Contribution of NHP Models to Advances in Human Health

NHPs serve as models across many biomedical research areas, including infectious disease; immunology; social, cognitive, and behavioral research; reproduction; regenerative medicine; aging; and neuroscience research. No model, animal or otherwise, can fully mimic the complexities of the human body; all have limitations, but that does not negate their usefulness. There remain research questions that currently cannot be answered outside of the context of a living organism, and in some cases, NHPs may be the most translationally relevant animal model available.

Although NHPs represent a small fraction of animals used in biomedical research, their critical importance is evident in the number of medical advances that have relied on their use as models of human disease and disability. Through an iterative combination of fundamental basic and translational biomedical research, NHPs have contributed to and continue to inform the development of numerous medical products, including vaccines, therapeutics, and other treatment strategies, that have improved and preserved the quality of life in the United States and beyond. While it is not feasible for this report to provide a complete cataloging of human health advances enabled through NHP research, illustrative examples include the development of deep brain stimulation as a treatment for Parkinson’s disease; vaccines for polio, measles, Ebola, and COVID-19; treatments for human immunodeficiency virus (HIV) and sickle cell disease; and monoclonal antibodies that reduce graft rejection in transplant patients. In each of these cases, NHPs played an essential role because

• vital elements of the research could not be conducted in humans for ethical or logistical reasons;
• nonanimal models (in vitro and in silico) could not fully recapitulate the integrative systems biology required in these specific contexts to demonstrate the effectiveness and safety of the preventive or therapeutic approach;
• other animal models lacked necessary anatomical, physiological, and/or biomolecular structures and processes required to model the human disease condition reliably; and
• the predictive validity of the NHP model was high because of its ability to recapitulate key aspects of the human disease.

Based on this assessment, the committee reached the following conclusions:

Conclusion 2-1: Nonhuman primates have contributed to numerous human health advances that have improved and preserved countless lives, demonstrating a track record of unique predictive relevance critical for supporting ongoing fundamental basic and translational research missions of the National Institutes of Health.

Conclusion 2-2: Nonhuman primate research resources continue to be vital to the nation’s ability to respond to public health emergencies, such as the recent COVID-19 pandemic.

Current Use and Availability of NHPs for NIH-Supported Biomedical Research

In examining the state of NHP use in NIH-supported biomedical research, the committee used as a starting point the 2018 report of the NIH Office of Research Infrastructure Programs (ORIP), Nonhuman Primate Evaluation and Analysis. The ORIP report provides a snapshot of NHP research priorities and NHP supply and demand from fiscal years 2013 to 2017. A key finding in that report is that the availability of NHPs at the time was insufficient to meet the projected demand for NIH-sponsored biomedical research. Those challenges related to NHP supply and demand have since been exacerbated by external events—the COVID-19 pandemic, which spurred a significant increase in demand for NHPs to support the development of vaccines and treatments for SARS-CoV-2, and a ban by China on all exports of NHPs.⁴ These challenges have been magnified by persistent inaction on addressing long-recognized NHP supply-and-demand issues. Consequently, this report addresses the need to reevaluate the state of NHP resources and their ability to support current and future priorities for NIH-funded research.

To inform its landscape analysis of current NHP use and availability, the committee collected information from NIH, the Centers for Disease Control and Prevention, the U.S. Department of Agriculture, the seven National Primate Research Centers (NPRCs), seven other institutions that receive NIH support for NHP breeding colonies,⁵ and more than 200 NIH-supported NHP investigators who responded to a committee-generated survey. Based on these data, the committee found that the NHP shortage projected in the 2018 ORIP report has been exceeded, and that its current severity limits not only immediate research capabilities but also the nation’s ability to conduct critical public health research years into the future. This threat is evidenced by the following findings from the committee’s assessment:

