Session moderators and panelists were given the opportunity to ask questions, and panelists supplied a key summary of their sessions. Summaries were reviewed by the authors for inclusion below. The take-home learnings are organized in the order of sessions and presentations held during the 2-day workshop. Key learnings from the leading session were: Key learnings from the session were: Introduction: This session focused on both the occupational health and environmental health and safety lessons learned. Key learnings from the session were: Key learnings from the session were: Key impacted stakeholders shared their thoughts with the following presentations on what worked and what is needed for future rapid response to emerging public health pathogens.
Abstract Developing strong animal models is essential for furthering our understanding of how the immune system functions in response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. The alarming speed at which SARS-CoV-2 has spread, and the high mortality rate of severe Coronavirus Disease 2019 (COVID-19), has required both basic science and clinical research to move at an unprecedented pace. Models previously developed to study the immune response against SARS-CoV have been rapidly deployed to now study SARS-CoV-2. To date, both small and large animal models are remarkably consistent when infected with SARS-CoV-2; however, certain models have proven more useful when answering specific immunological questions than others. Small animal models, such as Syrian hamsters, ferrets, and mice carrying the hACE2 transgene, appear to reliably recapitulate the initial cytokine surge seen in COVID-19 as well as show significant innate and adaptive cell infiltration in to the lung early in infection. Additionally, these models develop strong antibody responses to the virus, are protected from reinfection, and genetically modified versions exist that can be used to ask specific immunological questions. Large animal models such as rhesus and cynomologus macaques and African green monkeys are critical to understanding how the immune system responds to SARS-CoV-2 infection because they are considered to be the most similar to humans. These models are considered the gold standard for assessing vaccine efficacy and protection, and recapitulate the initial cytokine surge, immune cell infiltration into the lung, certain aspects of thrombosis, and the antibody and T-cell response to the virus. In this review, we discuss both small and large animal model studies previously used in SARS-CoV-2 research that may be useful in elucidating the immunological contributions to hallmark syndromes observed with COVID-19.
Animal research is currently an irreplaceable contributor to our efforts to protect and improve public health. Its relevance, importance, and contributions are represented in historical precedent, regulatory expectations, evidence of our rapidly developing understanding of human health and disease, as well as success in the development of novel therapeutics that are improving quality of life and extending human and animal life expectancy. The rapid and evolving success in responding to the current COVID pandemic significantly supported by animal studies is a clear example of the importance of animal research. But there is growing interest in reducing our dependence on animals and challenges to the effective translation of current animal studies to human applications. There are several potential contributors to gaps in the translatability of animal research to humans, including our approaches to choosing or rationalizing the relevance of a particular animal model, our understanding of their biological variability and how that applies to outcomes, the data we collect from animal studies, and even how we manage the animals. These important contributors to the success of animal research are explored in this issue of the ILAR Journal.
The failure of animal studies to translate to effective clinical therapeutics has driven efforts to identify underlying cause and develop solutions that improve the reproducibility and translatability of preclinical research. Common issues revolve around study design, analysis, and reporting as well as standardization between preclinical and clinical endpoints. To address these needs, recent advancements in digital technology, including biomonitoring of digital biomarkers, development of software systems and database technologies, as well as application of artificial intelligence to preclinical datasets can be used to increase the translational relevance of preclinical animal research. In this review, we will describe how a number of innovative digital technologies are being applied to overcome recurring challenges in study design, execution, and data sharing as well as improving scientific outcome measures. Examples of how these technologies are applied to specific therapeutic areas are provided. Digital technologies can enhance the quality of preclinical research and encourage scientific collaboration, thus accelerating the development of novel therapeutics.
