Experimental design strategies in primate trials that embrace the clinical schema to enhance translation

Primates have been essential in unlocking novel immune mechanisms that have driven development of groundbreaking new drugs in infectious disease and transplantation, amongst others related to the complexity of the primate immune system that is most similar to humans. As a result, primates have served as critical ‘gatekeepers’ in safety and efficacy evaluations of vaccines and immunotherapies.  Behind this success is a path with considerable examples of where primates have overestimated the effect, with an exaggerated immune response that is not present in clinical trials. The explanation for translational failures may partially relate to model-imposed stressors that affect the immune system. Common sampling practice in nonhuman primate (NHP) safety and toxicology studies involves serial sampling from a chemically or capture (mechanically) restrained animal. While sedation events may be required to protect researcher safety during studies of infectious disease and promote ease of sample collection, this comes at a cost to animal welfare and introduces confounding that reduces our ability to interpret data accurately. Study specific endpoints related to stress, immune response, and safety that are critical for vaccine development and toxicity studies are confounded by the effects of restraint stress and sedation on the research subjects. For example we have observed significant differences in cytokine levels by sex and cytokine levels were significantly blunted in sedated NHPs when compared to awake cooperating NHPs, highlighting the importance of model design on translational relevance for clinical settings. Acute and chronic stress alters immune responses by shifting immune cell populations or altering signaling, such that the model design must be carefully considered to be representative of the typical Phase I/II clinical studies in healthy immunocompetent adults to avoid misinterpretation of immune-based study endpoints. At the conclusion of this session, participants will develop an improved understanding of how model-related parameters affect study validity by influencing background immunologic and metabolic processes, impacting accurate disease characterization, and defining our ability to recapitulate the target disease state in ways that may confound outcome measures and impact translatability.

Learning Objectives:

1. An overview of the role of experimental design factors from animal selection to model handling in influencing animal welfare and scientific outcomes

2. Example strategies using behavioral management as a strategy to intentionally introduce variation for generalizability or reduce confounding to make an experiment more robust.