e.g., during cohort monitoring programs) or by private companies (e.g., pig trade movements such as in France, milk collection). This can limit accessibility to academics and public research. Globalisation and large-scale animal trade may generate the need to use data obtained at worldwide scale in AH, especially for quantitative epidemiology (e.g., transcontinental spread of pathogens, animal genetics and breed management) leading to standardisation issues [ 25 ].

Consideration should be given to future systems for observing, collecting and managing these data [ 26 ], and to practices aimed at better collaboration between stakeholders. While data management has always been an important element in applied research to facilitate their use and valorisation, it is now a strategic issue both in theoretical and more applied research, coupled with a technical and algorithmic challenge [ 27 , 28 , 29 ]. Indeed, producing algorithms to manage massive data flows and stocks, by optimising calculations, is a challenge, particularly in real time. It seems also necessary to make heterogeneous data sources interoperable, requiring dedicated methodological developments [ 25 ]. In addition, much of the data is private, with ownership often heterogeneous (e.g., multiple owners, non-centralised data, closed data) and sometimes unclear (e.g., lack of knowledge of the real owner of the data between, for example, farmers, the data collector or the farmers’ union). All this tends to considerably complicate access to the data, raises questions about intellectual property, and raises questions in relation to regulations with regards to data protection, e.g., the adaptation of regulation to AH while respecting the confidentiality of the personal data mobilised. What is the relevant business model for data collection or access to existing databases? What about the openness of AH data (e.g., duality between the notion of public good and the private nature of certain data) to make it possible to experiment in real situations and compare the performance of AI algorithms? Answering these questions would facilitate the collection and sharing of ad hoc data. AI, particularly when combining a participatory framework with expert systems and multi-agent systems, helps to build realistic representations of complex socio-biological systems. Thus, it proves to be an effective tool to promote the collaboration of different stakeholders in collective and optimised decision-making, and to assess of the impact of changes in uses and practices [ 30 ].

Encouraging experimentation of AI technologies at a territorial scale becomes crucial to favour their development, validate their performance, and measure their predictive quality. In AH, simplified access to data-generating facilities would allow innovative solutions to be tested on a larger scale and would accelerate their development and evaluation. Substantial expertise exists (e.g., epidemiological data platform, large cohorts, experimental farms) that could be put to good use. In addition, AI could help to revisit sampling methods for field data collection in AH and epidemiological surveillance, by better and more dynamically targeting the data to be collected while avoiding redundant collinear, non-necessary data.

3 Contribution of AI to better understand animal epidemiological systems

Recent technological advances involving AI approaches have made it possible to obtain vast quantities of measurements and observations, as well as to store and share these data more efficiently. This has resulted in an increasing requirement for appropriate data analytical methods. AI methods emerged as the response of the computer-science community to these requirements, leveraging the exponential improvements in computational power. In parallel, statistical methods have greatly evolved in the last few decades as well, e.g., with regards to dimensionality-reduction in the spaces of variables and parameters, variable selection, and model comparison and combination. The rise in computational power has unleashed the development of Bayesian inference through simulation or approximate methods [ 31 ]. Bayesian methods have, in turn, facilitated the integration of data from diverse sources, the incorporation of prior knowledge and allowed for inference on more complex and realistic models while changing the paradigm of statistical inference [ 32 , 33 , 34 ].

3.1 Better understanding the evolution of AH and socio-ecological systems in a One Health context

Learning methods can be used to do phylogenetic reconstructions, contributing in particular to new evolutionary scenarios of pathogens and their transmission pathways. For example, phylogenetic models offer an interesting perspective for identifying environmental bacterial strains with high infectious potentiality [ 35 ], or for predicting the existence of putative host reservoirs or vectors [ 36 ]. The analysis of pathogen sharing among hosts has been used to classify the potential reservoirs of zoonotic diseases using machine learning [ 37 ]. The analysis of pathogen genomes can also be used to identify genotypes of animal pathogens that are more likely to infect humans [ 38 ].

Using phenomenological niche models that rely on data distribution more than on hypotheses about ecological processes at play, disease occurrence data or retrospective serological data coupled with environmental variables can be related to the risk of being exposed to a pathogen. Thus, they can help monitor potential spillovers and emerging risks and anticipate the epidemic pathogen spread [ 39 ]. For instance, Artificial Neural Networks (ANN) have identified the level of genetic introgression between wild and domesticated animal populations in a spatialized context [ 40 ], which may help to understand gene diffusion in host × pathogen systems involving multiple host species, and characterise specimen pools at higher risk to act as pathogen spreaders or sinks. Other AI approaches such as multi-agent models, a more mechanistic approach, have been used in an explicit spatial context for vector-borne pathogen transmissions, and proved to be sufficiently versatile to be adapted to several other particular contexts [ 12 ].

It should be noted here that several studies reveal the relatively ancient nature of AI research in AH. Such AI methods have often made it possible to identify signals (e.g., genetic introgression) or even particular patterns or properties (e.g., importance of density-dependence in the vector-borne transmission) that are less visible or hardly detectable by more conventional statistical treatments.

All these approaches contribute to better understand pathogen transmission in complex system networks as generally observed for emerging infections in tropical, developing regions of the world. On this matter, an improved knowledge is key for protecting humans against these new threats, and AI/AH interfaces development and training in cooperation with the poorest countries would facilitate synergistic effects and actions to predict and tackle new disease threats.

3.2 Reliability, reproducibility and flexibility of mechanistic models in AH

Better understanding and predicting pathogen spread often requires an explicit and integrative representation of the mechanisms involved in the dynamics of AH systems, irrespective of the scale (within-host: [ 41 ]; along a primary production chain: [ 42 ]; in a territory: [ 43 , 44 ]; over a continent: [ 45 ]).

Mathematical (equations) or computer-based (simulations) models can be used. Such mechanistic models (i.e., which represent the mechanisms involved in the infection dynamics), when sufficiently modular to represent contrasted situations, make it possible to anticipate the effects of conventional but also innovative control measures (e.g., new candidate molecules, sensors, genomic selection; [ 46 ]).

However, to assess realistic control measures, mechanistic epidemiological models require the integration of observational data and knowledge from biology, epidemiology, evolution, ecology, agronomy, sociology or economics. Their development can rapidly face challenges of reliability, transparency, reproducibility, and usage flexibility. Moreover, these models are often developed de novo, making little use of previous models from other systems. Finally, these models, even based on realistic biological hypotheses, may be considered negatively as black boxes by end users (health managers), because the underlying assumptions often became hidden in the code or equations.

The integration of multiple modelling perspectives (e.g., disciplines, points of view, spatio-temporal scales) is an important question in the modelling-simulation field. Epidemiological modelling could benefit from existing tools and methods developed in this field [ 47 , 48 , 49 ]. Although essential, good programming practices alone [ 50 ] cannot meet these challenges [ 51 ]. Scientific libraries and platforms accelerate the implementation of the complex models often needed in AH. For example, the R library SimInf [ 52 ] helps integrate observational data into mechanistic models. The BROADWICK framework [ 53 ] provides reusable software components for several scales and modelling paradigms, but still requires modellers to write large amounts of computer code.

New methods at the crossroads between software engineering and AI can enhance transparency and reproducibility in mechanistic modelling, fostering communication between software scientists, modellers and AH researchers throughout the modelling process (e.g., assumption formulation, assessment, and revision). Knowledge representation methods from symbolic AI, formalised using advanced software engineering methods such as domain-specific languages (DSL, e.g., in KENDRICK for differential equation models: [ 54 ]), makes model components accessible in a readable structured text file instead of computer code. Hence, scientists from various disciplines and field managers can be more involved in the model design and evaluation. Scenario exploration and model revision also no longer require rewriting the model code.

Other AI methods can improve model flexibility and modularity. Autonomous software agents enable to represent various levels of abstraction and organisation [ 55 ], helping modellers go more easily back and forth within small and larger scales, and ensure that all relevant mechanisms are adequately formalised at proper scales (i.e., scale-dependency of determinants and drivers in hierarchical living systems). Combining knowledge representation (through a DSL) and such a multi-level agent-based simulation architecture (e.g., in EMULSION, Figure  2 , [ 56 ]) enables to encompass several types of models (e.g., compartmental, individual-based) and scales (e.g., individual, population, territory), and it tackles simultaneously the recurring needs for transparency, reliability and flexibility in modelling contagious diseases. This approach should also facilitate in the future the production of support decision tools for veterinary and public health managers and stakeholders.

AI at the service of mechanistic epidemiological modelling (adapted from [ 51 ] ) . A . Modellers develop each epidemiological model de novo, producing specific codes not easily readable by scientists from other disciplines or by model end-users. B . Using AI approaches to combine a domain-specific language and an agent-based software architecture enhances reproducibility, transparency, and flexibility of epidemiological models. A simulation engine reads text files describing the system to automatically produce the model code. Complementary add-ons can be added if required. Models are easier to transfer to animal health managers as decision support tools.

3.3 Extracting knowledge from massive data in basic AH biology

Supervised, unsupervised and semi-supervised learning methods facilitate basic research development in biology and biomedicine, for example by using morphological analyses to study cell mobility [ 57 ]. The use of classification approaches and smart filters allows nowadays to sort massive molecular data (e.g., data from high throughput sequencing and metagenomics). Metabolic, physiological and immunological signalling pathways are explored, and metabolites are identified and quantified in complex biological mixtures, which was before a major challenge [ 58 ]. In addition, diagnostic time may be reduced by developing image analysis processing (e.g., accelerated detection of clinical patterns; [ 59 , 60 ]), often necessary to study host–pathogen interactions in animal pathology. For example, the use of optimisation methods has improved the understanding of the fragmentation of prion assemblages, contributing to a significant reduction in the time required to diagnose neurodegenerative animal diseases, thus paving the way for identifying potential therapeutic targets [ 61 ]. In livestock breeding, there is a methodological transition underway from traditional prediction strategies to more advanced machine learning approaches including artificial neural networks, deep learning and Bayesian networks which are being used to improve the reliability of genetic predictions and further the understanding of phenotypes biology. [ 62 ].

In human health, new disciplines have emerged in the second half of the 20 th century at the interface between AI and flagship disciplines, such as cell biology and immunology. Interface disciplines have developed, e.g., computational biology and immunology, which today must spread to AH. Current human immunology is based on the description of fine molecular and cellular mechanisms (e.g., the number of known interleukins has increased considerably compared to the 1970s). The desire to understand the processes underlying immune responses has led to a revolution by inviting this discipline to focus on complex systems biology and AI-based approaches [ 63 ]. However, the imbalance between the numbers of immunologists and immunology modellers is hampering the fantastic growth of this new discipline.

As an additional level of complexity, the hierarchical nature of biological systems makes that at the individual level, animals including humans must be considered as holobionts made of myriads of hosted microbial forms that form discrete ecological units (i.e., infracommunities). The potential of AI to grasp such diversity and complexity (e.g., tissue-specific microbiotes) and to scaling-up to higher levels of organization (e.g., component and compound communities of microbes, including pathogens, circulating in herd and in a given region) is certainly tremendous and should be studied with the same vigour as recent development in computational biology and immunology [ 40 ].

4 Revisiting AH case detection methods at different scales

Managing livestock health issues requires effective case detection methods, at the individual or even infra-individual (organ) scale, at the group/herd scale, or at larger scales (e.g., territories, countries). Machine learning methods allow detecting patterns and signals in massive data, e.g., in spatial data or time-series of health syndromes and disease cases, contributing to the development of smart agriculture and telemedicine (Figure  3 ). Alerts can be produced, and contribute to management advice in numerical agriculture [ 64 ] and veterinary practices [ 65 ]. AI may contribute to an earlier detection of infected cases and the rationalisation of treatments (including antimicrobials) in farm animals, by analysing data collected from connected sensors [ 66 ], by targeting individuals or groups of animals [ 59 ], or even by using mechanistic models to predict the occurrence of case detections and their treatment [ 67 ]. Also, machine learning methods enable to discriminate pathogen strains and thus to better understand their respective transmission pathways if different [ 68 ]. Finally, therapeutic strategies can be reasoned through multi-criteria optimisation, by identifying whom to treat in a herd, when, according to what protocol and for how long, in order to maximise the probability of cure while minimising both the risk of drug resistance and the volume or number of doses that are necessary (i.e., individual-based and precision medicine).

Extracting information from massive data to monitor animal health and better rationalise treatments.

Nevertheless, alert quality depends on the quality and representativeness of the datasets used by the learning algorithms. Numerous biases (e.g., hardware, software, human) can affect prediction accuracy. Moreover, alerts produced after training necessarily reflect the specificities of the system from which the data originates (e.g., area, period, rearing practices). Thus, result transposition to other epidemiological systems or to the same system subjected to environmental or regulatory changes remains risky. Furthermore, while machine learning methods (e.g., classification, image analysis, pattern recognition, data mining) provide solutions for a wide range of biomedical and bio-health research questions, it is crucial to demonstrate the performance of these methods by measuring their predictive quality and comparing them to alternative statistical methods whenever possible [ 69 ].

At the population level, case detection is based on direct (detection of syndromes) or indirect surveillance, mobilising syndrome proxies. Hence, the emergence of some animal diseases can be detected by syndromic surveillance, by detecting abnormal or rare signals in routine data (e.g., mortality, reproduction, abortion, behaviour, milk production, increased drug use; [ 70 ]). Also, serological data can be used retrospectively to identify individual characteristics related to a risk of being exposed to a pathogen, and thus orientate management efforts (e.g., in wildlife; [ 71 ]). Statistics and AI are largely complementary to address such issues. Both mobilise the wide range of available data, which are highly heterogeneous, massive and mostly sparse, to detect signals that are often weak or scarce [ 28 , 72 , 73 ]. Such signals can be proxy records (e.g., emergence of infectious diseases following environmental disturbances), health symptoms and syndromes, or even metabolic pathways in cascades which can be precursors of chronic or degenerative diseases. AI also includes methods to mobilise information available on the web. For example, semi-automatic data mining methods enabled to identify emerging signals for international surveillance of epizooties [ 74 ] or to analyse veterinary documents such as necropsy reports [ 75 , 76 ]. Methods from the field of natural language processing can compensate the scarcity of data by extracting syntactic and semantic information from textual records, triggering alerts on new emerging threats that could have been missed otherwise.

On a large to very large scale (i.e., territory, country, continent, global), data analysis of commercial animal movements between farms makes it possible to predict the associated epidemic risk [ 77 , 78 ]. These movements are difficult to predict, particularly since animal trade is based on many factors associated with human activities and decisions. Methods for recognising spatio-temporal patterns and methodological developments for the analysis of oriented and weighted dynamic relational graphs are required in this field because very few of the existing methods allow large-scale systems to be studied, whereas datasets are often very large (e.g., several tens or even hundreds of thousands of interacting operations).

On this topic, the specific frontier between learning methods of AI and statistics is relatively blurred, lying most on the relative prominence of the computational performance of algorithms versus mathematics, probability and rigorous statistical inference. While machine learning methods are more empirical, focused on improving their predictive performance, statistics is more concerned with the quantification and modelling of uncertainties and errors [ 79 , 80 ]. In the last decade, both communities have started to communicate and to mix together. Methods have cross-fertilised, giving birth to statistical models using synthetic variables generated by AI methods, or AI algorithms optimising statistical measures of likelihood or quality. New research areas, such as Probabilistic Machine Learning, have emerged at the interface between the two domains [ 1 , 80 , 81 ]. Meanwhile, machine learning and statistics have kept their specific interests and complementarity; machine learning methods are especially well-suited to processing non-standard data types (e.g., images, sounds), while statistics can draw inference and model processes for which only few data are available, or where the quantities of interest are extreme events.

5 Targeted interventions, model of human decisions, and support of AH decisions

5.1 choosing among alternatives.

A challenge for animal health managers is to identify the most relevant combinations of control measures according to local (e.g., farm characteristics, production objectives) and territorial (e.g., available resources, farm location, management priorities) specificities. They have to anticipate the effects of health, environmental and regulatory changes, and deliver quality health advice. The question also arises of how to promote innovation in AH, such as to anticipate the required characteristics of candidate molecules in vaccine strategies or drug delivery [ 82 , 83 ], or to assess the competitive advantage of new strategies (e.g., genomic selection of resistant animals, new vaccines) over more conventional ones. Private (e.g., farmers, farmers’ advisors) and collective managers (e.g., farmer groups, public authorities) need support decision tools to better target public incentives, identify investments to be favoured by farmers [ 46 ] and target the measures as effectively as possible: who to target (which farms, which animals)?; with which appropriate measure(s)?; when and for how long? These questions become essential to reasoning about input usage (e.g., antimicrobials, pesticides, biocides) within the framework of the agro-ecological transition.

The use of mechanistic modelling is a solution to assess, compare and prioritise ex ante a wide range of options (Figure  4 ; [ 84 ]). However, most of the available models do not explicitly integrate human decision-making, while control decisions are often made by farmers (e.g., unregulated diseases), with sometimes large-scale health and decision-making consequences (e.g., pathogen spread, dissemination of information and rumours, area of influence). Recent work aims to integrate humans and their decisions by mobilising optimal control and adaptive strategies from AI [ 7 , 85 ] or health economics methods [ 86 , 87 ]. A challenge is to propose clear and context-adapted control policies [ 88 ]. Such research is just starting in AH [ 46 ] and must be extended as part of the development of agro-ecology, facing current societal demand for product quality and respect for ecosystems and their biodiversity on one side, animal well-being and ethics on the other side, and more generally international health security.