In accordance with the «Aims of ICLA» (ICLA Bulletin No. 26, March 1970) the Governing Board established in 1969 a Working Party to prepare an International Nomenclature System for Outbred Animals. The members were: Professor, Dr. A. Spiegel, Federal Republic of Germany, chairman.Dr. M. Festing, United KingdomDr. K. Kondo, JapanDr. R. Loosli, SwitzerlandMr. S. Poiley, U.S.A. The nomenclature rules, completed and approved by the ICLA Governing Board on 8 December 1971, are published herewith. I am convinced that this system will bring order out of the existing chaos. The system is an offer to the world laboratory animal science, particularly the breeders and users. Editors of scientific journals, catalogues, and indices all over the world are also encouraged to require and use animal stock identification by this system for outbred animals used in experimentation. The ICLA Governing Board would have preferred to have seen an international centralization of symbol registration. However, the ICLA Secretariat has not got the capacity necessary for such a task and some practical solution to the registration problem will have to be found by the Governing Board. A final aim should then be for ICLA to publish a comprehensive world list of breeder symbols at intervals. Oslo, January 1972 Stian Erichsen Secretary-General.
In silico predictions combined with in vitro, in vivo, and in situ observations collectively suggest that mouse adaptation of the severe acute respiratory syndrome 2 virus requires an aromatic substitution in position 501 or position 498 (but not both) of the spike protein's receptor binding domain. This effect could be enhanced by mutations in positions 417, 484, and 493 (especially K417N, E484K, Q493K, and Q493R), and to a lesser extent by mutations in positions 486 and 499 (such as F486L and P499T). Such enhancements, due to more favorable binding interactions with residues on the complementary angiotensin-converting enzyme 2 interface, are, however, unlikely to sustain mouse infectivity on their own based on theoretical and experimental evidence to date. Our current understanding thus points to the Alpha, Beta, Gamma, and Omicron variants of concern infecting mice, whereas Delta and "Delta Plus" lack a similar biomolecular basis to do so. This paper identifies 11 countries (Brazil, Chile, Djibouti, Haiti, Malawi, Mozambique, Reunion, Suriname, Trinidad and Tobago, Uruguay, and Venezuela) where targeted local field surveillance of mice is encouraged because they may have come in contact with humans who had the virus with adaptive mutation(s). It also provides a systematic methodology to analyze the potential for other animal reservoirs and their likely locations.
The Coronavirus Disease 2019 (COVID-19) pandemic has fueled unprecedented development of animal models to understand disease pathogenesis, test therapeutics, and support vaccine development. Models previously developed to study severe acute respiratory syndrome coronavirus (SARS-CoV) have been rapidly deployed to study SARS-CoV-2. However, it has become clear that despite the common use of ACE2 as a receptor for both viruses, the host range of the 2 viruses does not entirely overlap. Distinct ACE2-interacting residues within the receptor binding domain of SARS-CoV and SARS-CoV-2, as well as species differences in additional proteases needed for activation and internalization of the virus, are likely sources of host differences between the 2 viruses. Spontaneous models include rhesus and cynomolgus macaques, African Green monkeys, hamsters, and ferrets. Viral shedding and transmission studies are more frequently reported in spontaneous models. Mice can be infected with SARS-CoV; however, mouse and rat ACE2 does not support SARS-CoV-2 infection. Murine models for COVID-19 are induced through genetic adaptation of SARS-CoV-2, creation of chimeric SARS-CoV and SARS-CoV-2 viruses, use of human ACE2 knock-in and transgenic mice, and viral transfection of wild-type mice with human ACE2. Core aspects of COVID-19 are faithfully reproduced across species and model. These include the acute nature and predominantly respiratory source of viral shedding, acute transient and nonfatal disease with a largely pulmonary phenotype, similar short-term immune responses, and age-enhanced disease. Severity of disease and tissue involvement (particularly brain) in transgenic mice varies by promoter. To date, these models have provided a remarkably consistent template on which to test therapeutics, understand immune responses, and test vaccine approaches. The role of comorbidity in disease severity and the range of severe organ-specific pathology in humans remains to be accurately modeled.
