NHP USE ACROSS THE RESEARCH CONTINUUM

Biomedical research, like scientific research generally, is cumulative and iterative in nature. Individual biomedical research studies almost always seek knowledge relating to a narrow aspect of a disease or disability—knowledge that together with the results of other studies will eventually identify or establish the effectiveness of an approach to the prevention, treatment, or cure of a disease. Thus, the advancement of human health through biomedical research is a multiphase process that extends from the laboratory bench to the patient’s bedside. Rather than being distinct, the phases in this process are best understood as a continuum from basic to clinical research, with those two ends being bridged by and overlapping with translational research. Basic research serves to elucidate fundamental biological processes (NRC, 2005); basic research that is not translational in nature is referred to in this report as fundamental basic research. Translational research itself represents a spectrum of research stages (NCATS, 2021), each of which is characterized by questions with direct application to improving human health (e.g., through the prevention or treatment of human disease) (NCI, 2007; UVA, 2023) and includes research involving safety and efficacy testing for regulatory purposes. Importantly, translational research often builds on the findings of fundamental basic research that may or may not have originally been framed in translational terms, as discussed later in this chapter. Not surprisingly, the overlapping and nonlinear nature of research phases has fostered the adoption of somewhat fluid definitions (Kemp, 2018), which adds complexity to the evaluation of NHP use within the research ecosystem. NIH support for biomedical research encompasses both fundamental basic and translational research, reflecting the dual nature of the agency’s mission to “seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability” (NIH, 2015). For the purposes of this report, the committee views NHP use in the context of these two research phases.

When determining the appropriate model for a given scientific question, investigators must consider many factors, including ethical and scientific perspectives. This process includes assessing model validity, which encompasses the strengths and limitations of a model in relation to the scientific question of interest and balanced against the public health issue of concern (see Chapter 1 for discussion of translational relevance and predictive validity in NHP models) (Denayer et al., 2014). As noted previously, all models used across the biomedical research continuum have inherent limitations that impact their value as a translationally relevant research tool. Importantly, no one model—in vivo, in vitro, or in silico—can fully mimic the complexities of the human body or be generalized to the heterogeneity of target patient populations. This limitation is not unique to translational research; scientists face similar challenges in human clinical trials, knowing that trial results may not be reflective of treatment benefit and risk in all patient populations that will be treated in “real world” practice settings.

There remain fundamental basic and translational research questions that cannot be answered outside of the context of a living organism or cannot be studied directly in a human. In some of these cases, NHPs—given their genetic, physiologic, and behavioral similarities to humans (Estes et al., 2018; Phillips et al., 2014)—may be the most translationally relevant animal model available. Yet even when an NHP is the best available model, failures to predict human response can occur. For example, known challenges associated with the use of certain species-specific NHP models for research on biologics include seasonality of reproduction; lack of extensive genomic characterization; high sensitivity; and interanimal variability (e.g., differences in immune system functions and gene sequences across animals sourced from different areas), resulting in phenotypic differences (Cauvin et al., 2015). Importantly, however, failures in research using NHPs can provide opportunities to develop new understanding of model limitations and in some cases, help elucidate new pathways toward discoveries and advances.

EXAMPLES OF NHP USE ACROSS THE RESEARCH LANDSCAPE

The following sections and accompanying case studies are intended to convey the diversity of ways in which NHP models have been used across various phases and domains of the research landscape. The selected case studies—which are not exhaustive and include cases in which no alternative model was available at the time, or NHPs were used in combination with other animal models and approaches—illustrate the role of NHP models in understanding human physiology and mechanisms of disease, as well as in accelerating the development of therapies for prevention and treatment of disease that have improved or saved the lives of millions of patients. The discussion in this section focuses primarily on health advances emerging from the translational research space (e.g., therapeutics and interventions), thereby addressing the committee’s task to assess the contributions of NHP models to human health. It is important, however, to acknowledge the vital role of fundamental discoveries that serve as the foundation for this research. Also highlighted in the examples in this section are changes in NHP use over time, with specific attention to how scientific advances have led to reduced need for and reliance on NHP models in some cases, a topic reviewed further in Chapter 4. It should be noted that the discussion here addresses advances related to NHP use broadly; it does not constitute a systematic review of current NHP use and its associated successes and failures in the context of NIH-funded research, as such a review was not feasible given the limited data available to the committee (see Chapter 1).

Contributions of NHP Models to Research in Neurobiology and Neurodegenerative Disease

Neurological and neuropsychiatric disorders have major social and economic impacts on society. The global burden of neurological disease is staggering, and its prevalence continues to rise as the population ages (Riggs, 1998). Major neurological disorders, including stroke, dementia, and Parkinson’s disease, are among the leading causes of death and disability worldwide, with stroke being the second leading cause of death globally (Feigin et al., 2020; GBD 2016 Neurology Collaborators, 2019; WHO, 2020a, 2020b). Additionally, neuropsychiatric illnesses—especially depression and anxiety—are increasing, and substance use disorders—such as alcoholism and opioid dependence—are major contributors to the health burden of communities (GBD 2016 Alcohol and Drug Use Collaborators, 2018; GBD 2019 Diseases and Injuries Collaborators, 2020).