Identifying relevant strategies to control bovine paratuberculosis at a regional scale (adapted from [ 76 ] ) . Classically, identifying relevant strategies means defining them a priori and comparing them, e.g., by modelling. Only a small number of alternatives can be considered. If all alternatives are considered as in the figure, it results in a multitude of scenarios whose analysis becomes challenging. Here, each point corresponds to the epidemiological situation after 9 years of pathogen spread over a network of 12 500 dairy cattle herds for a given strategy (asterisk: no control). Initially, 10% of the animals are infected on average in 30% of the herds. The blue dots correspond to the most favourable strategies. Mobilizing AI approaches in such a framework, especially optimization under constraints, would facilitate the identification of relevant strategies by exploring the space of possibilities in a more targeted manner.

5.2 Accounting for expectations and fears of animal health managers

Animal health managers should have access to model predictions in a time frame compatible with management needs, which is problematic in the face of unpredictable emerging events (e.g., new epidemiological systems, transmission pathways, trade patterns, control measures). Developing a library of models included in a common framework would strengthen the responsiveness of modellers in animal epidemiology. Relevant models would be developed more quickly and would gain accuracy from real-time modelling as epidemics progress [ 89 , 90 ]. However, if this makes move more quickly from concepts (knowledge and assumptions) to simulations and support decision tools, a gain in performance is still required to perform analyses at a very large scale. The automatic generation of high-performance computer code could be a relevant solution, which however remains a crucial methodological lock to be addressed in AI. In addition, it is often required to perform a very large number of calculations or to analyse very large datasets, which call for a rational use of computing resources. Software transferred to health managers sometimes require the use of private cloud resources (i.e., it does not run on simple individual computers), highlighting the trade-offs between simulation cost, service continuity (e.g., failure management) and time required to obtain simulation results [ 91 ]. These questions are currently related to computer science research, and collaborations are desirable between these researchers and those from AH.

Managers also wish to rely on accurate predictions from realistic representations of the biological systems. Before being used, model behaviour should be analysed, which raises the questions of exploring the space of uncertainties and data, and of optimization under constraints. This often requires intensive simulations, which would benefit from optimization algorithms to explore more efficiently the space of possibilities. In turn, this would allow, for example, the automatic identification of how to achieve a targeted objective (e.g., reducing the prevalence of a disease below an acceptable threshold) while being constrained in resource allocation. While this issue finds solutions in modern statistics for relatively simple systems, it represents a science front for complex systems (e.g., large scale, multi-host/multi-pathogen systems) that are becoming the norm. In addition, optimization goals specific to AH may generate ad hoc methodological needs [ 92 ]. The needs in abstraction and analysis capacity are massive and could benefit from complementarities between AI (e.g., reasoned exploration, intelligent use of computer resources, optimized calculations) and statistics to extract as much information as possible from the data: (1) explore, analyse, predict; (2) infer processes and emergent properties. Methodological developments are still required and would benefit many health issues, particularly in relation to the currently evolving concepts of reservoir-host, edge-host and species barrier [ 93 ]. Furthermore, methodological developments and dissemination of existing methods should be reinforced.

Finally, three barriers have been identified to the development of support decision tools for health managers, related to the societal issue of the acceptability of AI sensu lato, as a major factor of progress. First, ethical issues, which are obvious when it comes to human health, are just as important to consider in AH. Which AI-based tools do we want for modern animal husbandries and trades, and for which objectives? Are these tools not likely to lead to discrimination against farms according to their health status, even when this status cannot be managed by the farmer alone? Second, in AH too, there is a fear that AI-tools may replace human expertise. However, automating does not mean replacing human, his expertise and decision [ 94 ], but rather supporting his capacities for abstraction and analysis, accelerating the global process, making predictions more reliable, guiding complementary research. Nevertheless, a significant development of computer resources and equipment is not without impacting the environment in terms of carbon footprint (e.g., energy-intensive servers, recycling of sensors), which must also be accounted for. Third, the very high complexity of analysing results and acculturating end-users with knowledge issued from academic research, particularly AI, is an obstacle to the appropriation of AI-tools by their users. This may lead to the preference for simpler and more easily accessible methods. However, the latter may not always be the most relevant or reliable. Citizen science projects, also known as community participation in human epidemiology, enable AH to co-design and co-construct the AI-tools of tomorrow with their end-users [ 95 ], to better meet their expectations and needs, and to increase their confidence in the predictions of sometimes obscure research models, especially when they are hard to read (e.g., lines of code). Similarly, these AI-tools could be developed together with public decision-makers, livestock farmers, agro-food industries and sectoral trade unions. Co-construction gives time to explain the science behind the tools and makes it more transparent and useful. This citizen participation, which is nowadays supported in many countries, guarantees decisions more in line with citizens’ expectations and corresponds to a general trend towards structured decision-making. AI must contribute to this democratisation of aid in public decision-making in AH.

6 Barriers to the development of research at the AI/AH interface

Research conducted at the interface between AI and AH requires strong interactions between biological disciplines (e.g., infectiology, immunology, clinical sciences, genetics, ecology, evolution, epidemiology, animal and veterinary sciences) and more theoretical disciplines (e.g., modelling, statistics, computer science), sometimes together with sociology and economics. Conducting research at this interface requires strengthening the few teams already positioned in Western Europe, but also bringing together teams working around the concepts of One Health, Ecohealth and Planetary Health to benefit from recent achievements in infectious disease ecology and modelling, plant health and environmental health [ 96 ]. This work must be based on a wide range of methodological skills (e.g., learning methods, data mining, information systems, knowledge representation, multi-agent systems, problem solving, metamodeling, optimisation, simulation architecture, model reduction, decision models). The need for research, training and support are crucial issues at national, European and international levels. Also, a facilitated and trusted connection is required between academics, technical institutes, and private partners, who are often the holders or collectors of data of interest to solve AH research questions through AI approaches. The construction of better inter-sectoral communication and coordination must be done at supra-institutional level, as this theme seems hyper-competitive and as some current divisions still go against information and data sharing.

An acculturation of researchers to AI, its methods and potential developments, but also its limitations, must be proposed to meet the challenges of 21 st century agriculture. Indeed, there are obstacles to conducting research on this scientific front. Establishing the new collaborations required between teams conducting methodological work and teams in the fields of application remains difficult given the low number of academic staff on these issues, their very high current mobilisation and their low availability to collaborate on new subjects, as well as the difficulty of understanding and mastering these methods. There is a need for watching and training on AI methods available or under development, new softwares/packages, and their applicability. To develop key collaborations and establish a strategic positioning, an interconnection can also be made via transversal teams which appears as a preferential path. Solutions must also be found to encourage method percolation in the community and the development of scientific and engineering skills.

Finally, AI methods, such as classification, machine learning, data mining, and the innovations in AH to which these methods can lead are rarely discussed in veterinary high school education, whereas these students represent the future professionals of AH [ 96 ]. Similarly, there is a quasi-absence of sentinel networks of veterinarians, even if it is developing, although AH questions can arise on a large and collective scale. The scientific community would also benefit from further increasing its skills and experience in the valuation, transfer and protection of intellectual property on these AI methods and associated outcomes.

7 Levers to create a fruitful AI/AH interface

7.1 data sharing and protection.

No innovation at the interface between AI and AH is possible without strong support for the organisation of data storage, management, analysis, calculation, and restitution. The major risk is that demands for AI developments inflate without being supported by available human resources. In addition, an expertise in law, jurisdiction and ethics is required with regard to the acquisition, holding, use and protection of data in AH. This question must be considered at least at the inter-institutional/national level, and could benefit from a similar thinking already engaged in human health. The issue is to be able to support any change with regard to data traceability to their ownership, whether being from public or private domains.

New data are rich and must be valued as much as possible, not by each owner separately, but through data sharing and the mobilisation of multi-disciplinary skills to analyse such heterogeneous and complex data. Hence, data interoperability skills are required and must be developed. Models for making federated data sustainable over decades are required [ 97 ]. In addition, further encouraging the publication of data papers as valuable research products can help to develop the necessary culture of sharing, documentation and metadata.

Finally, to be able to launch ambitious experiments with AI methods on real data, it is necessary to (1) remove unauthorised access to data by negotiating with owners at large scale; (2) analyse and understand the related effect on methodological developments; and (3) if necessary, extend such initiatives to other areas, at national scale, or even across European countries.

7.2 Attract the necessary skills

An undeniable barrier to conduct such research comes from human resources, in particular the current insufficient capacity of supervision by permanent scientists. Collaborations are a solution to attract new skills. However, initiating collaborations at the AH/AI interface becomes very complicated because the qualified teams are already overwhelmed. Skill development at this interface must be supported, the cross-fertilisation of disciplines being essential. A watch on methods must also be carried out, accompanied by explanations for application fields, to train researchers and engineers. Financial incentives for scientist internships in specialised laboratories would increase skill capitalisation in advanced methods, while facilitating future national or international collaborations. In a context of limited resources as observed in many countries nowadays (e.g., new opened positions in national institutions) and limited experts pool (e.g., skills), facilitating post-doctoral fellows and continuing education of researchers becomes crucial. Finally, to consolidate the pool of future researchers in AH, promoting basic AI education in initial training of AH researchers, engineers and veterinarians is paramount.

More specifically concerning current research in immunology, cell biology and infectiology, the contribution of AI has been more widely considered in human health, which could feed a similar reflection in AH as locks and advances are not very specific. Before embarking on the fronts of science (e.g., emerging epigenomics and metabolomics in AH), a few persons from these biological disciplines should acculturate into AI, or even acquire autonomy in the use of methods [ 98 ], which internationally tends to be the trend [ 63 ]. This can be done through the sharing of experiences and basic training on existing methods, their advantages and limitations compared to other methods coming from statistics and mathematical modelling.

7.3 Encourage the development of AH/AI projects

Projects at the AH/AI interface, like any interdisciplinary project, must mobilise teams from both groups of disciplines and allow everyone to progress in their own discipline. However, identifying the issues shared between the most relevant disciplines requires a good acculturation of the disciplines between them, as well as an otherness aimed at better understanding each other [ 95 ], which is not yet the case at the AH/AI interface.

In terms of funding, European project calls offer interesting opportunities, but a significant imbalance persists between the ability to generate data and analyse complex issues, and the availability of human resources and skills to address such issues through AI methods or other modern methods in statistics, mathematics and computer science. The major international foundations (e.g., Bill and Melinda Gates) can also be mobilised on emerging infectious diseases at the animal/human interface (e.g., characterisation of weak signals, phenologies, emergence precursors), with a more significant methodological value. However, risk-taking is rarely allowed by funding agencies, although it is crucial to initiate interdisciplinary work. Dedicated incentive funding would support projects in their initial phase and make larger projects emerge after consolidation of the necessary disciplinary interactions.

Finally, these projects are generally based on the use of significant computing resources. Thus, research institutes and private partners should contribute in a financial or material way to the shared development of digital infrastructures, data centres, supercomputing centres on a national scale, as well as support recognised open-source software platforms on which a large part of the research conducted is based (e.g., Python, R ).

7.4 Promoting innovation and public–private partnership

Encouraging public–private partnership would promote a leverage effect on public funding and would make it possible to place AI research and development on a long-term basis in AH. Mapping the highly changing landscape of companies in the AH/AI sector, whether international structures or start-ups, would provide a better understanding of the possible interactions. Similarly, mapping academic deliverables produced at this interface would increase their visibility and highlight their potential for valorisation or transfer. Finally, considering the production of documented algorithms as scientific deliverables, along with publications, would help support this more operational research. More broadly, it would be advisable to initiate a communication and education/acculturation policy around AI and its development in AH (e.g., links with the society, farmers, agricultural unions, public services).

8 Conclusion

The use of AI methods (e.g., machine learning, expert systems, analytical technologies) converges today with the collecting of massive and complex data, and allows these fields to develop rapidly. However, it is essential not to perceive massive data and AI as the same trend, because the accumulation of data does not always lead to an improvement in knowledge. Nevertheless, the more data are numerous and representative of working concepts and hypotheses, the more important results can be obtained from AI applications. The underlying ethical, deontological and legal aspects of data ownership, storage, management, sharing and interoperability also require that a reflection be undertaken nationally and internationally in AH to better manage these data of multi-sectoral origin and their various uses. Moreover, while the effort to acquire such data is impressive, the development of AI skills within the AH community remains limited in relation to the needs. Opportunities for collaborations with AI teams are limited because these teams are already in high demand. To ensure that AH researchers are well aware of the opportunities offered by AI, but also of the limits and constraints of AI approaches, a training effort must be provided and generalized. Finally, the current boom in AI now makes it possible to integrate the knowledge and points of view of the many players in the field of animal health and welfare further upstream. However, this requires that AI and its actors accept to deal with the specificity and complexity of AH, which is not a simple library of knowledge that can be digitised to search for sequences or informative signals.

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Acknowledgements

This work has benefited from interactions with many French researchers (Additional file 1 B) interested in the AI/AH interface, for which we thank them here. We also thank Stéphane Abrioux, Didier Concordet and Human Rezaie for participating to the discussions.

PE is supported by the French Research Agency (project CADENCE: ANR-16-CE32-0007). XB is involved in the project “MOnitoring Outbreak events for Disease surveillance in a data science context” supported by the EU Framework Programme for Research and Innovation H2020 (H2020-SC1-BHC-2018–2019, Grant 874850). JFG is supported by both an “Investissement d’Avenir” managed by the French Research Agency (LABEX CEBA: ANR-10-LABX-25-01) and a US NSF-NIH Ecology of infectious diseases award (NSF#1911457), and is also supported by IRD, INRAE, and Université of Montpellier. The funding bodies had no role in the study design, data analysis and interpretation, and manuscript writing.

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PE carried out the literature review and analysed the interviews. PE and JFG conducted the interviews, drafted and wrote the manuscript. SP, GB, FM, RD, HM provided complementary views and references in their respective disciplines. All authors read and approved the final manuscript.

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Systematic literature review, interviews, previous publication in French.

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Ezanno, P., Picault, S., Beaunée, G. et al. Research perspectives on animal health in the era of artificial intelligence. Vet Res 52 , 40 (2021). https://doi.org/10.1186/s13567-021-00902-4

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Toward innovative veterinary nanoparticle vaccines

• Meiqi Sun 1 ,
• Aldryan Cristianto Pratama 1 ,
• Zehui Liu 1 , 4 &
• Fang He 1 , 2 , 3  

Animal Diseases volume  4 , Article number:  14 ( 2024 ) Cite this article

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Nanoparticles are significant for veterinary vaccine development because they are safer and more effective than conventional formulations. One promising area of research involves self-assembled protein nanoparticles (SAPNs), which have shown potential for enhancing antigen-presenting cell uptake, B-cell activation, and lymph node trafficking. Numerous nanovaccines have been utilized in veterinary medicine, including natural self-assembled protein nanoparticles, rationally designed self-assembled protein nanoparticles, animal virus-derived nanoparticles, bacteriophage-derived nanoparticles, and plant-derived nanoparticles, which will be discussed in this review. SAPN vaccines can produce robust cellular and humoral immune responses and have been shown to protect against various animal infectious diseases. This article attempts to summarize these diverse nanovaccine types and their recent research progress in the field of veterinary medicine. Furthermore, this paper highlights their disadvantages and methods for improving their immunogenicity.

Introduction

Currently, one of the most effective methods for limiting the spread of several infectious illnesses affecting animal husbandry is to establish prophylactic vaccination policies whenever possible. Nevertheless, several current vaccines for animals still depend on conventional vaccination technologies, such as attenuated and inactivated vaccines, which might not offer the best safety and immunogenicity under certain conditions. Innovative vaccines comprising isolated, completely purified antigenic protein subunits have become the safest option, although they frequently fail to produce significant protective immunity (Vartak and Sucheck 2016 ). One option for improving the poor immunogenicity of epitope-based vaccines is to incorporate nanotechnology into vaccine research, which is a promising and quickly growing field.

Nanoparticles (NPs) are defined as any particulate material with a size of 1 to 100 nm or up to 1000 nm (Nguyen and Tolia 2021 ). Nanoscale materials consist of a variety of substances, including polymeric, inorganic, and biological building blocks (Doll et al. 2013 ). The use of nanotechnology in vaccine development is a particularly hot topic. They have been shown to be beneficial in the production of vaccines for infectious diseases and have been investigated for a variety of fungal, bacterial, viral and parasitic diseases (Tiwari, et al. 2023 ; Makabenta, et al. 2021 ; Kischkel, et al. 2020 ). Studies have been carried out using a variety of nanomaterials to generate promising vaccine candidates, among which self-assembled protein nanoparticles (SAPNs) and virus-like nanoparticles (VLPs) seem very promising.

SAPNs are secondary structures generated by oligomerizing a monomeric protein, including helical or β-sheet secondary structures, endogenous peptides, and de novo structures (Fujita and Taguchi 2011 ). These multicopy protein building blocks can immediately integrate into well-ordered nanoparticle structures (Indelicato, et al. 2016 ). They allow the inclusion of antigens in their component/subunit structures, displaying repeating antigen molecules on the surface of the nanoparticle, thereby building chimeric SAPNs and serving as a redundant antigen delivery platform. Virus-like nanoparticles (VLPs) are self-assembled proteins; however, they tend to be investigated separately because of their viral origin and distinctive shape. Viral capsid proteins self-assemble into multiprotein complexes known as VLPs. These viruses are unable to infect host cells because they do not have a viral genome despite having an appearance and structure similar to that of native viruses (Nooraei, et al. 2021 ).