The Animal Care Panel is a nonprofit educational association of individuals and institutions concerned with the production, care, and study of laboratory animals. The entire United States and several foreign countries are represented in its membership. The Panel provides for the exchange of scientific information on all phases of laboratory animal care. It compiles and distributes information on films dealing with the handling of laboratory animals, and has initiated an animal technicians' training program. It publishes a bimonthly journal, "Laboratory Animal Care;" sponsors annual awards designed to encourage and reward outstanding accomplishment in the improvement of the care and quality of laboratory animals; and maintains close liaison with the Institute of Laboratory Resources (National Research Council), the American Veterinary Medical Association (through the American College of Laboratory Animal Medicine), the Laboratory Animal Breeders Association, and the National Society for Medical Research. Through its Animal Facilities Standards Committee, the Panel gathers and examines information that will aid in the establishment of high standards for the care of animals. The GUIDE FOR LABORATORY ANIMAL FACILITIES AND CARE was adopted by the Institute of Laboratory Animal Resources, National Academy of Sciences-National Research Council, on January 28, 1963.
Developing strong animal models is essential for furthering our understanding of how the immune system functions in response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. The alarming speed at which SARS-CoV-2 has spread, and the high mortality rate of severe Coronavirus Disease 2019 (COVID-19), has required both basic science and clinical research to move at an unprecedented pace. Models previously developed to study the immune response against SARS-CoV have been rapidly deployed to now study SARS-CoV-2. To date, both small and large animal models are remarkably consistent when infected with SARS-CoV-2; however, certain models have proven more useful when answering specific immunological questions than others. Small animal models, such as Syrian hamsters, ferrets, and mice carrying the hACE2 transgene, appear to reliably recapitulate the initial cytokine surge seen in COVID-19 as well as show significant innate and adaptive cell infiltration in to the lung early in infection. Additionally, these models develop strong antibody responses to the virus, are protected from reinfection, and genetically modified versions exist that can be used to ask specific immunological questions. Large animal models such as rhesus and cynomologus macaques and African green monkeys are critical to understanding how the immune system responds to SARS-CoV-2 infection because they are considered to be the most similar to humans. These models are considered the gold standard for assessing vaccine efficacy and protection, and recapitulate the initial cytokine surge, immune cell infiltration into the lung, certain aspects of thrombosis, and the antibody and T-cell response to the virus. In this review, we discuss both small and large animal model studies previously used in SARS-CoV-2 research that may be useful in elucidating the immunological contributions to hallmark syndromes observed with COVID-19.
Non-mammalian vertebrates including birds, fish, and amphibians have a long history of contributing to ground-breaking scientific discoveries. Because these species offer several experimental advantages over higher vertebrates and share extensive anatomic and genetic homology with their mammalian counterparts, they remain popular animal models in a variety of fields such as developmental biology, physiology, toxicology, drug discovery, immunology, toxicology, and infectious disease. As with all animal models, familiarity with the anatomy, physiology, and spontaneous diseases of these species is necessary for ensuring animal welfare, as well as accurate interpretation and reporting of study findings. Working with avian and aquatic species can be especially challenging in this respect due to their rich diversity and array of unique adaptations. Here, we provide an overview of the research-relevant anatomic features, non-infectious conditions, and infectious diseases that impact research colonies of birds and aquatic animals, including fish and Xenopus species.
The organization and function of the institutional animal care and use committee (IACUC) is the key component of government regulation and oversight of necessary scientific research using live animals and of AAALAC - International accreditation of animal care and use programs in the United States. The regulations, roles, and responsibilities of IACUCs have evolved since their inception 35 years ago from a limited focus on animal welfare and specific animal procedures to embracing scientific quality, data reproducibility and translation, and animal welfare as inextricably interdependent and critical components of generation of new scientific knowledge and medical treatments. A current challenge for IACUCs is in evaluating whether benefits to be derived (eg, new knowledge or treatments) justify any unavoidable pain, stress, or injury associated with proposed research protocols, because the former are long-term and at best speculative outcomes, whereas the latter are immediate and tangible for the study animals. Scientific consensus is that research most likely to generate significant new knowledge and medical treatments is that conducted to high scientific, technical, and quality standards and reported with full transparency to facilitate reproducibility. As an alternative to current benefits evaluations included in risk benefit and harm benefit constructs, the authors propose that IACUCs assess the proposed research for scientific quality and alignment of study elements with the study purpose (e.g., Fit for Purpose [FfP]), including justifications for study design components, selection of primary endpoints and technologies, rationale for data and statistical analyses, and research communication plans. Fit for Purpose endpoints are objective, immediate, and impactful as are the potential risks for study animals, and at the same time they are the best predictors for achievement of longer-term benefits. We propose that IACUCs and any revision of The ILAR Guide consider FfP concepts in place of traditional benefits assessment to accelerate the generation of new knowledge and treatments benefiting medical and veterinary patients and the environment through better science and animal welfare rather than to continue to rely on speculative future outcomes.
