Valentino D’Onofrio, Marjolein Verstraete, Sharon Porrez, Bart Jacobs, Azhar Alhatemi, Simon De Gussem, Sara Verwilst, Anthony Willems, Gwenn Waerlop, Ellen De Meester, Sylvie Decraene, Filip Van Niewerburgh, Geert Leroux–Roels, Elly van Riet, Peter Paul Platenburg, Luuk Hilgers, Isabel Leroux-Roels
Vaccine immunogenicity declines with age due to immunosenescence, underscoring the need for improved adjuvants. LiteVax Adjuvant (LVA), a squalane-in-water emulsion containing carbohydrate fatty-acid monosulphate esters, has shown potential to enhance influenza vaccine responses, but its mechanisms in humans remain unclear. We performed a longitudinal systems vaccinology study in 56 younger (18-45 years) and older (≥60 years) adults receiving a quadrivalent influenza vaccine with or without LVA. Multi-omics analyses, including bulk and single-cell transcriptomics, flow cytometry, and serology, revealed that LVA induced a rapid, transient interferon-driven innate response, primarily in monocytes, associated with enhanced antigen processing and dendritic cell to T cell interactions. LVA promoted differentiation of influenza-specific CD4⁺ T cells toward CD45RO+ memory phenotypes, accelerated early IgG3 antibody responses, and increased IgG-producing plasmablast frequencies without affecting overall antibody magnitude. Importantly, LVA reduced age-related differences in early immune responses, improving response quality and supporting vaccine performance in older adults.