SAPN/VLPs, or antigens attached to the NP surface, can interact with pattern recognition receptors on innate immune cells, activating the adaptive immune system. As summarized in Fig.  1 , NPs (SAPN/VLP), with a size range of 20–200 nm, are able to traffic into lymph nodes freely and are recognized by dendritic cells (DCs), which are antigen-presenting cells (APCs) (Manolova, et al. 2008 ; Cubas, et al. 2009 ). Recognition and uptake of NPs initiate the DC maturation process, leading to lysosomal proteolysis and degradation of the NPs into peptides, allowing their presentation to CD4 + helper T cells as an MHC-peptide complex, which subsequently generates humoral immune responses (Look et al. 2010 ; Zabel et al. 2013 ; Win et al. 2011 ). The interaction between B cells and CD4 + helper T cells can elicit antigen-specific antibodies by creating plasma cells and B memory cells to destroy the infectious pathogen (Zabel et al. 2013 ). B cells can detect NPs and activate humoral immunity directly in some circumstances. In addition, DCs can activate immature CD8 +  cytotoxic T lymphocytes (CTLs), which differentiate into effector and memory CTLs to initiate immunological responses and directly kill infected cells (Buonaguro, et al. 2006 ; McFall-Boegeman and Huang 2022 ).

Adaptive immune activation induced by NP (SAPN/VLPS) vaccines. APCs recognize and take up NP-based vaccines when they are administered. After injection, NP-based vaccines are detected and taken up by APCs, which initiates DC maturation. Furthermore, DC maturation triggers the production of TNF-α (a proinflammatory factor) and the recruitment of more APCs to boost lysosomal proteolysis in the cell. Dendritic cells (DCs) process NP-based vaccines into small peptides, to form an MHC-peptide complex with T cell receptor (TCR) on CD8 + and CD4 + T cells. CD4 + T cells interact with B cells, resulting in B cells being activated and then differentiating into plasma cells, which can secrete antibodies and neutralize pathogens. CD4 + T-cell activation can also promote the development of B cells into memory B cells. CD8 +  cytotoxic T lymphocytes (CTLs) activated by APCs proliferate and differentiate into effector and specific memory CTLs. Effector CTLs are capable of causing apoptosis via the release of cytotoxic mediators to infected cells. Image created with BioRender.com

On the other hand, viral and bacterial pathogens trigger the production of interferon gamma (IFN-γ) and pro-inflammatory cytokines by activating the helper T1 cell (TH1), which stimulate the activation of APCs such as dendritic cells, natural killer (NK) cells, and macrophages (Pulendran and Ahmed 2011 ). Activation of TH1 cells and the production of IFN-γ have significant effects on viral elimination. Specifically, IFN-γ is a predominant cytokine in the TH1 response. IFN-γ has several biological functions related to viral infection, including antigen presentation by the MHC pathway, the stimulation of autophagy and apoptosis, the induction of antiviral mediator proteins by countering certain viral replication stages, viral RNA editing that leads to lethal virus mutations, and the facilitation of pathogen degradation by lysosome-mediated enzymatic processes (Kak et al. 2018 ). The broad functions of the TH1 response and IFN-γ due to pathogen stimulation will be beneficial for providing a deep understanding of the immunomodulatory mechanism of vaccination. Activating Th1-IFNγ responses is crucial for improving vaccine effectiveness (Ivashkiv 2018 ).

What are the advantages of the SAPN and VLP vaccines? As shown in Fig.  2 , the recurring array of antigens on SAPNs/VLPs replicates the recognition patterns on pathogens, allowing effective adhesion and stimulation of many B-cell receptors (BCRs) (Bachmann and Jennings 2010 ; Irvine and Read 2020 ; López-Sagaseta et al. 2016 ). Compared to single recombinant antigens that provide a 1:1 interaction with BCRs, SAPNs/VLPs enable the clustering of BCRs for multiple engagements (López-Sagaseta et al. 2016 ), which is a crucial phase in eliciting a robust immune response. Furthermore, the cumulative particle size of antigens and NPs is an ideal range for facilitating efficient uptake by APCs, promoting antigen presentation by APCs to stimulate helper T cells (Jia, et al. 2018 ; Oyewumi et al. 2010 ). NPs also efficiently trigger complement activation, which helps in binding to FDCs (follicular dendritic cells). In addition, the size of nanoparticles can prolong retention in lymph follicles and improve interactions with immune cells (Irvine and Read 2020 ). Naturally, adjuvants are used in combination with poorly immunogenic vaccines to improve their immunogenicity. Recent adjuvants offer a wide range of chemical substances with diverse mechanisms of action and potential side effects and hazards (Spickler and Roth 2003 ). Incomplete Freund's adjuvant (IFA) has been widely used due to its low toxicity and has been shown to increase the immune response in combination with conventional vaccines. However, IFA has one limitation regarding its inability to trigger a cellular immune response, which is important for viral infection and tumors (Jensen et al. 1998 ). Therefore, SAPNs/VLPs are more promising than the combination of adjuvants and commercial vaccines due to their high immunogenicity, adjuvant-like effects, safety benefits because of a lack of genetic material, and absence of the risk of pathogenicity and virulence.

Advantages of SAPN/VLP vaccines. a. SAPN/VLP vaccines with a repetitive array of antigens provide a molecular scenario in which antigens and B-cell receptors (BCRs) interact multiple times, increasing B-cell activation. b . Antigen attachment on particles creates an optimum range of sizes for interactions with APCs and other immune cells. NPs can improve the binding of complement to FDCs (complement receptors), and the bound complement promotes the retention of NPs in the lymph nodes and further enhances interactions with immune cells. SAPN/VLP vaccines are of the appropriate size for uptake by APCs, allowing for enhanced antigen presentation to stimulate T-helper cells. Image created with BioRender.com

This review provides a current overview of the use of SAPNs and various types of VLPs as vaccination platforms for a variety of animal infections. Figure  3 shows the NP vaccine nanostructures. Furthermore, we discuss the adjuvants used, the route of administration, the approval status, the optimization strategy, and other information on these NP vaccines.

Crystal structures of SAPN/VLPS scaffolds. Natural self-assembled protein nanoparticles, rationally designed self-assembled protein nanoparticles, animal virus-derived VLPs, bacteriophage-derived VLPs, and plant virus-derived VLPs are labeled in black, blue, red, purple, and green, respectively. NP structures were constructed in ChimeraX software by using the Protein Data Bank ID codes Ferritin (1mfr), mi3 (7b3y), PCV2 VLP (5zbo), RHDV VLP (3zue), FMDV VLP (7eno), PPV VLP (1k3v), P22 bacteriophage VLP (8eb7), Qβ bacteriophage VLP (7lge), MS2 bacteriophage VLP (6rrs), and TMV VLP (6r7m). Image created with ChimeraX software

Natural self-assembled peptide nanoparticles

This section will discuss the use of natural SAPNs as animal vaccination scaffolds for infectious illnesses. We will discuss the size, structure, self-assembly, antigen display, expression system, advantages and disadvantages, and immune effects of ferritin. A synopsis of these data is shown in Table  1 .

Ferritin is a self-assembling iron storage protein nanoparticle found in practically every organism, including bacteria, fungi, plants, and animals (Munro and Linder 1978 ). It consists of 24 self-assembled subunits, each containing a four-alpha-helix bundle, which forms a spherical cage-like shape with octahedral symmetry (Cho, et al. 2009 ; Ford, et al. 1984 ; Harrison and Arosio 1275 ). This structure is characterized as a ferritin cage, with inner and outer diameters of 8 and 12 nm, respectively (Theil 2013 ). Because of their spontaneous self-assembly, petite uniform size, biocompatibility, biodegradability, affordability, large-scale production, and ability to surface conjugate using chemical or genetic techniques, they are effective platforms for vaccine design (Silva et al.  2013 ; Khoshnejad et al. 2018 ). Antigens can be genetically fused to the N-terminus of a single ferritin subunit or directly adjacent to the surface of ferritin nanoparticles by modular assembly (Rodrigues et al. 2021 ). Ferritin synthesis using genetically fused antigens has been performed mainly in insect cells and baculovirus expression vector system (IC-BEVS) or HEK293 mammalian cells (Zhao, et al. 2021 ; Chen et al. 2020 ; Kanekiyo, et al. 2013 ; Yassine, et al. 2015 ; Ma, et al. 2021 ; Qu, et al. 2020 ). Furthermore, although there are few examples, Escherichia coli ( E. coli ) and CHO cells provide an alternative platform for manufacturing ferritin-based vaccines (Li, et al. 2019 ).

Ferritin-based nanoparticle vaccines are safe and can stimulate immune responses against a wide range of infections. Because of their remarkable thermal and chemical stability, these materials are less reliant on cold chains for transportation and storage. In addition, ferritin-based vaccines are inexpensive and easily produced (Weidenbacher, et al. 2149 ). Recently, a ferritin-hemagglutinin (HA) vaccine for influenza in phase 1 clinical trials (Clinical-Trials.gov ID: NCT03186781) was developed in 2019, demonstrating the increasing interest in this platform (Kanekiyo, et al. 2013 ; Yassine, et al. 2015 ). Modular assembly allows the conjugation of several types of antigens to ferritin, leading to the production of broad-spectrum vaccines. However, whether its structure can be preserved or elicit an immunological response is a significant challenge (Ma, et al. 2021 ).

Ferritin-based veterinary vaccines have been shown to stimulate humoral and cellular immune responses. For instance, vaccines containing classical swine fever virus (CSFV) E2 glycoproteins displayed on the exterior of ferritin NPs produced greater E2-specific antibody titers, neutralizing antibody titers, and innate immune cytokines in vivo than traditional subunit vaccines (Zhao, et al. 2021 ). Another investigation established a vaccine for foot and mouth disease virus (FMDV) by conjugating ferritin to the FMDV viral antigen VP1 through genetic fusion using a baculovirus expression system. NPs increase FMDV-specific IgG and IgG subclass antibody titers, IL-4 and IFN-γ production, and splenocyte proliferation and decrease the survival rate of mice (Chen et al. 2020 ). Ferritin has been evaluated in preclinical studies as a vaccine scaffold for influenza. Kanekiyo genetically attached the ectodomain of influenza virus hemagglutinin (HA) to ferritin, causing it to autonomously assemble and form eight trimeric viral spikes on its surface (Kanekiyo, et al. 2013 ). Immunization with this HA-nanoparticle vaccine produced antibody titers for hemagglutination inhibition (HAI) that were more than tenfold greater than those for the licensed inactivated vaccine, as well as broadly neutralizing antibodies against H1N1. Yassine reported that ferritin-based vaccines containing the stem region of the H1 HA glycoprotein elicited extensive cross-reactive antibodies, completely protecting mice from lethal dosages of heterosubtypic H5N1 virus and partially protecting ferrets (Yassine, et al. 2015 ). The ferritin platform has also been used for vaccine development for porcine reproductive and respiratory syndrome virus (PRRSV). In a recent investigation, multiple copies of the PRRSV envelope glycoprotein GP5 on ferritin were detected (Ma, et al. 2021 ). Compared with inactivated vaccines, it produced stronger antibody responses and neutralizing antibody titers against PRRSV in pigs at 28 and 35 days postimmunization (dpi). Immunization with the GP5m-ferritin (GP5m-Ft) nanoparticle vaccine encouraged all vaccinated groups to develop a TH1-dominant cellular immune response and to boost particular T lymphocyte immune responses. Vaccinating pigs with the GP5m-Ft vaccine dramatically reduced PRRSV viremia and the number of macroscopic and microscopic lung lesions.

In conclusion, the development of ferritin-based vaccines has enormous promise for treating a wide range of animal diseases. However, it has to address accompanying obstacles.

Rationally designed self-assembled peptide nanoparticles

Although nanoscale assemblies might serve as effective candidate platforms for vaccines, they are limited by the number of accessible scaffolds and the presence of specific physicochemical features. Another method for developing nanovaccines is to use rationally constructed SAPNs. This section reviews current breakthroughs in computationally created artificial nanoparticles used in infectious disease vaccinations, as summarized in Table  2 .

Recently, computational approaches for constructing protein nanocages with atomic-level accuracy have been promoted as a burgeoning topic, with the potential to create self-assembling proteins with customizable architectures. In terms of design methods, they typically apply symmetric principles to assemble naturally occurring or newly created cyclic oligomers into protein nanoparticles. This rationally- design based method is considered a bottom-up approach, using minor pieces and producing a more complicated assembly, considerably increasing the protein nanoparticle design space (Papapostolou and Howorka 2009 ). The main benefit is that rationally designed proteins can display a wider range of antigens, not limited by fixed configurations, and can induce strong immune responses by the addition of new antigenic domains. Kanekiyo performed antigen domain optimization by molecular design and presented trimeric HA spikes on HA-NPs to obtain the maximum potential for inducing neutralizing antibodies (Kanekiyo, et al. 2013 ). However, one important barrier to rational vaccination antigen design is that protein sequences may only sometimes align precisely with structure and function (Bromley et al. 2008 ). Many groups have investigated how to design and construct self-assembled protein nanoparticle components based on nonnative polyproteins. For example, Hsia and coworkers developed a self-assembling protein known as i301 based on 2-keto-3-deoxy-phosphogluconate (KDPG) aldolase from the hyperthermophilic bacterium Thermotoga maritima , which is composed of 60 subunits with a porous dodecahedral architecture (Hsia, et al. 2016 ). Brunn et al. reported that a mi3 platform, an i301 mutant, can display antigens of interest by fusing SpyCatcher and SpyTag (Bruun et al. 2018 ). Antigens can be genetically fused to either the N- or C-terminus of mi3 and produced in eukaryotic or bacterial cells.

Mi3 offers numerous benefits as a multimerization platform for presenting antigens. mi3 NPs can accommodate large target antigens or proteins of up to 354 amino acids while maintaining nanoparticle formation and stability (Liu, et al. 2021b ) and are larger than many other self-assembling nanoparticle platforms. In addition, miR3 has been shown to promote antigen uptake and maturation in dendritic cells and to induce potent neutralizing antibody responses and cytotoxic T lymphocyte responses (Liu, et al. 2021a , 2021b ; Tan, et al. 2021 ). However, in comparison to other platforms, mi3 is relatively new and has received less attention in terms of safety and efficacy; further validation is needed.

The mi3 platform was utilized to create a classical CSFV vaccine. Liu employed the mi3 platform to stimulate a stronger immune response. CSFV E2 was fused to mi3 (SP-E2-mi3), which was subsequently expressed and purified from the Bac-to-Bac system. The vaccination of pigs with SP-E2-mi3 NPs greatly enhanced humoral and cellular immune responses. Compared to monomeric E2, SP-E2-mi3 NPs can elicit CSFV-specific IFN-γ-cellular immunity and neutralize more than tenfold more antibodies. This formulation protected the pigs against deadly pathogen assaults (Liu, et al. 2021a ). The mi3 platform has also been utilized to generate influenza vaccines. One study developed a vaccine for the influenza virus by purifying and expressing mi3 NPs that were genetically fused to homotypic and heterotypic HA antigens. The results revealed that mi3-HA NPs could produce powerful immune responses in mice but did not cause obvious cross-reactivity compared to immunization with combinations of homotypic particles (Cohen, et al. 2021 ).

Based on the studies presented above, mi3 is a potential platform for veterinary vaccine development. However, more research must be done to fully characterize the immune responses generated by mi3 nanoparticles and their ability to provide protective immunity against different pathogens.

Virus-like particles (VLPs): Animal virus-derived

VLPs resemble natural viruses in size and structure. They are supramolecular complexes consisting of several protein subunits. They can utilize genetic fusion to bind antigenic peptides from multiple pathogens and have been investigated as vaccine platforms for a variety of infectious diseases. Table 3 shows a summary of this information. This section will concentrate on immunization research using animal viral-derived VLPs, including porcine circovirus type 2 (PCV2), rabbit hemorrhagic disease virus (RHDV), FMDV, porcine parvovirus (PPV), and influenza A viruses (IAVs), as vaccine platforms.

Porcine circovirus type 2 (PCV2)

PCV2 is a pig virus with a major economic impact. The lone structural protein of PCV2, the capsid (Cap) protein, can be assembled into an icosahedral spherical cage-like VLP with T = 1, making it a suitable vehicle for displaying foreign sequences. PCV2 VLPs consist of 60 Cap subunits, each with eight antiparallel β-sheets and seven loops produced between folded sheets (Khayat, et al. 2011 ). The loop CD region allows for the insertion or substitution of exogenous peptides and may not influence VLP assembly. In addition to the core region of the loop CD, the carboxyl terminus of the Cap also plays critical roles in immune recognition and can be fused to foreign peptides and assembled into chimeric virus-like particles (Wang, et al. 2016 ). PCV2 VLPs or chimeric PCV2 VLPs can be efficiently expressed in E. coli , yeast, and insect expression systems (Yin, et al. 2010 ; Bucarey, et al. 2009 ; López-Vidal, et al. 2015 ). PCV2 VLPs have been approved and are commercially available, and two Cap-based vaccines are now available on the market (Porci-lis® PCV and CircoFLEX®) (Pagot, et al. 2017 ).

