From MMR Sorbitol to Aluminum CNS Translocation: Aseptic Meningitis as a Sorbitol Excipient-Class Effect and Its Neurological Implications

Abstract Background: Aseptic meningitis (AM) is a recognised adverse event following administration of several parenteral biological products. Its occurrence appears to track the presence of sorbitol as a stabilising excipient rather than the specific active substance, suggesting an excipient-class effect. Every authorised parenteral product currently known to contain sorbitol — three vaccines (M-M-R II/M-M-RvaxPro, ProQuad®/MMRV, Stamaril®) and one intravenous immunoglobulin preparation (Flebogamma® DIF) — carries aseptic meningitis as a documented adverse reaction in its official prescribing information. Hypothesis: We propose a two-level mechanistic hypothesis. At the first level, sorbitol drives meningeal inflammation through two convergent pathways depending on dose and formulation: (i) hapten complex formation with viral proteins in live attenuated vaccines, activating Th1/Th17 lymphocytes with meningeal tropism (3–10 day latency); and (ii) direct osmotic stress on meningeal endothelium at the higher sorbitol concentrations present in IVIG preparations (hours–48h latency). The organ-selective meningeal tropism of sorbitol, as opposed to the renal tropism of sucrose, reflects the relatively low aldose reductase activity of cerebrovascular endothelial cells. At the second level, the transient blood-brain barrier (BBB) disruption induced by Th1/Th17-driven MMP-9 upregulation constitutes a window of opportunity for CNS infiltration by circulating macrophages already laden with aluminium adjuvant particles from prior vaccination, potentially perpetuating a neuroinflammatory cycle. Evidence base: Regulatory convergence across all sorbitol-containing parenterals; dose-response relationship in IVIG-associated AM; EMA acknowledgment of Flebogamma® DIF as the highest-sorbitol parenteral product in the EU; established IL-17/MMP-9 pathway for BBB disruption; experimental evidence for aluminium biopersistence and macrophage-mediated biodistribution (Gherardi et al.); and the clinical entity of macrophagic myofasciitis. Implications: The designation of sorbitol as an ‘inactive’ excipient is route-, concentration-, and formulation-dependent. The proposed mechanism is falsifiable and warrants prospective epidemiological investigation, particularly in patients receiving sequential immunological challenges combining sorbitol-containing biologicals and aluminium-adjuvanted vaccines.