Proceedings of a Workshop
Rapid Response by Laboratory Animal Research Institutions During the COVID-19 Pandemic: Lessons Learned
Proceedings of a Workshop—in Brief
The National Academies of Sciences, Engineering, and Medicine (the National Academies) appointed a committee of experts to plan and convene a workshop on lessons learned at animal research institutions in response to SARS-CoV-2, the cause of the COVID-19 pandemic. The aim of this workshop was to discuss institutional challenges and strategies for addressing them to provide guidance to the broader community for the ongoing pandemic and inform a rapid and sustainable response framework for future pandemics.1 Expert scientists conducting COVID-19 research, as well as institutional leadership responsible for oversight in areas such as, veterinary medical care, occupational health, risk assessment and biosafety, and public messaging and communications presented and participated in panel discussions. Topics included: rapidly developing and maintaining new animal models to support pandemic response efforts; ramping up research resources against a backdrop of supply line disruptions and resource shortages; protecting research and support staff while maintaining research operations during the pandemic; communicating updates and policies both within each organization and to the public; and developing strategies to accelerate COVID-19 research-related activities given the urgent need for emergency response for people, as well as other species potentially vulnerable to the virus.2
SESSION 1: KEYNOTE SPEAKER AND SCIENTIFIC BACKGROUND TO MEETING
Dr. Barney Graham of the National Institute of Allergy and Infectious Diseases (NIAID) opened the workshop by delivering a keynote address on how the biomedical research community was able to quickly develop effective therapeutics and vaccines against SARS-CoV-2. He explained that long-running basic and translational research on other viruses, such as the Middle East Respiratory Syndrome (MERS) and Respiratory Syncytial Virus (RSV), equipped the biomedical research community with effective methods for mapping the structural properties of viruses, which was crucial for rapid design of SARS-CoV-2 antibody and vaccine candidates. In studying MERS, RSV, and other viruses, such as Ebola and Zika, biomedical researchers recognized the need to first understand the protein structure of the virus of interest before developing and proving performance testing of diagnostic assays, isolating and identifying antibodies, and developing and testing new vaccine candidates. In the case of SARS-CoV-2, the genetic sequence of the virus was made publicly available on January 10, 2020. The next day NIAID researchers began to decode the structure of the SARS-CoV-2 spike protein found on the surface of the virus. This enabled them to create serological
1 See https://www.nationalacademies.org/our-work/rapid-and-sustained-response-by-the-laboratory-animal-research-community-during-an-infectious-disease-pandemic-lessons-being-learned-from-covid-19-a-workshop.
assays, develop Pseudovirus for neutralization assays, and launch mouse model experiments allowing them to isolate a SARS-CoV-2 neutralizing antibody and provide a vaccine sequence for messenger RNA (mRNA) therapeutics to Moderna Biotechnology company. In accordance with Good Manufacturing Practices (GMPs) embraced by regulators, Moderna returned test vaccine product to NIAID in just over six weeks. This test product entered Phase III clinical trials within approximately six months and is now licensed for use in the United States. In parallel to vaccine development, NIAID initiated a collaboration with Eli Lilly and Company, a pharmaceutical company, to develop the product into a monoclonal antibody therapy, which entered a Phase III clinical trial within approximately five months. This therapy was granted Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) to treat mild-to-moderate COVID-19 cases to prevent them from transitioning to more severe disease.
Dr. Graham noted that experiences with developing antibody therapies and vaccines against the novel SARS-CoV-2 virus highlight key lessons learned. As the biomedical research community and its supporters think strategically about rapid response to the next unforeseeable pandemic, he pointed out that both speed and precision are critically important to control the spread of a novel pathogen and prevent severe illness of individuals infected. To achieve this, Dr. Graham pointed out that researchers must first understand the biological principles underlying virus transmission, infection, replication, and evolution and develop agile technological platforms (e.g., mRNA vaccines) whose principles can be adapted to address novel pathogens. Ensuring rapid manufacturing of urgently needed therapies and vaccines also points to the importance of public–private partnerships (e.g., the NIAID and Moderna partnership) established before a pandemic emerges. This greatly facilitates rapid responses because time is not lost on negotiating contracts and organizing infrastructure that is crucial for basic pandemic preparedness. Dr. Graham advocated for launching a wide-ranging “prototype pathogen approach for pandemic preparedness” based on these lessons learned. Such an approach could involve proactive investments in the development of prototype vaccines against each family of viruses that can infect humans, as well as all viruses known to infect humans that have a potential for increasing human-to-human transmission and virulence.