• The absolute numbers of NHPs held or used for research purposes have decreased over the past decade.
• A more than 20 percent reduction in cynomolgus macaque imports was reported in 2020 following China’s export ban, highlighting the vulnerability of NHP research caused by undue reliance on imported NHPs subject to geopolitical pressures and logistical constraints that jeopardize reliable access.
• Approximately 64 percent of respondents to the committee’s survey reported challenges with obtaining NHPs for their currently funded NIH awards. For greater than half of all active NIH awards reported by survey respondents, fewer NHPs were enrolled than originally planned.
• In 2021, two-thirds of investigator requests for research-naïve macaques could not be met by the NPRCs because of a shortage of these animals.
• Impacts of NHP shortages have included increased wait times for NHP enrollment in studies and skyrocketing costs of individual NHPs (a 10–200 percent increase depending on the species and source).

While NIH and the NPRCs have taken initial steps to ameliorate the impacts of a limited supply of NHPs on NIH-supported biomedical research, these incomplete efforts represent only stopgap measures, not the sustained commitment of resources to existing NHP research infrastructure that is warranted by the current shortage. NPRCs and other institutions with NIH resource grants are the primary sources of NHPs for NIH-supported researchers. Accounting for inflation, funding in the form of base grants (P51 and P40 awards) for these institutions has generally declined over time, and increased supplemental funding provided by ORIP following its 2018 report and in 2020 through the Coronavirus Aid, Relief, and Economic Security (CARES) Act have not been sufficient to compensate for the decline. As a result of these budgetary shortfalls, these institutions have limited ability to expand breeding programs and infrastructure to meet domestic needs.

Based on this evaluation, the committee reached the following conclusions:

Conclusion 3-1: The shortage of nonhuman primate resources for National Institutes of Health (NIH)–supported biomedical research has continued to worsen, extending beyond concerns raised in the 2018 report of the NIH Office of Research Infrastructure Programs. This resource shortage has been exacerbated by export and transportation restrictions and global public health emergencies.

Conclusion 3-2: Without decisive action and a national commitment to a comprehensive plan for nonhuman primate (NHP) availability, the ability of National Institutes of Health (NIH)–supported extramural program investigators to conduct studies requiring the use of an NHP model will become a function more of access to NHPs than of a concerted response to national public health priorities. The core tenet of NIH that the most meritorious research should receive the highest priority will thereby be threatened.

Conclusion 3-3: Inadequate nonhuman primate (NHP), physical, financial, and human resources, along with the high costs of NHPs, severely limit the ability of National Institutes of Health–supported research programs to respond adequately to public health emergencies, as well as to carry out high-impact biomedical research requiring NHP models.

Conclusion 3-4: Biomedical and public health research in the United States is threatened by dependence on imported nonhuman primates (NHPs). This reliance on external resources is unsustainable and undermines the security of the U.S. biomedical research enterprise. To ensure that NHP resources are available to respond to public health threats, the United States needs to prioritize expansion of domestic NHP breeding programs.

Conclusion 3-5: The National Institutes of Health (NIH) has no central data management or reporting structure across its intramural and extramural programs to provide accurate tracking of the numbers of nonhuman primates (NHPs) required to meet current and future research needs. NIH thus has no way to collect the quantitative data needed to implement a comprehensive strategic management plan for its NHP research and resource portfolio.

Conclusion 3-6: Inadequate coordination of nonhuman primate (NHP) resources and research programs at the national level contributes to missed opportunities and diminished opportunities for efficient use of limited NHP resources.

Conclusion 3-7: Although the 2018 report of the National Institutes of Health Office of Research Infrastructure Programs (ORIP) identified a serious shortage of nonhuman primate (NHP) resources that was likely to worsen in the future, support for the ORIP-funded national NHP resource infrastructure remains inadequate.

Conclusion 3-8: Inadequate support for national nonhuman primate (NHP) resources by the National Institutes of Health (NIH) Office of Research Infrastructure Programs represents a major threat to NIH-supported NHP research programs nationwide. Funding will have to address current and future needs and the infrastructure required to support them.

