Central nervous system safety risks and evaluation strategies for mucosal vaccines: A review

Mucosal vaccines administered via noninjectable routes, such as intranasal and oral delivery, elicit both systemic and local immunity. Concurrent breakthroughs in nanocarriers and adjuvant technologies have significantly enhanced the precision of antigen delivery and immune persistence. However, these innovations introduce unique risks to the central nervous system (CNS). Particles <200 nm may penetrate the blood-brain barrier (BBB), whereas proinflammatory adjuvants can activate intracerebral glial cells, thereby inducing neuroinflammation and potential neurotoxicity. Intranasal administration may access the CNS via the olfactory pathway, whereas oral delivery may influence CNS function through the gut-brain axis. Adjuvant selection is critical for CNS safety because proinflammatory or bacterial toxin-based adjuvants may trigger neuroinflammation or abnormal vaccine protein distribution. Long-term exposure to aluminum-based adjuvants may also cause sustained microglial activation and accumulation. Although nanocarriers, such as chitosan, offer advantages, their bidirectional effects warrant comprehensive evaluation. To ensure the safe translation of mucosal vaccines, an integrated safety assessment framework spanning the preclinical, clinical, and postmarketing stages must be established. Preclinical studies should integrate mouse and nonhuman primate models, focus on BBB integrity and neurobehavioral changes, and conduct local tolerance and repeated-dose toxicity assessments. Clinicians should proactively monitor adverse neurological events, including olfactory function assessments, neuroimaging, and long-term follow-up. Postmarketing surveillance should leverage AI-assisted pharmacovigilance systems to enhance the detection and management of CNS risk signals. This review aims to systematically outline the key factors influencing mucosal vaccine CNS safety and the corresponding evaluation strategies, promoting their safe application while safeguarding public health benefits.