Researchers have increasingly turned to NHP models to better understand the functioning of the human brain and develop effective treatments for disease involving the neurologic system. In many instances, selection of an NHP model for this purpose is due to the similarities between NHPs and humans with respect to neuroanatomical and neurophysiological and behavioral characteristics, compared with major differences between the brains of primates and rodents.

The similarities between NHP and human brains are essential for understanding movement control, vision, cognition, and affect. The primate brain is not simply a larger version of the rodent brain, as exemplified by the multiple brain regions that are present in primates but not in rodents (Hutchinson and Everling, 2012). Further, primates share a number of important neural pathways from the periphery to the brain that are either less complex or absent in rodents. For example, 25–30 percent of corticospinal systems in primates originate from areas that are completely absent in the rodent corticospinal system (Strick et al., 2021). An example is the supplementary motor area, which is involved in preparation for voluntary movement and generation of complex movement sequences and is implicated in Parkinson’s disease (Cañas et al., 2018; Rahimpour et al., 2022). Additionally, multiple areas in the brain’s frontal lobe that control movement, vision, cognition, and affect are present in primates but absent, less complex, or radically underdeveloped in rodents (Hutchinson and Everling, 2012; Laubach et al., 2018; Molnár and Clowry, 2012; Preuss and Wise, 2022). The “failure to translate” treatments developed in rodent models is, in multiple instances, due to these types of brain differences (Azkona and Sanchez-Pernaute, 2022; Buffalo et al., 2019; Scott and Bourne, 2022). For these reasons, NHPs are critical for discovering how to prevent, treat, and cure disorders of the human nervous system.

Many examples of discoveries from fundamental basic research demonstrate the value of NHP models for developing new treatments for human neural dysfunction. For example, understanding of brain anatomy and function through NHP studies has informed treatment strategies for lazy eye in children to reduce the risk of long-term vision problems (Foundation for Biomedical Research, 2022), and has enabled the development of brain–machine interface technology that allows people living with paralysis due to brain injury to operate robotic prosthetics (Feng et al., 2020; Lebedev and Nicolelis, 2017; Yonkovich, 2022). Recent research building upon prior, extensive work using NHP models has demonstrated how neurostimulation can restore arm movement capabilities to patients following a stroke (Barra et al., 2022; Powell et al., 2023). Similarly, advances originating from fundamental basic research using NHPs have led to the use of DBS as a treatment for Parkinson’s disease (see Box 2-1), and more recent research suggests that this intervention holds promise for the treatment of amyotrophic lateral sclerosis, spinal cord injury, peripheral neuropathy, stroke, resistant depression, Alzheimer’s disease, and obsessive-compulsive disorder (Blomstedt et al., 2013; Elias et al., 2018; Ni and Chen, 2015; Schlaepfer et al., 2013). NHP studies also have enabled clinical trials for optogenetic therapy to restore vision for individuals living with degenerative eye diseases, such as retinitis pigmentosa (Mustari, 2017; Picaud et al., 2019).

BOX 2-1

CASE STUDY: HOW FUNDAMENTAL BASIC RESEARCH CONDUCTED TO UNDERSTAND NEURAL CIRCUITRY LED TO SUCCESSFUL TREATMENT FOR PARKINSON’S DISEASE.

NHP models, specifically aging rhesus macaques, are used to investigate Alzheimer’s-like pathology, as well as other forms of age-related cognitive decline (Gray and Barnes, 2019; Messaoudi and Ingram, 2012), although there has been little success in the development of effective treatments for dementia and cognitive decline despite research employing a variety of models, including NHPs (Feng et al., 2020). These failures may be attributable in part to the lack of a clear underlying mechanism (Guo et al., 2020), illustrating the interplay between fundamental and translational research that is typical in the development of novel therapeutics.

Similarities in behavior between humans and NHPs also make NHPs good models for the study of neurodevelopmental conditions (including autism) (Aida and Feng, 2020), addiction, and anxiety and depression (Buffalo et al., 2019; Ding and Ko, 2021; Rudebeck et al., 2019; Scott and Bourne, 2022; Willard and Shively, 2012). NHPs have several advantages over other models that have made them instrumental in addiction research, especially their longer life span and ability to carry out drug self-administration procedures that more closely replicate the human experience (Banks et al., 2017; Czoty and Nader, 2015; Huskinson et al., 2016; Maguire et al., 2013; Phillips et al., 2014; Wade-Galuska et al., 2011). Moreover, phylogenetic similarities in the brains of NHPs and humans allow for the coordination of behavioral procedures with noninvasive brain imaging techniques (Banks et al., 2017; Bradberry, 2011; Gould et al., 2012; Howell and Murnane, 2008), and phenotypic similarities have provided the ability to study how environmental and lifestyle factors, such as stress and social behavior, influence the effects of drug abuse (Banks et al., 2017; Ewing Corcoran and Howell, 2010; Morgan et al., 2002; Nader et al., 2012).