This case report discusses Type I hypersensitivity in ferrets following exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inoculum, observed during a study investigating the efficacy of candidate COVID-19 vaccines. Following a comprehensive internal root-cause investigation, it was hypothesized that prior prime-boost immunization of ferrets with a commercial canine C3 vaccine to protect against the canine distemper virus had resulted in primary immune response to fetal bovine serum (FBS) in the C3 preparation. Upon intranasal exposure to SARS-CoV-2 virus cultured in medium containing FBS, an allergic airway response occurred in 6 out of 56 of the ferrets. The 6 impacted ferrets were randomly dispersed across study groups, including different COVID-19 vaccine candidates, routes of vaccine candidate administration, and controls (placebo). The root-cause investigation and subsequent analysis determined that the allergic reaction was unrelated to the COVID-19 vaccine candidates under evaluation. Histological assessment suggested that the allergic response was characterized by eosinophilic airway disease; increased serum immunoglobulin levels reactive to FBS further suggested this response was caused by immune priming to FBS present in the C3 vaccine. This was further supported by in vivo studies demonstrating ferrets administered diluted FBS also presented clinical signs consistent with a hyperallergic response, while clinical signs were absent in ferrets that received a serum-free SARS-CoV-2 inoculum. It is therefore recommended that vaccine studies in higher order animals should consider the impact of welfare vaccination and use serum-free inoculum whenever possible.
There is no prescribed stage or standardized point at which an animal model protocol is reviewed for reproducibility and translatability. The method of review for a reproducible and translatable study is not consistently documented in peer literature, and this is a major challenge for those working with animal models of human diseases. If the study is ill designed, it is impossible to perform an accurate harm/benefit analysis. In addition, there may be an ethical challenge if the work is not reproducible and translatable. Animal welfare regulations and other documents of control clearly state the role of the Institutional Animal Care and Use Committees are to look at science justification within the context of animal welfare. This article, concentrating on models not governed by regulations, outlines issues and offers recommendations for refining animal model review with a goal to improve study reproducibility and translatability.
ICLAS Laboratory Animal Quality Network (LAQN) programs currently consist of the Performance Evaluation Program (PEP), which focuses on microbial monitoring by and for laboratory animal diagnostic laboratories, and the Genetic Reference Monitoring Program (GENRef), which provides assay-ready reference DNA for genetic testing of mouse strains. Since 2008, PEP has grown to become a truly international program with participating laboratories in 5 continents. Launched in 2016, GENRef currently distributes DNA from 12 common inbred mouse strains for use in genetic monitoring of locally inbred colonies as well as for genetic testing of stocks, particularly genetically engineered stocks, of uncertain origins. GENRef has the capacity to include additional strains as well as additional species. PEP and GENRef provide the reagents at cost, as a resource to the international scientific community, in the interest of improving research quality in an environment of growing concern for research quality, rigor, and reproducibility.
Laboratory registration codes, also known as laboratory codes or lab codes, are a key element in standardized laboratory animal and genetic nomenclature. As such they are critical to accurate scientific communication and to research reproducibility and integrity. The original committee on Mouse Genetic Nomenclature published nomenclature conventions for mice genetics in 1940, and then conventions for inbred strains in 1952. Unique designations were needed, and have been in use since the 1950s, for the sources of animals and substrains, for the laboratories that identified new alleles or mutations, and then for developers of transgenes and induced mutations. Current laboratory codes are typically a 2- to 4-letter acronym for an institution or an investigator. Unique codes are assigned from the International Laboratory Code Registry, which was developed and is maintained by ILAR in the National Academies (National Academies of Sciences Engineering and Medicine and previously National Academy of Sciences). As a resource for the global research community, the registry has been online since 1997. Since 2003 mouse and rat genetic and strain nomenclature rules have been reviewed and updated annually as a joint effort of the International Committee on Standardized Genetic Nomenclature for Mice and the Rat Genome and Nomenclature Committee. The current nomenclature conventions (particularly conventions for non-inbred animals) are applicable beyond rodents, although not widely adopted. Ongoing recognition, since at least the 1930s, of the research relevance of genetic backgrounds and origins of animals, and of spontaneous and induced genetic variants speaks to the need for broader application of standardized nomenclature for animals in research, particularly given the increasing numbers and complexities of genetically modified swine, nonhuman primates, fish, and other species.
