IL-1 delineates squalene-based adjuvant efficacy and reactogenicity in a cell-type-specific manner.

Area of Science:

• Immunology
• Vaccinology
• Molecular Biology

Background:

• Squalene-based adjuvants, like A-910823 and AS03, are crucial for vaccine efficacy.
• These adjuvants contain α-tocopherol and enhance immune responses, but their mechanisms are not fully understood.
• Existing knowledge suggests they boost humoral immunity and cytokine production.

Purpose of the Study:

• To elucidate the mechanisms by which squalene-based adjuvants, specifically A-910823, enhance immune responses.
• To investigate the role of α-tocopherol in adjuvant-mediated IL-1 signaling.
• To differentiate the pathways regulating adjuvant efficacy and reactogenicity.

Main Methods:

• Analysis of IL-1 signaling pathway gene and protein expression.
• Identification of cell types responsible for IL-1α and IL-1β production.
• Investigation of key molecular axes (e.g., IL-1β/CD11c+ cell-IL-1R1/MyD88) in adjuvant function and reactogenicity.

Main Results:

• A-910823 regulates IL-1 signaling and IL-1α/IL-1β expression in an α-tocopherol-dependent manner.
• IL-1α originates mainly from eosinophils, while IL-1β is produced by various myeloid cells.
• Adjuvant efficacy is mediated by the IL-1β/CD11c+ cell-IL-1R1/MyD88 axis.
• Systemic reactogenicity involves the IL-1β/IL-1R1/MyD88/IL-6/cyclooxygenase 2 axis.
• Local reactogenicity is mediated by the eosinophil-derived IL-1α/IL-1R1/MyD88 axis.

Conclusions:

• Adjuvant efficacy and reactogenicity are governed by distinct pathways and cell types.
• The study reveals novel insights into squalene-based adjuvant mechanisms.
• Findings support the development of safer and more effective vaccines.