The creation of novel NHP disease models via genome editing technology has advanced rapidly in the last decade and has been of particular interest in the neuroscience community (Feng et al., 2020; NASEM, 2019; Park and Silva, 2019; Sato and Sasaki, 2018). The simultaneous evolution of understanding of the genetic and epigenetic changes associated with human nervous system disorders (through such investments as the NIH-funded BRAIN [Brain Research Through Advancing Innovative Neurotechnologies] Initiative¹ and the ability to recreate such changes in NHPs through genome editing are generating new opportunities for higher-fidelity modeling of neurodevelopmental conditions, such as autism (Zhao et al., 2018; Zhou et al., 2019), and neurodegenerative disorders, such as Alzheimer’s and Huntington’s disease (Aron Badin, 2018; Rizzo et al., 2021).

Contributions of NHP Models to Research in Reproductive Health and Fertility Disorders

Infertility affects approximately 10 percent of people of reproductive age in the United States, and is usually diagnosed when they fail to conceive (Stouffer and Woodruff, 2017). The inability to have children has significant societal, emotional, and financial implications. Scientific understanding of infertility is limited in part because of ethical restrictions on research. In this context, research involving use of tissues from early pregnancy, including early embryo implantation, and use of fetal tissues and embryonic stem cells, is either restricted or impermissible (Lo and Parham, 2009; Stouffer and Woodruff, 2017).² Given the close phylogenetic relationship between NHPs and humans and similarities in their hormonal, neural, and local control of reproduction, as well as maternal, fetal, and placental interactions during pregnancy, NHPs offer significant advantages as models for research related to reproductive disorders that impact predominantly women.

Old-world primates, primarily rhesus macaques, cynomolgus macaques, and baboons, have been used extensively in reproductive health research. Each of these species has specific advantages and limitations that make it well suited to research addressing different scientific questions (Cauvin et al., 2015). Importantly, all three species have menstrual cycle lengths, ovulation periods, and implantation processes similar to those seen in humans (Carson et al., 2000; Carter et al., 2015; Cauvin et al., 2015; Shimizu, 2008; Siriwardena and Boroviak, 2022; Stouffer and Woodruff, 2017). Baboons in particular offer unique advantages for the study of reproductive biology, some of which include the ability to determine the phase of the menstrual cycle though noninvasive perineal skin monitoring (Bauer, 2015; D’Hooghe, 1997) and access to the uterus transcervically (Stouffer and Woodruff, 2017), which permits endometrial biopsies, embryo transfer, preimplantation embryo flushing, and hysteroscopy (D’Hooghe et al., 2008).

Research using NHPs has yielded significant insights into conditions that can impact fertility and pregnancy, such as polycystic ovarian disease, endometriosis (see Box 2-2), placental dysfunction, preterm labor, and abnormal fetal development (Stouffer and Woodruff, 2017). Spermatogenesis in all species of NHPs is also highly comparable to that in humans, which makes NHP models suitable for studying the male reproductive system (Luetjens et al., 2005). Additionally, NHPs can provide insight into the consequences of mitochondrial DNA transfer, genome editing, and other novel technologies before they are used in humans (Stouffer and Woodruff, 2017). At the same time, however, NHP models have both general and species-specific limitations for reproductive research. Generally, many NHPs have inaccessible early implantation sites (Su and Fazleabas, 2015) and a relatively long gestation period (Silk et al., 1993), and they typically bear a single offspring (Chapman et al., 1990), limiting their use as models for fertility testing. Common marmosets may be an exception, as this species has a higher rate of conception compared with other NHP species (Nubbemeyer et al., 1997), but their translational relevance for reproductive health research is not fully established. Likewise, the use of rhesus macaques in certain aspects of reproductive and developmental research is limited by seasonal variations in reproduction (i.e., fertility limited to 4–5 months per year) (Cauvin et al., 2015).

BOX 2-2

CASE STUDY: NHP MODELS UNIQUELY SUITED TO THE DEVELOPMENT OF TREATMENTS TO IMPROVE WOMEN’S REPRODUCTIVE HEALTH BY SLOWING THE PROGRESSION OF ENDOMETRIOSIS.