Adding to the pandemic preparedness principles outlined by Dr. Graham, Dr. Paul Duprex of the University of Pittsburgh’s Center for Vaccine Research discussed strategies for rapidly retuning biocontainment laboratory facilities to support preclinical research to address an emerging pandemic. Animal model studies are a crucial component of intervention development against emerging infectious agents. Specialized facilities, such as the Biological Safety Level (BSL-3) facility at the University of Pittsburgh, face critical challenges when novel pathogens emerge causing disease outbreaks. Laboratory biomedical research institutions are forced to reorganize their facilities and research efforts to address the public health emergency. Once the biomedical research community determined that the spike protein of SARS-CoV-2, and in particular, its receptor binding domain (RBD), was the crucial target for virus neutralization, the Center’s BSL-3 facility quickly adapted its operations to begin to conduct in vitro and in vivo studies. In vivo studies utilized animals, such as murine, hamster, ferret, and African green monkey models. Dr. Duprex and colleagues began to study the characteristics of the virus, such as its infectivity and transmissibility in various animal models. They also investigated viral replication throughout different regions of the different species under study. They explored creative approaches to mitigating SARS-CoV-2, such as engineering a safe and effective measles vaccine to express the SARS-CoV-2 spike protein on its surface for generating immunity to the virus and testing the modified vaccine in animal models.
The Center for Vaccine Research has also developed nanobodies against SARS-CoV-2, which are small, single-antigen-binding-domain molecules that primarily target the RBD of the SARS-CoV-2 spike glycoprotein for virus neutralization. Nanobodies penetrate target tissues very effectively and can be inhaled, making them very attractive for respiratory pathogenesis studies. Nanobodies can be robustly and affordably manufactured in the laboratory. They bind to multiple neutralization epitopes on the SARS-CoV-2 RBD, the virus antigenic determinants that are recognized by the immune system, making them a potentially effective therapy against multiple emerging variants. The Center is studying its SARS-CoV-2 nanobodies in nonhuman primate (NHP) models, while maintaining its readiness to quickly shift its research priorities if necessary. Dr. Duprex stressed that, even with the potential for nanobodies to protect against multiple variants of SARS-CoV-2, the unpredictable nature typical of rapidly evolving RNA viruses makes development of a “universal vaccine” unlikely. He thus considered it crucial that BSL-3 research facilities, such as the Center for Vaccine Research, remain nimble and ready to rapidly adjust their research efforts. He also noted that, although in vitro platforms such as microphysiological systems (MPS) can serve as crucial bridges between animal models and clinical trials, animal model studies remain the fastest and most reliable way to predict clinical safety and effectiveness of novel therapeutics and vaccines. Animal models therefore remain an indispensable component of efforts to prepare for and respond to pathogens with pandemic potential.
SESSION 2: RAMPING UP: ANIMALS AND OTHER RESOURCES FOR INFECTIOUS DISEASE RESEARCH—PART 1
Dr. Ian Moore, Investigative Veterinary Pathologist at NIAID, opened the session by discussing the triumphs and challenges of the use of animal models during the pandemic. He emphasized the acute dangers posed by zoonotic pathogens and the need for the animal research enterprise to proactively study such pathogens. Dr. Moore noted that 60 percent of all existing human diseases are zoonotic, 75 percent of emerging diseases that infect humans (e.g., Ebola and influenza) originated in animals, 80 percent of agents with potential bioterrorist applications are zoonotic pathogens, and on average three of the five new human diseases that emerge each year are of animal origin. Particularly during the early stages of the COVID-19 pandemic, animal researchers faced enormous pressure to quickly develop and study interventions for SARS-CoV-2. Leadership at biomedical research institutions faced logistical challenges, such as providing sufficient amounts of personal protective equipment (PPE) and reorganizing personnel work shifts to ensure physical distancing to protect research and support staff from infection and, at the same time, creating detailed plans to advance SARS-CoV-2 research despite ongoing logistical constraints and complications. Researchers dealt with these challenges in part by leveraging lessons learned from failures in previous research on pathogens, such as influenza viruses and SARS-CoV-1—for example, by using redundant measures and multiple assays to evaluate a given endpoint and reduce the risk of misleading measures biasing interpretation of study results. Dr. Moore highlighted the importance of overpreparing for worst-case scenarios (e.g., establishing multiple supply lines for key resources) so that unforeseen challenges can be successfully mitigated when they arise. Key considerations when scaling up animal model use might include reagent availability, advantages of various genetic strains, availability of comparable datasets, colony sizes and general husbandry, immune attributes of animal models and anatomic and physiologic homology to humans.
Dr. Franziska Grieder, Director of the NIH Office of Research Infrastructure Programs (ORIP), presented on the inherent difficulties of scaling up NHP study colonies, especially considering their longer breeding timelines relative to small animals, such as mice, hamsters, and ferrets. ORIP published a two-part report in 2018 that warned of shortages of NHPs for biomedical research, especially rhesus macaques and marmosets.3,4 Ongoing shortages limited the amount of NHP research that could be conducted to rapidly address the COVID-19 pandemic, highlighting the fact that NHP resource management (including access to BSL facilities) is a key component of long-term pandemic preparedness and response. Dr. Grieder highlighted the wide range of stakeholders who need to be involved in developing these resource management plans, including (1) researchers, (2) resource managers/NHP breeders with specialized knowledge in veterinary care, (3) funders and logistical managers with specialized knowledge of strategic management, and (4) coordinators, organizers, and negotiators who can facilitate collaborations among groups (1), (2), and (3). She also emphasized the need for these stakeholders to have access to, and to consistently communicate with, institutional leaders and decision makers, so that all stakeholders across the NHP research enterprise understand and participate in implementing long-term strategies when they are developed.