In Vitro Models

The discovery of human induced pluripotent stem cells (iPSCs) has transformed cell systems and their use by scientists to answer critical human health questions. Under specific differentiation conditions, most human tissue and organ cell types can now be reliably generated from iPSCs. These tractable and renewable cell systems can be used to generate foundational knowledge regarding human gene functions, biochemistry, physiology, and molecular mechanisms. Additionally, iPSCs generated from patients provide unprecedented opportunities for revealing disease-related phenotypes; understanding pathology; identifying disease-specific biomarkers; and screening for potential treatments, including personalized treatment strategies.

Two-dimensional cell cultures are the most simplified cellular model systems. Recent advances in bioengineering have led to the generation of three-dimensional human tissue–specific organoids and microphysiological systems (MPS; commonly referred to as organ or tissue chips) that resemble human tissues/organs in cell-type composition; architecture; and, to a certain extent, function. As such, they represent physiologically relevant in vitro models.

The committee identified numerous ways in which in vitro models are being used to complement NHP research—for example, in the study of pathogen–host interactions—but few concrete examples of a demonstrated role in reducing reliance on NHPs. One of the best examples of reduced reliance is testing to predict cytokine-mediated toxicity associated with biological therapeutics, such as monoclonal antibodies, using in vitro immunoassays. Yet while organoids and MPS have successfully mimicked many aspects of the complex physiology of organs and even interactions among organ systems, they cannot in their current state be used to replicate the full complexity of in vivo systems or to study processes that require systemic regulation. Therefore, these in vitro systems cannot yet be used to answer human health and safety questions that require this level of complexity. Furthermore, certain outcomes, such as behavior, can reliably be studied only using living organisms. Results from studies using in vitro models can, however, be used to inform the design of experiments using NHPs so as to reduce reliance on these animal models. For example, initial drug screening conducted in vitro can identify promising candidates that can then be tested and validated in vivo, ultimately limiting the number of NHPs used to evaluate drug candidates and potentially reducing the likelihood that subsequent testing in NHPs will cause harm.

In Silico Models

Over the years, a wide array of quantitative and computational methods has been used in an attempt to model the properties of biological systems—with greater or lesser degrees of success. Machine learning (ML), a subset of artificial intelligence (AI), has been recognized as having the potential to overcome some of the limitations of other computational modeling tools. AI/ML methods are generally capable of finding patterns in large, complex data sets that can be used to draw inferences about the system being studied. Improvements in both AI/ML methodology and computational speed and power have led to dramatic increases in performance capabilities, enabling improvements in speed and efficiency for in silico drug development and other applications. AI/ML methods have shown their utility in prescreening of large compound libraries to identify high-priority candidates; although these candidates will still need to be tested in a model system such as NHPs, narrowing the field of drug candidates will naturally reduce the use of NHPs in validation experiments. Thus these and other applications of AI/ML have the potential to aid in designing new experimental approaches and in reducing reliance on NHP studies. At the same time, however, all in silico methodsare limited by the available input data, and these methods cannot fully obviate the need for in vitro or in vivo testing.

With adequate high-quality training and validation data and informed knowledge about the limitations of the technology, both AI/ML tools and more well-established computational modeling methods have the potential to learn from past NHP studies and provide additional insights. Through modeling using previously collected data, it may be possible to create virtual NHP control groups that could be used in place of NHPs receiving a placebo. In particular, AI/ML could provide opportunities to develop virtual NHP tissue and organ models to guide drug formulation, design, and dosing regimens and to predict toxicological and efficacy endpoints. In addition to informing NHP studies, these applications could potentially reduce the numbers of animals used in nonclinical studies—an outcome that would both increase the utility of NHP models and make better use of these models at a time when their availability is severely limited.