Contributions of NHP Models to Research in Immunobiology and Host–Pathogen Interaction

The immune system is a large network of cells, organs, antibodies, and chemical messengers that protect the body from such diverse pathogens as bacteria, viruses, parasites, and fungi that cause infection, as well as from cancer cells and foreign material. The immune system can be broadly divided into two categories—innate and adaptive—with the main distinguishing characteristic being how a pathogen is recognized (Vivier and Malissen, 2005). Unlike the innate immune system, whose response does not depend on recognition of specific pathogens, adaptive immunity relies on the development of immune memory that is expressed in the function and frequency of cells that respond to the same or a similar pathogen (Vivier and Malissen, 2005). Immune dysfunction can cause autoimmune disease or cancer or trigger inflammatory disease, and immune cross-regulation with other systems in the body influences many other disease outcomes (e.g., cardiac, metabolic, pulmonary, and neurodegenerative diseases).

Studies of the human immune system are performed primarily using peripheral blood rather than samples from lymph nodes or spleen that drive the immune response (Farber et al., 2014; Park and Kupper, 2015) because of the difficulty and sometimes impossibility of accessing and collecting sufficient tissue to fully characterize the human immune response. As a result, many key advances in immunology have relied on rodent models, whose tissues can be better characterized than those of humans during the development of the immune system and its response to stimuli under controlled conditions. However, the translation of immunologic principles from rodent models to humans has been notoriously difficult (Meyer er al., 2012). Despite considerable similarities between the rodent and human immune systems, there are significant physiological and genetic differences, such as animal size, lifespan, and aging, all of which affect immune function (Mestas and Hughes, 2004; Meyer et al., 2012; Tarantal et al., 2022) and thus are important variables to consider when selecting an appropriate model at each stage of research (Godec et al., 2016; Mestas and Hughes, 2004; Payne and Crooks, 2007; Rivera and Tessarollo, 2008; Seok et al., 2013; Takao and Miyakawa, 2015; von Herrath and Nepom, 2005). Beyond differences in genetics, lifespan, and species–pathogen relationships, environmental factors profoundly influence the immune profile and function in mammals. For example, very “clean” laboratory mice raised under specific pathogen-free conditions do not share the robust, pathogen-educated immune system that is present in NHPs and humans (Masopust et al., 2017). This difference can result in a less stringent immune response, which may result in an over- or underestimation of the therapeutic effects of interventions modeled in mice.

In contrast, the similarities between the innate and adaptive immune systems of NHPs and humans make NHP models advantageous for unraveling the fundamental aspects of immunology, including immune dominance, T cell memory, immune tolerance, and the aging immune system. NHP models have therefore been essential in bridging the gaps in understanding of how findings in mice might generalize in an immune system with human-like complexity (Hérodin et al., 2005; Messaoudi et al., 2011).

As with all models, understanding the limitations of NHP models is important to guide appropriate model selection and use. For example, many important pathogens have species-specific idiosyncrasies. Viruses, for instance, are exquisitely tailored to their host species. Consequently, viruses that replicate in humans may not replicate in nonprimates or even some NHP species, and when they do, they may not cause human-like disease. Since NHPs are the animals genetically closest to humans, disease progression and host–pathogen responses to viral infections in NHPs are often the most similar to those of humans. Even among NHP species, however, there can be heterogenous responses to infection that must be considered to apply the model appropriately. Understanding the factors influencing host specificity can influence intervention strategies, a notable example being HIV. The discovery of factors that protected NHP species that were natural hosts for the simian immunodeficiency virus (SIV) from disease informed successful antiretroviral treatments for HIV (see Box 2-3).

BOX 2-3

CASE STUDY: GROUNDBREAKING ADVANCES IN HIV TREATMENT AND THE ONGOING PURSUIT OF AN EFFECTIVE VACCINE.

The utility of NHP models for understanding infectious disease extends beyond viral pathogens to such bacterial and parasitic infections as tuberculosis (Foreman et al., 2017) and malaria, both of which are leading threats to public health (Bourzac, 2014). With an estimated 247 million cases of malaria globally and more than 600,000 deaths from the disease in 2021 (WHO, 2022b), there remains an urgent need to understand the pathogenesis of this parasite. NHPs have a rich history of advancing malaria research to deepen understanding of the overwhelmingly complex host–parasite interactions and chronic infections, relapses, anemia, and immune memory associated with this disease (Galinski, 2022). Systems-based longitudinal studies can be performed in NHPs over the entire course of the disease (i.e., pre- to postinfection scenarios) and in reinfection or coinfection. New techniques using NHP models can be used to characterize immune cell types, niches, and memory recall responses in each of the malaria infection stages. Further progress has been achieved through the integration of multiomic data to address gaps in understanding of the multitude of host–parasite interactions and biological pathways seen with these parasites (Galinski, 2022).