Mr. Kurt Derfler, Director of Primate Operations at Charles River Laboratories, reiterated that NHP availability for research was already tight going into the pandemic, and expanded on the additional challenges created as SARS-CoV-2 emerged as a global pandemic. He highlighted several factors that contributed to the short supply of NHPs (i.e., rhesus and cynomolgus macaques) which included increased use of NHPs by China for research, noting that pre-COVID-19, 60 percent of the cynomolgus macaques used for research in the United States were imported from China. Other factors included: air transport restrictions caused by decreases in passenger flights; use of cargo space for transport of emergency supplies and cost increases for cargo shipments and the use of charters; increases in the global demand for the limited NHP supply; uncertainty about which species of NHP were most appropriate for SARS-CoV-2 research; fears of inadvertently shipping NHPs that were infected with SARS-CoV-2; and cost increases from suppliers during 2020. Strategies to help ensure adequate NHP supplies during future pandemics might include diversifying sources of NHPs for research, increasing domestic breeding of NHPs within the United States, expanding NHP carriers to overcome transportation challenges, coordinating research groups and NHP suppliers to identify and reserve as early as possible those NHP species or strains that are most relevant for studying an emerging pathogen, and preparing for extra costs that can result from a sudden rise in demand for NHPs after detection of an emerging pathogen.
Dr. Stephen Festin of Charles River Laboratories described some of the challenges that animal resource laboratories faced with regard to rodent model development and preservation during the COVID-19 pandemic. Laboratory animal operations at many institutions were significantly reduced during the pandemic. Outsourcing some of the services related to rodent model development could help institutions with reduced levels of operations within their animal facilities. After normal animal facilities operations resume, this could also help to ensure the continuity of access to and availability of critical models for current and future studies. He highlighted strategies to help ensure post-pandemic continuity of rodent lineages, including those that had been genetically engineered, after laboratory operations have been disrupted by a pandemic or other unusual situation. For example, services include: cryopreservation of embryo and sperm to help establish recoverable colony-line backup; reconstitution of embryo and sperm to provide for colony-line recovery; and IVF-based colony development and colony-line expansion for immediate study. Contingency plans for offsite breeding can also safeguard animal colony maintenance.
Dr. Festin emphasized the value of the CRISPR-Cas9 (Clustered Regularly Interspaced Palindromic Repeats-CRISPR-associated protein 9), an efficient genome-editing tool that enables the rapid generation of animal models on the background of a standard animal life cycle. To prepare for the emergence of future pandemics, animal research facilities may benefit from developing animal colony production strategies and recovery plans, particularly for those animal models that are key to deciphering mechanisms of virologic and immunologic features and for drug development and safety testing. Researchers may be able to deepen their understanding of human diseases and immune responses by improving methods for building adaptable genetic and humanized small animal models, which could then be leveraged in rapid response to the next emerging pandemic pathogen.
Dr. Gale Galland of the Centers for Disease Control and Prevention (CDC) provided further details on NHP shortages in the United States during the COVID-19 pandemic. She reported that NHP importation decreased by 21 percent from fiscal year (FY) 2019 to FY 2020 with imports from China and Vietnam decreasing and imports from Cambodia, Mauritius, St. Kitts and Nevis, Barbados, and South Africa increasing during the same period; with imports from China decreasing by approximately 82% and imports from Cambodia increasing by approximately 83%. Decreases in the number of NHPs imported were observed from January to March 2020 partly because NHPs are no longer being imported to the United States from China. It was also very difficult to get NHPs out of Asia and Mauritius, as required transfers at airports in countries that would not allow transit essentially cut off travel routes to the United States. Since April 2020, NHP importation rates have been slowly rebounding.
SESSION 3: RAMPING UP ANIMAL-BASED INFECTIOUS DISEASE RESEARCH—PART 2
In addition to scientific challenges, the COVID-19 pandemic created health and safety challenges for those working in animal research facilities. Ms. Maureen Thompson, Environmental Health and Safety Officer at the Yerkes National Primate Research Center (NPRC) at Emory University, provided basic information about an occupational health program, which supports a healthy workforce by implementing policies, procedures, and guidelines to prevent workplace injuries and preparedness for potential injuries, exposures, and illnesses than may occur, especially in research with animals. As noted in the Guide for the Care and Use of Laboratory Animals, each institution that conducts animal research must establish an occupational health and safety program as an essential part of the overall Program of animal care and use, and each institution should also focus on maintaining a safe and healthy workplace (see page 17 of the Guide for regulatory phraseology).5, 6 Such programs often include comprehensive risk assessment protocols involving both researchers and safety staff in a team-based hazard identification approach. Ms. Thompson noted that it is critical that this risk assessment is accomplished with a team and in concert with safety department staff. Identification of hazards can be achieved through a number of different processes, such as literature reviews, or for SARS, through subject matter experts. Probability-versus-consequence graphs can then be used to plot identified hazards, prioritize mitigation efforts, and develop mitigation tools and strategies so that risks are reduced to a tolerable level. Ms. Thompson emphasized the difficulties of identifying hazards during the early stages of the COVID-19 pandemic, when it was not yet known how the pathogen spread or how to predict the consequences of an infection.