While such applications are currently aspirational for NHPs, efforts to develop virtual dog tissues are under way, and if successful, could guide similar approaches for NHPs. Implementation of such a strategy will require high-quality training and validation data, investment in education and training, and further methodologic development and validation. One key to the success of AI/ML methods (and indeed any computational methods) would be a commitment to open, reproducible research through a requirement that data, models, and code be shared without restriction in public data archives.

Need for Collaboration

The establishment of collaboration opportunities for investigators developing and using different model systems, including NHP researchers, bioengineers, and computational biologists, could reduce barriers to the adoption of new approach methodologies. Strategies pairing investigators with different ways of approaching the same problems can enhance the complementarity and translatability of the work. Yet the committee found few examples of interaction between research groups developing and using new approach methodologies and NHP researchers. Efforts to facilitate such interactions could enhance awareness among NHP researchers regarding the evolving capabilities of in vitro and in silico systems, and enable improvements in the design of in vitro systems such that they would be better positioned to answer research questions for which NHPs are currently used. Likewise, reciprocal interaction could educate investigators developing new approach methodologies about the needs and priorities of NHP researchers.

Based on its evaluation of the research and development status of new approach methodologies, the committee reached the following conclusions:

Conclusion 4-1: Based on the current state of the science, there are no alternative approaches that can replace nonhuman primate (NHP) models to answer research questions that require complete multiorgan interactions and integrated biology. Thus, NHPs continue to be essential for the conduct of National Institutes of Health–supported biomedical research.

Conclusion 4-2: Select new approach methodologies (in vitro and in silico models) can replicate certain complex cellular interactions and functions. As such, these new approach methodologies may be used to answer specific research questions that contribute to understanding human biology to prevent and treat human disease. Although there currently exist no alternatives that can fully replace nonhuman primates, it is reasonable to be optimistic that this may change in the years ahead as new approach methodologies continue to advance.

Conclusion 4-3: Furthering the adoption of new approach methodologies (including in vitro and in silico model systems and approaches) with the intent of reducing reliance on nonhuman primate models will require planning and support for studies that can demonstrate adequate performance for specific contexts of use or intended purposes. Expectations for qualification or validation of new approach methodologies depend on the decisions to be made using the data derived from their use and the potential human health consequences of those decisions.

Conclusion 4-4: While nonhuman primates have been regarded as preeminent models for the evaluation of human safety and efficacy, recent guidance demonstrates that the Food and Drug Administration and other regulatory agencies are supportive of the use of new technologies and approaches for regulatory decision making once they have been adequately qualified or validated.

Conclusion 4-5: Efforts to reduce reliance on nonhuman primates (NHPs) in biomedical research will require investment in opportunities to facilitate direct interaction and collaborative research among investigators using NHP models and those developing in vitro and in silico approaches to expand the applicability of new approach methodologies to research questions for which NHPs are currently needed. At present, however, few mechanisms for fostering such interaction and collaborative research are available.

Research Domains for Which the Need for NHPs Is Likely to Grow

Neuroscience and infectious disease are domains of NHP research likely to grow in the future, as reflected in the NIH priorities for NHP research. The complexity of the primate brain is not adequately modeled by any in silico or in vitro system or other animal species, and the burden of neurologic disease continues to rise as the population ages. Likewise, certain infectious diseases have a pathogenic mechanism seen only in primate species, and the COVID-19 pandemic and Zika, Ebola, and recent epidemics have highlighted the importance of NHP models for understanding novel diseases and testing the safety and efficacy of vaccines and therapeutics.

Other domains of NIH-supported biomedical research using NHPs are likely to see future growth as well. Immunotherapy using cellular-, protein-, or nucleic acid–based therapeutics has emerged as a vital area of NHP research, and the molecular similarity between humans and NHPs is key to understanding the effectiveness of these novel therapies. Another area ripe for future growth is reproductive biology, some aspects of which are primate specific, and the public health, social, and economic burdens associated with infertility and diseases of the reproductive system will continue to drive needs for research using NHPs in this area. Finally, NHP research in the areas of aging and chronic inflammatory diseases is likely to increase given the enormous public health burden associated with such diseases in the United States and the opportunities arising from long-term care that increasingly is being provided to aging NHP research subjects.