PCV2 VLPs can be adorned with immunostimulatory peptides or epitopes from other pathogens, which allows the production of bivalent vaccines (Mo, et al. 2019 ; Liu et al. 2020 ). In general, Cap can be modularly assembled with foreign antigens, allowing for the delivery of full-length proteins. PCV2 VLPs are not infectious because they lack a viral genome, making them safe for use as vaccines. In addition, PCV2 VLPs can elicit both cell-mediated and humoral immune responses, leading to a robust immune reaction against the target virus (Jung et al. 2020b ; Li, et al. 2018 ; Hu, et al. 2016 ). It has shown broad cross-neutralizing activities, meaning that it can protect against different genotypes or strains of PCV. However, current strategies for integrating exogenous antigens into PCV2 Cap VLPs are limited to the introduction of small epitopes/peptides (Lei et al. 2020 ). Steric hindrance can hinder strategies such as tandem core, split core, and mosaic particle technologies. Furthermore, PCV Cap VLPs may exhibit antigenic diversity, compromising the accuracy of immunological evaluation and diagnostic performance of commercial ELISAs (Kang, et al. 2021a ).

The PCV2 VLP platform was tested for its ability to prevent various swine viral infections. In one study, investigators developed dual nanoparticle vaccination based on SpyTag/SpyCatcher technology to avoid PCV2 and CSFV coinfection. In this study, CSFV E2 was coupled to SpyTag and surface-displayed on SpyCatcher-decorated PCV2 Cap via in vitro conjugation based on isopeptide bonds generated between SpyCatcher and SpyTag. Compared to unconjugated vaccines (Cap + E2 and E2 alone), high-density E2 on Cap resulted in significantly greater antibody levels and neutralizing antibody responses. Compared with Cap VLPs, Cap-E2 NPs elicited equal quantities of PCV2-specific and neutralizing antibodies. Furthermore, Cap-E2 NPs significantly enhanced CSFV E2-specific cellular immunity. Cap-E2 nanoparticles stimulated lymphoproliferative responses and increased TH1-type cytokine production (IL-2 and IFN-γ) (Liu et al. 2022 ). Li isolated two epitopes, epitopes B and 7, from the highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) Gp5 for use in PRRSV vaccination research. These epitopes were selected for display on PCV2 VLPs. Research on animals has shown that the VLP vaccine may promote the development of neutralizing and specific antibodies against epitopes B and 7 and lower viral loads following HP-PRRSV challenge (Li, et al. 2021 ). In a similar study, Cap VLPs were altered by replacing the decoy epitope of the Cap protein with the PRRSV GP3, GP5 or GP3-GP5 epitope. Cap-GP3, Cap-GP5 and Cap-GP35 produced high GP3/GP5 and Cap antibody titers, while animals immunized with Cap-GP3 VLPs had high levels of both PCV2- and PRRSV-neutralizing antibodies (Jung et al. 2020b ). PCV2 VLPs have also been used to enhance influenza vaccines. In one study, various copies of theIAV matrix protein 2 (M2e) were inserted into PCV2 Cap and expressed in E. coli to produce VLPs. The Cap-3M2e VLP nanomicroline produced the greatest levels of M2e-specific and neutralizing antibodies, and it entirely prevented deadly infection by H1N1 and H3N2. Furthermore, Cap-3M2e VLPs produce enormous levels of PCV2-specific neutralizing antibodies in pigs (Ding, et al. 2019 ).

These findings suggest that the PCV2 VLP platform can be used for dual nanoparticle vaccination to stimulate a strong immune response to PCV2 and other veterinary illnesses.

Rabbit hemorrhagic disease virus (RDHV)

RHDV usually causes highly contagious and fatal sickness in rabbits. It is a nonenveloped RNA virus with a capsid (about 40 nm diameter) composed of 180 monomeric units of VP60 (also termed VP1), which integrate into 90 dimers to create a T = 3 icosahedral form (Valícek et al. 1990 ; Wang, et al. 2013 ). The VP60 capsid protein can be expressed in heterologous recombinant systems such as recombinant baculovirus, plants, mammalian cell cultures, or yeasts, and this often leads to the formation of VLPs that resemble natural virions both morphologically and antigenically (Boga, et al. 1994 ; Fernández-Fernández, et al. 2001 ; Bertagnoli, et al. 1996a , 1996b ; Pérez-Filgueira, et al. 2007 ; Laurent et al. 1994 ; Escribano, et al. 2020 ). The VP60 VLP is composed of an internally positioned N-terminal arm (NTA), a shell domain (S), which creates an unbroken scaffold, and a flexible protrusion domain (P) on the capsid surface. The latter can be further divided into P1 (aa 238–286, 450–466, 484–579) and P2 (aa 287–449 and 467–483) subdomains, with the P2 subdomain residing in the most accessible region of the VP60 VLP and possibly containing determinants of cell attachment and antigenic diversity (Wang, et al. 2013 ; Bárcena, et al. 2004 , 2015 ; Leuthold et al. 2015 ). RHDV VLPs have been shown to be both an efficient preventive vaccine in rabbits and a vehicle for the delivery of heterologous antigens. Structural analysis indicated that the VP60 protein can accommodate the introduction of foreign antigenic sequences (chimeric VLPs) to the N-terminus without disrupting VLP assembly, yet the C-terminus is not suitable for introducing antigens due to the disruption of VLP assembly and antigen presentation (Leuthold et al. 2015 ).

RHDV VLPs are noninfectious and lack the genetic material required for replication, which reduces the likelihood of disease transmission in vaccinated patients. It closely resembles the native virus in structure, allowing for better recognition by the immune system and potentially enhancing the effectiveness of the vaccine (Laurent et al. 1994 ). Moreover, the use of Trichoplusia ni insect pupae as natural bioreactors for VLP production simplifies vaccine manufacturing and reduces downstream production-associated costs (Dalton, et al. 2021 ; Escribano, et al. 2020 ). Unfortunately, although numerous candidates for RHDV VLP vaccines are currently being studied, none have been effectively commercialized.

The RHDV VLP vaccine has been shown to produce widespread immunity in inoculated rabbits. VP60 VLP vaccination for RHDV was developed using E. coli expression systems according to one study. Following a two-dose schedule, vaccinated rabbits showed greater specific antibody titers and cell-mediated immune responses (Guo, et al. 2016 ). A different study used recombinant baculovirus vectors to coexpress VP60 proteins from the two RHDV prevalent serotypes, resulting in chimeric VLPs that included both proteins. Rabbits were vaccinated with chimeric RHDV VLPs and subsequently challenged with two RHDV serotypes, resulting in total protection against the deadly challenge of both serotypes of infection (Dalton, et al. 2021 ). RHDV VLPs have also been tested as a vaccine scaffold for FMDV infections. To address FMDV, the coat protein epitopes of FMDV (T-cell epitope and neutralizing B-cell epitope) are genetically fused into two different locations of RHDV VP60. Extensive in vivo studies have shown that this chimeric VLP vaccine elicits potent FMDV-specific antibodies and strong neutralizing immune reactions in mice and pigs but is insufficient to induce complete protection at the level of cellular immune responses. Consequently, it provides partial clinical protection against FMDV infection (Rangel, et al. 2021 ). In another similar study, Crisci demonstrated that the FMDV-RHDV chimeric VLP vaccine can induce specific cellular immunity. The chimeric VLP vaccine can produce specific IFN-γ-secreting cells and lymphoproliferative T cells against FMDV and RHDV (Crisci, et al. 2012 ).

In recent years, major advances in tumor treatment involving RHDV VLPs have been achieved. However, its application in veterinary medicine is limited; it is mainly used as a carrier for FMDV. Therefore, further exploration of the application of RHDV in other veterinary diseases is urgently needed.

Foot and mouth disease virus (FMDV)

FMDV is a highly contagious and lethal disease in agricultural animals. The FMDV genome has one large open reading frame that codes for the P1-2A precursor polyprotein, which is processed by the 3C protease into mature VP0, VP1 and VP3 and assembled to form the icosahedral capsid (Ryan et al. 1989 ; Abrams et al. 1995 ). FMDV VLPs consist of 60 copies of capsid protein monomers (VP0, VP1 and VP3) arranged into 12 pentameric subunits that function as intermediates in capsid construction and disassembly (Han et al. 2015 ). There are currently two forms of FMDV VLP vaccines: one composed of FMDV capsid proteins and one composed of chimeric FMDV VLPs created by incorporating critical epitopes from multiple serotypes. FMDV VLPs or chimeric VLPs can be efficiently expressed in E. coli , mammalian cells, and insect expression systems (Silva, et al. 2013 ; Xiao, et al. 2016 ; Oem, et al. 2007 ; Felberbaum 2015 ; Ruiz, et al. 2014 ; Gullberg, et al. 2013 ). Previous research has shown that FMDV VLPs, as FMDV vaccines, can induce long-lasting humoral and cellular immune responses. Unfortunately, FMDV VLPs have been less frequently used as a carrier model for other pathogens.

2021 ; 2017 ; 2013 ). Similar to other VLPs, FMDV VLPs are not contagious due to their lack of infectious viral genetic material, which limits the possibility of infection. However, 3C-protease, which is typically used in the production of VLPs, can be harmful when present in large quantities, suggesting a potential disadvantage of its use in production systems (Veerapen et al. 2018 ).

FMDV VLPs have been studied as a vaccine platform for managing FMDV infection. In one study, an enhanced SUMO fusion protein system in E. coli produced the VP0, VP1 and VP3 proteins; removing the SUMO moiety from the fusion proteins resulted in the assembly of FMDV VLPs. The results revealed that FMDV VLP vaccination can promote specific antibodies, neutralizing antibodies, T-cell proliferation, and IFN-γ secretion in guinea pigs, swine and cattle. Vaccination with one dose of the VLP may elicit a high level of immunological response, which is adequate to protect against virulent viral infection (Guo, et al. 2013 ). In a similar study, researchers coexpressed FMDV capsid proteins (VP0, VP1and VP3) in E. coli . FMDV VLP vaccination successfully induced FMDV-specific cellular and humoral immune responses in pigs (Xiao, et al. 2021 ). Liu created a chimeric FMDV VLP vaccine using the baculovirus system, combining the antigenic structural protein VP1 from serotype O with viral capsid protein segments (VP2, VP3 and VP4) from serotype A. Animal tests demonstrated that the chimeric VLP vaccine increased the levels of anti-FMDV antibodies and cytokines (IFN-γ, IL-4, and IL-6) and strongly protected guinea pigs from FMDV challenge (Liu, et al. 2017 ). As a result, FMDV VLPs have the potential to be good vaccine candidates for treating FMDV infection.

Porcine parvovirus (PPV)

The primary cause of sow reproductive failure syndrome is PPV. The PPV capsid is an icosahedral, nonenveloped, and spherical shell with a diameter of approximately 20 ~ 25 nm. It is composed of 60 copies of a combination of VPs, VP1, VP2 and VP3 (Molitor et al. 1983 ). The primary capsid protein, VP2, can self-assemble into VLPs, a key antigen that triggers neutralizing antibodies (Ridpath and Mengeling 1988 ). It can successfully self-assemble in a variety of expression systems, including baculovirus/insect, mammalian cell, yeast and E. coli expression systems (Antonis, et al. 2006 ; Guo et al. 2014 ; Yang, et al. 2021 ; Wang, et al. 2020 ). According to previous studies, adding or deleting amino acids at the N-terminus of the VP2 protein does not affect VLP assembly (Wang, et al. 2021 ), opening up the prospect of using PPV VLPs as a vaccine carrier model for multiple diseases. Nonetheless, the processes controlling PPV VP2 self-assembly remain unknown.

PPV VLPs are very biologically safe and have been proven to induce high hemagglutination inhibition antibodies and neutralizing antibody responses in animals, indicating their usefulness in triggering immunological responses (Hua, et al. 2020a , 2020b ; Liu, et al. 2020 ; Anwar, et al. 2021 ). PPV VLPs have demonstrated the ability to act as a vaccine carrier model for multiple pathogens that provide protection against PPV and other pathogen infections. However, the expression of the PPV VP2 protein was relatively low under the current expression conditions, which may require further optimization in high-density fermenters to increase yield (Hua, et al. 2020a ; Zhou et al. 2010 ). Furthermore, the underlying processes of PPV VP2 protein synthesis in prokaryotic systems and its ability to generate VLPs in vitro still need to be fully characterized and may require further investigation and development (Liu, et al. 2020 ).

VP2-based VLP is the most commonly used for PPV infection. In one work, VLPs were generated by effectively expressing the PPV VP2 protein in E. coli , which had a structure and hemagglutination capabilities identical to those of natural PPV. Guinea pigs, weaned piglets, and primiparous gilts were vaccinated with VLPs, which elicited strong hemagglutination inhibition and neutralizing antibodies. In guinea pigs, inoculation with 20 μg or 10 μg of VLPs resulted in neutralizing antibody and HI antibody titers comparable to those of 200 μL of the commercial inactivated vaccine 28 dpi. Immunization with the VLP vaccine protected against reproductive failure following pathogenic PPV challenges in primiparous gilts (Hua, et al. 2020a ). In another study, Liu described a combination vaccine that addresses PCV2 and PPV coinfections. The PPV-VP2 and PCV2-Cap proteins, which self-assemble into VLPs, were expressed in E. coli . The combined VLP vaccine generated robust cellular and humoral immune responses against PPV and PCV2, reduced the viral load in the tissue and serum, and eliminated clinical disease in pigs (Liu, et al. 2020 ). PPV VLP-based technology has also been utilized to prevent zoonotic diseases. In a single investigation, VLPs were created by introducing six JEV E protein epitopes into various loop areas of the pig parvovirus (PPV) VP2 protein. Mice and guinea pigs immunized with VLP(VP2-JEVe) vaccines developed impressive cell-mediated and humoral immune responses, providing complete protection against lethal JEV challenge in mice. It demonstrated effective hemagglutination inhibition (HI) and neutralizing reactions as well as a reduction in the amount of virus in guinea pig tissues (Anwar, et al. 2021 ).

For example, the VP2-based VLP platform has been effectively used to generate vaccines against PPV and other veterinary illnesses, eliciting robust cellular and humoral immune responses and providing defense against pathogenic challenges.

Influenza A viruses (IAVs)

IAVs are highly contagious viral diseases isolated from people, birds, horses, pigs, cats, dogs and marine mammals. They pose a substantial hazard to human and animal health (Sandrock and Kelly 2007 ). The IAV genome encodes a variety of polypeptides, including two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), as well as two matrix proteins (M1 and M2) that are necessary for protective immunity. A self-assembly method can produce VLPs from influenza proteins (HA, NA and M1) (Haynes 2009 ). The choice of a core component determines its size and shape. The creation of influenza VLPs has been achieved mostly in insect expression systems that involve insect cells infected with recombinant baculovirus expressing the HA, NA and M1 influenza genes, which leads to protein expression and VLP formation (Cox 2008 ). SIV, an acute and highly contagious IAV (subtypes H1N1, H1N2 or H3N2), poses a significant hazard to pig and human health. Thus, the VLP from the SIV will be emphasized.

SIV VLPs mimic the internal structure and conformation of the parent virus and display surface proteins in a highly immunogenic state. It does not require chicken embryos for production and can be mass-produced in cells, allowing for rapid updates in response to emerging antigens (Cai, et al. 2022b ). Furthermore, SIV VLP vaccines can induce potent immune responses and elicit cross-protective immunity against different influenza strains (Cai, et al. 2022b ; Mai, et al. 2023b ). However, baculovirus virions and influenza VLPs have highly comparable densities, making it challenging to eradicate baculoviruses during purification (Margine et al. 2012 ). Furthermore, contradictory data have been reported regarding the protective efficacy of VLPs in various animal models, indicating potential differences in their effectiveness.

Influenza virus vaccination has been routinely utilized to prevent influenza virus infections. In one study, Cai created HA-M1 VLPs from H1N1 and H3N2 SIVs and tested their immunogenicity and protective qualities in a mouse model. The results demonstrated that bivalent VLP vaccines can induce higher levels of HI antibodies, neutralizing antibodies, specific IgG antibodies, and cytokines than can inactivated vaccines and provide sufficient protection against lethal challenges from homologous and heterologous H3N2 and H1N1 influenza viruses (Cai, et al. 2022a ). Furthermore, he also investigated the immunological protective effects of the bivalent VLP vaccines H1 and H3 in piglets. After immunization with the SIV VLP vaccine, piglets produced high HI titers of antibodies, induced more neutralizing antibodies than did piglets immunized with inactivated vaccines, and were protected against H1 and H3 influenza virus challenge (Mai, et al. 2023a ). Pliasas constructed an NA2 VLP vaccine using the matrix 1 (M1) protein from H1N1 and the NA protein from H3N2. Pigs vaccinated with the NA2 VLP vaccine developed high levels of anti-NA antibodies and NAI titers. Compared to the commercially available QWIV, NA2 VLPs provided comparable protection against clinical IAV challenges, reduced virus replication in lung diseases, and decreased lung inflammation (Pliasas, et al. 2022 ). These findings revealed that vaccine design based on SIV VLPs provides excellent protection in piglets against H1N1 or other relevant influenza viruses. As a result, more emphasis should be given to its use in the creation of influenza virus vaccines.

Bacteriophage-derived VLPs

Bacteriophages are viruses that attack bacteria. There are several varieties of bacteriophages. VLPs from Qβ, P22, MS2, λ, T4 and filamentous phages have been created to prevent animal diseases. This section examines the current developments in these platforms (Table  4 ).