Contributions of NHP Models to Vaccine Development

Vaccines are among the most successful public health interventions in history. NHPs have been used for almost a century in developing vaccines for diseases posing a major public health threat, from polio and measles in the 1950s to COVID-19 today. This section describes the historical and current uses of NHPs for vaccine development, beginning with polio—a historical case in which no alternative model was available at the height of the disease—to the more recent use of NHPs to develop groundbreaking mRNA vaccine technology, which was used in developing multiple vaccines in response to the COVID-19 pandemic. Acknowledging that it is primarily the pharmaceutical industry that is responsible for bringing vaccines to market, it is important to note that research enabling vaccine approval relies and builds on earlier NIH-funded basic and translational research.

Poliomyelitis (commonly referred to as polio) is an ancient disease caused by a highly infectious virus that attacks the nervous system and spreads easily through communities. Before the polio vaccine was developed, the virus infected millions of people, primarily children, around the world (WHO, 2022a). In the early 1950s, it resulted in more than 16,000 paralytic polio cases annually in the United States, and many others worldwide (CDC, 1999). Among those who develop paralysis, 5–10 percent die as a result of the immobilization of their breathing muscles (WHO, 2022c). Today there is still no cure, but the disease has been controlled by an effective preventive vaccine, whose creation relied on decades of research using NHPs (see Box 2-4). As a result of widespread vaccination campaigns, polio has been nearly eradicated.

BOX 2-4

CASE STUDY: THE CRITICAL ROLE OF NHPs IN THE WAR AGAINST POLIO.

Around the same time that the polio vaccine was being developed, NHPs were also being used to study measles. Measles virus is one of the most contagious human pathogens, spread by airborne transmission and responsible for frequent outbreaks with high morbidity and mortality (Morens, 2015; Morens and Taubenberger, 2015; Rota et al., 2016). NHPs were the model of choice for studying measles, as small-animal models are generally not susceptible to infection or do not develop the complex disease pathology seen in primates (de Swart, 2017). Measles virus serially cultured in vitro was studied in NHPs, thus forming the basis for successful live-attenuated measles virus vaccines in the 1960s (de Swart, 2017). While cases continue to occur in unvaccinated individuals, the long incubation period of the measles virus makes it difficult to study early disease pathogenesis. Basic aspects of virus tropism and replication can be studied in cell lines, primary cells, organoids, or tissue culture. However, experimental infection of NHPs with labeled measles virus has made it possible to determine accurately how the virus enters the body, causes disease to develop, and disseminates, as well as the resulting changes in the immune system, which involve many organs and cell types (de Swart, 2009). The findings from research using NHP models have been used to optimize the existing measles vaccine, offer promising new modes of vaccine delivery, and provide a platform on which other vaccines can be developed (de Swart, 2017).

Recent decades have seen waves of severe viral infectious disease epidemics and pandemics, including influenza, severe acute respiratory syndrome, Middle East respiratory syndrome, Ebola and Zika virus disease, and COVID-19, each of which has had devastating impacts on lives and livelihoods around the globe (Baker et al., 2022). Changes in the transmission, infectivity, and pathogenicity of infectious agents continue to generate high demand for ongoing research and the discovery of new therapies. In many cases, there are no validated correlates of protection against these pathogens, necessitating challenge studies for assessment of the efficacy of new vaccines (Klasse and Moore, 2022; Meyer et al., 2021; Triplett et al., 2022). Ethical and safety concerns prohibit human challenge studies with virulent pathogens that are incompletely understood and have no cure or limited treatment options, as in the case of Ebola virus. In such cases, NHP models play an essential role in the conduct of challenge studies.

Vaccine development for pathogens that cannot undergo human challenge studies can be performed in animals under the Food and Drug Administration’s (FDA’s) Animal Rule regulatory pathway. The Animal Rule states that when human efficacy studies are not ethical and field trials are not feasible for drugs being developed to ameliorate or prevent serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic substances, the FDA may grant marketing approval for such drugs based on adequate and well-controlled animal efficacy studies if the results of those studies establish that a drug is reasonably likely to produce clinical benefit in humans (FDA, 2022).

A major breakthrough has been the success of a vaccine for Ebola virus in humans, whose protection was predicted using NHP models (Geisbert, 2017). Ebola causes acute hemorrhagic fever that is fatal in up to 90 percent of cases. While rodent models have been used to develop and test Ebola vaccines, candidates found to be efficacious in these models were not found to be protective when subsequently tested in NHPs. These failures may be due to differences across the animal models (Geisbert et al., 2002), and suggests that protection may require targeting of different mechanisms (Davis et al., 1997; Geisbert et al., 2002; Jaax et al., 1996). NHPs are susceptible to infection and disease caused by the wild-type Ebola virus, with disease pathogenesis—including clinical presentation, chemistry, and hematology values, and ultimately mortality—closely aligning with that in humans (Geisbert et al., 2002; St Claire et al., 2017). Consequently, NHP models are valuable for evaluation of Ebola vaccine candidates and drug therapies, as they are considered to have high predictive value (Roozendaal et al., 2020).