Rhesus macaques are likely to remain the predominant NHP species required to support these areas of research, based on input received by the committee from multiple stakeholders, including NIH, the NPRCs and National Resources, and NIH-funded investigators. Marmosets are increasingly being used in NIH-supported research as well, particularly in the area of neuroscience, and in the development of transgenic NHP models.

Conclusion 5-1: Given the nation’s most pressing public health needs and the evolving state of the science, specific domains of research—including neuroscience and neurodegenerative disorders, preparedness for unanticipated communicable infectious threats, immunotherapy, reproduction, aging, and chronic inflammatory diseases—are likely to require increased use of nonhuman primates in the future. The species distribution of future need for such research is likely to remain weighted toward macaques (particularly rhesus and cynomolgus), with increased use of marmosets.

Meeting Future NHP Resource Needs

Adequate investment in NHP research resources is necessary to support key strategic priorities for the United States, including maintaining global leadership in biomedical science and safeguarding the nation against unexpected public health threats. It is presently unclear how far into the future the United States will be able to continue importing NHPs for research purposes, and continued reliance on external sources of NHPs is therefore unsustainable. A national commitment and commensurate investment are needed to ensure that NHP research infrastructure, including domestic breeding colonies, supports the projected NHP needs of NIH-funded investigators. A critical window of opportunity now exists during which domestic investments in NHP research resources can be made while NHP species such as cynomolgus macaques, marmosets, and African green monkeys remain accessible from other countries and can be imported to establish breeding stocks. The development of purpose-bred, self-sustaining domestic populations of NHPs also offers the benefits of reducing the impact of increasingly limited options for international transport of imported NHPs and providing assurance of the responsible sourcing of animals. Domestic NHP breeding can also provide a greater degree of regulatory control over the health and well-being, as well as the social and genetic backgrounds, of NHPs used in research, which in turn can support improved experimental rigor and the quality of the data generated; help prevent misrepresentation of data related to animal origin, age, or prior use; and reduce the impact on wild populations of NHPs in their countries of origin.

Beyond domestic breeding programs, future NHP research will depend on investment in human resources and physical and data infrastructure. Ensuring a scientific workforce with the skills needed to conduct NHP research will require support for training for early-career investigators and the support staff needed for NHP care. Likewise, experience with shortages of laboratory space during the COVID-19 pandemic demonstrated the importance of adequate facilities for NHP research, including biocontainment spaces. Moreover, the expansion of physical infrastructure supporting NHP breeding programs will provide opportunities to ensure optimal housing and husbandry conditions that align with best practices based on the evolving science of animal welfare. Investment in data infrastructure, within NIH and nationally, will be necessary as well to improve tracking of NHP demand and use so as to better support planning and coordination, both of which are essential to guide effective and appropriate use and management of NHP resources going forward. Importantly, such data infrastructure investments will also be integral to future efforts to reduce reliance on NHPs by enabling accurate measurement of the impact of changes in policy and the implementation of nonanimal models.

Given that NHPs are likely to remain a limited and high-cost resource—even with the necessary further investment in domestic breeding to address current shortages—advances in new approach methodologies offer the additional potential benefits of helping to reduce costs and mitigate future NHP shortages. In anticipation of these advances, attention is needed to the development of a strategy on the use of new approach methodologies in conjunction with NHP models to optimize the application of NHP research in the future.

Conclusion 5-2: The 2018 report of the National Institutes of Health (NIH) Office of Research Infrastructure Programs, Nonhuman Primate Evaluation and Analysis, included recommendations for improving communication and collaboration within the nonhuman primate (NHP) research community, increasing domestic NHP supply capabilities, addressing limitations in NIH funding mechanisms, promoting training in NHP care and research, and enhancing the utility and value of existing NHP resources. These solutions and recommendations have not yet been fully implemented and remain critically important.

