Rethinking non-human primate models for emerging viral infections after COVID-19.

Non-human primates (NHPs) retain particular value in emerging viral infection research when questions require integrated analysis of systemic viral kinetics, protective immunity, tissue pathology, or longitudinal outcomes. However, their cost, limited availability, specialized husbandry, and ethical constraints preclude their routine use as default screening platforms. Using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a case study, we compare how rhesus macaques, cynomolgus macaques, African green monkeys, baboons, and marmosets have contributed to studies of pathogenesis, vaccine protection, therapeutic efficacy, immune memory, and post-acute outcomes. We emphasize that these species-question relationships cannot be transferred uncritically to future pathogens; model suitability must be re-established according to receptor usage, tissue tropism, disease phenotype, and experimental objective. AI-guided prediction, human organoids, and organ-on-chip systems can support this process by prioritizing variants and candidates, identifying tissue-specific mechanisms, and refining endpoints before NHP studies begin. We therefore propose a question-driven workflow in which computational and human-relevant platforms narrow the evidence gap before fit-for-purpose NHP validation. This strategy can improve interpretability, reproducibility, and alignment with the 3Rs while preserving NHP use for questions that require intact organism-level biology.