6 See also the National Research Council publications, Occupational Health and Safety in the Care and Use of Research Animals (1997), https://www.nap.edu/catalog/4988/occupational-health-and-safety-in-the-care-and-use-of-research-animals; and Occupational Health and Safety in the Care and use of Nonhuman Primates (2003), https://www.nap.edu/catalog/10713/occupational-health-and-safety-in-the-care-and-use-of-nonhuman-primates; as well as the joint publication by CDC and NIH, Biosafety in Microbiological and Biomedical Laboratories, 6th Edition (2020), https://www.cdc.gov/labs/BMBL.html.
Risk assessments revealed two potential ways that this virus could infect research staff at Yerkes NPRC: exposure of a person during research, and exposure to a person from the community who then introduces the virus into the research environment.
Ms. Thompson stated that Yerkes NPRC rapidly ramped up COVID-19 NHP studies to help address the pandemic, despite having limited resources. The safety team had to develop novel protocols for staff organization, testing, training, and protection, with special attention to safeguarding staff morale as extreme working conditions and fear of infection threatened to further diminish already limited staff resources. These changes disrupted routine onboarding health assessments as well as routine vaccination programs for staff. Further, more extensive changes were made to prevent an outbreak of COVID-19 among research staff, which could have crippled Yerkes NPRC when its services were most needed. One important measure used to help prevent an outbreak in the facility was the introduction of “COVID time,” which enabled staff who experienced any potential symptoms of COVID-19 to stay home with pay even if they had no sick leave. Reflecting on her experiences at Yerkes NPRC during the pandemic, Ms. Thompson stressed the importance of establishing multiple supply chains for equipment such as face shields and thermometers, centralizing key processes such as equipment purchasing, maximizing the value of available PPE (e.g., via decontamination), working from home when possible, adjusting ventilation systems when necessary to introduce outside air into research spaces, introducing flexible human resource (HR) policies to prevent outbreaks, and establishing protocols for contact tracing and regular asymptomatic testing during a pandemic.
Dr. Molly S. Stitt-Fischer and Rebecca A. Lingenfelter, from the University of Pittsburgh Department of Environmental Health and Safety (EH&S), presented on challenges in established Animal Biosafety Level (ABSL)-2 and ABSL-3 research programs. Dr. Stitt-Fischer opened with a description of the institution’s approach to pandemic preparedness, noting that the University established their Pandemic Preparedness Plan in 2007 and since then has regularly reviewed and revised the plan. The University has also held multiple tabletop and live exercises with city, county, and state emergency responders and has a well-established operational working relationship between its occupational and student health clinics and local county health department. The plan was activated in late January 2020 in response to the growing pandemic.
Drs. Stitt-Fischer and Lingenfelter shared that the University Emergency Operations Center (EOC) is staffed by representatives of the University Emergency Command Committee. This committee includes key representatives from all university administrative and operations groups, including EH&S, the Office of Research Protections (including the Institutional Animal Care and Use Committee and Institutional Biosafety Committee), and the Division of Laboratory Animal Research (the University’s animal care, animal husbandry, and veterinary care group). The EOC served as the foundation of response efforts, and guidelines were consistently developed, communicated, and implemented with input from multiple administrative and operation stakeholders. Daily update meetings led to efficient decision-making in the midst of a deluge of information changing on a daily, and sometimes hourly, basis. This collaborative environment helped the university develop new connections between departments and improved efficiency. For example, the Purchasing Department worked with EH&S, and research and animal care groups to leverage institutional purchasing power. The purchasing group now seeks expert review before purchasing disinfectants and PPEs. The group also has experience using safety resources, such as the EPA List N-Tool, for choosing appropriate disinfectants for COVID-19.7
However, Dr. Stitt-Fischer noted, risk assessment is always situation specific, and corresponding guidelines should be tailored to the situation. For on-campus student housing, isolation, and quarantine facilities, rooms were left unoccupied for 72 hours whenever possible. Facilities management and housing groups designated personnel for decontamination teams and EH&S provided in-person training. Having EH&S available on-site for the first decontamination with each team alleviated concerns and increased confidence in donning and doffing of PPEs and waste handling procedures. Dr. Stitt-Fischer also emphasized that, no matter what specific guidelines are established, there should be dedicated communication personnel embedded within an EOC-like leadership group, as their ability to organize and present complex information is extremely valuable for communications with both the University community and the broader surrounding communities.