Conclusion 5-3: Addressing the challenges posed for the national research infrastructure by a persistent lack of nonhuman primates (NHPs) will require a commitment and comprehensive national effort focused on expanding domestic NHP resources.

Conclusion 5-4: The creation of a national plan for allocation and expansion of nonhuman primate resources is necessary to optimize the use of this critical scientific resource. Such a plan will require adequate monetary, physical, and personnel resources, as well as a centralized tracking system to match need to investment in a data-driven fashion.

Conclusion 5-5: Continued development and validation of new approach methodologies (in vitro and in silico model systems) is critically important to support further advances in biomedical research. This may reduce the need for nonhuman primate (NHP) models in the future, and/or enhance their utility. Additionally, this may help to mitigate shortages in NHP supply and the high cost of NHP research.

Enhancing NIH-Supported NHP Research Going Forward

Given the need for continued use of NHPs in NIH-supported biomedical research, it is incumbent on those supporting and conducting such research to ensure that these animal models are used as effectively as possible. NHP resources demand strong stewardship and research conducted in a way that maximizes the knowledge and actionable insights obtained from each individual animal in every study. Technologies and approaches including noninvasive monitoring and imaging approaches (e.g., digital biomarkers such as in home enclosure neural recordings, magnetic resonance imaging), AI/ML, and minimally invasive research procedures (e.g., laparoscopy, positive reinforcement training for voluntary provision of samples) can be applied to increase the impact and rigor of NHP research and improve alignment with processes implemented in the clinical setting. Additional opportunities to enhance NIH-supported NHP research include implementing thoughtful approaches for sample collection and sharing, fostering openness and data sharing, expanding and implementing data-driven NHP care and management practices (e.g., social housing), further characterizing NHP models, and learning from natural variation and disease in NHPs, as well as incentivizing collaboration among NHP and non-NHP research groups.

Conclusion 5-6: Given the limited numbers of nonhuman primates (NHPs) available for research, it is incumbent upon investigators and the National Institutes of Health (NIH) to make the best use of each animal through cooperative efforts, data sharing, purposeful planning, and use of data-driven care and management methods for the long-term care and use of NHPs in research. Examples of successful cooperative efforts from the community of NIH-funded NHP researchers—including collaborative working groups; data-sharing resources for clinical and clinical pathology data, gene expression profiling, and genotype data; and biospecimen repositories—can serve as models for broader adoption.

Conclusion 5-7: A system for consistent reporting is needed to adequately capture the life, scientific, and medical history, including experimental treatments and procedures, of individual nonhuman primates (NHPs). The need for complete NHP life histories further supports the development of increased domestic breeding capacity in the United States to maximize the accurate and complete sharing of clinical and experimental data. Currently, the incentives, mandates, and infrastructure within the National Institutes of Health research enterprise are insufficient to support uniform data management and reporting across all NHP research programs.

Conclusion 5-8: Recent advances in genomics, bioinformatics, imaging, digital biomarkers (e.g., noninvasive home enclosure neural and behavioral recordings), extended reality, and artificial intelligence/machine learning have revealed opportunities to understand normal biology and the mechanisms of disease. Such technologies and approaches have the potential to augment the scientific knowledge that can be gained from individual nonhuman primate (NHP) studies and, in some cases, enable less invasive use of NHPs. Leveraging these opportunities for NHP research will require tracking the genotype, phenotype, and history of each animal used, as well as transdisciplinary interactions.

Conclusion 5-9: Additional investments will be needed to implement, maintain, train, and use current and emerging technologies (such as digital biomarkers, artificial intelligence/machine learning, imaging, extended reality, and laparoscopy), as well as data-driven husbandry practices, with the potential to enhance nonhuman primate research funded by the National Institutes of Health.