To support regulatory submissions and the subsequent licensure of Ebola vaccines, a meta-analysis of NHP control data from multiple Ebola challenge studies was conducted by government sponsors of the studies. This meta-analysis and the supporting dataset were submitted to the FDA as a master file in lieu of the natural history studies from each testing facility (Taylor et al., 2022). This example of a successful strategy for vaccine development has both important scientific and animal welfare implications. First, the data from the meta-analysis can be leveraged to demonstrate the consistency of results obtained by using a standardized animal model for vaccine development instead of conducting separate natural history studies at multiple testing facilities, which allows for more timely vaccine development during a public health emergency. Second, this achievement serves as an important example of reducing the use of NHPs, a strategy that could be applied to other pathogens and that demonstrates the value of partnerships among different groups using NHP models.

The most recent example of the importance of NHPs for vaccine development is COVID-19 (see Box 2-5). Each lead COVID-19 vaccine candidate that progressed to approval for use in humans in the United States was evaluated in NHPs simultaneously with corresponding clinical trials (Jackson et al., 2020; Keech et al., 2020; Sadoff et al., 2021; Walsh et al., 2020). These nonclinical studies using NHPs were used to demonstrate the safety and efficacy of the vaccines (Corbett et al., 2020; Mercado et al., 2020; Tian et al., 2021; Vogel et al., 2021), supporting the FDA’s decision to approve Emergency Use Authorization requests.

BOX 2-5

CASE STUDY: ACCELERATING VACCINE DEVELOPMENT DURING THE GLOBAL COVID-19 PANDEMIC.

Contributions of NHP Models to the Development of Therapeutics

The treatment of human disease has historically been dominated by small-molecule drugs. In the last 30 years, however, biologics have become important new therapies. Instead of chemical synthesis, biologic processes are used to create or derive a wide variety of medicinal products, such as blood or blood components, cells, or tissues; gene therapies; and recombinant therapeutic proteins. NHPs have played a pivotal role in the development of biologics used to treat cancer, autoimmune diseases, and heart disease, as well as to protect against infectious disease and prevent organ rejection after transplant (Geisbert et al., 2002; Lu et al., 2020).³ The importance of NHPs in the development of biologics stems in part from the fact that many such therapeutics are designed to engage their human targets with high specificity and may be effective only in other primates. A classic example is the protease-activated receptors (PARs) that mediate platelet activation in response to thrombin (Hamilton and Trejo, 2017). In mice, PAR-3 and PAR-4, but not PAR-1, reside on platelets. In contrast, primate platelets possess only PAR-1 and PAR-4. As a result, antithrombotic drugs initially developed in mice missed their intended target in humans, highlighting the need for studies in NHPs to validate antithrombotic therapies (Hamilton and Trejo, 2017).

Therapeutic antibodies lead the biologics category of drug development. Remarkably, in just 25 years, monoclonal antibodies (mAbs) have become the dominant treatment for a range of diseases (Grilo and Mantalaris, 2019; Lu et al., 2020). Behind their development is more than 50 years of foundational research combining what was learned from cells in culture, rodents, and NHPs. mAbs are engineered in the laboratory to mimic antibodies, or protective proteins, that the body produces naturally as part of an immune response. In silico and in vitro studies, as well as data from knockout/knockin rodents, can be used to predict adverse events with mAbs. These models can limit the use of NHPs in routine safety and efficacy studies for standard immunoglobulin G–based mAbs. However, the use of rodent models does not easily extend to development that involves novel targets, mechanisms of action, or mAb scaffold and structures, which is where much of the pharmacology is unknown and unpredictable (Brennan et al., 2018). NHP and human antibodies are so similar that they often cross-react (Bjornson-Hooper et al., 2022), so the exact human drugs and assays under evaluation can be used directly with NHPs. NHPs are often the only relevant model for mAb testing because of the high species specificity of most immune receptors targeted by mAbs (Chapman et al., 2009). Therefore, this application of NHP modeling also demonstrates the need for careful understanding of species-related differences if the data derived from the modeling are to be properly interpreted.

NHPs have meaningfully informed mAb development and have predicted the efficacy, safety, and limitations of numerous new therapeutic strategies. Such NHP research has resulted in cancer-targeted mAbs—including Herceptin to treat HER2-positive breast cancer (Lewis Phillips et al., 2022) and rituximab for non-Hodgkin’s lymphoma (Maloney et al., 1994; Pierpont et al., 2018)—that have fundamentally improved cancer therapy to dramatically improve quality of life and survival in circumstances previously considered untreatable or terminal (Zahavi and Weiner, 2020). Anti-inflammatory mAbs have revolutionized treatment for immune-mediated diseases such as rheumatoid arthritis, multiple sclerosis, Crohn’s disease, ulcerative colitis, and other inflammatory disorders (Lisa et al., 2017; Tanaka et al., 2014; Voge and Alvarez, 2019), and more recently have proven to be some of the most effective COVID-19 treatments (Marovich et al., 2020; Taylor et al., 2021).