Dr. Stitt-Fischer transitioned to presenting experiences in preparing for SARS-CoV-2 research in their established BSL-3/ABSL-3 program. The NIAID-funded Regional Biocontainment Laboratories (RBL) at the University of Pittsburgh specializes in high-risk infectious agents (such as SARS-CoV-2) in a variety of animal models, with a focus on supporting
nonhuman primate models. Even with a well-established program, there were a few unexpected challenges. For example, it needed to rapidly develop golden Syrian hamster models that appeared well-suited to studying SARS-CoV-2. Yet, there was a lack of personnel with training and skills for handling hamsters. Further, the RBL had to adapt to the sudden influx of COVID-19-related research and discontinuing much of its ongoing non-COVID-19 related research. At the same time, other ongoing research activities occurring University-wide needed to be ramped down. State and local classifications of research activities as “essential” and “nonessential” was an unexpected challenge, given stay-at-home orders. The University was able to obtain clear and timely answers to its questions because the EOC and local and state authorities were already well connected. For staff continuing to be involved in research activities during the pandemic, the University had to assess human, as well as animal, health hazards, including securing stocks of PPE despite nationwide shortages, and guarding against the danger of inadvertently purchasing counterfeit N95s as prices soared.
Dr. Stitt-Fischer stressed the importance of maintaining critical infrastructure of National and Regional Biocontainment Laboratories that provide BSL4/3/2 and BSL3/2 biocontainment facilities, respectively, for critical research on biodefense and emerging infectious disease agents. She noted that investments are also needed to support the next generation of public health professionals and other pandemic response personnel. In addition, she stressed the importance of developing and maintaining lines of communication with local public health and emergency responders and national preparedness and response resources.8,9,10,11,12,13
SESSION 4: ANIMAL RESEARCH DURING COVID-19: CHALLENGES AND OPPORTUNITIES TO ADDRESS FUTURE PANDEMICS
Mr. James O’Reilly, President of the Massachusetts Society for Medical Research (MSMR), described animal rights activist groups’ public messaging campaigns against MSMR and other organizations that conduct animal research. Such groups have issued press releases portraying animal research negatively, and have obtained information through Freedom of Information Act requests to make misleading claims that animal research organizations misuse taxpayer money and hide their activities. Activists have been encouraged to unearth home addresses of animal researchers and send condemnatory letters. Animal rights activist groups have leveraged the distinction between “essential” and “nonessential” research to reframe animal research deemed nonessential to be “unethical,” arguing that animals are being harmed for nonessential reasons. Mr. O’Reilly stressed that the animal research community should use the COVID-19 pandemic to engage positively in the public relations narrative by educating the public about the central role that animal research plays in the development of therapeutics and vaccines for both humans and animals against SARS-CoV-2. He also proposed that research should not be described as “essential” or “nonessential,” but as either “immediately critical to COVID-19” or “able to be suspended but resumed once the pandemic is better controlled.” These strategies can help clarify the meaning of “essential” and “nonessential” research and can reduce activists’ ability to attack, and potentially to disrupt, critical animal model research.
Dr. Eneida Hatcher of the National Center for Biotechnology Information (NCBI) presented on NCBI’s efforts to collect and analyze viral sequencing data in order to predict and respond to zoonotic disease outbreaks. NCBI tracks mutations and quantifies mutation rates of viruses of interest; this information may indicate how likely a particular virus is to escape vaccines, resist therapeutics, or evade antibodies, as well as to increase infectivity and transmissibility. Dr. Hatcher noted, however, that collecting too much viral sequencing data can pose its own challenges. For example, analysts may become overwhelmed by information that then becomes difficult to interpret. NCBI currently holds approximately 100,000 SARS-CoV-2 sequences, which are difficult to parse. Computational biologists and data scientists can use mutations to track and define lineages in certain contexts, such as when they track transmission trends. However, different approaches are needed for other applications, such as understanding a change in virus
8 See Solid Waste Association of North America, https://swana.org/initiatives/guidance-on-coronavirus-(covid-19).
9 See International Sanitary Supply Association, https://www.issa.com/cleaning-and-disinfecting-for-the-coronavirus-sars-cov-2.
11 See CDC/NIOSH Reuse and Decontamination of N95s Guidelines, https://www.cdc.gov/coronavirus/2019-ncov/hcp/ppe-strategy/decontamination-reuse-respirators.html.
biology, which depends on a subset of mutations within the set used to define a lineage. Dr. Hatcher explained that the COVID-19 pandemic has demonstrated the need to describe viral strains in terms of the total number of mutations in a strain, because doing so is precise and avoids vague lineage definitions. This naming approach also distinguishes between individual reads to reflect the diversity of strains evolving within one host. By comparison, consensus sequences blot out that level of variation, challenging efforts to detect new variants of potential concern.