P22 bacteriophage

The P22 bacteriophage is a short-tailed phage with a 60-nm icosahedral capsid bearing double-stranded DNA (dsDNA) (Wang et al. 2019 ). The P22 phage capsid was constructed using 415 copies of coat protein (CP) and approximately 300 scaffolding proteins (SPs) (Kang, et al. 2010 ). VLPs from the Salmonella typhimurium bacteriophage P22 can be produced by coexpressing CP and SP, resulting in a T = 7 icosahedral structure with an outside diameter of 56 nm (Prevelige et al. 1988 ). Target antigens can be directed by the fusion of the target gene to the scaffolding domain of SP and subsequent coexpression with CP (O'Neil et al. 2011 ). P22 VLPs were found to be a suitable platform for delivering protein cargo.

P22 viral capsids are active macromolecules that can self-assemble. This structural flexibility allows for the genetic manipulation and modification of their interior surfaces, making them versatile nanoplatforms. As a result, P22 VLPs have been exploited as molecular structures for rapid modular high-density bioconjugation of antigens, including complete protein antigens, increasing the immunogenicity of the linked target antigen (Kang, et al. 2010 ).

The P22 platform was used to develop a vaccine against the iIAV. One study employed an enzymatic conjugation approach (SpyTag/SpyCatcher) to combine P22 VLPs with multiple copies of the HA protein's globular do-main head. Mice vaccinated with this formulation and challenged with the PR8 strain of IAV demonstrated 100% survival relative to unvaccinated animals. Furthermore, this formulation increased antigen-specific IgG antibody levels by twofold relative to controls (Sharma, et al. 2020 ). P22 is one of the most promising models for creating VLP nanocages. The utilization of the influenza virus prompted further investigations into the use of P22 VLPs for a variety of infectious illnesses.

Qβ bacteriophage

Qβ is a positive single-stranded RNA bacteriophage that infects E. coli (Singleton, et al. 2018 ). The capsid of Qβ is composed of 180 monomeric proteins that self-assemble into an icosahedral VLP with a diameter of 28 nm (Golmohammadi et al. 1996 ; Machida and Imataka 2015 ). Qβ VLPs have been studied as a model for veterinary infectious disease vaccine applications. This modularity allows for greater freedom in the size and structure of the recombinant target antigen since the folding restrictions of the VLP monomer and subsequent self-assembly do not limit it. This scalability is beneficial for vaccine development and production since it enables the manufacture of large volumes of vaccines with short production timeframes (Skamel et al. 2014 ). Furthermore, antigens coupled to Qβ VLPs have been shown to induce highly enhanced antibody responses in both mice and humans compared to immunization with free antigens (Jegerlehner, et al. 2013 ; Alam, et al. 2021 ). However, the current size of Qβ limits the display of large protein domains (Skamel et al. 2014 ).

The Qβ platform was used to develop influenza vaccines. A study revealed a new influenza vaccine that uses Qβ phages coupled with the H1N1 virus antigen. Compared with those immunized with free antigens, vaccinated mice have shown increased antibody titers and survival rates (Jegerlehner, et al. 2013 ). The Qβ platform has also been used for preventing FMDV infection. For example, the VP1 G-H loop peptide of FMDV was attached to the Qβ VLP, resulting in significant antibody affinity for complete FMDV (Skamel et al. 2014 ). The Qβ phage platform is versatile and has shown promising results in developing vaccines for several animal illnesses.

MS2 bacteriophage

MS2, an icosahedral RNA bacteriophage, has a triangulation of T = 3 (Fu and Li 2016 ). Its genome encodes four proteins: the main coat protein (CP), the maturation protein (A-protein), the lysis protein, and the replicase (Bleckley and Schroeder 2012 ). A total of 180 copies of MS2 CP can join to form VLPs, monodisperse icosahedral capsids with a diameter of 22–29 nm (Mastico et al. 1993 ). The AB loop of MS2 phage CP can accept exogenous peptide insertion without compromising the self-assembly capabilities of CP. As a result, MS2-mediated chimeric nanoparticles provide an excellent platform for displaying foreign epitopes. Furthermore, MS2 VLP vaccines are known for their good stability and correct size, which is beneficial for vaccine development (Dong et al. 2015 ; Wang, et al. 2018 ). However, the limited tolerance of MS2 phage to long amino acid insertions may result in the aggregation, misfolding, or degradation of proteins (Caldeira and Peabody 2011 ; Peabody 1997 ). As a result, chimeric MS2 VLPs require additional optimization procedures.

MS2 VLP platforms have been evaluated for their ability to prevent FMDV infection. Dong YM and colleagues created an effective MS2-based FMDV vaccine by genetically modifying MS2 VLPs to express an epitope peptide of VP1. Vaccinating mice, guinea pigs, and swine with MS2 VLPs containing VP1 peptides not only elicited high-titer neutralizing antibodies but also protected the majority of the animals from FMDV challenge (Dong et al. 2015 ). In a similar study, mice were immunized with the FMDV-MS2 chimeric vaccine, which elicited more specific antibodies and stronger humoral immune responses (specific IFN-γ responses and lymphocyte proliferation) than were elicited by repeat peptide epitopes (Wang, et al. 2018 ). These findings show that MS2 VLP vaccination could provide possible preventative options for more widespread animal disease.

Plant virus-derived VLPs

Currently, plant virus-derived VLPs have been investigated as vaccine platforms for a variety of animal diseases (see Table  5 ). In this section, we will focus on the immunization research of these platforms.

Tobacco mosaic virus (TMV)

TMV is a plant virus with a 300 nm × 20 nm rod-shaped capsid (Butler 1984 ). VLP derived from TMV is a high-surface nanotube structure with an 18 nm diameter constructed from helical arrangements of modified capsid coat proteins (CPs) (Lomonossoff and Wege 2018 ). As discussed, TMV has been studied as an antigen display scaffold. Most TMV formulations use conjugation or genetic fusion to load linear peptide epitopes and tiny immunological domains onto their capsid proteins.

TMV VLPs have many advantages (Mansour, et al. 1195 ; Liu et al. 2013 ; Jennings and Bachmann 2008 ). First, TMV VLPs provide a flexible backbone for the attachment of any subunit protein antigen of interest from any source, making TMV VLPs versatile carriers for a variety of antigens. Second, TMV VLPs have been stable at ambient temperature for decades, raising the possibility that vaccination formulations containing TMV do not require refrigeration. Finally, the TMV structure and size allow for quick uptake by antigen-presenting cells, and the positive sense RNA core of TMV provides an extra adjuvant effect. However, unlike plant-produced TMV, bacterial TMV VLPs have limited self-assembly properties and can only form nanorods under specific conditions (Lee, et al. 2021 ), which may limit their suitability for particular applications.

TMV VLP-based vaccines have been shown to protect against veterinary viral infections. In attempts to construct an influenza vaccine, TMV combined with peptides from the influenza HA protein has been demonstrated to elicit not only antigen-specific antibodies but also better protection against H1N1 influenza virus challenge in mice than the commercially available vaccine (Mallajosyula, et al. 2014 ). In another study, the defined epitope peptide F11 of VP1 from FMDV was genetically fused into a novel TMV VLP vector, which protected guinea pigs and swine from FMDV challenge. The TMV platform has also been used to develop tularemia vaccines (Jiang, et al. 2006 ). The TMV platform has also been used to develop tularemia vaccines. Utilizing genetic fusions, the anti-gens OmpA, DnaK, Tul4 and SucB proteins of Francisella have been conjugated to TMV to improve the immune response against Francisella tularensis. Immunization studies in mice revealed a significant humoral immune response and protected the majority of animals against deadly pathogen exposure (Mansour, et al. 1195 ).

Papaya mosaic virus (PapMV)

PapMV is a filamentous plant virus. It is composed of 1400 coat protein (CP) subunits that may self-assemble into a flexible rod-shaped VLP with a diameter of 14 nm and a length of 500 nm (Sit et al. 1989 ). PapMV VLPs have many features, such as stability. PapMV VLPs are highly stable even at temperatures exceeding 37°C. This stability ensures that VLPs can maintain their structural integrity and immunogenicity. Second, PapMV VLPs are highly immunogenic, meaning that they can effectively stimulate an immune response in the body. They cause the development of antibodies, specifically IgG2a antibodies, which are linked to a TH1-biased immune response. While PapMV VLPs can generate a robust immune response against the fused peptide, their ability to provide broad protection against other antigens may be limited. To widen the spectrum of protection, more antigens need to be added to VLPs.

PapMV VLPs have been demonstrated to be an effective adjuvant and vaccine platform for the development and enhancement of flu vaccines. One study fused influenza M2e peptides to PapMV particles. Mice vaccinated with PapMV-M2e generated a strongly specific antibody and protected them from H1N1 challenge (Carignan, et al. 2015 ). To improve the protection efficacy, another study designed a multimerized nucleoprotein PapMV nanoparticle vaccine combining M2e and nucleoprotein antigens of influenza strains, which protected mice from challenges by both H1N1 and H3N2 (Bolduc, et al. 2018 ). As a result, PapMV VLPs are an efficient adjuvant and vaccination platform for influenza vaccines. This is an encouraging alternative that warrants further examination.

Optimization strategies for SAPN/VLPS vaccines

As discussed above, the NP vaccine platform can improve the immune response to subunit vaccines. However, compared with live attenuated vaccines, SAPN and VLP vaccines, which are made of pure protein or viral protein components, may not adequately elicit the innate immune response. Therefore, further optimization of NP vaccines is necessary. This section will concentrate on the optimal strategy for SAPN and VLP vaccination.

Adjuvant formulations

Adjuvants are functional excipients that are added to vaccines to boost immunogenicity and produce protection against infection. An adjuvant can enhance the quality, duration, and magnitude of an antigen-specific immune response through APC recruitment at the injection or administration site (Gregorio et al. 2013 ; Coffman et al. 2010 ). According to chemical composition, adjuvants are classified into mineral salt-based adjuvants, emulsion-based adjuvants, and liposome-based adjuvants (Firdaus et al. 2412 ). Mineral salt-based adjuvants such as aluminum salts, calcium phosphate, and AS04 are commonly utilized. What adjuvants are suitable for SAPN and VLPs? As mentioned above, SAPNs and VLPs are beneficial for APC recognition and uptake, as well as BCR crosslinking. Thus, aluminum salts, an adjuvant that is beneficial for the delivery of subunit vaccine antigens to APCs, may not necessitate the use of SAPN and VLP vaccines. Furthermore, because VLPs have a shape and surface antigenic configuration comparable to those of natural virions, the best adjuvant formulation should avoid interfering with complex structures.

One promising adjuvant formulation is cytosine phosphate guanosine (CpG) oligodeoxynucleotides (ODNs), a class of DNA analogs that trigger the innate immune system by binding to Toll-like receptor 9 (TLR9). CpG-ODN binding to TLR9 increases immunostimulatory activity due to the activation and maturation of APCs, including NK cells and dendritic cells. APC activation leads to a TH1 response that increases the production of IFN-γ and other cytokines, such as TNF-α and IL-6. Therefore, proinflammatory cytokines directly activate and transform B cells into plasma cells that produce antigen-specific antibodies with high affinity. The expression of MHC, CD40 and CD86 due to the TLR9 signaling pathway also leads to increased antigen presentation and processing, as well as IFN-γ production and CTL activation (Dongye et al. 2022 ).

In one study, FMDV VLPs vaccinated with CpG demonstrated stronger cell-mediated immunity in guinea pigs than did those vaccinated with ISA206 and the poly I:C adjuvant (Terhuja et al. 2015 ). In another similar study, Shi used a squalene adjuvant containing CpG. The immunization of BALB/c mice and guinea pigs with FMDV VLPs and this adjuvant elicited specific antibodies, including higher levels of IgG1 and IgG2a, and increased the production of IFN-γ and IL-1β and the survival rate when the adjuvant was used (Shi, et al. 2022 ). In another study, Toxoplasma gondii VLP vaccination with a CpG adjuvant improved IgG and IgA antibody responses and elicited greater CD4 + and CD8 + T-cell responses than unadjuvanted immunization (Kang, et al. 2021b ).

Flagellin, a potent TLR5 agonist, is a known immunostimulator that causes APC maturation and TH1- and TH2-mediated immunological responses, which are followed by B-cell activation and high antibody titers (Mizel and Bates 2010 ). Several investigations revealed that flagellin augmented the efficacy of H1N1 VLP vaccination by increasing humoral and cellular immunity (Wang, et al. 2008 , 2010 ). Ren reported that H5N1 VLP membrane-anchored heat-labile enterotoxin B and flagellin produced stronger cellular and humoral immune responses than unadjuvanted H5N1 VLPs. It protected mice against lethal H5N1 challenge and showed tenfold higher IgG titers than unadjuvanted groups (Ren, et al. 2018 ). Furthermore, a flagellin-based HA vaccine and an M2e vaccine against influenza are being tested in clinical studies (Taylor, et al. 2012 ; Turley, et al. 2011 ). In another study, a truncated flagellin was inserted into the PCV2 Cap and displayed on VLPs. Compared with those of mice injected with wild-type Cap VLPs, Cap-flagellin-treated vaccinated mice produced more neutralizing antibodies and Cap-specific antibodies (Lu, et al. 2022a ). The ability of flagellin to stimulate the immune response and improve the efficacy of influenza vaccines suggests that flagellin could play an important role as an adjuvant in the development of future vaccines.

ISCOMATRIX (CSL), a particulate complex of saponin, cholesterol, and phospholipids, is another adjuvant formulation that can deliver antigens to APCs and induce NALP3-, inflammasome-, TH1- and TH2-mediated responses and antibody formation (Baz Morelli, et al. 2012 ; Wilson, et al. 2014 ). In a phase I clinical trial of the H7N9 VLP flu vaccine, a researcher demonstrated the role of the ISCOMATRIX adjuvant in enhancing seroconversion; 80.6% of subjects receiving the H7N9 VLP vaccine containing HA with the ISCO-MATRIX™ adjuvant achieved HI responses, yet those receiving the unadjuvanted H7N9 VLP vaccine responded poorly (only 15.6% seroconversion rates) (Chung, et al. 2015 ). Overall, ISCOMATRIX (CSL) is a promising adjuvant that improves vaccine effectiveness by boosting immune system responses.

Targeting peptides

Another technique for improving vaccination efficacy is to include tailored peptides and ligands on the surface of protein cage nanoparticles, which aids in the transport of SAPN and VLPs to specific receptors. The primary target cells are DCs, which have many specialized receptors called pattern recognition receptors (PRRs), including TLRs, NOD-like receptors (NLRs), C-lectin type receptors (CLRs), helicases, and RIG-1-like receptors (RLRs) (Mazzoni and Segal 2004 ; Desmet and Ishii 2012 ; Figdor et al. 2002 ). SAPN and VLPs can be delivered to DCs via endocytic receptors on their surface.

Targeted APC strategies have been applied to various NP vaccines. In one study, multiple DC-binding peptides (DCbps) were added to PCV2 Cap to create chimeric VLPs. Mice vaccinated with Cap-DCbp VLPs exhibited improved cellular and humoral immune responses. Compared to wild-type Cap VLPs, Cap-DCbp VLPs exhibited higher levels of Cap protein-specific antibodies, intracellular cytokines, and neutralizing antibodies and an enhanced proliferation index in lymphocytes (Lu, et al. 2022b ).

Lectin, such as DC-SIGN or CD209, dendritic cell-associated lectin-1 (dectin-1), dectin-2, macrophage-inducible C-type lectin receptor (MINCLE), and mannose receptor, is an appealing DC-targeting receptor for which VLP vaccines are used (Johannssen and Lepenies 2017 ; García-Vallejo, et al. 2013 ). Studies have demonstrated that mannosylation can result in enhanced antigen presentation on MHC class I and II through mannose receptors, leading to improved cell-mediated and humoral immunity. In another study, Al-Barwani conjugated a monoman-noside and novel dimanoside to the RHDV VLP capsid protein. This mannosylation greatly improved RHDV VLP adhesion and internalization by human dendritic cells, macrophages, B cells, and murine dendritic cells (Al-Barwani et al. 2014 ). Antigens that connect to the C-type lectin receptor DC-SIGN can be internalized and trafficked to endolysosomal regions before being processed and presented on MHC class II molecules, resulting in CD4 + T-cell activation. In another study, Man (a natural DC-SIGN ligand) was conjugated to the bacteriophage Qβ-VLPs, which can enhance CD4 + TH1 responses and promote inflammatory and TH1-type cytokine production (Alam, et al. 2021 ). In conclusion, targeted APC methods for VLP vaccines increase both humoral and cellular immune responses.

Conclusions and future perspectives

Vaccination has long been one of the most common strategies for preventing infectious diseases and minimizing the occurrence of global pandemics. Since the COVID-19 pandemic, nanoparticle-based vaccines have provided numerous candidates for clinical trials and other disease models. Because of their biodegradability, multivalency, molecular specificity, and biocompatibility, protein-based nanoparticles can be employed in vaccine manufacturing to improve vaccine immunogenicity and durability without requiring a cold chain. SAPN and VLP platforms, in particular, may carry antigens on their surfaces, resulting in an orderly repeated array of antigens on nanoparticles with small diameters that resemble PAMPs, leading to delivery, presentation, and robust immune reactions. Overall, the use of SAPNs and VLPs in vaccine development appears promising.