The Institute for Laboratory Animal Research (ILAR) was created within the National Academies of Sciences, Engineering, and Medicine (National Academies) in 1953 when biomedical research using animals was in its infancy in terms of quantity, quality, complexity, sophistication, and care. Over the intervening 69 years, ILAR has witnessed unprecedented growth, followed by unprecedented decline, and then regrowth in usage of specific species and models and an overall shift in experimental burden away from larger to smaller species (ie, mice, fish, and rats). ILAR has contributed much to the evolution of necessary research using animals and animal models for the benefit of humans, animals, and the environment and to the development and implementation of humane principles and standards for care and use of research animals. ILAR has served as a "neutral broker" seeking consensus, solutions, common ground, and pathways forward for all professional constituencies engaged in conduct of animal research. In 2022, ILAR will become the Board on Animal Health Sciences, Conservation, and Research (BAHSCR) within the Division on Earth and Life Studies of the National Academies and the ILAR Journal will pause publication with volume 62. This manuscript recounts the history and accomplishments of ILAR 1953-2022, emphasizing the past 2 decades. The manuscript draws upon ILAR's communications and previously published histories to document ILAR's leaders, reports, publications, conferences, workshops, and roundtables using text, tables, references, and extensive supplemental tables. The authors' intention is to provide the scientific community with a single source document for ILAR, and they apologize for any omissions and errors.
Research involving the study of animals in laboratory settings over the past century has transformed our understanding of human and animal health.1 In recent decades, the study of animal life has shifted with expansion into disciplines and domains beyond traditional laboratory-based approaches.2 From studies of behavioral changes in wildlife species to clinical studies on pet dogs and cats, studies of animal life are increasingly integral to a widening range of research domains.3–6 Novel and critical insights are emerging from this broadened research landscape, but at the center of all studies on animal life are the basic biological insights that laboratory animal research exposes.1,2 For over 60 years the Institute for Laboratory Animal Research (ILAR), a program unit within the Division of Earth and Life Sciences of the National Academies of Sciences, Engineering and Medicine, has provided support, guidance, and leadership in laboratory animal research.1 Throughout the 20th and 21st centuries, ILAR has focused on developing research activities to expand and advance animal laboratory research, publicizing laboratory animal guidelines, joining medical organization committees (The United Nations Educational, Scientific, and Cultural Organization; International Union of Biological Sciences; Council for International Organizations of Medical Sciences), and creating global standards for laboratory animal studies.7 Over time, ILAR publications have emphasized both traditional animal models and other species in providing crucial information about human health.8–10 Today, ILAR activities such as workshops and roundtables are calling attention to the importance of animals outside the laboratory—from discussions on animal welfare challenges and the accurate taxonomy of wildlife to predicting zoonotic spillover and pandemic threats.11–13
Animal studies in pharmaceutical drug discovery are common in preclinical research for compound evaluation before progression into human clinical trials. However, high rates of drug development attrition have prompted concerns regarding animal models and their predictive translatability to the clinic. To improve the characterization and evaluation of animal models for their translational relevance, the authors developed a tool to transparently reflect key features of a model that may be considered in both the application of the model but also the likelihood of successful translation of the outcomes to human patients. In this publication, we describe the rationale for the development of the Animal Model Quality Assessment tool, the questions used for the animal model assessment, and a high-level scoring system for the purpose of defining predictive translatability. Finally, we provide an example of a completed Animal Model Quality Assessment for the adoptive T-cell transfer model of colitis as a mouse model to mimic inflammatory bowel disease in humans.