Dr. Koen Van Rompay from the California National Primate Research Center (NPRC) at the University of California at Davis presented on the use of NHP models to test therapeutic strategies against SARS-CoV-2. He noted that animal studies facilitated rapid clinical trials of therapeutics that were granted EUA by the FDA. The pandemic pressured animal researchers to compress into a 1-year timeframe vaccine and drug development processes that normally take 10 to 15 years. Animal model researchers recognized that NHP models are more likely to closely model the biology of humans, but NHPs were in very short supply, especially during the earliest stages of the pandemic. To conserve limited NHP resources, researchers had to rapidly establish an efficient small animal-to-NHP-to-human trials pipeline to test therapeutics. These efforts led to proof-of-concept small animal and NHP studies that enabled crucial clinical trials and ultimately supported EUA for antivirals such as remdesivir, anti-inflammatory agents such as baricitinib, monoclonal antibodies and antibody combinations, and convalescent plasma, as well as various combinations of these agents (e.g., remdesivir and baricitinib) against SARS-CoV-2. Dr. Van Rompay concluded that these successes underscore the central role of animal model research in rapid and effective pandemic response. He also suggested that, for future pandemic preparedness, NHP models be utilized in proof-of-concept studies to investigate different routes of administration for different kinds of compounds.
Dr. Isis Kanevsky of the Vaccine Research Unit at Pfizer described how public–private partnerships and rapid animal model development helped generate the preclinical data needed to select antigens for vaccine development. In response to the pandemic, Pfizer and BioNTech launched Project Lightspeed, which progressed from obtaining the SARS-CoV-2 genome sequence to obtaining an EUA for an mRNA vaccine against SARS-CoV-2 within 11 months. Pfizer overlapped timelines for research activities such as target discovery, preclinical development, advance manufacturing, and clinical trials, which normally occur sequentially. Through its pre-existing collaboration with BioNTech, which had previously focused on mRNA vaccines for influenza, Pfizer developed four potential vaccine candidates that were considered for clinical trials and that varied in their antigen targets, RNA constructs, and immunization schedules. By rapidly developing appropriate animal models, Pfizer/BioNTech delivered key preclinical data on each vaccine candidate within 6 months. Dr. Kanevsky highlighted several key considerations for selection of immunogenicity models as well as of challenge models. She also emphasized the importance of harmonizing newly developed animal models with models already being used by other researchers to accelerate the field’s ability to identify a correlate of protection. Such harmonization facilitates interpretation of data across studies and thereby discovery of effective therapeutics and vaccines.
Dr. Joyce Cohen of Yerkes NPRC presented on the challenges of managing existing animal colonies and protecting them from unintentional infection during the COVID-19 pandemic. She reported on how Yerkes NPRC managed its NHP colonies by adopting protective measures, such as canceling tours or visits and restricting access to essential personnel, modifying food preparation practices, providing PPE and enforcing PPE policies, and increasing physical barriers within animal housing and laboratory environments. Yerkes NPRC also monitored its NHP colonies for sickness and isolated any animals with detectable clinical signs, conducted NHP contact tracing, and developed NHP testing protocols through the NIH/trans-NPRC Pathogen Detection Working Group (PDWG). Dr. Cohen explained that interrupting NHP studies is particularly challenging because of the long-term and complex nature of these studies and the high value of each NHP, given the limited supplies of replacement animals. Yerkes NPRC decided to postpone initiation of any new research unrelated to SARS-CoV-2, decrease experimental collection timepoints, and halt new experimental NHP surgeries to avoid creating additional work. Each NPRC developed its own strategies for NHP colony maintenance and management, although NPRCs did harmonize their COVID-19 research agendas and protocols through the Coronavirus Vaccine and Therapeutic Evaluation Network (CoVTEN), which was managed by the public–private partnership known as Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV). Dr. Cohen listed several lessons learned by Yerkes NPRC leadership during the pandemic: (1) secure resources such as PPE, animals, and funding to protect colonies from emerging pathogens, (2) develop disaster plans before any disasters occur, and (3) convene staff with critical expertise on working with animals under unusual conditions, such as those imposed by the increased protective measures adopted during the pandemic.
SESSION 5: RESILIENCY IN ANIMAL RESEARCH OPERATIONS—COVID-19 LESSONS LEARNED
Dr. Michael Huerkamp of Emory University’s Division of Animal Resources (DAR) program presented on how his facility has successfully maintained animal research continuity throughout the COVID-19 pandemic. He noted that the dedicated employees at DAR are conditioned to using PPE to manage outbreaks. Moreover, they have ample experience working alone managing short-staffing scenarios, accepting ambiguity, and maintaining adaptable facilities. DAR, as a result of its preexisting emergency preparedness plans, had backup animal food stocks, backup vendor agreements for emergencies, and supply lines for PPE and powered air-purifying respirators in place before the pandemic. Dr. Huerkamp described how he regularly monitored news and public health messaging from January 22, 2020 onward and thus was able to report developments to his team and anticipate some effects, such as the demand for certain PPE to exceed supply. Emory University’s Center for Emergency Preparedness and Response was critical in coordinating response efforts across the university to optimize efficiency and ensure clear and consistent communication.
Commander Temeri Wilder-Kofie of NIH NIAID described the impacts of the COVID-19 pandemic on animal research staff. She emphasized the importance of maintaining staff morale during the intense and stressful conditions of emergency pandemic research. Conflicting messages in the media increased staff fears, and many researchers worried about what might happen to them if they continued to go into work despite a statewide stay-at-home order (e.g., if stopped by police on their way to or from work or stuck at work during a curfew). CDR Wilder-Kofie also described several strategies that NIAID used to boost morale among its staff, including provision of food items and dry goods, display of motivational posters and notes of appreciation, provision of “essential personnel” letters to mitigate fears of consequences for violating stay-at-home orders, and granting emergency leave for COVID-19 testing, quarantine, and contact tracing.