Several VLP-based vaccines, including those for malaria, hepatitis B virus (HBV), and human papillomavirus, are commercially marketed. However, SAPN- and VLP-based veterinary vaccines are still in their infancy and face a few challenges. The first challenge is the need for an in-depth understanding of the antigen release properties, internal distribution, or prophylactic mechanism of each nanoparticle-based platform in vivo. We still need to find an optimum way to achieve precise targeting and biodistribution of nanoparticles, which is critical for advancing this field. The second limitation is determining the synthesis and large-scale production of commercial nanoparticle vaccines. The current majority of SAPN and VLP-based veterinary vaccines are products of experimental studies and may take a considerable amount of time to complete clinical trials and licensing. However, we believe that it is only a matter of time. Recently, the development of low-cost expression systems, including the E. coli expression system, has facilitated easy manipulation, rapid growth, and cost efficiency. Compared to mammalian cell expression systems and insect cell expression systems, both have high yield and good safety but require longer expression times and higher costs. Additionally, the yeast expression system has several similarities to the E. coli expression system regarding production time and cost-effectiveness. However, the yeast expression system has potential disadvantages because of the thick and dense yeast cell wall, which interferes with cell disruption during protein extraction. The creation of nanoparticle vaccines using the E. coli expression system will enable large-scale manufacture and commercialization of nanoparticle vaccines.

Furthermore, we should focus more on enhancing immunological efficacy through a variety of approaches. In addition to CpG, flagellin, and CSL adjuvants, which are currently used in nanoparticle vaccine development research, additional novel adjuvants, such as liposomes, AS04, chitosan and PRR agonist adjuvants, which have achieved phased results in the field of human vaccines, should also be actively explored. Furthermore, we can combine several adjuvant compositions to achieve optimal targeting and distribution.

Despite these challenges, this sector anticipates commercial uses for veterinary vaccines based on the SAPN and VLP platforms described in this research, which can prevent and treat a wide range of illnesses. As vaccine research advances and numerous malignant and infectious diseases spread, SAPN and VLP nanoparticle-based platforms have demonstrated enormous promise and should be considered promising techniques in veterinary vaccine development.

Availability of data and materials

Not applicable.

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Meiqi Sun, Aldryan Cristianto Pratama, He Qiu, Zehui Liu & Fang He

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F.H., M.-Q.S., A. C. P., Z.-H.L., and H.Q. conceived the study; M.-Q.S. and A. C. P. performed the literature search; M.-Q.S. and H.Q. wrote the manuscript; F.H. critically reviewed it. All authors have reviewed the published version of the manuscript and given their approval.

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A New Decade of Veterinary Research: Societal Relevance, Global Collaboration, and Translational Medicine

Mary m. christopher.

1 Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California–Davis, Davis, CA, USA

Veterinary research and clinical contributions reach into every aspect of biomedical health and science: livestock production and food safety; zoonotic diseases, epidemiology, and public health; comparative basic and translational research; companion animal medicine and surgery; animal welfare and the human-animal bond; and wildlife and ecosystem health. Diversity is not only a key strength of veterinary science but also a challenge. Veterinary research in the next decade must strengthen the scientific impact of its core mission in animal health while firmly reinforcing its societal and global relevance. Key research challenges include water- and food-borne pathogens and drug residues, zoonotic pathogens and infectious diseases, and evidence-based companion animal medicine and its translational applications to human health. Meeting these challenges will require cross-disciplinary global collaborations, significant national research investment, and innovative online publishing tools to facilitate networking and open scientific exchange.

A Glance Over Our Shoulder: Veterinary Research 2010–2014

Future research builds on past achievements and responds to emerging needs. Veterinary research publications in the past 5 years provide a snapshot of recent accomplishments and serve as a pivot point for identifying future challenges. A Web of Science search (2010–2014) was done to identify top-cited articles, group authors, and funding agencies in the veterinary science research area ( 1 ). The search was conducted on all databases to identify veterinary research within a broad context, and then on the Web of Science Core Collection for a more specific veterinary focus. Citations are only one metric of scientific impact, but were used here to identify research areas receiving relatively high attention from other researchers; they were calculated per year so recent articles were not disadvantaged.

Highly cited articles fell into three major areas that point to challenges for veterinary research in the future: environmental threats to animal and human health, pathogens and zoonoses, and comparative medicine and pathology (Table ​ (Table1). 1 ). These areas stress the global reach of veterinary science and the strong momentum of the One Health Initiative, which emphasizes interconnectedness between animal, human, and environmental health ( 2 ). They also reflect a growing emphasis on diseases of companion animals and their expanding role as translational models of human disease.

Top-cited veterinary science articles in the Web of Science (2010–2014) .

Funding was led by Brazilian government ministries and Sao Paolo Research Foundation, which together supported 66 veterinary publications, compared with the European Union (29), UK Department for Environment, Food, and Rural Affairs (24), and US National Institutes of Health (18). Several articles funded by the Korean government and National Research Foundation and the National Natural Science Foundation of China suggest that increased veterinary research output from Asia is poised to continue ( 3 ).

Common Ground: Environmental Threats

Animals and humans share the same environment. Threats to environmental quality by pharmaceutical and pesticide contamination of food and water, and evolving bacterial drug resistance, including methicillin-resistant Staphylococcus aureus (MRSA), jeopardize human and animal health and will continue to present a major research challenge for veterinary scientists in the next decade ( 4 ). Potential health risks for people who work closely with animals are a top priority. Research also is needed to identify sources of animal and veterinary drugs; assess the role of animals as reservoirs of resistant pathogens; establish interspecies transmission routes (including human to animal); determine risk factors and epidemiology; monitor and adapt agricultural practices; standardize laboratory testing of food pathogens and drug residues; and develop new and effective treatments. Aquaculture-related environmental residues and impact are also a priority ( 5 ). Environmental threats require a global collaborative approach by veterinarians, physicians, microbiologists, pharmacologists, toxicologists, analytical chemists, and environmental scientists, as well as a focus on rapidly developing and highly populated countries such as China and India to address agricultural practices, environmental degradation, and their links with animal and human health ( 6 ).

Tracking Pathogens: Zoonotic and Infectious Diseases

Animals and humans share pathogens. One need only consider the origin of the Ebola epidemic: fruit bats living in a hollow tree in Guinea ( 7 ). Zoonotic and infectious diseases – bacterial, viral, fungal, protozoal, and parasitic – will continue to dominate veterinary research efforts on a global basis, including novel research on parasite communities ( 8 ), small animal infectious diseases, and emerging zoonotic threats posed by rotaviruses, hepatitis E virus, and coronaviruses (Table ​ (Table1). 1 ). Animal infections such as white-nose disease of bats, Schmallenberg virus in livestock, and microsporidia in honeybees ( 9 ) underlie the very sustainability of agriculture and of wildlife populations. The role of climate change and other anthropogenic factors on emerging pathogens, such as chytridiomycosis in amphibians ( 10 ) is a key research priority.

Infectious and zoonotic diseases intersect with the realities of porous borders, regional conflicts, and a range of agricultural, economic, and political systems that affect veterinary and public health. Outbreaks of foot-and-mouth disease and mutations in avian influenza virus in Egypt exemplify the difficulty many countries face in disease surveillance and vaccine compliance. Consortia such as Partners for Rabies Prevention, Cysticercosis Working Group of Peru, and Emerging Babesioses and One Health are important strategies for galvanizing global research support, expertise, and resources. The $100 million PREDICT project brings together ecosystem, wildlife, and disease experts is an unprecedented effort to detect and respond to viruses that move among people, livestock, and wildlife ( 11 ).

Companion Animal Medicine and Pathology: The New Translational Model

Animals and humans share disease concerns, from diabetes to cancer to kidney disease. Continued specialization of companion animal practice – dogs, cats, and horses – has emerged as a parallel microcosm of its human counterpart. Research that advances high quality, evidence-based veterinary practice is essential for improving clinical outcomes and quality of life. Challenges include coordination of clinical trials and multi-institutional studies, improved database quality, and implementation of reporting guidelines ( 12 ). Technological advances in diagnostic imaging, laboratory testing, surgical techniques, epidemiologic modeling, and drug therapy of companion animals are accelerating and globalizing. The past 5 years have seen a surge in evidence-based practice guidelines ranging from dental care for dogs and cats ( 13 ) to quality assurance in clinical laboratories (Table ​ (Table1) 1 ) to advanced life support and CPR ( 14 ). These guidelines promote evidence-based medicine, raise the level of veterinary care, and stimulate discussion within the profession.

Companion animal medicine and pathology is the new frontier of translational medicine, engaging both veterinary and medical scientists in the real-world clinical laboratory of naturally occurring disease in animals. While veterinary researchers have long relied on medical research as a basis for investigation and therapy in animals, medical researchers now increasingly look to veterinary research and veterinarians to gain insights and develop translational models of human disease. Important recent examples include novel therapies for melanoma and lymphoma; obesity, nutritional and metabolic disease; aging and degenerative diseases such as osteoarthritis; behavioral and cognitive disorders; and regenerative medicine and stem cell therapy (Table ​ (Table1). 1 ). The Veterinary Comparative Oncology Working Group ( 15 ) and the comparative sequencing program of the National Institutes of Health ( 16 ) exemplify the productive collaborations possible between veterinary and medical clinicians and scientists.

An Emerging Frontier: Veterinary and Social Science Research

Animals and humans share a social context. The interface between animals and humans in mental health, cancer detection, war, elder care, legal guardianship, and domestic abuse highlights the diverse societal relevance of veterinary science outside traditional biomedical fields and warrants scientifically rigorous research. In addition to well-established research on the human–animal bond, veterinary research also must contribute to the scientific discussion on human euthanasia, healthcare economics, and disaster management and planning. More research is also needed on people who live and work with animals to address addiction, stress, and suicide risk (Table ​ (Table1), 1 ), moral behavior, and the cultural, religious, and ethical issues affecting animal and human health and welfare.

Publishing Tools to Advance Veterinary Research

Frontiers in Veterinary Science is a networked, collaborative, open access journal dedicated to the communication, discussion, and dissemination of all aspects of veterinary research. The journal’s core mission in animal health embraces the One Health concept in all of its specialty sections, from Animal Behavior and Welfare to Zoological and Aquatic Medicine. Frontiers in Veterinary Science is closely linked with medicine, public health, and environmental and social science domains, facilitating a seamless, integrative approach to biomedical research that emphasizes the societal relevance and global reach of veterinary science while highlighting new developments in veterinary practice and their translational potential for human medicine.

Open access and online publishing open exciting new ways to share, discuss, and publish veterinary research. The Frontiers collaborative peer review system engages authors and reviewers cooperatively and enhances editors’ ability to bring cross-disciplinary expertise to manuscript evaluation. Post-publication commenting enables “audience participation” and social networking redefines research communities. These novel approaches help us think about and solve today’s interconnected biomedical problems in new ways.

Challenges in the next decade of veterinary research, including environmental threats, pathogens, and comparative medicine, will be driven by societal relevance, global engagement, and the need for new translational models. With the help of online publishing innovations such as Frontiers in Veterinary Science , the unique contributions made by veterinary science will be both reinforced and integrated within the broader context of biomedical and social sciences, united in the shared goal of improving the health of animals, people, and the planet.

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Veterinary Medicine Research Paper Topics

Veterinary medicine research paper topics encompass a wide range of subjects that contribute to the advancement of animal healthcare. This page provides a comprehensive guide for students studying veterinary medicine who are tasked with writing research papers. Explore the intricacies of this field, delve into diverse categories, and discover a multitude of compelling topics to delve into. Whether you’re interested in animal behavior, infectious diseases, pharmacology, or veterinary surgery, this guide will help you navigate the realm of veterinary medicine research paper topics. By offering expert advice on topic selection and providing valuable insights on how to write an impactful research paper, we aim to empower students to make significant contributions to the field of veterinary medicine. Furthermore, iResearchNet’s writing services ensure that students receive top-quality, customized research papers tailored to their unique requirements. Let us help you unleash your academic potential and make a lasting impact in the world of veterinary medicine.

100 Veterinary Medicine Research Paper Topics

Introduction: The field of veterinary medicine encompasses a vast array of disciplines and areas of study, offering a wealth of research opportunities for students. This comprehensive list of veterinary medicine research paper topics is divided into 10 categories, each containing 10 unique topics. By exploring these topics, students can gain a deeper understanding of various aspects of veterinary medicine and contribute to the advancement of animal healthcare.

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Animal Behavior and Psychology:

• The impact of environmental enrichment on animal behavior and welfare
• Behavioral interventions for managing aggression in dogs
• Understanding the role of animal cognition in training and behavior modification
• The relationship between human-animal interaction and animal behavior
• Investigating stress and coping mechanisms in companion animals
• The effects of socialization on the behavior and development of puppies and kittens
• Exploring the psychological well-being of captive animals in zoos
• Behavioral indicators and management strategies for pain in animals
• Understanding the behavior and welfare of farm animals in intensive production systems
• Investigating the impact of fear and anxiety on animal welfare in veterinary settings

Infectious Diseases:

• Emerging zoonotic diseases and their impact on public health
• Antimicrobial resistance in veterinary medicine: challenges and strategies
• The role of vaccination in preventing infectious diseases in companion animals
• Epidemiology and control measures for common bacterial infections in livestock
• Investigating the transmission dynamics of vector-borne diseases in animals
• Diagnostic methods and advancements in the detection of viral infections in animals
• One Health approach: addressing the link between animal and human infectious diseases
• The impact of climate change on the prevalence and distribution of infectious diseases in wildlife
• Surveillance and control measures for emerging viral diseases in aquaculture
• Exploring the impact of biosecurity measures in preventing the spread of infectious diseases in veterinary clinics and hospitals

Pharmacology and Therapeutics:

• Investigating the efficacy and safety of new veterinary drugs and therapies
• Pharmacokinetics and pharmacodynamics of commonly used drugs in veterinary practice
• Adverse drug reactions and drug interactions in veterinary medicine
• Exploring alternative therapies in veterinary medicine: acupuncture, herbal medicine, and more
• The role of personalized medicine in veterinary practice
• Drug-resistant parasites and strategies for their control in companion animals
• Investigating the use of pain management protocols in veterinary surgery
• The impact of nutraceuticals and dietary supplements on animal health
• Pharmacogenomics in veterinary medicine: implications for personalized treatment
• Exploring the challenges and opportunities in veterinary drug development

Veterinary Surgery and Anesthesia:

• Advancements in minimally invasive surgery in veterinary medicine
• Anesthetic management and monitoring in exotic animal species
• Investigating surgical techniques for the treatment of orthopedic conditions in companion animals
• Complications and management of anesthesia in geriatric patients
• Exploring the role of regenerative medicine in veterinary surgery
• Surgical interventions for the management of oncological conditions in animals
• Investigating novel approaches for pain management in postoperative veterinary patients
• Surgical techniques and rehabilitation strategies for the treatment of spinal cord injuries in animals
• Exploring the use of robotic surgery in veterinary medicine
• Investigating the impact of surgical interventions on the quality of life in animals

Diagnostic Imaging and Radiology:

• Advancements in imaging techniques for the early detection of cancer in animals
• Investigating the use of magnetic resonance imaging (MRI) in veterinary neurology
• The role of ultrasound in diagnosing and managing cardiovascular diseases in animals
• Radiographic evaluation and interpretation of musculoskeletal disorders in small animals
• Investigating the use of computed tomography (CT) in veterinary oncology
• Diagnostic imaging in avian and exotic animal medicine
• The impact of advanced imaging modalities on the diagnosis of gastrointestinal diseases in animals
• Exploring the role of nuclear medicine in veterinary diagnostics
• Radiographic evaluation and interpretation of respiratory disorders in large animals
• Investigating the use of contrast-enhanced imaging techniques in veterinary medicine

Veterinary Public Health and Epidemiology:

• One Health approach in the surveillance and control of zoonotic diseases
• Investigating foodborne pathogens and their impact on animal and human health
• The role of veterinarians in disaster preparedness and response
• Veterinary epidemiology: studying disease patterns and risk factors in animal populations
• Investigating the impact of environmental factors on animal health and well-being
• Exploring the relationship between animal agriculture and antimicrobial resistance
• Veterinary public health interventions for the prevention of zoonotic diseases
• The role of wildlife in the transmission of infectious diseases to domestic animals
• Investigating the impact of climate change on vector-borne diseases in veterinary medicine
• Surveillance and control measures for emerging and re-emerging diseases in veterinary public health

Animal Nutrition and Feed Science:

• Investigating the impact of diet and nutrition on companion animal health
• The role of nutritional interventions in the management of obesity in animals
• Exploring the nutritional requirements and feed formulations for exotic animal species
• Nutritional strategies for the prevention and management of metabolic diseases in livestock
• Investigating the impact of feed additives on animal performance and health
• The role of probiotics and prebiotics in promoting gut health in animals
• Nutritional management of common gastrointestinal disorders in companion animals
• Exploring sustainable and environmentally friendly feed options for livestock
• Investigating the impact of nutrition on reproductive performance in animals
• Nutritional considerations for the optimal growth and development of neonatal animals

Veterinary Education and Professional Development:

• Evaluating the effectiveness of veterinary education programs in preparing students for practice
• Investigating the role of simulation-based training in veterinary education
• Exploring innovative teaching methods in veterinary schools
• Assessing the impact of continuing education on veterinary professionals’ knowledge and skills
• Investigating the factors influencing career choices among veterinary students
• The impact of telemedicine on veterinary practice and client communication
• Exploring the challenges and opportunities in veterinary entrepreneurship
• Veterinary leadership and management skills for effective practice management
• Investigating the role of mentorship in veterinary education and professional development
• Exploring the ethical considerations in veterinary practice and research

Equine Medicine and Surgery:

• Investigating advancements in diagnostic imaging techniques for equine lameness
• Management strategies for musculoskeletal disorders in performance horses
• The impact of nutrition and exercise on the prevention and management of metabolic diseases in horses
• Exploring the use of regenerative therapies in equine orthopedics
• Investigating the impact of respiratory diseases on the performance and welfare of horses
• Equine dentistry: advancements in dental care and oral health management
• Exploring novel surgical interventions for the treatment of orthopedic conditions in horses
• The role of physical therapy and rehabilitation in equine medicine
• Investigating the impact of exercise physiology on performance enhancement in horses
• Infectious diseases and vaccination strategies in equine healthcare

Wildlife Medicine and Conservation:

• Investigating the impact of habitat loss on wildlife health and conservation
• Wildlife forensic medicine: techniques for investigating wildlife crimes
• The role of veterinarians in wildlife rehabilitation and release programs
• Exploring the impact of emerging infectious diseases on wildlife populations
• Investigating the use of contraception in wildlife population management
• Wildlife anesthesia and immobilization techniques for veterinary interventions
• Exploring the role of veterinary medicine in endangered species conservation
• Investigating the impact of pollution and environmental contaminants on wildlife health
• Wildlife diseases and their potential for spillover to domestic animal populations
• Conservation genetics: utilizing molecular techniques in wildlife management

This comprehensive list of veterinary medicine research paper topics provides students with a wide range of subjects to explore within the field. Whether you are interested in animal behavior, infectious diseases, pharmacology, surgery, or any other aspect of veterinary medicine, there are countless opportunities for research and innovation. By selecting a topic that aligns with your interests and career goals, and following the expert advice on how to choose and write a research paper, you can contribute to the advancement of veterinary medicine and make a lasting impact on animal health and welfare.