Blood products have become such a mainstay of clinical medicine that someone in the United States needs blood or platelets every 2 seconds (American Red Cross, 2023). These products are used to treat patients with life-threatening inherited disorders such as hemophilia or immune deficiency and acquired conditions such as cancer or trauma, to support complex surgical procedures, and to address maternal health. In 1940, the Rh blood group system was identified—named after the rhesus monkey blood cells used in making the discovery—and was recognized as the cause of dangerous transfusion reactions to blood products and incompatibility between mother and fetus, a condition that can cause fertility issues, fetal death, and hemolytic disease of the newborn (HDN) (Treichel, 1987). By examining NHP species such as rhesus macaques, which are one of four NHP species that do not develop HDN, researchers discovered that newborn red cells survive because of differences in the level and binding ability of maternal antibodies (Treichel, 1987). Based on this observation, anti-Rh immunoglobulin (rhoGAM) was developed. It is used to stop the generation of antibodies that attack Rh-positive cells (Kedrion Biopharma, 2023), which mirrors the natural protective mechanism in NHP species that do not develop HDN. As a result, this disease, which once killed 10,000 newborns a year and caused brain damage, has now been nearly eradicated (Neighbor, 2018).

Considering the value of NHPs in transfusion medicine, it is no surprise that they also have a place of prime importance in cell and tissue transplantation (Fitch et al., 2019; Kirk, 1999, 2003). More than 40,000 organ and tissue transplants (grafts) are performed each year in the United States as treatment for most end-stage organ diseases (OPTN, 2022). Graft and patient outcomes have steadily improved over the decades because of improved understanding of donor and recipient factors that affect transplant outcomes and the ability to manipulate the immune system more effectively. The major determinant of acceptance or rejection is the magnitude of the response to the graft by the host’s immune system. Chronic immunosuppression strategies are used in patients to prevent graft rejection, and the development of increasingly potent immunosuppressive agents has been a major factor in longer graft survival. Safety and efficacy evaluations of certain immunosuppressive agents, such as humanized mAbs, can be performed only in NHP models in which antibodies cross-react between primates (see Box 2-6).

BOX 2-6

CASE STUDY: THE DEVELOPMENT OF BREAKTHROUGH BIOLOGICS FOR ORGAN TRANSPLANTATION.

Likewise, NHP studies can combine existing drugs used in clinical transplantation in novel ways alongside cutting-edge reagents and strategies to show proof of concept before clinical trials are initiated in human patients (Anderson and Kirk, 2013; McDaid et al., 2015). In transplant recipients, lifelong immunosuppression comes with an increased likelihood of cancer, infection, and premature death (Claeys and Vermeire, 2019), so the goal in transplantation research continues to be minimizing or eliminating immunosuppression. Strategies to this end involve inducing immune tolerance by conditioning the immune system to be unresponsive to specific antigens (Alpdogan and van den Brink, 2012). In transplantation, this means that the immune system does not respond to the transplanted tissue even as it maintains important responses against infection or malignancies. Studies in NHPs are considered a scientific and ethical requirement before any such tolerance-inducing strategies are tested in humans (Knechtle et al., 2019), given the enormous consequences of graft loss in a patient after complete withdrawal of immunosuppression that might otherwise be successful under the standard of care. NHP models cannot fully recapitulate the human condition. Nonetheless, the similarity of NHPs to humans in environmental exposures, size, effects of drugs, and long lifespan makes them the most stringent, informative, and predictive nonclinical model for transplantation (Kirk, 2003), as is demonstrated by new immunosuppressive drugs and regimens that have been successfully translated from NHPs to the clinic, including alemtuzumab, belatacept, and regimens promoting immune tolerance (Fitch et al., 2019; Knechtle et al., 2019).