Dr. Jill Ascher, Director of NIH’s Division of Veterinary Resources (DVR), presented on leadership strategies for assessing and mitigating risks in animal research. She suggested that institutions establish a clear chain of command and consider who is at greatest risk of infection based on their position within the animal research enterprise. She also suggested designing protocols (e.g., remote work and physical distancing) to ensure that staff are protected while critical research projects continue uninterrupted. DVR divided its research staff into two teams and established a policy under which only one team would work on site on any given day, to ensure that if SARS-CoV-2 spread within one team, the other team could continue DVR’s care of animals being studied in COVID-19 research. DVR also developed guidance to ensure that laboratory spaces were as safe as possible for research staff and that updates were communicated regularly and consistently across the DVR staff so that everyone remained fully aware of the latest information.
Dr. Lori Palley of the Center for Comparative Medicine (CCM) at Massachusetts General Hospital highlighted the importance of developing disaster preparedness plans, creating robust staff communication channels, and establishing an agile and adaptable workforce. For future pandemic preparedness, she also reflected on what did and did not work while responding to the COVID-19 pandemic. For example, CCM attempted to establish a room reservation system to enhance physical distancing, which was ineffective and received negative staff feedback. Dr. Palley also emphasized the role of continuity planning, suggesting that research support services such as ordering, transferring, and exporting or importing new animals, should be integrated into disaster preparedness plans.
Dr. Lucy Kennedy of the Unit of Laboratory Animal Medicine at the University of Michigan presented on the financial impacts of COVID-19 on academic animal care programs. She described massive financial losses incurred by such programs, noting that unexpected costs of the pandemic were generally incurred, within academia, from the preexisting budgets of the animal care programs themselves. Increased costs for animal care programs at some institutions resulted from universities offering financial perks to employees, such as 1.5 or 2 times pay, compensation time, and free parking and meals. By late spring 2020, universities forecasted large financial losses and formed economic recovery plans that included cutting salaries and benefits for staff and faculty, eliminating merit increases, introducing layoffs and hiring freezes, and halting spending for nonessential activities such as travel.
Dr. Sean Maguire of GlaxoSmithKline (GSK) described the difficulties of ensuring the health and wellbeing of both the people and the animals in GSK’s charge while responding to the pandemic, ensuring business continuity, and meeting all ethical and regulatory requirements as a private enterprise. Most pharmaceutical research facility operations are departmentally funded and charged with meeting drug discovery timelines for many projects in parallel. Moreover, most of these projects and timelines were established before COVID-19 emerged. GSK therefore had to prioritize in vivo work across all of its departments and projects and therapeutic areas. GSK created a decision framework with three basic options for each project: continue, stop, and start. To choose among these options, GSK
developed a two-step decision-making blueprint that asked two questions in sequence: (a) can GSK complete this project? and (b) should GSK complete this project? Dr. Maguire noted that when COVID-19 emerged, GSK’s business continuity plans, although imperfect, provided a useful starting point for refinement and elaboration as the pandemic evolved.
Dr. Stephen Denny of NIH’s Office of Animal Care and Use noted that during a rapidly evolving pandemic, animal research organizations should seek ways to effectively communicate decisions to staff and stakeholders as they are made. These organizations face a variety of communications challenges during pandemics, stemming from issues such as supply chain disruptions, staff shortages, and research program transitions. Dr. Denny recommended several strategies that organizations can deploy to meet and overcome these challenges, including the following: (1) establish a specific time for daily or periodic all-hands meetings, (2) disseminate previously vetted disaster response plans, (3) create a pandemic-specific animal program website, (4) use standard or common terminology across all communications, (5) make clear who is in charge and maintain clear lines of authority within the organization, (6) affirm institutional officials’ responsibilities and establish clear lines of communication between those officials and the animal program, and (7) encourage problem resolution at the lowest levels possible within the organizational hierarchy. Dr. Denny recommended that animal research organizations focus on developing stronger pandemic response communications programs before the next pandemic pathogen emerges. In particular, he highlighted the Incident Command System’s communication strategies as a good model.
SESSION 6: PANEL DISCUSSION—RESILIENCY IN ANIMAL RESEARCH OPERATIONS
Panelists responded to questions from workshop attendees covering various topics, including those listed below:
- techniques for maintaining high staff morale under difficult circumstances
- strategies for communicating rapidly evolving decisions without compromising credibility
- methods for combating misinformation about animal research
- practices for vaccinating NHPs against emerging pathogens to protect animal health, stop the spread of the pathogen, and reduce the risk of newly emerging variants
Responses from the panelists reinforced the value of supporting staff morale through creative means such as “virtual water cooler” forums; providing regular updates to staff on rapidly evolving situations, even if only to say that nothing has changed since the last update; proactively communicating to the public the paramount importance of animal research for addressing emergencies such as a novel pandemic; and vaccinating NHPs when possible without compromising supplies of pathogen-naive NHPs that are needed for animal research itself. Panelists also provided leadership suggestions. For example, they emphasized the importance of honesty in establishing credibility in a context such as a pandemic in which information is constantly in flux and decisions are constantly changing. Panelists also highlighted the value of taking seriously any negative feedback received from research and support staff in order to rapidly identify and fix problems, as well as maintain positive morale and establish leadership credibility.