Veterinary Medicine: Exploring the Range of Research Paper Topics

Veterinary medicine plays a vital role in the health and well-being of animals, from beloved pets to livestock and wildlife. As a student studying veterinary medicine, you have the opportunity to delve into various research areas and contribute to advancements in animal healthcare. This article will explore the diverse range of research paper topics available within the field of veterinary medicine, offering you insights into the exciting and impactful areas of study.

• Animal Nutrition and Feed Science : Proper nutrition is fundamental to the health and well-being of animals. Research topics in this area could include investigating the impact of diet and nutrition on companion animal health, exploring nutritional interventions for managing metabolic diseases in livestock, and examining sustainable and environmentally friendly feed options for animals.
• Infectious Diseases : Infectious diseases pose significant challenges to animal health and public health. Research paper topics in this category could encompass emerging zoonotic diseases and their impact on human health, antimicrobial resistance in veterinary medicine, vaccination strategies for preventing infectious diseases in animals, and exploring the transmission dynamics of vector-borne diseases.
• Animal Behavior and Psychology : Understanding animal behavior and psychology is essential for providing optimal care. Research topics in this field may involve studying the impact of environmental enrichment on animal behavior and welfare, behavioral interventions for managing aggression in dogs, investigating the cognitive abilities of animals, and exploring the role of human-animal interaction in animal behavior.
• Pharmacology and Therapeutics : Pharmacology plays a critical role in treating and preventing diseases in animals. Research paper topics in this area could include investigating the efficacy and safety of new veterinary drugs and therapies, exploring alternative therapies such as acupuncture and herbal medicine, and studying the pharmacokinetics and pharmacodynamics of commonly used drugs in veterinary practice.
• Veterinary Surgery and Anesthesia : Surgical interventions are often necessary for diagnosing and treating various conditions in animals. Research topics in this category could focus on advancements in minimally invasive surgery, investigating anesthesia management and monitoring in different animal species, exploring regenerative medicine in veterinary surgery, and studying the impact of surgical interventions on the quality of life in animals.
• Diagnostic Imaging and Radiology : Diagnostic imaging techniques play a crucial role in diagnosing and monitoring diseases in animals. Research paper topics in this field may include advancements in imaging techniques for detecting cancer in animals, exploring the use of magnetic resonance imaging (MRI) and computed tomography (CT) in veterinary diagnostics, and investigating the application of radiography and ultrasound in diagnosing specific conditions.
• Veterinary Public Health and Epidemiology : Veterinary medicine intersects with public health in various ways. Research topics in this area could involve the One Health approach in the surveillance and control of zoonotic diseases, studying the impact of environmental factors on animal and human health, and investigating the link between animal agriculture and antimicrobial resistance.
• Equine Medicine and Surgery : Horses require specialized veterinary care due to their unique physiology and performance demands. Research paper topics in this category may include investigating advancements in diagnostic imaging techniques for equine lameness, studying the management strategies for musculoskeletal disorders in performance horses, and exploring the impact of respiratory diseases on horse performance and welfare.
• Wildlife Medicine and Conservation : The health and conservation of wildlife are essential for maintaining biodiversity. Research topics in this field could include studying the impact of habitat loss on wildlife health, investigating wildlife rehabilitation and release programs, exploring the role of veterinarians in wildlife conservation, and understanding the diseases that affect wildlife populations.
• Veterinary Education and Professional Development : Ensuring the competency and continuous development of veterinary professionals is crucial. Research paper topics in this area may involve evaluating veterinary education programs, exploring innovative teaching methods, studying the impact of continuing education on veterinary professionals’ knowledge and skills, and investigating the factors influencing career choices among veterinary students.

The field of veterinary medicine offers a wide range of research opportunities, spanning various disciplines and species. Whether you are interested in animal nutrition, infectious diseases, surgery, diagnostic imaging, public health, or any other aspect of veterinary medicine, there are numerous fascinating topics to explore. By selecting a research paper topic that aligns with your interests and goals, you can contribute to the advancement of veterinary medicine, improve animal health and welfare, and make a meaningful impact in the field.

Choosing Veterinary Medicine Research Paper Topics

Selecting the right research paper topic is crucial for your success as a student of veterinary medicine. It allows you to delve into an area of interest, contribute to existing knowledge, and explore the latest advancements in the field. In this section, we will provide you with expert advice on how to choose veterinary medicine research paper topics that align with your interests and academic goals.

• Identify Your Interests : Start by reflecting on your personal interests within the field of veterinary medicine. Consider the areas that fascinate you the most, such as animal behavior, infectious diseases, surgery, diagnostic imaging, wildlife medicine, or public health. Identifying your passions will make the research process more enjoyable and rewarding.
• Consult Your Professors and Mentors : Seek guidance from your professors and mentors who have expertise in different veterinary medicine disciplines. They can provide valuable insights into current research trends, emerging topics, and areas that need further exploration. Discuss your interests with them, and they can help you narrow down potential research paper topics based on their knowledge and experience.
• Stay Updated with Current Literature : Stay abreast of the latest research publications, scientific journals, and conference proceedings in the field of veterinary medicine. Regularly reading scientific literature will expose you to new research findings, innovative techniques, and emerging topics. This will help you identify gaps in the existing knowledge that you can address through your research paper.
• Consider Relevance and Impact : When selecting a research topic, consider its relevance and potential impact on veterinary medicine. Look for topics that address current challenges, emerging issues, or areas where advancements are needed. Research that can contribute to animal health, welfare, conservation, or public health will not only be academically fulfilling but also have real-world implications.
• Analyze Feasibility : Assess the feasibility of your chosen research topic in terms of available resources, time constraints, and access to data. Consider the availability of research materials, laboratory facilities, animal populations, or specialized equipment required for your study. Ensure that your chosen topic is practical and achievable within the given timeframe and available resources.
• Collaborate with Peers : Consider collaborating with your peers or fellow researchers who share similar research interests. Collaborative research projects can broaden your perspective, enhance the quality of your research, and facilitate knowledge sharing. Engaging in interdisciplinary collaborations can also help you explore topics that combine veterinary medicine with other fields, such as biology, ecology, or public health.
• Seek Inspiration from Case Studies and Clinical Experience : Drawing inspiration from case studies, clinical experiences, or real-world scenarios can lead to intriguing research topics. Reflect on challenging cases you have encountered during clinical rotations, unique observations, or clinical questions that have piqued your interest. These experiences can spark ideas for research that address practical veterinary medicine issues.
• Consider Ethical Considerations : When choosing a research topic, consider ethical considerations related to animal welfare and human subjects. Ensure that your research adheres to ethical guidelines and regulations. If your research involves animal subjects, be mindful of the ethical treatment and use of animals, and obtain necessary approvals from relevant ethics committees.
• Explore Emerging Technologies and Techniques : Advancements in technology and techniques have a significant impact on veterinary medicine. Consider topics that explore the application of emerging technologies such as genomics, telemedicine, artificial intelligence, or novel diagnostic tools in veterinary practice. Research in these areas can contribute to the evolution of veterinary medicine and improve animal healthcare outcomes.
• Seek Practical Relevance and Application : Choose research topics that have practical relevance and application in the veterinary field. Look for topics that address challenges faced by veterinarians, animal owners, or the industry. Research that can provide evidence-based solutions, improve clinical practices, or enhance disease prevention and management will have a direct impact on veterinary medicine.

Selecting a suitable research paper topic is a crucial step in your journey as a veterinary medicine student. By identifying your interests, seeking guidance, staying updated with current literature, considering relevance and impact, and analyzing feasibility, you can choose a research topic that is both intellectually stimulating and practically valuable. Remember to consider ethical considerations, collaborate with peers, and explore emerging technologies. By following these expert tips, you will be well-equipped to embark on a research project that contributes to the advancement of veterinary medicine and makes a positive impact on animal health and welfare.

How to Write a Veterinary Medicine Research Paper

Writing a research paper in veterinary medicine allows you to contribute to the field, explore new knowledge, and develop critical thinking and scientific communication skills. In this section, we will guide you through the process of writing a veterinary medicine research paper, from selecting a topic to crafting a compelling paper that effectively communicates your findings.

• Define Your Research Objectives : Clearly define the objectives of your research paper. Determine what you aim to accomplish and the specific research questions you want to answer. This will provide a clear focus and direction for your study.
• Conduct a Thorough Literature Review : Begin by conducting a comprehensive literature review to gather existing knowledge and identify gaps in the research. Analyze and critically evaluate relevant studies, articles, and scientific literature to establish the context for your research.
• Refine Your Research Question : Based on your literature review, refine your research question or hypothesis. Ensure that your question is specific, measurable, achievable, relevant, and time-bound (SMART). This will guide your research and help you stay focused.
• Design Your Study : Select an appropriate research design and methodology that aligns with your research question and objectives. Determine the sample size, data collection methods, and statistical analyses required. Ensure that your study design is rigorous and ethically sound.
• Gather and Analyze Data : Collect relevant data using appropriate research methods, whether it involves conducting experiments, surveys, interviews, or analyzing existing datasets. Ensure that your data collection is thorough, reliable, and accurately recorded. Use appropriate statistical tools to analyze your data and draw meaningful conclusions.
• Organize Your Paper : Structure your research paper in a logical and organized manner. Include sections such as the introduction, literature review, methods, results, discussion, and conclusion. Follow a clear and coherent flow of information that guides the reader through your research process.
• Write an Engaging Introduction : Start your paper with an engaging introduction that provides background information on the topic, states the research problem, and highlights the significance of your study. Clearly articulate your research objectives and hypotheses to set the stage for the rest of the paper.
• Present a Comprehensive Literature Review : Incorporate a thorough literature review in the body of your paper. Summarize and critically analyze relevant studies, theories, and findings that inform your research. Identify gaps in the literature and highlight the unique contribution of your study.
• Describe Your Methods and Results : Clearly explain the methods you employed to conduct your research and gather data. Provide sufficient detail for others to replicate your study. Present your results objectively, using appropriate tables, graphs, or figures to support your findings. Interpret the results and discuss their implications.
• Engage in a Thoughtful Discussion : In the discussion section, interpret your findings in the context of existing knowledge and theories. Discuss the implications of your results, their limitations, and any future directions for research. Address any unanswered questions and propose areas for further investigation.
• Write a Strong Conclusion : Summarize your main findings and their significance in a concise and impactful conclusion. Restate your research objectives and hypotheses, and emphasize how your study contributes to the field of veterinary medicine. Avoid introducing new information in the conclusion.
• Cite Sources Accurately : Ensure that you cite all the sources used in your research paper accurately. Follow the appropriate citation style, such as APA, MLA, or Chicago, and adhere to the specific guidelines for referencing scientific literature and other relevant sources.
• Revise and Proofread : After completing the initial draft, revise your paper for clarity, coherence, and logical flow. Check for grammatical and spelling errors, and ensure that your writing is concise and precise. Seek feedback from peers, mentors, or professors to improve the quality of your paper.

Writing a veterinary medicine research paper requires careful planning, attention to detail, and effective communication skills. By defining your research objectives, conducting a thorough literature review, designing a rigorous study, and organizing your paper coherently, you can produce a high-quality research paper. Remember to write an engaging introduction, present a comprehensive literature review, describe your methods and results accurately, engage in thoughtful discussion, and provide a strong conclusion. Cite your sources properly and revise your paper meticulously. Through this process, you will contribute to the field of veterinary medicine and advance knowledge in the domain.

iResearchNet’s Writing Services

At iResearchNet, we understand the challenges that students face when it comes to writing research papers in veterinary medicine. We are here to provide you with professional writing services that cater to your specific needs. Our team of expert writers and researchers are well-versed in the field of veterinary medicine and can assist you in producing high-quality research papers. In this section, we will outline the range of services we offer and the benefits of choosing iResearchNet for your veterinary medicine research paper needs.

• Expert Degree-Holding Writers : Our team consists of expert writers with advanced degrees in veterinary medicine and related fields. They have a deep understanding of the subject matter and can deliver well-researched and meticulously written research papers.
• Custom Written Works : We provide custom written works that are tailored to your specific requirements. Whether you need a research paper from scratch or assistance with specific sections, our writers can create unique and original content that meets your academic standards.
• In-Depth Research : Our writers conduct extensive research to gather the most relevant and up-to-date information for your research paper. They have access to reputable sources and scientific databases to ensure the accuracy and validity of the information presented in your paper.
• Custom Formatting : We understand the importance of adhering to specific formatting styles required by academic institutions. Our writers are well-versed in various citation styles, including APA, MLA, Chicago/Turabian, and Harvard. They will format your paper according to the specific guidelines provided.
• Top Quality : Quality is our utmost priority. We strive to deliver research papers that meet the highest standards of academic excellence. Our writers pay attention to every detail, ensuring that your paper is well-structured, coherent, and free from grammatical errors.
• Customized Solutions : We recognize that each research paper is unique. Our writers work closely with you to understand your specific research objectives, requirements, and preferences. They can customize their approach to meet your specific needs and deliver a paper that aligns with your expectations.
• Flexible Pricing : We offer flexible pricing options to accommodate the budgetary constraints of students. Our pricing is competitive and transparent, ensuring that you receive the best value for your investment. We offer affordable rates without compromising on the quality of our services.
• Short Deadlines : We understand that students often face tight deadlines. Our team is equipped to handle urgent requests and can deliver high-quality research papers within short timeframes, even as tight as 3 hours. You can rely on us to meet your deadlines without compromising on quality.
• Timely Delivery : We prioritize timely delivery to ensure that you have sufficient time to review and submit your research paper. Our writers work diligently to complete your paper within the agreed-upon timeframe, allowing you ample time for any revisions or modifications you may require.
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Choosing iResearchNet for your veterinary medicine research paper needs ensures that you receive professional, reliable, and customized writing services. Our team of expert writers, in-depth research capabilities, adherence to formatting guidelines, and commitment to quality will ensure that your research paper meets the highest academic standards. With flexible pricing options, timely delivery, 24/7 support, absolute privacy, and easy order tracking, we strive to make your experience with iResearchNet seamless and rewarding. Place your trust in us and let our expertise guide you towards academic success.

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Are you struggling with your veterinary medicine research papers? Do you find it challenging to choose the right topics, conduct in-depth research, and meet the high academic standards of your institution? Look no further! iResearchNet is here to provide you with the professional support you need to excel in your veterinary medicine studies. Our team of expert writers and researchers is ready to assist you in crafting top-quality research papers that will impress your professors and elevate your academic performance.

By choosing iResearchNet, you gain access to a range of benefits that will make your research paper writing experience smooth, efficient, and stress-free. Our team consists of highly qualified writers with expertise in veterinary medicine and related fields. They are equipped with the necessary knowledge and skills to tackle even the most complex research topics. Whether you need assistance in selecting research paper topics, conducting thorough research, or structuring your paper, our experts are here to guide you every step of the way.

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Back to Journals » Veterinary Medicine: Research and Reports

Veterinary Medicine: Research and Reports

Issn: 2230-2034.

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Editor-in-Chief: Professor Young S. Lyoo

Veterinary Medicine: Research and Reports is an international, peer-reviewed, open access journal publishing original research, case reports, editorials, reviews and commentaries on all aspects of preclinical and clinical veterinary medicine. The journal is characterized by the rapid reporting of new and emerging diagnostic protocols and therapeutic strategies to overcome a wide range of veterinary diseases, as well as reporting the biological basis of these.

For specific topics covered in this journal please see the Aims and Scope .

This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE).