Even with these important advances, the shortage of organ donors leaves more than 100,000 patients on the waiting list annually, and many die from their condition before receiving a donor organ (HRSA, 2022). To address this critical organ shortage, grafts derived from domesticated animals—specifically pigs (i.e., xenografts)—are a novel source of replacements for failed organs. Pig-to-NHP xenograft modeling has allowed researchers to gain a deeper understanding of the key biological differences between pigs and primates that affect graft rejection, and to identify targets for gene editing as a strategy for intervention (Lu et al., 2019; Niu et al., 2021; Sykes and Sachs, 2022). This same model has also demonstrated that conventional immunosuppression is insufficient in the xenograft context, and that an alternative immunosuppressive approach (blockade of the CD40-CD154 costimulatory pathway) is a highly effective strategy for preventing rejection of xenograft cells and organs (Coe et al., 2020; Cooper et al., 2021; Graham et al., 2022). While the pig-to-NHP model can inform many aspects of xenograft safety, scientists have extensively characterized the model to determine when it is not informative (Denner and Graham, 2015; Graham and Schuurman, 2013; Wijkstrom et al., 2013). These efforts have shown that while NHPs are an excellent overall model for screening for zoonotic infection risk, this model cannot be used to evaluate the risk around transmission of porcine endogenous retrovirus (PERV) since the PERV receptor in NHPs is not fully functional (Denner, 2018). Nonetheless, decades of research using the pig-to-NHP model has advanced clinical xenotransplantation to a reality (Choi and Han, 2022; Griffith et al., 2022; Längin et al., 2018).

Stem cell therapy is another approach for replacing tissues damaged by disease. Stem cells can adapt and differentiate into different cell types in the body. Similar to conventional transplant modeling, NHP models have been critical in developing and evaluating the therapeutic efficacy of induced pluripotent stem cell–based therapies (Li et al., 2019), most prominently for treatment of myocardial infarction, Parkinson’s disease, and type 1 diabetes. Modeling of myocardial infarction in NHPs has been used to evaluate the regenerative capacity of stem cell–derived cardiomyocytes in the heart (Blin et al., 2010; Chong et al., 2014). Parkinson’s disease models in NHPs have been used to study the differences between autologous and allogeneic stem cell–derived neural cells, innervation, differentiation profile, and safety and efficacy to support Phase 1 clinical trials (Daadi et al., 2012; Doi et al., 2012; Emborg et al., 2013a,b; Kefalopoulou et al., 2014; Kriks et al., 2011; Morizane et al., 2013; Takagi et al., 2005). The most advanced stem cell–based strategy is pancreatic islet cell replacement, an effective therapy for patients with type 1 diabetes that is difficult to control (Ricordi and Strom, 2004; Shapiro et al., 2000). The use of cell-derived islets has created an unprecedented opportunity to mass-produce insulin-producing cells and to overcome the challenges of a limited donor supply, which is a main barrier to the widespread use of islet transplantation as a therapy (Verhoeff et al., 2021). The first beta cell transplants to determine whether stem cell therapy can successfully produce insulin in people with type 1 diabetes are currently under way (Markmann et al., 2022; Ramzy et al., 2021; Shapiro et al., 2021). Persistent challenges in optimizing dose, control over immune response, and delivery (Butler and Gale, 2022) will likely require NHP modeling that facilitates longitudinal studies of transplant function and risk.

Gene therapy, another approach to treating human disease, entails replacement of a missing gene, addition of genes to help treat a disease, or deletion or correction of mutations in genes that contribute to a disease. Gene therapy offers the potential to develop treatments for rare genetic diseases, more than 7,000 of which currently affect 30 million Americans (Genetic and Rare Diseases Center, n.d.). Box 2-7 describes how this approach has led to a treatment for sickle cell disease. NHP modeling has supported multiple gene therapy treatments now approved for human use (Day et al., 2021; Mendell et al., 2021; Weed et al., 2019). It has been especially valuable in understanding factors affecting sustained therapeutic gene expression from adeno-associated virus (AAV) vectors that carry the replacement gene (transgene), including immune responses to the vector and transgene product and the stability of the vector genome (Herzog et al., 2011). Like humans, NHPs are naturally infected with AAV, and so can be used to model how preexisting AAV antibodies affect safety and efficacy in humans with variable antibody expression (Hurlbut et al., 2010). NHPs have also been used to understand outcomes observed in clinical trials, such as the cause of death of a patient in a gene therapy trial. In this case, the treatment of NHPs with high dosages of AAV—similar to those used in the human trial—revealed massive cytokine release related to the protein coat of the vector (Stephenson, 2001). Similarly, an NHP model was used to understand cytokine release syndrome and neurotoxicity associated with chimeric antigen receptor (CAR) T cell immunotherapy in the clinic (Taraseviciute et al., 2018). CAR-T cell–based gene therapy has revolutionized the treatment of leukemia and lymphoma, and enabling the discovery of interventions that could prevent adverse outcomes is key to extending its utility.

BOX 2-7

CASE STUDY: USE OF NHP MODELS TO GUIDE A GENE THERAPY APPROACH TO SICKLE CELL DISEASE.

CONCLUSIONS

This chapter has examined the vital role of NHPs in biomedical research designed to enhance understanding of the human body and the progression of disease, discover new targets for disease prevention and treatment, and maximize the safety and efficacy of novel therapeutics. Although NHPs make up a very small fraction of animals used in biomedical research, their critical importance is evident in the number of modern medical advances that have relied on the use of NHP models. Based on this evaluation of the current landscape for NHP research, 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.

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