DISCLAIMER: This Proceedings of a Workshop—in Brief was prepared by Rose Li and Associates, Inc. as a factual summary of what occurred at the workshop. The statements recorded here are those of the individual workshop participants and do not necessarily represent the views of all participants, the committee, the Institute for Laboratory Animal Research, or the National Academies of Sciences, Engineering, and Medicine. Preparation of earlier versions of this meeting summary by the following individuals is gratefully acknowledged: Lucas Smalldon, Dana Carluccio, and Nancy Tuvesson. References to proprietary products or services does not imply adoption or endorsement of any product or service by the National Academies or any participant in the Workshop.
REVIEWERS: To ensure that it meets institutional standards for quality and objectivity, this Proceedings of a Workshop—in Brief was reviewed by Jill Ascher, National Institutes of Health; Bonnie V. Beaver, Texas A&M University; Carol Clarke, U.S. Department of Agriculture; Patricia Turner, Charles River Laboratories.
PLANNING COMMITTEE: Jill Ascher (Chair), National Institutes of Health; Joyce Cohen, Yerkes National Primate Research Center; Michael Huerkamp, Emory University; David M. Kurtz, National Institute of Environmental Health Sciences; Joseph T. Newsome, University of Pittsburgh; Brianna Skinner, U.S. Food and Drug Administration.
ABOUT THE NAS ROUNDTABLE ON SCIENCE AND ANIMAL WELFARE IN LABORATORY ANIMAL USE
This Roundtable was created to promote the responsible use of animals in science, provide a balanced and civil forum to stimulate dialogue and collaboration, and help build trust and transparency among stakeholders. Roundtable members comprise entities with strong interests in the use of laboratory animals in research, testing, and education, including government agencies, leading pharmaceutical and consumer product companies, contract research organizations, animal advocacy groups, professional societies, and prominent academic institutions.
ROUNDTABLE MEMBERS: Bonnie V. Beaver (Chair), Texas A&M University; Joseph T. Newsome (Vice-Chair), University of Pittsburgh; Jill Ascher (Past Chair), National Institutes of Health (NIH); Szczepan Baran, Novartis Institutes for Biomedical Research, Inc.; Carol L. Clarke, U.S. Department of Agriculture, Animal and Plant Health Inspection Service; Joyce Cohen, Emory University School of Medicine; Robert C. Dysko, University of Michigan; James G. Fox, Massachusetts Institute of Technology; Gloria J. Gaito, Pfizer Worldwide Research and Development; Alema Galijatovic-Idrizbegovic, Merck and Co., Inc.; Jim Gnadt, NIH Blueprint for Neuroscience Research; Gail C. Golab, American Veterinary Medical Association (AVMA); Neera V. Gopee, NIH Office of Laboratory Animal Welfare; Debra L. Hickman, Indiana University School of Medicine; LaWanda Holland, Janssen, Pharmaceutical Companies of Johnson & Johnson; Michael Huerkamp, Emory University; Rich Krauzlis, NIH, National Eye Institute; David M. Kurtz, NIH, National Institutes of Environmental Health Sciences; Margaret S. Landi, GlaxoSmithKline; George Lathrop, Veterans Administration; Malcolm Martin, NIH, National Institute of Allergy and Infectious Diseases, Viral Pathogenesis and Vaccine Section; Lori S. Palley, Massachusetts General Hospital; Patricia Preisig, Yale University; Barry Richmond, NIH, National Institute of Mental Health; Brianna L. Skinner, U.S. Food and Drug Administration; Edda (Floh) Thiels, National Science Foundation; Sally Thompson-Iritani, University of Washington; Joseph Thulin, Medical College of Wisconsin; Patricia V. Turner, Charles River Laboratories; and Robert H. Wurtz, National Academy of Sciences and National Academy of Medicine.
SPONSORS: The workshop was sponsored by the Janssen Pharmaceutical Companies of Johnson & Johnson; National Institute of Allergy and Infectious Diseases; NIH Office of Animal Care and Use; U.S. Department of Veterans Affairs Office of Research and Development; U.S. Food and Drug Administration; and USDA Animal and Plant Health Inspection Service, Animal Care.
For additional information regarding the workshop, https://www.nationalacademies.org/event/03-09-2021/rapid-response-by-laboratory-animal-research-institutions-during-the-covid-19-pandemic-lessons-learned.
Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2021. Rapid Response by Laboratory Animal Research Institutions During the COVID-19 Pandemic: Lessons Learned: Proceedings of a Workshop—in Brief. Washington, DC: The National Academies Press. http://doi.org/10.17226/26189.
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