• View all (271)
• Volume 15, 2024 (17)
• Volume 14, 2023 (21)
• Volume 13, 2022 (33)
• Volume 12, 2021 (41)
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Latest articles:

- 5 records -

Validation of Noninvasive Methemoglobin and Carboxyhemoglobin Measurements Using Pulse Co-Oximeter in Healthy Dogs

Her J, Roh J, Keys DA

Veterinary Medicine: Research and Reports 2024 , 15:197-203

Published Date: 16 August 2024

Helminth Control Practices in Sheep and Cattle in Urban and Peri-Urban Areas of Adea District, Central Ethiopia

Alkadir G, Ayana D

Veterinary Medicine: Research and Reports 2024 , 15:181-195

Published Date: 12 July 2024

Fecal Microbiota Transplantation in a Domestic Ferret Suffering from Chronic Diarrhea and Maldigestion–Fecal Microbiota and Clinical Outcome: A Case Report

Ravel SJ, Hollifield VM

Veterinary Medicine: Research and Reports 2024 , 15:171-180

Published Date: 28 May 2024

Extended-Spectrum Beta-Lactamase Producing Escherichia coli in Raw Cow Milk At Selling Points and Determinants of Contamination in and Around Chencha, Southern Ethiopia

Veterinary Medicine: Research and Reports 2024 , 15:159-169

Published Date: 18 May 2024

Molecular Detection and Characterization of Newcastle Disease Virus from Chickens in Mid-Rift Valley and Central Part of Ethiopia

Alemu EE, Senbata B, Sombo M, Guyassa C, Alemayehu DH, Kidane E, Mihret A, Mulu A, Dinka H

Veterinary Medicine: Research and Reports 2024 , 15:149-157

Published Date: 8 May 2024

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Nikola Danev: Finding a place where community meets research

Most people may not think of the importance of community and research, but that is a large focus at the Baker Institute for Animal Health in the College of Veterinary Medicine at Cornell University. “It was difficult to find a community and a sense of belonging until I encountered the Baker Institute,” says Baker trainee Nikola Danev. While completing his Ph.D., Danev not only found belonging, but in turn gave back to the local community by working as a volunteer firefighter with the Varna Volunteer Fire Company. 

This week Danev is presenting his Ph.D. thesis on “Bovine adult stem and progenitor cells: from transcriptomics to therapeutic potential,” which poses the use of cows as a therapeutic research model and the use of mammosphere-derived epithelial cells as a potential novel treatment for mastitis. While working on his dissertation, he is also reminiscing, “I fondly think of all the incredible connections and friendships forged through my time here, as well as the collaboration and pooling of resources that allowed me to have fun, learn and feel at ease, while doing challenging research.”

Danev’s journey began in 2016 when he was selected as a John Jay scholar to attend Columbia University in New York City, N.Y. Originally born and raised in Skopje, Macedonia, Danev moved to the United States by himself. While at Columbia, Danev joined the student-run ambulance service and obtained his certification as a New York State emergency medical technician (EMT). His plan was to gain clinical experience to help with his path to medical school, however, through his volunteer work he realized he was more passionate about community service than medicine. In addition, he became more interested in biology and the study of different diseases through his course work. It was the combination of his work as an EMT and change in course interest that led him to pursue a degree in biology, with an emphasis on genetics. These passions ultimately guided him to Cornell University’s Genetics, Genomics and Development Ph.D. program.   

In 2020 amidst a global pandemic, Danev moved to Ithaca, N.Y. to start his Ph.D. program. It was difficult for him to find a sense of community and belonging until he joined the lab of Gerlinde Van de Walle, D.V.M., Ph.D., at the Baker Institute for Animal Health . What drew him to join her lab was his interest in pharmaceutical applications in biology and the opportunity to collaborate with industry partners, like Elanco. When joining the Baker Institute he states, “I was welcomed by incredible friends and colleagues.” One of these friends is Mason Jager, D.V.M. ’12, Ph.D. ’22, DACVP, assistant research professor and anatomic pathologist at Cornell University College of Veterinary Medicine, who at the time was a graduate student in the Van de Walle Lab. Jager had just recently joined the Varna Volunteer Fire Company and after finding out about Danev’s EMT training encouraged him to join. 

Over three years, both Jager and Danev climbed the ranks of the fire department, now serving as chief and deputy chief, and helped increase the membership 10-fold since 2021. 

Danev attributes his success to being in an extremely supportive lab, which has allowed him to pursue his interests leading to a diverse range of opportunities. In 2023, Danev participated in the Cornell Animal Health Hackathon and his team won for a device that could be built into current milking systems and cow transponders that can be used to automatically screen animals for signs of pre-clinical mastitis. This project introduced him to the cross-disciplinary nature of scientific work by interacting with students in MBA, D.V.M., and MPH programs, as well as the Center for Technology Licensing and Business School. Ultimately, it was these additional experiences that led him to pursue an interest in industry. “I was able to see the impact of our scientific research on the economy, on veterinarians, on farmers and on food sustainability,” Danev states. After successful completion of his Ph.D., Danev will be joining the Boston Consulting Group, where he will be able to merge his passions for service and research to make meaningful impact. 

When asked about his time at the Baker Institute he said, “[This] has been some of the most fulfilling and memorable years of my life.” Danev hopes that when students come to Cornell, they take advantage of all the incredible opportunities offered by the University, the College and of course, the Baker Institute. “People can pursue many options after completing their Ph.Ds., and I hope that by speaking about my experience I am able to help people explore all of their options for their future careers,” says Danev. 

Written by Junelle King, marketing and social media specialist with the Animal Health Centers of the Cornell University College of Veterinary Medicine.

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Innovation clinic—significant achievements for 2023-24.

The Innovation Clinic continued its track record of success during the 2023-2024 school year, facing unprecedented demand for our pro bono services as our reputation for providing high caliber transactional and regulatory representation spread. The overwhelming number of assistance requests we received from the University of Chicago, City of Chicago, and even national startup and venture capital communities enabled our students to cherry-pick the most interesting, pedagogically valuable assignments offered to them. Our focus on serving startups, rather than all small- to medium-sized businesses, and our specialization in the needs and considerations that these companies have, which differ substantially from the needs of more traditional small businesses, has proven to be a strong differentiator for the program both in terms of business development and prospective and current student interest, as has our further focus on tackling idiosyncratic, complex regulatory challenges for first-of-their kind startups. We are also beginning to enjoy more long-term relationships with clients who repeatedly engage us for multiple projects over the course of a year or more as their legal needs develop.

This year’s twelve students completed over twenty projects and represented clients in a very broad range of industries: mental health and wellbeing, content creation, medical education, biotech and drug discovery, chemistry, food and beverage, art, personal finance, renewable energy, fintech, consumer products and services, artificial intelligence (“AI”), and others. The matters that the students handled gave them an unparalleled view into the emerging companies and venture capital space, at a level of complexity and agency that most junior lawyers will not experience until several years into their careers.

Representative Engagements

While the Innovation Clinic’s engagements are highly confidential and cannot be described in detail, a high-level description of a representative sample of projects undertaken by the Innovation Clinic this year includes:

Transactional/Commercial Work

• A previous client developing a symptom-tracking wellness app for chronic disease sufferers engaged the Innovation Clinic again, this time to restructure its cap table by moving one founder’s interest in the company to a foreign holding company and subjecting the holding company to appropriate protections in favor of the startup.
• Another client with whom the Innovation Clinic had already worked several times engaged us for several new projects, including (1) restructuring their cap table and issuing equity to an additional, new founder, (2) drafting several different forms of license agreements that the company could use when generating content for the platform, covering situations in which the company would license existing content from other providers, jointly develop new content together with contractors or specialists that would then be jointly owned by all creators, or commission contractors to make content solely owned by the company, (3) drafting simple agreements for future equity (“Safes”) for the company to use in its seed stage fundraising round, and (4) drafting terms of service and a privacy policy for the platform.
• Yet another repeat client, an internet platform that supports independent artists by creating short films featuring the artists to promote their work and facilitates sales of the artists’ art through its platform, retained us this year to draft a form of independent contractor agreement that could be used when the company hires artists to be featured in content that the company’s Fortune 500 brand partners commission from the company, and to create capsule art collections that could be sold by these Fortune 500 brand partners in conjunction with the content promotion.
• We worked with a platform using AI to accelerate the Investigational New Drug (IND) approval and application process to draft a form of license agreement for use with its customers and an NDA for prospective investors.
• A novel personal finance platform for young, high-earning individuals engaged the Innovation Clinic to form an entity for the platform, including helping the founders to negotiate a deal among them with respect to roles and equity, terms that the equity would be subject to, and other post-incorporation matters, as well as to draft terms of service and a privacy policy for the platform.
• Students also formed an entity for a biotech therapeutics company founded by University of Chicago faculty members and an AI-powered legal billing management platform founded by University of Chicago students.
• A founder the Innovation Clinic had represented in connection with one venture engaged us on behalf of his other venture team to draft an equity incentive plan for the company as well as other required implementing documentation. His venture with which we previously worked also engaged us this year to draft Safes to be used with over twenty investors in a seed financing round.

More information regarding other types of transactional projects that we typically take on can be found here .

Regulatory Research and Advice

• A team of Innovation Clinic students invested a substantial portion of our regulatory time this year performing highly detailed and complicated research into public utilities laws of several states to advise a groundbreaking renewable energy technology company as to how its product might be regulated in these states and its clearest path to market. This project involved a review of not only the relevant state statutes but also an analysis of the interplay between state and federal statutes as it relates to public utilities law, the administrative codes of the relevant state executive branch agencies, and binding and non-binding administrative orders, decisions and guidance from such agencies in other contexts that could shed light on how such states would regulate this never-before-seen product that their laws clearly never contemplated could exist. The highly varied approach to utilities regulation in all states examined led to a nuanced set of analysis and recommendations for the client.
• In another significant research project, a separate team of Innovation Clinic students undertook a comprehensive review of all settlement orders and court decisions related to actions brought by the Consumer Financial Protection Bureau for violations of the prohibition on unfair, deceptive, or abusive acts and practices under the Consumer Financial Protection Act, as well as selected relevant settlement orders, court decisions, and other formal and informal guidance documents related to actions brought by the Federal Trade Commission for violations of the prohibition on unfair or deceptive acts or practices under Section 5 of the Federal Trade Commission Act, to assemble a playbook for a fintech company regarding compliance. This playbook, which distilled very complicated, voluminous legal decisions and concepts into a series of bullet points with clear, easy-to-follow rules and best practices, designed to be distributed to non-lawyers in many different facets of this business, covered all aspects of operations that could subject a company like this one to liability under the laws examined, including with respect to asset purchase transactions, marketing and consumer onboarding, usage of certain terms of art in advertising, disclosure requirements, fee structures, communications with customers, legal documentation requirements, customer service and support, debt collection practices, arrangements with third parties who act on the company’s behalf, and more.

Miscellaneous

• Last year’s students built upon the Innovation Clinic’s progress in shaping the rules promulgated by the Financial Crimes Enforcement Network (“FinCEN”) pursuant to the Corporate Transparency Act to create a client alert summarizing the final rule, its impact on startups, and what startups need to know in order to comply. When FinCEN issued additional guidance with respect to that final rule and changed portions of the final rule including timelines for compliance, this year’s students updated the alert, then distributed it to current and former clients to notify them of the need to comply. The final bulletin is available here .
• In furtherance of that work, additional Innovation Clinic students this year analyzed the impact of the final rule not just on the Innovation Clinic’s clients but also its impact on the Innovation Clinic, and how the Innovation Clinic should change its practices to ensure compliance and minimize risk to the Innovation Clinic. This also involved putting together a comprehensive filing guide for companies that are ready to file their certificates of incorporation to show them procedurally how to do so and explain the choices they must make during the filing process, so that the Innovation Clinic would not be involved in directing or controlling the filings and thus would not be considered a “company applicant” on any client’s Corporate Transparency Act filings with FinCEN.
• The Innovation Clinic also began producing thought leadership pieces regarding AI, leveraging our distinct and uniquely University of Chicago expertise in structuring early-stage companies and analyzing complex regulatory issues with a law and economics lens to add our voice to those speaking on this important topic. One student wrote about whether non-profits are really the most desirable form of entity for mitigating risks associated with AI development, and another team of students prepared an analysis of the EU’s AI Act, comparing it to the Executive Order on AI from President Biden, and recommended a path forward for an AI regulatory environment in the United States. Both pieces can be found here , with more to come!

Innovation Trek

Thanks to another generous gift from Douglas Clark, ’89, and managing partner of Wilson, Sonsini, Goodrich & Rosati, we were able to operationalize the second Innovation Trek over Spring Break 2024. The Innovation Trek provides University of Chicago Law School students with a rare opportunity to explore the innovation and venture capital ecosystem in its epicenter, Silicon Valley. The program enables participating students to learn from business and legal experts in a variety of different industries and roles within the ecosystem to see how the law and economics principles that students learn about in the classroom play out in the real world, and facilitates meaningful connections between alumni, students, and other speakers who are leaders in their fields. This year, we took twenty-three students (as opposed to twelve during the first Trek) and expanded the offering to include not just Innovation Clinic students but also interested students from our JD/MBA Program and Doctoroff Business Leadership Program. We also enjoyed four jam-packed days in Silicon Valley, expanding the trip from the two and a half days that we spent in the Bay Area during our 2022 Trek.

The substantive sessions of the Trek were varied and impactful, and enabled in no small part thanks to substantial contributions from numerous alumni of the Law School. Students were fortunate to visit Coinbase’s Mountain View headquarters to learn from legal leaders at the company on all things Coinbase, crypto, and in-house, Plug & Play Tech Center’s Sunnyvale location to learn more about its investment thesis and accelerator programming, and Google’s Moonshot Factory, X, where we heard from lawyers at a number of different Alphabet companies about their lives as in-house counsel and the varied roles that in-house lawyers can have. We were also hosted by Wilson, Sonsini, Goodrich & Rosati and Fenwick & West LLP where we held sessions featuring lawyers from those firms, alumni from within and outside of those firms, and non-lawyer industry experts on topics such as artificial intelligence, climate tech and renewables, intellectual property, biotech, investing in Silicon Valley, and growth stage companies, and general advice on career trajectories and strategies. We further held a young alumni roundtable, where our students got to speak with alumni who graduated in the past five years for intimate, candid discussions about life as junior associates. In total, our students heard from more than forty speakers, including over twenty University of Chicago alumni from various divisions.

The Trek didn’t stop with education, though. Throughout the week students also had the opportunity to network with speakers to learn more from them outside the confines of panel presentations and to grow their networks. We had a networking dinner with Kirkland & Ellis, a closing dinner with all Trek participants, and for the first time hosted an event for admitted students, Trek participants, and alumni to come together to share experiences and recruit the next generation of Law School students. Several speakers and students stayed in touch following the Trek, and this resulted not just in meaningful relationships but also in employment for some students who attended.

More information on the purposes of the Trek is available here , the full itinerary is available here , and one student participant’s story describing her reflections on and descriptions of her experience on the Trek is available here .

The Innovation Clinic is grateful to all of its clients for continuing to provide its students with challenging, high-quality legal work, and to the many alumni who engage with us for providing an irreplaceable client pipeline and for sharing their time and energy with our students. Our clients are breaking the mold and bringing innovations to market that will improve the lives of people around the world in numerous ways. We are glad to aid in their success in any way that we can. We look forward to another productive year in 2024-2025!

• Frontiers in Immunology
• Cancer Immunity and Immunotherapy
• Research Topics

Unveiling New Frontiers in Unlocking Immunotherapy: The Puzzle of Intratumor Heterogeneity

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The advent of tumor immunotherapy heralds a significant leap towards addressing malignant afflictions including gastric, colorectal, and lung cancers, showcasing substantial therapeutic advancements. However, the universal applicability of immunotherapy remains elusive, with certain patient groups and specific tumor types showcasing resistance or non-responsiveness to such treatments. Intratumor heterogeneity, emanating from diverse genetic, cellular, and tissue landscapes, is postulated to be a critical underpinning of this disparate therapeutic responsiveness. The convoluted nature of cancer, underscored by its broad genetic and phenotypic spectrum, further compounds the challenge in harnessing immunotherapy's full potential. The primary objective of this Research Topic is to provide a dedicated platform for the dissemination of pioneering research, novel insights, and methodological advancements aimed at demystifying the enigma of intratumor heterogeneity and its impact on immunotherapeutic efficacy. By fostering a rigorous academic discourse around this pivotal issue, we aspire to propel forward the understanding of the underlying mechanisms mediating intratumor heterogeneity and immunotherapy resistance. Through this scholarly endeavor, we envision bridging theoretical knowledge with practical applications in cancer medicine, thereby contributing to more personalized and effective immunotherapeutic strategies. We invite submissions of Original Research articles, Comprehensive Reviews, and Insightful Commentaries that delve into the molecular, cellular, and systemic aspects of intratumor heterogeneity and its interplay with immunotherapeutic approaches. Through a rigorous peer-review process, we aim to ensure the highest level of scholarly integrity, while promoting a vibrant academic dialogue to foster breakthroughs in the field of cancer immunotherapy. Topics of interest include: (1) Role of non-mutational epigenetic reprogramming, polymorphic microbiomes, senescent cells, and phenotypic plasticity in mediating immunotherapeutic responsiveness. (2) Exploring novel computational and experimental tools aimed at elucidating the multifaceted nature of intratumor heterogeneity. (3) Leveraging the “big data” paradigm to advance the understanding and overcoming of the hurdles posed by intratumor heterogeneity in the realm of immunotherapy, from a multidisciplinary perspective. Please NOTE: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases that are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of the scope for this section and will not be accepted as part of this Research Topic.

Keywords : Intratumor Heterogeneity

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